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Outpatient CAR T infusions feasible using liso-cel
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High-risk lymphoma patients had more than 6 fewer inpatient days with outpatient CAR T infusion.
Study details: Seamless phase 1 trial initially evaluating 91 patients with relapsed/refractory diffuse large B cell lymphoma.
Disclosures: Juno Therapeutics sponsored the study. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
Source: Abramson J et al. Abstract 5.
Best options for treating relapsed/refractory PTCL
LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.
Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).
“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.
She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.
Complex disease, multiple therapies
The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.
She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.
By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.
She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.
A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.
An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.
In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.
In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.
Therapeutic rationale
Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.
However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.
“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.
Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.
“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,
A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.
Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).
“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.
Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.
For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.
Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.
“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.
LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.
Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).
“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.
She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.
Complex disease, multiple therapies
The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.
She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.
By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.
She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.
A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.
An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.
In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.
In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.
Therapeutic rationale
Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.
However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.
“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.
Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.
“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,
A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.
Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).
“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.
Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.
For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.
Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.
“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.
LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.
Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).
“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.
She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.
Complex disease, multiple therapies
The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.
She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.
By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.
She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.
A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.
An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.
In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.
In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.
Therapeutic rationale
Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.
However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.
“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.
Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.
“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,
A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.
Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).
“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.
Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.
For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.
Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.
“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.
EXPERT ANALYSIS FROM TCLF 2018
Ibrutinib linked to invasive fungal infections
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
FROM BLOOD
Key clinical point:
Major finding: Of 33 identified cases, 27 were invasive aspergillosis.
Study details: Retrospective review of case reports from 16 French centers.
Disclosures: Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees with the company. All other authors declared no competing financial interests.
Source: Ghez D et al. Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
Acalabrutinib shows less off-target activity in mantle cell lymphoma
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
FROM THE LANCET
Key clinical point:
Major finding: Eighty-one percent of patients with relapsed or refractory mantle cell lymphoma showed a partial or complete response to Bruton tyrosine kinase inhibitor acalabrutinib.
Study details: An open-label, phase 2 study in 124 patients with relapsed or refractory mantle cell lymphoma.
Disclosures: The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
Source: Wang M et al. Lancet. 2018;391:659-67.
Mycosis fungoides increases risk for second cancers
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
REPORTING FROM TCLF 2018
Key clinical point:
Major finding: Patients with MF have a 730% greater likelihood of developing a second primary hematologic malignancy.
Study details: A retrospective review of data on 6,196 patients in the SEER-18 database.
Disclosures: The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest.
Source: Goyal A et al. TCLF 2018 Abstract EP18_2.
Basiliximab/BEAM may improve post-ASCT outcomes in PTCL
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
REPORTING FROM TLCF 2018
Key clinical point:
Major finding: Median progression-free survival posttransplant was 10.6 months.
Study details: A phase 1, dose-finding trial in 13 patients with PTCL.
Disclosures: Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center, Duarte, Calif., and the National Cancer Institute.
Source: Zain J et al. TLCF 2018.
NF-kappaB pathway could help solve resistance problem in mantle cell lymphoma
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
FROM CELL DEATH & DISEASE
A view from the bridge to transplant for PTCL
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
Getting hematologic cancer drugs on the fast track
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
T-cell lymphoma therapies on the horizon
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018