HT Staff

Photo by Rhoda Baer

Better communication between cancer patients and healthcare providers may provide tangible benefits, according to research published in JNCCN.

Cancer survivors who reported greater satisfaction in communicating with healthcare providers had better general health and mental health, fewer doctor visits, and reduced healthcare spending, when compared to patients who were less satisfied with communication.

“Our study suggests that when cancer care providers are more effective communicators, their patients are more likely to follow medical advice and medication protocols,” said study author Ashish Rai, PhD, of the American Cancer Society in Framingham, Massachusetts.

For this study, Dr Rai and his colleagues analyzed data from the Medical Expenditure Panel Survey (MEPS) from 2008 through 2014.

The researchers evaluated 4588 cancer survivors, dividing them into non-elderly and elderly groups. The non-elderly patients (n=2257) had a median age of 54 (range, 18-64), and the elderly patients (n=2331) had a median age of 75.

Communication satisfaction was measured by the Consumer Assessment of Healthcare Providers and Systems (CAHPS), in conjunction with the MEPS data.

Patients used a 4-point scale ranging from “never” to “always” to track whether their providers did the following:

• Listened carefully
• Explained things in a way that was easy to understand
• Showed respect for what the respondent had to say
• Spent enough time with the respondent.

A global satisfaction rating scale (0 to 10) was factored into a composite score and tracked across 12 months.

The researchers then assessed various patient outcomes.

Satisfaction and outcomes

Overall, patients who were the most satisfied with communication had the best outcomes with regard to general, physical, and mental health; fewer emergency department, hospital, and office visits; and reduced drug, out-of-pocket, and total healthcare expenditures.

However, the associations between communication satisfaction and outcomes were not always significant.

In an adjusted analysis, the elderly patients who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for general health, mental health, and total healthcare expenditures.

For the non-elderly patients, those who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for physician office visits and mental health.

Baseline health and satisfaction

In both age groups, patients with better baseline health reported higher satisfaction with communication. Conversely, the more comorbidities patients had, the lower their satisfaction rating.

The researchers said this suggests that more complex circumstances negatively impacted patients’ perception of their communication, and the finding highlights the importance of coordinating care across a team of providers.

“The results of this study present an interesting challenge: those survivors most in need of good communication about complex medical issues may not be receiving the information they seek in a manner that they find helpful. That, in turn, results in higher healthcare utilization and expenditure,” said Crystal Denlinger, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was not involved in this study.

“This could be due to many factors, including time constraints, competing priorities, and increasingly complex cancer therapies. This study highlights the need for additional research into how to tailor the healthcare experience both during and after cancer treatment in order to communicate more effectively.”

Conclusions

“Communication needs vary from patient to patient,” Dr Rai noted. “While time constraints do pose a challenge, the amount of time spent is only one of the attributes of effective communication. By tailoring their communication strategy to a patient’s specific needs, providers may be able to communicate more effectively in the same amount of time.”

Dr Rai also pointed out the importance of delegating both clinical and communication duties as needed. Dr Rai and his colleagues also cited earlier research demonstrating better outcomes for patients who had the option of communicating with their provider electronically.^1,2

Ultimately, the researchers concluded that effective provider communication can improve outcomes by streamlining care, alleviating anxiety, boosting mutual trust, and increasing treatment adherence.

1. Basch E, Deal AM, Dueck AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318:197–198.

2. Smith AB, Basch E. Role of patient-reported outcomes in postsurgical monitoring in oncology. J Oncol Pract 2017;13:535–538.

Photo by Rhoda Baer

Better communication between cancer patients and healthcare providers may provide tangible benefits, according to research published in JNCCN.

Cancer survivors who reported greater satisfaction in communicating with healthcare providers had better general health and mental health, fewer doctor visits, and reduced healthcare spending, when compared to patients who were less satisfied with communication.

“Our study suggests that when cancer care providers are more effective communicators, their patients are more likely to follow medical advice and medication protocols,” said study author Ashish Rai, PhD, of the American Cancer Society in Framingham, Massachusetts.

For this study, Dr Rai and his colleagues analyzed data from the Medical Expenditure Panel Survey (MEPS) from 2008 through 2014.

The researchers evaluated 4588 cancer survivors, dividing them into non-elderly and elderly groups. The non-elderly patients (n=2257) had a median age of 54 (range, 18-64), and the elderly patients (n=2331) had a median age of 75.

Communication satisfaction was measured by the Consumer Assessment of Healthcare Providers and Systems (CAHPS), in conjunction with the MEPS data.

Patients used a 4-point scale ranging from “never” to “always” to track whether their providers did the following:

• Listened carefully
• Explained things in a way that was easy to understand
• Showed respect for what the respondent had to say
• Spent enough time with the respondent.

A global satisfaction rating scale (0 to 10) was factored into a composite score and tracked across 12 months.

The researchers then assessed various patient outcomes.

Satisfaction and outcomes

Overall, patients who were the most satisfied with communication had the best outcomes with regard to general, physical, and mental health; fewer emergency department, hospital, and office visits; and reduced drug, out-of-pocket, and total healthcare expenditures.

However, the associations between communication satisfaction and outcomes were not always significant.

In an adjusted analysis, the elderly patients who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for general health, mental health, and total healthcare expenditures.

For the non-elderly patients, those who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for physician office visits and mental health.

Baseline health and satisfaction

In both age groups, patients with better baseline health reported higher satisfaction with communication. Conversely, the more comorbidities patients had, the lower their satisfaction rating.

The researchers said this suggests that more complex circumstances negatively impacted patients’ perception of their communication, and the finding highlights the importance of coordinating care across a team of providers.

“The results of this study present an interesting challenge: those survivors most in need of good communication about complex medical issues may not be receiving the information they seek in a manner that they find helpful. That, in turn, results in higher healthcare utilization and expenditure,” said Crystal Denlinger, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was not involved in this study.

“This could be due to many factors, including time constraints, competing priorities, and increasingly complex cancer therapies. This study highlights the need for additional research into how to tailor the healthcare experience both during and after cancer treatment in order to communicate more effectively.”

Conclusions

“Communication needs vary from patient to patient,” Dr Rai noted. “While time constraints do pose a challenge, the amount of time spent is only one of the attributes of effective communication. By tailoring their communication strategy to a patient’s specific needs, providers may be able to communicate more effectively in the same amount of time.”

Dr Rai also pointed out the importance of delegating both clinical and communication duties as needed. Dr Rai and his colleagues also cited earlier research demonstrating better outcomes for patients who had the option of communicating with their provider electronically.^1,2

Ultimately, the researchers concluded that effective provider communication can improve outcomes by streamlining care, alleviating anxiety, boosting mutual trust, and increasing treatment adherence.

1. Basch E, Deal AM, Dueck AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318:197–198.

2. Smith AB, Basch E. Role of patient-reported outcomes in postsurgical monitoring in oncology. J Oncol Pract 2017;13:535–538.

Photo by Rhoda Baer

Better communication between cancer patients and healthcare providers may provide tangible benefits, according to research published in JNCCN.

Cancer survivors who reported greater satisfaction in communicating with healthcare providers had better general health and mental health, fewer doctor visits, and reduced healthcare spending, when compared to patients who were less satisfied with communication.

“Our study suggests that when cancer care providers are more effective communicators, their patients are more likely to follow medical advice and medication protocols,” said study author Ashish Rai, PhD, of the American Cancer Society in Framingham, Massachusetts.

For this study, Dr Rai and his colleagues analyzed data from the Medical Expenditure Panel Survey (MEPS) from 2008 through 2014.

The researchers evaluated 4588 cancer survivors, dividing them into non-elderly and elderly groups. The non-elderly patients (n=2257) had a median age of 54 (range, 18-64), and the elderly patients (n=2331) had a median age of 75.

Communication satisfaction was measured by the Consumer Assessment of Healthcare Providers and Systems (CAHPS), in conjunction with the MEPS data.

Patients used a 4-point scale ranging from “never” to “always” to track whether their providers did the following:

• Listened carefully
• Explained things in a way that was easy to understand
• Showed respect for what the respondent had to say
• Spent enough time with the respondent.

A global satisfaction rating scale (0 to 10) was factored into a composite score and tracked across 12 months.

The researchers then assessed various patient outcomes.

Satisfaction and outcomes

Overall, patients who were the most satisfied with communication had the best outcomes with regard to general, physical, and mental health; fewer emergency department, hospital, and office visits; and reduced drug, out-of-pocket, and total healthcare expenditures.

However, the associations between communication satisfaction and outcomes were not always significant.

In an adjusted analysis, the elderly patients who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for general health, mental health, and total healthcare expenditures.

For the non-elderly patients, those who were more satisfied with communication in year 1 had significantly better outcomes in year 2 for physician office visits and mental health.

Baseline health and satisfaction

In both age groups, patients with better baseline health reported higher satisfaction with communication. Conversely, the more comorbidities patients had, the lower their satisfaction rating.

The researchers said this suggests that more complex circumstances negatively impacted patients’ perception of their communication, and the finding highlights the importance of coordinating care across a team of providers.

“The results of this study present an interesting challenge: those survivors most in need of good communication about complex medical issues may not be receiving the information they seek in a manner that they find helpful. That, in turn, results in higher healthcare utilization and expenditure,” said Crystal Denlinger, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was not involved in this study.

“This could be due to many factors, including time constraints, competing priorities, and increasingly complex cancer therapies. This study highlights the need for additional research into how to tailor the healthcare experience both during and after cancer treatment in order to communicate more effectively.”

Conclusions

“Communication needs vary from patient to patient,” Dr Rai noted. “While time constraints do pose a challenge, the amount of time spent is only one of the attributes of effective communication. By tailoring their communication strategy to a patient’s specific needs, providers may be able to communicate more effectively in the same amount of time.”

Dr Rai also pointed out the importance of delegating both clinical and communication duties as needed. Dr Rai and his colleagues also cited earlier research demonstrating better outcomes for patients who had the option of communicating with their provider electronically.^1,2

Ultimately, the researchers concluded that effective provider communication can improve outcomes by streamlining care, alleviating anxiety, boosting mutual trust, and increasing treatment adherence.

1. Basch E, Deal AM, Dueck AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318:197–198.

2. Smith AB, Basch E. Role of patient-reported outcomes in postsurgical monitoring in oncology. J Oncol Pract 2017;13:535–538.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Larry Young

Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.

In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.

The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.

Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.

The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.

The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.

Treatment

For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.

The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.

Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.

There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.

The median duration of follow-up was 17.0 months.

Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:

• Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
• AEs (n=28)
• Withdrawn consent (n=13)
• Investigator decision (n=9)
• Patient decision (n=6)
• Death (n=2)
• Noncompliance (n=1).

Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.

Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:

• Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
• Patient decision (n=9)
• Withdrawn consent (n=5)
• AEs (n=5)
• Death (n=2)
• Lost to follow-up (n=1).

At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.

Patient characteristics

Baseline characteristics were similar between the treatment arms.

PFS and ORR

Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in ORR with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Responses by disease compartment were superior with mogamulizumab as well.

The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.

The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.

Crossover

Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.

In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.

Safety

The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Thrombocytopenia (14% vs 34%)
• Diarrhea (23% vs 57%)
• Nausea (15% vs 41%)
• Fatigue (22% vs 32%)
• Increased blood creatinine (3% vs 28%)
• Decreased appetite (7% vs 24%)
• Dysgeusia (3% vs 28%)
• Drug eruptions (20% vs 1%)
• Infusion-related reactions (32% vs 1%).

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

Photo by Larry Young

Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.

In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.

The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.

Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.

The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.

The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.

Treatment

For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.

The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.

Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.

There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.

The median duration of follow-up was 17.0 months.

Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:

• Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
• AEs (n=28)
• Withdrawn consent (n=13)
• Investigator decision (n=9)
• Patient decision (n=6)
• Death (n=2)
• Noncompliance (n=1).

Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.

Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:

• Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
• Patient decision (n=9)
• Withdrawn consent (n=5)
• AEs (n=5)
• Death (n=2)
• Lost to follow-up (n=1).

At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.

Patient characteristics

Baseline characteristics were similar between the treatment arms.

PFS and ORR

Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in ORR with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Responses by disease compartment were superior with mogamulizumab as well.

The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.

The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.

Crossover

Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.

In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.

Safety

The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Thrombocytopenia (14% vs 34%)
• Diarrhea (23% vs 57%)
• Nausea (15% vs 41%)
• Fatigue (22% vs 32%)
• Increased blood creatinine (3% vs 28%)
• Decreased appetite (7% vs 24%)
• Dysgeusia (3% vs 28%)
• Drug eruptions (20% vs 1%)
• Infusion-related reactions (32% vs 1%).

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

Photo by Larry Young

Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.

In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.

The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.

Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.

The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.

The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.

Treatment

For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.

The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.

Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.

There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.

The median duration of follow-up was 17.0 months.

Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:

• Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
• AEs (n=28)
• Withdrawn consent (n=13)
• Investigator decision (n=9)
• Patient decision (n=6)
• Death (n=2)
• Noncompliance (n=1).

Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.

Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:

• Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
• Patient decision (n=9)
• Withdrawn consent (n=5)
• AEs (n=5)
• Death (n=2)
• Lost to follow-up (n=1).

At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.

Patient characteristics

Baseline characteristics were similar between the treatment arms.

PFS and ORR

Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in ORR with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Responses by disease compartment were superior with mogamulizumab as well.

The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.

The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.

Crossover

Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.

In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.

Safety

The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Thrombocytopenia (14% vs 34%)
• Diarrhea (23% vs 57%)
• Nausea (15% vs 41%)
• Fatigue (22% vs 32%)
• Increased blood creatinine (3% vs 28%)
• Decreased appetite (7% vs 24%)
• Dysgeusia (3% vs 28%)
• Drug eruptions (20% vs 1%)
• Infusion-related reactions (32% vs 1%).

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Image by Spencer Phillips

A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.

Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.

Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.

“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”

Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.

The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.

The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.

The treatments (given alone or in combination) were:

• Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
• Venetoclax (n=8)—recommended because of high BCL2 expression
• Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
• Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
• Etoposide (n=2)—selected by RNA-based drug repurposing.

Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.

One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.

That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).

The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).

Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.

“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.

“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”

Image by Spencer Phillips

A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.

Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.

Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.

“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”

Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.

The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.

The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.

The treatments (given alone or in combination) were:

• Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
• Venetoclax (n=8)—recommended because of high BCL2 expression
• Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
• Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
• Etoposide (n=2)—selected by RNA-based drug repurposing.

Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.

One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.

That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).

The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).

Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.

“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.

“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”

Image by Spencer Phillips

A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.

Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.

Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.

“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”

Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.

The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.

The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.

The treatments (given alone or in combination) were:

• Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
• Venetoclax (n=8)—recommended because of high BCL2 expression
• Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
• Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
• Etoposide (n=2)—selected by RNA-based drug repurposing.

Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.

One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.

That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).

The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).

Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.

“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.

“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”

multiple myeloma

Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).

Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.

The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.

Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.

The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.

To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).

The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.

The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.

The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.

This revealed the top 3 combinations:

• Decitabine and mitomycin C
• Mechlorethamine hydrochloride, decitabine, and mitomycin C
• Bortezomib, mechlorethamine hydrochloride, and mitomycin C.

The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.

The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.

The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.

The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.

Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).

The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.

There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).

Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).

Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.

multiple myeloma

Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).

Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.

The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.

Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.

The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.

To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).

The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.

The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.

The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.

This revealed the top 3 combinations:

• Decitabine and mitomycin C
• Mechlorethamine hydrochloride, decitabine, and mitomycin C
• Bortezomib, mechlorethamine hydrochloride, and mitomycin C.

The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.

The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.

The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.

The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.

Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).

The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.

There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).

Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).

Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.

multiple myeloma

Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).

Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.

The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.

Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.

The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.

To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).

The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.

The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.

The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.

This revealed the top 3 combinations:

• Decitabine and mitomycin C
• Mechlorethamine hydrochloride, decitabine, and mitomycin C
• Bortezomib, mechlorethamine hydrochloride, and mitomycin C.

The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.

The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.

The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.

The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.

Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).

The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.

There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).

Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).

Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.

mycosis fungoides

The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.

The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms.

The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).

mycosis fungoides

The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.

The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms.

The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).

mycosis fungoides

The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.

The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms.

The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).