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‘Superior’ CLL regimen cuts chemo in half
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
FROM EHA 2022
COVID vaccination in DMT-treated MS patients: New data
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
AT CMSC 2022
Debated: Nonfactor versus gene therapy for hemophilia
Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.
“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
Game changers emerge
Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.
Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.
However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.
There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.
Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.
“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”
Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.
“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
Pros of nonfactor therapy
Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.
With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.
The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.
She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”
The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.
“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”
Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.
“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
Limitations of nonfactor therapy
Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.
“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.
Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.
“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.
In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.
That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
Normal hemostasis ‘only achievable with gene therapy’
In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”
He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”
Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.
Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.
For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
Nonfactor therapies as bridge?
That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.
“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”
While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.
“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”
Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.
“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”
Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.
“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”
Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials
“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”
She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.
Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”
Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.
Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.
“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
Game changers emerge
Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.
Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.
However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.
There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.
Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.
“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”
Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.
“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
Pros of nonfactor therapy
Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.
With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.
The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.
She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”
The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.
“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”
Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.
“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
Limitations of nonfactor therapy
Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.
“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.
Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.
“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.
In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.
That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
Normal hemostasis ‘only achievable with gene therapy’
In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”
He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”
Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.
Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.
For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
Nonfactor therapies as bridge?
That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.
“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”
While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.
“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”
Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.
“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”
Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.
“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”
Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials
“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”
She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.
Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”
Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.
Ultimately, results of a very informal polling of the online audience suggested a strong leaning toward the known benefits of nonfactor therapy, as opposed to as-yet unapproved gene therapy. Although Benjamin Samelson-Jones, MD, PhD, argued for gene therapy, he also saluted the progress made that had enabled such choices.
“Our patients and the field have greatly benefited from this broad spectrum of different therapies and how they’ve been implemented, and it’s a truly exciting time because there will continue to be advancements in both these therapeutic modalities in the next 5-10 years,” said Dr. Samelson-Jones, an assistant professor of pediatrics in the division of hematology at the Children’s Hospital of Philadelphia.
Game changers emerge
Hemophilia A, characterized by a hereditary deficiency in factor VIII disorder, has long involved prophylaxis treatment with procoagulant factor replacement therapy that requires intravenous injection as often as several times a week. This can cause problems with venous access that are particularly burdensome for child patients.
Nonfactor therapy, currently consisting of the approved emicizumab but with more agents in development, provides coagulation without replacement of factor VIII. Importantly, this treatment requires only subcutaneous injection which, after a loading dose period, may be needed weekly or even just once a month.
However, in 2018, at approximately the same time that emicizumab was approved, patients with hemophilia A became eligible to enroll in clinical trials for the far more revolutionary concept of gene therapy, with the chance to become infusion free after just a single infusion.
There are caveats aplenty. Four of the therapies now in phase 3 development are adeno-associated viral vectors that are liver directed, meaning that patients need to be closely followed in the first months post infusion, with regular blood tests and other monitoring.
Notably, once patients receive an infusion, they cannot receive another, because of the buildup of antibodies.
“I think [this is] most important when considering current gene therapy – a patient can only receive it once, based on current technology,” Dr. Samelson-Jones said in an interview.“That means if a patient received gene therapy in 2023, and something better is developed in 2025, they are unlikely to be able to receive it.”
Nevertheless, with favorable phase 3 data reported in March 2022 in the New England Journal of Medicine, the first gene therapy for hemophilia A, valoctocogene roxaparvovec (BioMarin), appears poised for possible regulatory approval very soon.
“I expect this product to be approved in the next year, though I been previously surprised before about delays in this product’s clinical development,” Dr. Samelson-Jones said.
Pros of nonfactor therapy
Arguing on the side of nonfactor therapy in the debate, Roseline d’Oiron, MD, underscored the extent to which nonfactor therapy has dramatically transformed lives.
With intravenous injections, “the burden of the stress and anxiety of the injections is underestimated, even when you don’t have venous access problems,” said Dr. d’Oiron, a clinician investigator at the University Paris XI.
The heavy toll that these therapeutic challenges have had on patients’ lives and identities has been documented in patient advocacy reports, underscoring that “the availability of subcutaneous therapies through the nonfactor therapies for hemophilia A has really been a game changer,” said Dr. d’Oiron, who is also the associate director of the Reference Centre for Hemophilia and Other Congenital Rare Bleeding Disorders, Congenital Platelets Disorders, and von Willebrand Disease at Bicêtre (France) Hospital AP-HP.
She noted that newer therapies in development show the potential to offer longer half-lives, providing “even more improvement with wider intervals between the subcutaneous injections.”
The efficacy of nonfactor therapies also translates to lower rates of joint bleeding, which represent the most common complication in hemophilia, potentially causing acute or chronic pain.
“These therapies allow a life that is much closer to what would be considered a normal life, and especially allowing some physical activities with the prevention of bleeding episodes,” Dr. d’Oiron said. “The drugs have a good safety profile and are completely changing the picture of this disease.”
Dr. d’Oiron noted that, in the real-world clinical setting, there is no debate over nonfactor versus gene therapy. Most prefer to stick with what is already working well for them.
“In my clinical practice, only a very limited number of patients are really willing and considering the switch to gene therapy,” she said. “They feel that the nonfactor therapy is filling their previous unmet needs quite well, and the impression is that we don’t necessarily need look for something different.”
Limitations of nonfactor therapy
Echoing that he has had the same favorable experiences with patients on emicizumab as described by Dr. d’Oiron, Dr. Samelson-Jones, pointed out key caveats that significantly differentiate it from gene therapy, not the least of which is the basic issue of the requirement of injections.
“Even with longer half-lives, approximately monthly injections are still required with nonfactor therapy,” which can – and have – been compromised by any range of societal disruptions, including a pandemic or supply issues.
Furthermore, the mechanism of nonfactor therapies in providing hemostatic regulation outside of normal factor VIII is unregulated, with ‘no easy ‘off’ switch,’ he explained.
“The balance that nonfactor agents provide between pro- and anticoagulant forces is inherently more fragile – more like a knife’s edge, and has resulted in the risk for thrombotic complications in most examples of nonfactor therapies,” he said.
In addition, the therapies have unknown immunogenicity, with an increased risk of the development of antidrug antibodies, called inhibitors, a theoretical complication of nonfactor therapies, if factor VIII is only administered in the setting of bleeds or perioperatively, Dr. Samelson-Jones said.
That being said, “nonfactor agents are not for all patients with hemophilia A in the future – but rather gene therapy is,” he noted.
Normal hemostasis ‘only achievable with gene therapy’
In contrast to nonfactor therapy, just one infusion of gene therapy “ideally offers many years of potentially curative hemostatic protection,” Dr. Samuelson-Jones said. “The ultimate goal, I believe, is to achieve normal hemostasis and health equity, and I contend this goal is only really achievable with gene therapy.”
He noted that, while gene therapies will require initial monitoring, “once the gene therapy recipient is 3 or 12 months out, the monitoring really de-escalates, and the patient is free from all drug delivery or needing to be in close contact with their treatment center.”
Regarding concerns about not being able to receive gene therapy more than once, Dr. Samuelson-Jones said that work is underway to develop alternative viral vectors and nonviral vectors that may overcome those challenges.
Overall, he underscored that challenges are par for the course in the development of any novel therapeutic approach.
For instance, similar challenges were experienced 10 years ago in the development of gene therapy for hemophilia B. However, with advances, “they’ve now been able to achieve long-term sustained levels in the normal ordinary curative range. And I’m optimistic that similar advances may be able to be achieved for factor VIII gene transfer,” he said.
Nonfactor therapies as bridge?
That being said, nonfactor therapies are going to be essential in treating patients until such advances come to fruition, Dr. Samelson-Jones noted.
“I would agree that nonfactor therapies in 2022 have really simplified and improved the convenience of prophylaxis,” he said, “but I would view them as a bridging therapy until gene therapy goes through clinical development and are licensed for all patients with hemophilia.”
While Dr. d’Oiron agreed with that possibility, she countered that, when it comes to crossing over to gene therapy, some very long bridges might be needed.
“I would love to have a therapy that would be both extremely safe and effective and offering a cure and normalization of hemostasis,” she said. “But I’m afraid that the current available gene therapy that might be arriving soon still does no fulfill all of these criteria. I think there are a lot of questions so far.”
Ultimately, Dr. Samelson-Jones conceded that the success of emicizumab has set a high bar in the minds of clinicians and patients alike, which will strongly influence perceptions of any alternative approaches –and of participation in clinical trials.
“I think that, unequivocally, emicizumab has changed the risk-benefit discussion about enrolling in clinical trials, and in gene therapy in particular,” he said. “And I think it also has set the threshold for efficacy – and if a gene therapy product in development can’t achieve bleeding control that is similar to that provided with emicizumab, then that is not a product that is going to be able to continue in clinical development.”
Importantly, both debaters underscored the need for ongoing efforts to make the novel – and therefore costly therapies accessible to all, through organizations including the World Federation of Hemophilia Humanitarian Aid Program.
“It would be my hope that we can then extend all of these great therapies to the majority of undertreated patients with hemophilia around the world,” Dr. Samelson-Jones said. “I think that’s an issue that must be addressed with all of these novel therapies.”
Commenting on these issues, Riitta Lassila, MD, professor of coagulation medicine at the Comprehensive Cancer Center at Helsinki University Hospital, , who moderated the debate, said it has also been her experience that some patients express reluctance to enter the gene therapy trials
“There are two groups of patients, just as in the healthy population as well,” she said in an interview. “Some more ready to take risks and some are very hesitant [regarding] anything new. We do have the saying: If something is not broken, don’t fix it.”
She noted the additional concern that while the therapy has been successful in hemophilia B, factor VIII involves a larger construct and may have limitations with hemophilia A.
Furthermore, “the sustainability of factor VIII production may decrease in a couple of years, and the treatment duration could remain suboptimal,” Dr. Lassila said. “However, hemostasis seems to still [be achieved] with gene therapy, so maybe there will be more efficient solutions in the future.”
Dr. Samuelson-Jones has been a consultant for Pfizer, Bayer, Genentech, Frontera, and Cabaletta and serves on the scientific advisory board of GeneVentiv. Dr. d’Oiron has reported relationships with Baxalta/Shire, Bayer, Biomarin, CSL Behring, LFB, NovoNordisk, Octapharma, Pfizer, Roche, and Sobi. Dr. Lassila has been an adviser for Roche (emicizumab) and Biomarin and CSL for gene therapy.
FROM EHA 2022
Venetoclax combos prolong progression-free CLL survival
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EHA 2022
Severe COVID-19 and blood cancer: Plasma therapy may help
, new research shows.
The study demonstrated that “plasma from convalescent or vaccinated individuals shortens the time to improvement in hematological and solid cancer patients with severe COVID-19” and “prolongs overall survival,” said study coauthor Maike Janssen, MD, of the department of internal medicine at Heidelberg (Germany) University Hospital.
Dr. Janssen presented the study findings at the annual congress of the European Hematology Association held in Vienna.
Although people with COVID-19 do not appear to benefit from treatment with convalescent plasma, some data indicate that certain patients who cannot mount a strong immune response to SARS-CoV-2 infection may benefit.
In this recent multicenter study, 134 patients with confirmed COVID-19 whose oxygen saturation was 94% or lower were randomly assigned to undergo treatment with convalescent or vaccinated SARS-CoV-2 plasma (n = 68) or to receive standard of care (n = 66). Patients fell into four clinical groups: those with a hematologic malignancy or who had undergone active cancer therapy for any cancer within the past 24 months; those with chronic immunosuppression; those between the ages of 50 and 75 with lymphopenia and/or elevated D-dimer levels; and those older than 75 years.
The convalescent or vaccinated SARS-CoV-2 plasma was administered in two bags (238-337 mL plasma each) from different donors on days 1 and 2. Only plasma from donors with high levels of neutralizing activity (titers above 1:80) were included. The primary endpoint was time to improvement by 2 points on a 7-point scale or discharge from the hospital. The secondary endpoint was improvement in overall survival.
The authors found that overall, patients in the plasma group demonstrated a shorter time to improvement – median of 12.5 days, vs. 18 days – but the difference was not significant (P = .29).
However, for the subgroup of 56 patients with hematologic/solid cancers, the time to improvement was significantly shorter: 13 days vs. 31 days (hazard ratio [HR], 2.5; P = .003).
Similarly, plasma therapy did not improve overall survival in the study population overall – there were 12 deaths in the plasma group over 80 days, vs. 15 in the control group (P = .80). Patients in the hematologic/solid cancer subgroup who received plasma therapy did demonstrate significantly better overall survival (HR, 0.28; P = .042).
No similar significant differences in time to improvement or overall survival were observed in the other three groups. “We found that plasma did not improve outcomes in immune-competent patients with other risk factors and/or older age,” Dr. Janssen said.
Although study enrollment ended when the Omicron variant began surging, Dr. Janssen noted that plasma from Omicron patients may also be of benefit to those with hematologic cancers.
“We have treated some patients in individual cases using plasma from Omicron patients who were already vaccinated or with breakthrough infections, and we did see benefits in those cases,” she noted.
The study was funded by the Federal Ministry of Education and Research, Germany. Dr. Janssen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows.
The study demonstrated that “plasma from convalescent or vaccinated individuals shortens the time to improvement in hematological and solid cancer patients with severe COVID-19” and “prolongs overall survival,” said study coauthor Maike Janssen, MD, of the department of internal medicine at Heidelberg (Germany) University Hospital.
Dr. Janssen presented the study findings at the annual congress of the European Hematology Association held in Vienna.
Although people with COVID-19 do not appear to benefit from treatment with convalescent plasma, some data indicate that certain patients who cannot mount a strong immune response to SARS-CoV-2 infection may benefit.
In this recent multicenter study, 134 patients with confirmed COVID-19 whose oxygen saturation was 94% or lower were randomly assigned to undergo treatment with convalescent or vaccinated SARS-CoV-2 plasma (n = 68) or to receive standard of care (n = 66). Patients fell into four clinical groups: those with a hematologic malignancy or who had undergone active cancer therapy for any cancer within the past 24 months; those with chronic immunosuppression; those between the ages of 50 and 75 with lymphopenia and/or elevated D-dimer levels; and those older than 75 years.
The convalescent or vaccinated SARS-CoV-2 plasma was administered in two bags (238-337 mL plasma each) from different donors on days 1 and 2. Only plasma from donors with high levels of neutralizing activity (titers above 1:80) were included. The primary endpoint was time to improvement by 2 points on a 7-point scale or discharge from the hospital. The secondary endpoint was improvement in overall survival.
The authors found that overall, patients in the plasma group demonstrated a shorter time to improvement – median of 12.5 days, vs. 18 days – but the difference was not significant (P = .29).
However, for the subgroup of 56 patients with hematologic/solid cancers, the time to improvement was significantly shorter: 13 days vs. 31 days (hazard ratio [HR], 2.5; P = .003).
Similarly, plasma therapy did not improve overall survival in the study population overall – there were 12 deaths in the plasma group over 80 days, vs. 15 in the control group (P = .80). Patients in the hematologic/solid cancer subgroup who received plasma therapy did demonstrate significantly better overall survival (HR, 0.28; P = .042).
No similar significant differences in time to improvement or overall survival were observed in the other three groups. “We found that plasma did not improve outcomes in immune-competent patients with other risk factors and/or older age,” Dr. Janssen said.
Although study enrollment ended when the Omicron variant began surging, Dr. Janssen noted that plasma from Omicron patients may also be of benefit to those with hematologic cancers.
“We have treated some patients in individual cases using plasma from Omicron patients who were already vaccinated or with breakthrough infections, and we did see benefits in those cases,” she noted.
The study was funded by the Federal Ministry of Education and Research, Germany. Dr. Janssen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows.
The study demonstrated that “plasma from convalescent or vaccinated individuals shortens the time to improvement in hematological and solid cancer patients with severe COVID-19” and “prolongs overall survival,” said study coauthor Maike Janssen, MD, of the department of internal medicine at Heidelberg (Germany) University Hospital.
Dr. Janssen presented the study findings at the annual congress of the European Hematology Association held in Vienna.
Although people with COVID-19 do not appear to benefit from treatment with convalescent plasma, some data indicate that certain patients who cannot mount a strong immune response to SARS-CoV-2 infection may benefit.
In this recent multicenter study, 134 patients with confirmed COVID-19 whose oxygen saturation was 94% or lower were randomly assigned to undergo treatment with convalescent or vaccinated SARS-CoV-2 plasma (n = 68) or to receive standard of care (n = 66). Patients fell into four clinical groups: those with a hematologic malignancy or who had undergone active cancer therapy for any cancer within the past 24 months; those with chronic immunosuppression; those between the ages of 50 and 75 with lymphopenia and/or elevated D-dimer levels; and those older than 75 years.
The convalescent or vaccinated SARS-CoV-2 plasma was administered in two bags (238-337 mL plasma each) from different donors on days 1 and 2. Only plasma from donors with high levels of neutralizing activity (titers above 1:80) were included. The primary endpoint was time to improvement by 2 points on a 7-point scale or discharge from the hospital. The secondary endpoint was improvement in overall survival.
The authors found that overall, patients in the plasma group demonstrated a shorter time to improvement – median of 12.5 days, vs. 18 days – but the difference was not significant (P = .29).
However, for the subgroup of 56 patients with hematologic/solid cancers, the time to improvement was significantly shorter: 13 days vs. 31 days (hazard ratio [HR], 2.5; P = .003).
Similarly, plasma therapy did not improve overall survival in the study population overall – there were 12 deaths in the plasma group over 80 days, vs. 15 in the control group (P = .80). Patients in the hematologic/solid cancer subgroup who received plasma therapy did demonstrate significantly better overall survival (HR, 0.28; P = .042).
No similar significant differences in time to improvement or overall survival were observed in the other three groups. “We found that plasma did not improve outcomes in immune-competent patients with other risk factors and/or older age,” Dr. Janssen said.
Although study enrollment ended when the Omicron variant began surging, Dr. Janssen noted that plasma from Omicron patients may also be of benefit to those with hematologic cancers.
“We have treated some patients in individual cases using plasma from Omicron patients who were already vaccinated or with breakthrough infections, and we did see benefits in those cases,” she noted.
The study was funded by the Federal Ministry of Education and Research, Germany. Dr. Janssen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EHA 2022
Inebilizumab beneficial across genotypes in NMOSD
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT CMSC 2022
Schizophrenia patients in long-term facilities benefit from lower-dose antipsychotics
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
FROM APA 2022
Surgical site infections not increased in immunocompromised patients after Mohs surgery
, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.
The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.
The study was presented at the annual meeting of the American College of Mohs Surgery.
Mohs surgery is increasingly being performed for patients who are immunosuppressed because of the higher incidence of skin cancer in this group of patients and their higher risk of more aggressive skin cancers.
Overall, the rate of surgical site infections following Mohs surgery generally ranges from 0.5% to 2.4%. However, research is lacking on the risk among patients who are immunosuppressed and on how effective the use of prophylactic antibiotics is for these patients.
For the retrospective study, Dr. Nguyen and her colleagues evaluated data on 5,886 patients who underwent Mohs surgery at Cedars-Sinai between October 2014 and August 2021. Among these patients, 741 (12.6%) were immunocompromised.
Causes of immunosuppression in the cohort included the following: immunosuppression after transplant surgery; having HIV, chronic myeloid leukemia, multiple myeloma, or other hematogenous forms of immunosuppression; or immunosuppression related to other conditions, such as chronic inflammatory diseases.
Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).
Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).
The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).
The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.
Yet the risk of infection among those patients has been shown to be high and of consequence. Data indicate that infections account for 13%-16% of deaths among kidney and heart transplant patients and up to 21% of deaths among lung transplant patients. The rate of mortality appears to parallel the level of immunosuppression, Dr. Nguyen explained.
Furthermore, up to 25% of patients who undergo heart and lung transplantation develop bacteremia.
In terms of why worse infections or bacteremia surgeries may not occur in association with Mohs, Dr. Nguyen speculated that, as opposed to other surgeries, those involving the skin may benefit from unique defense mechanisms.
“The skin is a complex system in its defense against foreign pathogens and infectious agents,” she explained during her presentation. “There is the physical barrier, the antimicrobial peptides, and an adaptive as well as innate immune response.”
“In immunosuppressed patients, with the decrease in adaptive immunity, it’s possible this loss is less important because the skin has such a robust immune system in general.”
In her presentation, Dr. Nguyen noted that “further studies are necessary to investigate why patients aren’t presenting with greater severity, and we plan to try to investigate whether the unique nature of skin-mediated immunity makes this organ less susceptible to severe or life-threatening infections in patients on immunosuppression.”
Of note, the rate of prophylactic antibiotic prescriptions was no higher for those who were and those who were not immunosuppressed (37.9% vs. 34.1%; P = .14), which Dr. Nguyen said is consistent with recommendations.
“Immunosuppression is not an indication for antibiotic use, and hence, we did not have a higher rate of antibiotics use in this population,” she told this news organization. However, a 2021 ACMS survey found that a high percentage of Mohs surgeons prescribe antibiotics for procedures in which antibiotics are not indicated so as to reduce the risk of infections and that immunosuppression is a common reason for doing so.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.
The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.
The study was presented at the annual meeting of the American College of Mohs Surgery.
Mohs surgery is increasingly being performed for patients who are immunosuppressed because of the higher incidence of skin cancer in this group of patients and their higher risk of more aggressive skin cancers.
Overall, the rate of surgical site infections following Mohs surgery generally ranges from 0.5% to 2.4%. However, research is lacking on the risk among patients who are immunosuppressed and on how effective the use of prophylactic antibiotics is for these patients.
For the retrospective study, Dr. Nguyen and her colleagues evaluated data on 5,886 patients who underwent Mohs surgery at Cedars-Sinai between October 2014 and August 2021. Among these patients, 741 (12.6%) were immunocompromised.
Causes of immunosuppression in the cohort included the following: immunosuppression after transplant surgery; having HIV, chronic myeloid leukemia, multiple myeloma, or other hematogenous forms of immunosuppression; or immunosuppression related to other conditions, such as chronic inflammatory diseases.
Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).
Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).
The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).
The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.
Yet the risk of infection among those patients has been shown to be high and of consequence. Data indicate that infections account for 13%-16% of deaths among kidney and heart transplant patients and up to 21% of deaths among lung transplant patients. The rate of mortality appears to parallel the level of immunosuppression, Dr. Nguyen explained.
Furthermore, up to 25% of patients who undergo heart and lung transplantation develop bacteremia.
In terms of why worse infections or bacteremia surgeries may not occur in association with Mohs, Dr. Nguyen speculated that, as opposed to other surgeries, those involving the skin may benefit from unique defense mechanisms.
“The skin is a complex system in its defense against foreign pathogens and infectious agents,” she explained during her presentation. “There is the physical barrier, the antimicrobial peptides, and an adaptive as well as innate immune response.”
“In immunosuppressed patients, with the decrease in adaptive immunity, it’s possible this loss is less important because the skin has such a robust immune system in general.”
In her presentation, Dr. Nguyen noted that “further studies are necessary to investigate why patients aren’t presenting with greater severity, and we plan to try to investigate whether the unique nature of skin-mediated immunity makes this organ less susceptible to severe or life-threatening infections in patients on immunosuppression.”
Of note, the rate of prophylactic antibiotic prescriptions was no higher for those who were and those who were not immunosuppressed (37.9% vs. 34.1%; P = .14), which Dr. Nguyen said is consistent with recommendations.
“Immunosuppression is not an indication for antibiotic use, and hence, we did not have a higher rate of antibiotics use in this population,” she told this news organization. However, a 2021 ACMS survey found that a high percentage of Mohs surgeons prescribe antibiotics for procedures in which antibiotics are not indicated so as to reduce the risk of infections and that immunosuppression is a common reason for doing so.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.
The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.
The study was presented at the annual meeting of the American College of Mohs Surgery.
Mohs surgery is increasingly being performed for patients who are immunosuppressed because of the higher incidence of skin cancer in this group of patients and their higher risk of more aggressive skin cancers.
Overall, the rate of surgical site infections following Mohs surgery generally ranges from 0.5% to 2.4%. However, research is lacking on the risk among patients who are immunosuppressed and on how effective the use of prophylactic antibiotics is for these patients.
For the retrospective study, Dr. Nguyen and her colleagues evaluated data on 5,886 patients who underwent Mohs surgery at Cedars-Sinai between October 2014 and August 2021. Among these patients, 741 (12.6%) were immunocompromised.
Causes of immunosuppression in the cohort included the following: immunosuppression after transplant surgery; having HIV, chronic myeloid leukemia, multiple myeloma, or other hematogenous forms of immunosuppression; or immunosuppression related to other conditions, such as chronic inflammatory diseases.
Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).
Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).
The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).
The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.
Yet the risk of infection among those patients has been shown to be high and of consequence. Data indicate that infections account for 13%-16% of deaths among kidney and heart transplant patients and up to 21% of deaths among lung transplant patients. The rate of mortality appears to parallel the level of immunosuppression, Dr. Nguyen explained.
Furthermore, up to 25% of patients who undergo heart and lung transplantation develop bacteremia.
In terms of why worse infections or bacteremia surgeries may not occur in association with Mohs, Dr. Nguyen speculated that, as opposed to other surgeries, those involving the skin may benefit from unique defense mechanisms.
“The skin is a complex system in its defense against foreign pathogens and infectious agents,” she explained during her presentation. “There is the physical barrier, the antimicrobial peptides, and an adaptive as well as innate immune response.”
“In immunosuppressed patients, with the decrease in adaptive immunity, it’s possible this loss is less important because the skin has such a robust immune system in general.”
In her presentation, Dr. Nguyen noted that “further studies are necessary to investigate why patients aren’t presenting with greater severity, and we plan to try to investigate whether the unique nature of skin-mediated immunity makes this organ less susceptible to severe or life-threatening infections in patients on immunosuppression.”
Of note, the rate of prophylactic antibiotic prescriptions was no higher for those who were and those who were not immunosuppressed (37.9% vs. 34.1%; P = .14), which Dr. Nguyen said is consistent with recommendations.
“Immunosuppression is not an indication for antibiotic use, and hence, we did not have a higher rate of antibiotics use in this population,” she told this news organization. However, a 2021 ACMS survey found that a high percentage of Mohs surgeons prescribe antibiotics for procedures in which antibiotics are not indicated so as to reduce the risk of infections and that immunosuppression is a common reason for doing so.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACMS ANNUAL MEETING
Mohs surgery in the elderly: The dilemma of when to treat
As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.
In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.
“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”
That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.
Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.
When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”
Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.
Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
When appropriate – Mohs is safe in the very elderly
Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.
The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.
In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.
She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.
The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.
The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.
She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.
Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.
Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.
Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.
“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.
“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.
“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”
Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.
A version of this article first appeared on Medscape.com.
As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.
In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.
“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”
That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.
Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.
When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”
Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.
Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
When appropriate – Mohs is safe in the very elderly
Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.
The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.
In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.
She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.
The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.
The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.
She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.
Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.
Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.
Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.
“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.
“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.
“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”
Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.
A version of this article first appeared on Medscape.com.
As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.
In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.
“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”
That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.
Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.
When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”
Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.
Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
When appropriate – Mohs is safe in the very elderly
Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.
The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.
In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.
She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.
The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.
The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.
She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.
Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.
Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.
Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.
“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.
“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.
“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”
Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.
A version of this article first appeared on Medscape.com.
FROM ACMS 2022
High-dose antipsychotics show some benefit in treatment-resistant cases
NEW ORLEANS – Patients with severe schizophrenia who fail to respond to treatment with standard doses of second-generation antipsychotics show significant improvement with – and tolerance of – higher maintenance doses of the drugs, new research shows.
“The use of [higher doses of] long-acting injectable second-generation antipsychotics shows improvement not only in treatment adherence, but also in diminished relapses and suicide attempts compared with other previous treatment options used with these severely ill patients,” lead author Juan Jose Fernandez-Miranda, MD, said in an interview.
Dr. Fernandez-Miranda, of the Mental Health Service of the Principality of Asturias, in Gijón, Spain, underscored the tolerability of the novel approach of high doses: “No important side effects were found, and less than occurred with previous treatments,” he said.
While higher doses of second-generation antipsychotics for patients with treatment refractory schizophrenia are sometimes considered necessary, particularly with acute psychosis, evidence of benefits of the approach is lacking, and there are concerns about adverse events such as extrapyramidal symptoms and hyperprolactinemia.
To investigate the effects, the authors evaluated patients in a community-based, case managed program with severe, (CGI-S = 5), resistant schizophrenia.
All had been treated in the previous 3 years with at least two different antipsychotics, including clozapine in a few cases, with poor outcomes when receiving standard doses, and eligibility included being at risk of medication noncompliance, and/or experiencing a lack of effectiveness or adverse effects with previous antipsychotics.
For the second 3 years of the observational study, they were treated with doses of at least 75 mg of risperidone long-acting injectable (n = 60), 175 mg or more of monthly paliperidone palmitate (n = 60), or 600 mg or higher of aripiprazole once monthly (n = 30).
During the study, the average antipsychotic doses were: risperidone 111.2 mg/14 days; paliperidone palmitate 231.2 mg. eq./28 days; and aripiprazole 780 mg/28 days. In addition to the intensive pharmacological intervention, patients received psychosocial integrated intervention, as in the previous 3 years.
Over the 3 years with the higher maintenance doses, significant improvements were observed with all of the injectable treatment groups in terms of decreases on the Clinical Global Impression Scale – Severity score (CGI-S; P < .01) and in the four areas of the World Health Organization Disability Schedule (WHO-DAS), including in self-care, occupational, family, and social measures (P < .01 through P < .001).
Scores on the Medication Adherence Rating Scale (MARS), increased with all of the long-acting injectables (P < .01), particularly with paliperidone palmitate and aripiprazole.
Patients had significant decreases in hospital admissions at the end of the 36-month treatments and reductions in suicide attempts (both P < .001), compared with the previous 3 years, without any differences across the three injectables.
Importantly, tolerability was good for all of the long-acting antidepressants, with reductions in side effects as well as biological parameters compared with previous treatments, notably in the aripiprazole group.
While reductions in weight and prolactin levels were observed in all long-acting treatments, the differences were statistically significant only among patients treated with aripiprazole (P < .05), as was expected.
Two patients treated with aripiprazole discontinued treatment because of side effects from treatment, and the rate was five with paliperidone palmitate and nine with risperidone.
One person in the aripiprazole group discontinued because of a lack of effectiveness, while two discontinued in the paliperidone palmitate group and four with risperidone.
Dr. Fernandez-Miranda noted that “both the intensive case-managed multicomponent treatment and use of high doses of long-acting antipsychotics were in all probability linked to the high adherence and positive clinical outcomes.”
The results provide evidence that “long-acting second-generation antipsychotics are a remarkable option for patients with severe schizophrenia and a background of treatment discontinuation or intolerable adverse effects with other antipsychotics,” Dr. Fernandez-Miranda added.
“We suggest that, in some illness critical conditions, high doses of long-acting second-generation antipsychotics could represent an alternative to clozapine,” he added.
Some hesitation warranted
Commenting on the study, T. Scott Stroup, MD, MPH, professor of psychiatry at Columbia University, New York, noted the key limitations of a lack of randomization and comparison group of clozapine or typical-dose long-acting injectables.
“In addition, pre-post or mirror-image designs may be affected by expectation bias and regression to the mean,” he said in an interview.
“I don’t doubt that some patients do well on relatively high doses of long-acting injectable medications and that some tolerate these doses,” he noted “Most adverse effects are dose related, but without a typical-dose comparison group we cannot assess this.”
Ultimately, Dr. Stroup recommends sticking with standard recommendations – at least to start.
“My take-home message is that clozapine remains the treatment of choice for treatment-resistant schizophrenia, and in most cases clozapine should be tried before considering high-dose long-acting injectables,” he said.
“If there is uncertainty about whether someone is taking a prescribed oral antipsychotic medication, then a trial of a typical dose of a long-acting injectable is a good option to rule out pseudo-treatment resistance.”
Furthermore, “this study doesn’t affect the recommendation that people who need antipsychotic medications should receive the lowest effective dose,” he said.
The authors and Dr. Stroup had no disclosures to report.
NEW ORLEANS – Patients with severe schizophrenia who fail to respond to treatment with standard doses of second-generation antipsychotics show significant improvement with – and tolerance of – higher maintenance doses of the drugs, new research shows.
“The use of [higher doses of] long-acting injectable second-generation antipsychotics shows improvement not only in treatment adherence, but also in diminished relapses and suicide attempts compared with other previous treatment options used with these severely ill patients,” lead author Juan Jose Fernandez-Miranda, MD, said in an interview.
Dr. Fernandez-Miranda, of the Mental Health Service of the Principality of Asturias, in Gijón, Spain, underscored the tolerability of the novel approach of high doses: “No important side effects were found, and less than occurred with previous treatments,” he said.
While higher doses of second-generation antipsychotics for patients with treatment refractory schizophrenia are sometimes considered necessary, particularly with acute psychosis, evidence of benefits of the approach is lacking, and there are concerns about adverse events such as extrapyramidal symptoms and hyperprolactinemia.
To investigate the effects, the authors evaluated patients in a community-based, case managed program with severe, (CGI-S = 5), resistant schizophrenia.
All had been treated in the previous 3 years with at least two different antipsychotics, including clozapine in a few cases, with poor outcomes when receiving standard doses, and eligibility included being at risk of medication noncompliance, and/or experiencing a lack of effectiveness or adverse effects with previous antipsychotics.
For the second 3 years of the observational study, they were treated with doses of at least 75 mg of risperidone long-acting injectable (n = 60), 175 mg or more of monthly paliperidone palmitate (n = 60), or 600 mg or higher of aripiprazole once monthly (n = 30).
During the study, the average antipsychotic doses were: risperidone 111.2 mg/14 days; paliperidone palmitate 231.2 mg. eq./28 days; and aripiprazole 780 mg/28 days. In addition to the intensive pharmacological intervention, patients received psychosocial integrated intervention, as in the previous 3 years.
Over the 3 years with the higher maintenance doses, significant improvements were observed with all of the injectable treatment groups in terms of decreases on the Clinical Global Impression Scale – Severity score (CGI-S; P < .01) and in the four areas of the World Health Organization Disability Schedule (WHO-DAS), including in self-care, occupational, family, and social measures (P < .01 through P < .001).
Scores on the Medication Adherence Rating Scale (MARS), increased with all of the long-acting injectables (P < .01), particularly with paliperidone palmitate and aripiprazole.
Patients had significant decreases in hospital admissions at the end of the 36-month treatments and reductions in suicide attempts (both P < .001), compared with the previous 3 years, without any differences across the three injectables.
Importantly, tolerability was good for all of the long-acting antidepressants, with reductions in side effects as well as biological parameters compared with previous treatments, notably in the aripiprazole group.
While reductions in weight and prolactin levels were observed in all long-acting treatments, the differences were statistically significant only among patients treated with aripiprazole (P < .05), as was expected.
Two patients treated with aripiprazole discontinued treatment because of side effects from treatment, and the rate was five with paliperidone palmitate and nine with risperidone.
One person in the aripiprazole group discontinued because of a lack of effectiveness, while two discontinued in the paliperidone palmitate group and four with risperidone.
Dr. Fernandez-Miranda noted that “both the intensive case-managed multicomponent treatment and use of high doses of long-acting antipsychotics were in all probability linked to the high adherence and positive clinical outcomes.”
The results provide evidence that “long-acting second-generation antipsychotics are a remarkable option for patients with severe schizophrenia and a background of treatment discontinuation or intolerable adverse effects with other antipsychotics,” Dr. Fernandez-Miranda added.
“We suggest that, in some illness critical conditions, high doses of long-acting second-generation antipsychotics could represent an alternative to clozapine,” he added.
Some hesitation warranted
Commenting on the study, T. Scott Stroup, MD, MPH, professor of psychiatry at Columbia University, New York, noted the key limitations of a lack of randomization and comparison group of clozapine or typical-dose long-acting injectables.
“In addition, pre-post or mirror-image designs may be affected by expectation bias and regression to the mean,” he said in an interview.
“I don’t doubt that some patients do well on relatively high doses of long-acting injectable medications and that some tolerate these doses,” he noted “Most adverse effects are dose related, but without a typical-dose comparison group we cannot assess this.”
Ultimately, Dr. Stroup recommends sticking with standard recommendations – at least to start.
“My take-home message is that clozapine remains the treatment of choice for treatment-resistant schizophrenia, and in most cases clozapine should be tried before considering high-dose long-acting injectables,” he said.
“If there is uncertainty about whether someone is taking a prescribed oral antipsychotic medication, then a trial of a typical dose of a long-acting injectable is a good option to rule out pseudo-treatment resistance.”
Furthermore, “this study doesn’t affect the recommendation that people who need antipsychotic medications should receive the lowest effective dose,” he said.
The authors and Dr. Stroup had no disclosures to report.
NEW ORLEANS – Patients with severe schizophrenia who fail to respond to treatment with standard doses of second-generation antipsychotics show significant improvement with – and tolerance of – higher maintenance doses of the drugs, new research shows.
“The use of [higher doses of] long-acting injectable second-generation antipsychotics shows improvement not only in treatment adherence, but also in diminished relapses and suicide attempts compared with other previous treatment options used with these severely ill patients,” lead author Juan Jose Fernandez-Miranda, MD, said in an interview.
Dr. Fernandez-Miranda, of the Mental Health Service of the Principality of Asturias, in Gijón, Spain, underscored the tolerability of the novel approach of high doses: “No important side effects were found, and less than occurred with previous treatments,” he said.
While higher doses of second-generation antipsychotics for patients with treatment refractory schizophrenia are sometimes considered necessary, particularly with acute psychosis, evidence of benefits of the approach is lacking, and there are concerns about adverse events such as extrapyramidal symptoms and hyperprolactinemia.
To investigate the effects, the authors evaluated patients in a community-based, case managed program with severe, (CGI-S = 5), resistant schizophrenia.
All had been treated in the previous 3 years with at least two different antipsychotics, including clozapine in a few cases, with poor outcomes when receiving standard doses, and eligibility included being at risk of medication noncompliance, and/or experiencing a lack of effectiveness or adverse effects with previous antipsychotics.
For the second 3 years of the observational study, they were treated with doses of at least 75 mg of risperidone long-acting injectable (n = 60), 175 mg or more of monthly paliperidone palmitate (n = 60), or 600 mg or higher of aripiprazole once monthly (n = 30).
During the study, the average antipsychotic doses were: risperidone 111.2 mg/14 days; paliperidone palmitate 231.2 mg. eq./28 days; and aripiprazole 780 mg/28 days. In addition to the intensive pharmacological intervention, patients received psychosocial integrated intervention, as in the previous 3 years.
Over the 3 years with the higher maintenance doses, significant improvements were observed with all of the injectable treatment groups in terms of decreases on the Clinical Global Impression Scale – Severity score (CGI-S; P < .01) and in the four areas of the World Health Organization Disability Schedule (WHO-DAS), including in self-care, occupational, family, and social measures (P < .01 through P < .001).
Scores on the Medication Adherence Rating Scale (MARS), increased with all of the long-acting injectables (P < .01), particularly with paliperidone palmitate and aripiprazole.
Patients had significant decreases in hospital admissions at the end of the 36-month treatments and reductions in suicide attempts (both P < .001), compared with the previous 3 years, without any differences across the three injectables.
Importantly, tolerability was good for all of the long-acting antidepressants, with reductions in side effects as well as biological parameters compared with previous treatments, notably in the aripiprazole group.
While reductions in weight and prolactin levels were observed in all long-acting treatments, the differences were statistically significant only among patients treated with aripiprazole (P < .05), as was expected.
Two patients treated with aripiprazole discontinued treatment because of side effects from treatment, and the rate was five with paliperidone palmitate and nine with risperidone.
One person in the aripiprazole group discontinued because of a lack of effectiveness, while two discontinued in the paliperidone palmitate group and four with risperidone.
Dr. Fernandez-Miranda noted that “both the intensive case-managed multicomponent treatment and use of high doses of long-acting antipsychotics were in all probability linked to the high adherence and positive clinical outcomes.”
The results provide evidence that “long-acting second-generation antipsychotics are a remarkable option for patients with severe schizophrenia and a background of treatment discontinuation or intolerable adverse effects with other antipsychotics,” Dr. Fernandez-Miranda added.
“We suggest that, in some illness critical conditions, high doses of long-acting second-generation antipsychotics could represent an alternative to clozapine,” he added.
Some hesitation warranted
Commenting on the study, T. Scott Stroup, MD, MPH, professor of psychiatry at Columbia University, New York, noted the key limitations of a lack of randomization and comparison group of clozapine or typical-dose long-acting injectables.
“In addition, pre-post or mirror-image designs may be affected by expectation bias and regression to the mean,” he said in an interview.
“I don’t doubt that some patients do well on relatively high doses of long-acting injectable medications and that some tolerate these doses,” he noted “Most adverse effects are dose related, but without a typical-dose comparison group we cannot assess this.”
Ultimately, Dr. Stroup recommends sticking with standard recommendations – at least to start.
“My take-home message is that clozapine remains the treatment of choice for treatment-resistant schizophrenia, and in most cases clozapine should be tried before considering high-dose long-acting injectables,” he said.
“If there is uncertainty about whether someone is taking a prescribed oral antipsychotic medication, then a trial of a typical dose of a long-acting injectable is a good option to rule out pseudo-treatment resistance.”
Furthermore, “this study doesn’t affect the recommendation that people who need antipsychotic medications should receive the lowest effective dose,” he said.
The authors and Dr. Stroup had no disclosures to report.
AT APA 2022