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M. Alexander Otto began his reporting career early in 1999 covering the pharmaceutical industry for a national pharmacists' magazine and freelancing for the Washington Post and other newspapers. He then joined BNA, now part of Bloomberg News, covering health law and the protection of people and animals in medical research. Alex next worked for the McClatchy Company. Based on his work, Alex won a year-long Knight Science Journalism Fellowship to MIT in 2008-2009. He joined the company shortly thereafter. Alex has a newspaper journalism degree from Syracuse (N.Y.) University and a master's degree in medical science -- a physician assistant degree -- from George Washington University. Alex is based in Seattle.
Can immunotherapy replace surgery for stomach cancer?
GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.
Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.
After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.
If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.
The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.
At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.
They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.
Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.
Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.
Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.
There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.
The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.
Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.
GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.
Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.
After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.
If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.
The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.
At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.
They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.
Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.
Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.
Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.
There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.
The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.
Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.
GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.
Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.
After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.
If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.
The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.
At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.
They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.
Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.
Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.
Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.
There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.
The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.
Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.
FROM GI CANCERS SYMPOSIUM 2022
‘Highly encouraging’ MRD results for zanubrutinib add-on in CLL
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
Treatment was stopped in the single-arm phase 2 trial when patients reached undetectable MRD, a novel use of MRD to guide treatment duration. At a median of 16 months after discontinuation, MRD remained undetectable in 31 of 33 patients (94%).
The team also found that a reduction to 1/400 of baseline MRD (delta-MRD400) by day 1 of cycle five predicted undetectable bone marrow MRD within eight treatment cycles.
delta-MRD400 is “a potential biomarker” to identify patients who’ll do well with a shorter treatment and flag others who require longer courses of therapy, said investigators led by Jacob Soumerai, MD, a hematologist/oncologist at Massachusetts General Hospital, Boston.
Overall, the results “are highly encouraging,” they said, with efficacy and safety comparing favorably to trials that added other BTK inhibitors – namely ibrutinib and acalabrutinib – to the standard obinutuzumab/venetoclax backbone, with a shorter treatment duration.
They said the novel triplet warrants further study in the first line and noted that they also “plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration.” The study was published recently in The Lancet Haematology.
Two editorialists – Davide Rossi, MD, PhD, and Joyce Marques De Almeida, both of the of the Oncology Institute of Southern Switzerland, Bellinzona – were encouraged by the findings and wanted future research to assess how well MRD-guided treatment duration works in patients with tumor protein p53-disrupted disease, who “benefit less from time-limited therapies” then patients with wild-type TP53; the trial was too small to address the issue.
There was a two-cycle lead-in with zanubrutinib and obinutuzumab then venetoclax ramp-up starting at cycle 3, with each cycle running 28 days.
Zanubrutinib is approved in the U.S. for mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.
In a previous phase 2 trial of ibrutinib add-on to venetoclax-obinutuzumab for 14 cycles followed by ibrutinib monotherapy, the rate of undetectable MRD in both peripheral blood and bone marrow was 67%. The rate of bone marrow undetectable MRD was 77% in another phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab for at least 15 cycles.
Dr. Soumerai and his team cautioned, however, that “comparisons across trials are fraught with selection bias resulting in differences in treated patient populations, and randomized data are needed to establish the optimal BTK inhibitor to combine with venetoclax with or without obinutuzumab, and to establish whether” the zanubrutinib triplet “improves progression-free survival and overall survival compared with current standard first-line therapy.”
There was grade 3 or worse neutropenia in 18% of subjects (7/39), one episode of febrile neutropenia (3%), lung infections in three patients (8%) patients, and five cases of hypertension (13%).
The editorialists characterized the numbers as low and the regimen as well tolerated. Past studies of ibrutinib, a first generation BTK, with venetoclax and obinutuzumab have pegged grade 3 or worse neutropenia at 56% and the hypertension incidence at 48%.
Granulocyte colony-stimulating factor administration “could partially account for the low incidence of severe neutropenia” in the trial, the investigators said.
The study was funded by zanubrutinib marketer Beigene as well as Genentech, the National Cancer Institute, and others. Many of the authors had industry ties, including Dr. Soumerai who reported being a consultant and researcher for Beigene and other companies. Dr. Rossi reported honoraria and research grants from AbbVie, AstraZeneca, and Janssen.
FROM THE LANCET HEMATOLOGY
Fitusiran: Great ‘leap forward’ in hemophilia treatment
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
Fitusiran is a small interfering RNA molecule that blocks antithrombin production in liver cells. Instead of taking the traditional approach in hemophilia treatment of boosting the coagulation cascade by replacing what’s missing, the idea of fitusiran is to short circuit the body’s anticoagulation system by targeting antithrombin.
Patients in two trials presented at the meeting, ATLAS-A/B and ATLAS-INH, had about a 90% reduction in their annualized bleeding rates when treated with prophylactic fitusiran, with half or more having no bleeds that required treatment during the 9-month trials. The median annualized bleeding rate fell to 0, trial investigators reported at the meeting.
These findings held in both hemophilia A and B with and without inhibitors, which are antibodies formed against exogenous clotting factors, and on subanalysis of spontaneous and joint bleeding rates. Reduced bleeding was associated with substantial improvements in health-care related quality of life, particularly in the physical health domain.
A question about study design
An audience member at ASH noted that the trials didn’t compare fitusiran against prophylactic treatment, which is standard of care for hemophilia, but rather against episodic treatment – concentrated factors or bypassing agents in subjects with inhibitors – once subjects in the control groups started to bleed.
Still, the numbers reported in the studies “have never been achieved with standard prophylaxis in the past.” Furthermore, standard prophylaxis requires lifelong intravenous infusions, sometimes several a week, said lead ATLAS-A/B investigator Alok Srivastava, MD, a hematologist at the Christian Medical College in Vellore, India.
Fitusiran was dosed in the studies as a once-a-month 80 mg subcutaneous injection, so is much less bothersome. Also, it seems likely that some patients will only need dosing every other month. Maker Sanofi Genzyme is exploring lower and less frequent dosing to reduce thrombotic event risks that emerged in earlier studies, said Steven Pipe, MD, a pediatric hematologist at the University of Michigan, Ann Arbor, and the senior investigator on ATLAS-A/B, which assessed fitusiran in patients without inhibitors.
Serious thrombotic events occurred in two fitusiran patients in the trials, one of which led to discontinuation.
No pricing information
Overall, “I think [fitusiran] is a tremendous leap forward” with “the opportunity to transform the day-to-day lives of patients,” particularly those with hemophilia B, who have limited treatment options, Dr. Pipe said.
If approved for the U.S. market, fitusiran will go up against the monoclonal antibody emicizumab (Hemlibra), a subcutaneous injection dosed weekly to monthly that mimics the function of factor VIII, so it’s approved only for hemophilia A with or without inhibitors.
Several audience members at ASH noted that a major consideration for fitusiran, if approved, will be its cost. There’s no pricing information yet, but annual list price for emicizumab is reported to be in the $500,000 range.
For hemophilia A, “it will come to what proves to be the most efficacious and safe, with also consideration given to pricing,” Nigel Key, MD, a hematologist at the University of North Carolina at Chapel Hill, said in a comment.
Trial details
In ATLAS-A/B, 80 male patients were randomized to prophylactic fitusiran once monthly and 40 to continue with clotting factors as needed for bleeding. Just over 20% had hemophilia B, the rest hemophilia A. The mean age was 34 years, and subjects had a mean of about 12 bleeds in the 6 months leading up to the study.
Half of the fitusiran group had no treated bleeds during the study period versus only 5% in the control arm.
The five treatment emergent serious adverse events in the fitusiran arm included cholelithiasis in two subjects, plus cholecystitis, lower respiratory tract infection, and asthma in one each. Two fitusiran patients discontinued treatment because of cholecystitis and increased alanine aminotransferase.
ATLAS-INH had the same study design, and investigated patients with inhibitors; again, just over 20% had hemophilia B, the rest A. Mean age was 28 years, and patients had a mean of about 13 bleeds over the 6 months before the study. A total of 38 subjects were randomized to fitusiran, and 19 to bypassing agents as needed.
Almost 66% of fitusiran patients had no treated bleeds versus about 5% in the control arm.
There “was far less bleeding both for hemophilia A and B. It’s definitely a clinically meaningful and important” effect, said ATLAS-INH lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles.
He said the improved quality of life with fitusiran noted in both trials was “not surprising. If you only have to dose once a month subcutaneously, and you are not bleeding, of course your quality of life is going to improve.”
Both fitusiran thrombotic events occurred in ATLAS-INH. One patient developed deep vein thrombosis, subclavian vein thrombosis, and superficial thrombophlebitis but stayed in the study. Another discontinued after developing suspected spinal vessel thrombosis. Serious adverse events among five other subjects included acute cholecystitis and hematuria.
Fitusiran was associated with liver enzyme elevations in both trials, but they were generally mild to moderate.
The studies were funded by fitusiran maker Sanofi Genzyme. Several investigators were employees. Dr. Pipe is a consultant, Dr. Srivastava is a researcher and adviser, and Dr. Young is a speaker and consultant for the company and disclosed honoraria from it. Dr. Key had no relevant disclosures.
FROM ASH 2021
DLBCL: PFS but no OS benefit with polatuzumab-vedotin add-on
Two-year progression free survival (PFS) was 76.7% for the 440 patients randomized to polatuzumab-vedotin (PV) add-on, versus 70.2% for the 439 randomized to R-CHOP, which translated to a 27% reduction in the risk of progression, relapse, or death (P = .02). However, overall survival (OS) at 2 years was just under 89% in both arms of the trial, dubbed POLARIX. Toxicity was comparable between the two arms.
The investigators swapped out the vincristine in R-CHOP for PV to avoid overlapping neurotoxic side effects and called their modified regimen “pola-R-CHP.”
“We believe these results support use of pola-R-CHP in the initial management of patients with DLBCL,” senior investigator Gilles Salles, MD, PhD, a hematologic oncologist at Memorial Sloan Cancer Center in New York, said at the American Society of Hematology annual meeting.
The study (ASH 2021 abstract LBA-1), was published simultaneously in the New England Journal of Medicine.
Worth the cost?
The investigators reported that the median follow up of 28.2 months may simply have been too short to see if the PFS benefit translates into better overall survival. Also, newer treatments for relapsed/refractory disease might have masked any OS benefit.
With the PFS benefit, however, “what we think we are seeing is a deeper, more profound complete remission that hopefully will translate into [better] overall survival, but it may be a while until that can be demonstrated,” said Jane N. Winter, MD, a hematologic oncologist at Northwestern University, Chicago, who moderated Dr. Salles’ presentation.
“If the improvement in PFS at 2 years represents a true higher cure rate and plateau rather than a simple delay in relapse,” the “results from the POLARIX trial are likely to be practice-changing,” blood cancer specialist Ajay K. Gopal, MD, professor of medicine at the University of Washington, Seattle, told this news organization when asked for comment.
With additional OS results pending, an audience member at ASH wondered if “the cost of this highly expensive monoclonal antibody drug conjugate is worth the small improvement in PFS.”
“We have to further study this point, but at this moment what is important is to have a treatment with better efficacy and no more toxicity” than R-CHOP, lead investigator Herve Tilly, MD, a hematologic oncologist at the University of Rouen, France, said at the meeting.
Dr. Gopal said the cost concerns are legitimate, but also pointed out that they “may be somewhat offset by the potential reduction in downstream use of expensive cellular therapies.”
The findings support his assertion. With reduced PFS, R-CHOP subjects were more likely than were pola-R-CHP subjects to go on to subsequent lines of therapy (30.3% versus 22.5%).
PV is already approved in the United States for relapsed or refractory DLBCL in combination with bendamustine and rituximab after failure of at least two previous regimens.
Defining a target population
R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone – has been the first-line standard of care for DLBCL for 2 decades, but it cures only about 60%-70% of patients. Researchers have tried for years to improve the cure rate by adding novel agents and other means, but outcomes haven’t been clinically meaningful, the investigators explained.
Polatuzumab, the antibody component of PV, zeroes in on a ubiquitous target on mature B-cell lymphomas, delivering vedotin, a potent microtubule inhibitor, directly to tumor cells.
Study subjects were treatment naive and a median of 65 years old with intermediate-risk or high-risk DLBCL. About a third had activated B-cell–like DLBCL, and almost two-thirds had baseline International Prognostic Index (IPI) scores between 3 and 5.
Each arm of the trial underwent six treatment cycles, plus two cycles of rituximab monotherapy.
On subgroup analysis, PFS benefit clustered among higher risk patients, namely patients older than 60 years, those with IPI scores between 3 and 5, and patients with the activated B-cell–like subtype.
Younger patients, subjects with lower IPI scores, patients with bulky disease, and those who had germinal-center B-cell–like DLBCL “did not show a clear [PFS] benefit,” the study team said.
Ongoing trial in the elderly
Adverse events in POLARIX were in line with the component drugs’ known toxicity profiles, with no new safety signals identified.
The most common grade 3/4 adverse events were neutropenia (28.3% in the pola-R-CHP group and 30.8% in the R-CHOP group), febrile neutropenia (13.8% and 8.0%, respectively), and anemia (12.0% and 8.4%). A bit over 6% of subjects in both arms discontinued because of adverse events.
The higher incidence of febrile neutropenia with pola-R-CHP “did not translate into a higher overall incidence of infection, treatment discontinuation, or dose reductions,” the investigators said.
They noted that patients with lymphoma arising from previously diagnosed indolent lymphoma, those with a primary mediastinal lymphoma, and people older than 80 years were not included in the study. A phase 3 trial in patients 75 years and up is recruiting.
The work was funded by PV maker Genentech/Roche. Many of the investigators disclosed ties to the companies, including Dr. Tilly, an adviser and speaker for Roche, and Dr. Salles, an adviser for Genentech. Three investigators were Genentech employees. Dr. Gopal is a consultant for Genentech/Roche. Dr. Winter did not have any ties to the companies.
Two-year progression free survival (PFS) was 76.7% for the 440 patients randomized to polatuzumab-vedotin (PV) add-on, versus 70.2% for the 439 randomized to R-CHOP, which translated to a 27% reduction in the risk of progression, relapse, or death (P = .02). However, overall survival (OS) at 2 years was just under 89% in both arms of the trial, dubbed POLARIX. Toxicity was comparable between the two arms.
The investigators swapped out the vincristine in R-CHOP for PV to avoid overlapping neurotoxic side effects and called their modified regimen “pola-R-CHP.”
“We believe these results support use of pola-R-CHP in the initial management of patients with DLBCL,” senior investigator Gilles Salles, MD, PhD, a hematologic oncologist at Memorial Sloan Cancer Center in New York, said at the American Society of Hematology annual meeting.
The study (ASH 2021 abstract LBA-1), was published simultaneously in the New England Journal of Medicine.
Worth the cost?
The investigators reported that the median follow up of 28.2 months may simply have been too short to see if the PFS benefit translates into better overall survival. Also, newer treatments for relapsed/refractory disease might have masked any OS benefit.
With the PFS benefit, however, “what we think we are seeing is a deeper, more profound complete remission that hopefully will translate into [better] overall survival, but it may be a while until that can be demonstrated,” said Jane N. Winter, MD, a hematologic oncologist at Northwestern University, Chicago, who moderated Dr. Salles’ presentation.
“If the improvement in PFS at 2 years represents a true higher cure rate and plateau rather than a simple delay in relapse,” the “results from the POLARIX trial are likely to be practice-changing,” blood cancer specialist Ajay K. Gopal, MD, professor of medicine at the University of Washington, Seattle, told this news organization when asked for comment.
With additional OS results pending, an audience member at ASH wondered if “the cost of this highly expensive monoclonal antibody drug conjugate is worth the small improvement in PFS.”
“We have to further study this point, but at this moment what is important is to have a treatment with better efficacy and no more toxicity” than R-CHOP, lead investigator Herve Tilly, MD, a hematologic oncologist at the University of Rouen, France, said at the meeting.
Dr. Gopal said the cost concerns are legitimate, but also pointed out that they “may be somewhat offset by the potential reduction in downstream use of expensive cellular therapies.”
The findings support his assertion. With reduced PFS, R-CHOP subjects were more likely than were pola-R-CHP subjects to go on to subsequent lines of therapy (30.3% versus 22.5%).
PV is already approved in the United States for relapsed or refractory DLBCL in combination with bendamustine and rituximab after failure of at least two previous regimens.
Defining a target population
R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone – has been the first-line standard of care for DLBCL for 2 decades, but it cures only about 60%-70% of patients. Researchers have tried for years to improve the cure rate by adding novel agents and other means, but outcomes haven’t been clinically meaningful, the investigators explained.
Polatuzumab, the antibody component of PV, zeroes in on a ubiquitous target on mature B-cell lymphomas, delivering vedotin, a potent microtubule inhibitor, directly to tumor cells.
Study subjects were treatment naive and a median of 65 years old with intermediate-risk or high-risk DLBCL. About a third had activated B-cell–like DLBCL, and almost two-thirds had baseline International Prognostic Index (IPI) scores between 3 and 5.
Each arm of the trial underwent six treatment cycles, plus two cycles of rituximab monotherapy.
On subgroup analysis, PFS benefit clustered among higher risk patients, namely patients older than 60 years, those with IPI scores between 3 and 5, and patients with the activated B-cell–like subtype.
Younger patients, subjects with lower IPI scores, patients with bulky disease, and those who had germinal-center B-cell–like DLBCL “did not show a clear [PFS] benefit,” the study team said.
Ongoing trial in the elderly
Adverse events in POLARIX were in line with the component drugs’ known toxicity profiles, with no new safety signals identified.
The most common grade 3/4 adverse events were neutropenia (28.3% in the pola-R-CHP group and 30.8% in the R-CHOP group), febrile neutropenia (13.8% and 8.0%, respectively), and anemia (12.0% and 8.4%). A bit over 6% of subjects in both arms discontinued because of adverse events.
The higher incidence of febrile neutropenia with pola-R-CHP “did not translate into a higher overall incidence of infection, treatment discontinuation, or dose reductions,” the investigators said.
They noted that patients with lymphoma arising from previously diagnosed indolent lymphoma, those with a primary mediastinal lymphoma, and people older than 80 years were not included in the study. A phase 3 trial in patients 75 years and up is recruiting.
The work was funded by PV maker Genentech/Roche. Many of the investigators disclosed ties to the companies, including Dr. Tilly, an adviser and speaker for Roche, and Dr. Salles, an adviser for Genentech. Three investigators were Genentech employees. Dr. Gopal is a consultant for Genentech/Roche. Dr. Winter did not have any ties to the companies.
Two-year progression free survival (PFS) was 76.7% for the 440 patients randomized to polatuzumab-vedotin (PV) add-on, versus 70.2% for the 439 randomized to R-CHOP, which translated to a 27% reduction in the risk of progression, relapse, or death (P = .02). However, overall survival (OS) at 2 years was just under 89% in both arms of the trial, dubbed POLARIX. Toxicity was comparable between the two arms.
The investigators swapped out the vincristine in R-CHOP for PV to avoid overlapping neurotoxic side effects and called their modified regimen “pola-R-CHP.”
“We believe these results support use of pola-R-CHP in the initial management of patients with DLBCL,” senior investigator Gilles Salles, MD, PhD, a hematologic oncologist at Memorial Sloan Cancer Center in New York, said at the American Society of Hematology annual meeting.
The study (ASH 2021 abstract LBA-1), was published simultaneously in the New England Journal of Medicine.
Worth the cost?
The investigators reported that the median follow up of 28.2 months may simply have been too short to see if the PFS benefit translates into better overall survival. Also, newer treatments for relapsed/refractory disease might have masked any OS benefit.
With the PFS benefit, however, “what we think we are seeing is a deeper, more profound complete remission that hopefully will translate into [better] overall survival, but it may be a while until that can be demonstrated,” said Jane N. Winter, MD, a hematologic oncologist at Northwestern University, Chicago, who moderated Dr. Salles’ presentation.
“If the improvement in PFS at 2 years represents a true higher cure rate and plateau rather than a simple delay in relapse,” the “results from the POLARIX trial are likely to be practice-changing,” blood cancer specialist Ajay K. Gopal, MD, professor of medicine at the University of Washington, Seattle, told this news organization when asked for comment.
With additional OS results pending, an audience member at ASH wondered if “the cost of this highly expensive monoclonal antibody drug conjugate is worth the small improvement in PFS.”
“We have to further study this point, but at this moment what is important is to have a treatment with better efficacy and no more toxicity” than R-CHOP, lead investigator Herve Tilly, MD, a hematologic oncologist at the University of Rouen, France, said at the meeting.
Dr. Gopal said the cost concerns are legitimate, but also pointed out that they “may be somewhat offset by the potential reduction in downstream use of expensive cellular therapies.”
The findings support his assertion. With reduced PFS, R-CHOP subjects were more likely than were pola-R-CHP subjects to go on to subsequent lines of therapy (30.3% versus 22.5%).
PV is already approved in the United States for relapsed or refractory DLBCL in combination with bendamustine and rituximab after failure of at least two previous regimens.
Defining a target population
R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone – has been the first-line standard of care for DLBCL for 2 decades, but it cures only about 60%-70% of patients. Researchers have tried for years to improve the cure rate by adding novel agents and other means, but outcomes haven’t been clinically meaningful, the investigators explained.
Polatuzumab, the antibody component of PV, zeroes in on a ubiquitous target on mature B-cell lymphomas, delivering vedotin, a potent microtubule inhibitor, directly to tumor cells.
Study subjects were treatment naive and a median of 65 years old with intermediate-risk or high-risk DLBCL. About a third had activated B-cell–like DLBCL, and almost two-thirds had baseline International Prognostic Index (IPI) scores between 3 and 5.
Each arm of the trial underwent six treatment cycles, plus two cycles of rituximab monotherapy.
On subgroup analysis, PFS benefit clustered among higher risk patients, namely patients older than 60 years, those with IPI scores between 3 and 5, and patients with the activated B-cell–like subtype.
Younger patients, subjects with lower IPI scores, patients with bulky disease, and those who had germinal-center B-cell–like DLBCL “did not show a clear [PFS] benefit,” the study team said.
Ongoing trial in the elderly
Adverse events in POLARIX were in line with the component drugs’ known toxicity profiles, with no new safety signals identified.
The most common grade 3/4 adverse events were neutropenia (28.3% in the pola-R-CHP group and 30.8% in the R-CHOP group), febrile neutropenia (13.8% and 8.0%, respectively), and anemia (12.0% and 8.4%). A bit over 6% of subjects in both arms discontinued because of adverse events.
The higher incidence of febrile neutropenia with pola-R-CHP “did not translate into a higher overall incidence of infection, treatment discontinuation, or dose reductions,” the investigators said.
They noted that patients with lymphoma arising from previously diagnosed indolent lymphoma, those with a primary mediastinal lymphoma, and people older than 80 years were not included in the study. A phase 3 trial in patients 75 years and up is recruiting.
The work was funded by PV maker Genentech/Roche. Many of the investigators disclosed ties to the companies, including Dr. Tilly, an adviser and speaker for Roche, and Dr. Salles, an adviser for Genentech. Three investigators were Genentech employees. Dr. Gopal is a consultant for Genentech/Roche. Dr. Winter did not have any ties to the companies.
REPORTING FROM ASH 2021
ASH studies look at racial disparities in ALL care, outcomes
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.
When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.
However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.
Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.
Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.
However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.
“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.
Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.
Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.
Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.
Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.
FROM ASH 2021
Talk early to patients with high-risk AML about end-of-life decisions
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
aotto@mdedge.com
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
aotto@mdedge.com
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
aotto@mdedge.com
FROM ASH 2021
Myeloid patients respond robustly to Moderna COVID vaccine
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
FROM ASH 2021
FDA approves new interferon for polycythemia vera
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
, according to an agency press release.
Besremi has a longer half-life than do other pegylated interferon-alfas, allowing for dosing every 2 weeks instead of weekly. If red blood cell counts remain normal for a year, patients have the option of switching to once-monthly dosing. As with similar products, Besremi is self-administered as a subcutaneous injection.
It’s the first interferon approved in the United States specifically for polycythemia vera. Besremi is also approved for upfront therapy, unlike FDA’s first approval for the condition, the oral JAK inhibitor ruxolitinib (Jakafi), which is indicated only after hydroxyurea failure.
Taiwan-based maker PharmaEssentia said in another press release that it will roll Besremi out to the U.S. market in the coming weeks.
“As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule,” said Ko-Chung Lin, PhD, the company’s CEO.
As for unlocking the full potential, Besremi is under investigation for other interferon indications, including myelofibrosis, leukemia, and chronic hepatitis.
The FDA’s approval was based on results in 51 adults treated for an average of 5 years; 31 (61%) had a complete hematologic response, defined as a hematocrit below 45% with no phlebotomy for at least 2 months, plus normal platelet and white cell counts, normal spleen size, and no blood clots.
“Noninferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months,” investigators noted in an earlier report (Lancet Haematol. 2020 Mar;7[3]:e196-e208).
Besremi carries the same boxed warning as those of peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys), which notes the risk of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Related contraindications include severe depression and other psychiatric problems; liver impairment; serious or untreated autoimmune disease, and immunosuppression following organ transplant.
Influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain were the most common adverse events in studies, occurring in over 40% of subjects. Urinary tract infections, transient ischemic attacks, and depression were the most frequent serious complications, occurring in over 4%.
Labeling also notes the risk for fetal harm and the need for effective contraception.
Besremi was approved in Europe in 2019 and is approved in Taiwan and South Korea.
Polycythemia vera is a rare condition thought to be caused by acquired bone marrow stem cell mutations that trigger an overproduction of red blood cells. Patients are at increased risk of blood clots and emboli, and subsequent heart attacks, strokes, and other problems. There’s also the risk of transformation to secondary myelofibrosis or leukemia.
Tolerability doesn’t explain why kids do better than adults on ALL regimens
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
FROM BLOOD ADVANCES
Genes related to osteosarcoma survival identified
When they combined them into a risk score and added one additional factor – metastases at diagnosis – the model was an “excellent” predictor of 1-year survival, the team said (area under the curve, 0.947; 95% confidence interval, 0.832-0.972).
“The survival-associated” immune-related genes (IRGs) “examined in this study have potential for identifying prognosis in osteosarcoma and may be clinically useful as relevant clinical biomarkers and candidate targets for anticancer therapy,” said investigators led by Wangmi Liu, MD, of Zhejiang University in Hangzhou, China. The study was published in JAMA Network Open.
They explained that it’s often difficult to distinguish high- and low-risk patients at osteosarcoma diagnosis. To address the issue, they analyzed the genomic signatures of 84 patients in the Cancer Genome Atlas and their associated clinical information.
The team split their subjects evenly into high-risk and low-risk groups based on a score developed from their genetic signatures. A total of 26 patients in the high-risk group (61.9%) died over a median follow up of 4.1 years versus only 1 (2.4%) in the low-risk group.
The risk score also correlated positively with B-cell tumor infiltration, and negatively with infiltration of CD8 T cells and macrophages.
Overall, 16 genes were significantly up-regulated, and 187 genes were significantly down-regulated in the high-risk group, including three survival-associated IRGs: CCL2, CD79A, and FPR1.
The differentially expressed genes were most significantly associated with transmembrane signaling receptor activity and inflammatory response. The team noted that “it has been reported that inflammatory response plays a critical role in tumor initiation, promotion, malignant conversion, invasion, and metastases.”
Of the 14 survival-associated IRGs, 5 have been reported before in osteosarcoma. The other nine were deduced from computational analysis and may be potential treatment targets, including bone morphogenetic protein 8b (BMP8b). Another member of the BMP family, BMP9, has been shown to promote the proliferation of osteosarcoma cells, “which is similar to this study’s finding that BMP8b was a risk factor in osteosarcoma. Therefore, the role of BMP8b in osteosarcoma needs further research,” the team said.
“Because the database provides limited clinical information, other important factors, such as staging and grading, were not included in our analysis. Therefore, extrapolation based on the findings must be done very carefully,” they cautioned.
The work was supported by the National Natural Science Foundation of China and others. The investigators didn’t have any disclosures.
When they combined them into a risk score and added one additional factor – metastases at diagnosis – the model was an “excellent” predictor of 1-year survival, the team said (area under the curve, 0.947; 95% confidence interval, 0.832-0.972).
“The survival-associated” immune-related genes (IRGs) “examined in this study have potential for identifying prognosis in osteosarcoma and may be clinically useful as relevant clinical biomarkers and candidate targets for anticancer therapy,” said investigators led by Wangmi Liu, MD, of Zhejiang University in Hangzhou, China. The study was published in JAMA Network Open.
They explained that it’s often difficult to distinguish high- and low-risk patients at osteosarcoma diagnosis. To address the issue, they analyzed the genomic signatures of 84 patients in the Cancer Genome Atlas and their associated clinical information.
The team split their subjects evenly into high-risk and low-risk groups based on a score developed from their genetic signatures. A total of 26 patients in the high-risk group (61.9%) died over a median follow up of 4.1 years versus only 1 (2.4%) in the low-risk group.
The risk score also correlated positively with B-cell tumor infiltration, and negatively with infiltration of CD8 T cells and macrophages.
Overall, 16 genes were significantly up-regulated, and 187 genes were significantly down-regulated in the high-risk group, including three survival-associated IRGs: CCL2, CD79A, and FPR1.
The differentially expressed genes were most significantly associated with transmembrane signaling receptor activity and inflammatory response. The team noted that “it has been reported that inflammatory response plays a critical role in tumor initiation, promotion, malignant conversion, invasion, and metastases.”
Of the 14 survival-associated IRGs, 5 have been reported before in osteosarcoma. The other nine were deduced from computational analysis and may be potential treatment targets, including bone morphogenetic protein 8b (BMP8b). Another member of the BMP family, BMP9, has been shown to promote the proliferation of osteosarcoma cells, “which is similar to this study’s finding that BMP8b was a risk factor in osteosarcoma. Therefore, the role of BMP8b in osteosarcoma needs further research,” the team said.
“Because the database provides limited clinical information, other important factors, such as staging and grading, were not included in our analysis. Therefore, extrapolation based on the findings must be done very carefully,” they cautioned.
The work was supported by the National Natural Science Foundation of China and others. The investigators didn’t have any disclosures.
When they combined them into a risk score and added one additional factor – metastases at diagnosis – the model was an “excellent” predictor of 1-year survival, the team said (area under the curve, 0.947; 95% confidence interval, 0.832-0.972).
“The survival-associated” immune-related genes (IRGs) “examined in this study have potential for identifying prognosis in osteosarcoma and may be clinically useful as relevant clinical biomarkers and candidate targets for anticancer therapy,” said investigators led by Wangmi Liu, MD, of Zhejiang University in Hangzhou, China. The study was published in JAMA Network Open.
They explained that it’s often difficult to distinguish high- and low-risk patients at osteosarcoma diagnosis. To address the issue, they analyzed the genomic signatures of 84 patients in the Cancer Genome Atlas and their associated clinical information.
The team split their subjects evenly into high-risk and low-risk groups based on a score developed from their genetic signatures. A total of 26 patients in the high-risk group (61.9%) died over a median follow up of 4.1 years versus only 1 (2.4%) in the low-risk group.
The risk score also correlated positively with B-cell tumor infiltration, and negatively with infiltration of CD8 T cells and macrophages.
Overall, 16 genes were significantly up-regulated, and 187 genes were significantly down-regulated in the high-risk group, including three survival-associated IRGs: CCL2, CD79A, and FPR1.
The differentially expressed genes were most significantly associated with transmembrane signaling receptor activity and inflammatory response. The team noted that “it has been reported that inflammatory response plays a critical role in tumor initiation, promotion, malignant conversion, invasion, and metastases.”
Of the 14 survival-associated IRGs, 5 have been reported before in osteosarcoma. The other nine were deduced from computational analysis and may be potential treatment targets, including bone morphogenetic protein 8b (BMP8b). Another member of the BMP family, BMP9, has been shown to promote the proliferation of osteosarcoma cells, “which is similar to this study’s finding that BMP8b was a risk factor in osteosarcoma. Therefore, the role of BMP8b in osteosarcoma needs further research,” the team said.
“Because the database provides limited clinical information, other important factors, such as staging and grading, were not included in our analysis. Therefore, extrapolation based on the findings must be done very carefully,” they cautioned.
The work was supported by the National Natural Science Foundation of China and others. The investigators didn’t have any disclosures.
FROM JAMA NETWORK OPEN