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Cerdulatinib yields ‘encouraging’ results in CTCL, PTCL
LA JOLLA, CALIF. – The spleen tyrosine kinase/Janus kinase inhibitor cerdulatinib has demonstrated activity against relapsed and refractory T-cell lymphomas.
In a phase 2 trial, cerdulatinib produced responses in 34% of patients with peripheral T-cell lymphoma (PTCL) and 26% of those with cutaneous T-cell lymphoma (CTCL).
The best responders were patients with angioimmunoblastic T-cell lymphoma, half of whom achieved a complete response (CR).
The most common grade 3 or higher adverse events (AEs) were amylase increase and lipase increase. However, these increases resolved with dose reduction or interruption, and there were no cases of clinical pancreatitis.
“The data is very encouraging,” said Tatyana Feldman, MD, of the John Theurer Cancer Center in Hackensack, N.J.
Dr. Feldman and her colleagues previously presented results from the phase 2 trial of cerdulatinib (NCT01994382) at the 2018 annual congress of the European Hematology Association.
Dr. Feldman and her colleagues presented data from expansion cohorts of the ongoing trial at the annual T-cell Lymphoma Forum. The cohorts included patients with PTCL or CTCL who had received at least one prior systemic therapy.
PTCL cohort
The 45 PTCL patients had a median age of 65 years (range, 21-84). They had received a median of 3 (range, 1-12) prior therapeutic regimens, 51% were refractory to their last therapy, and 27% had undergone stem cell transplant (SCT).
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 41 patients were evaluable for response.
The overall response rate was 34% (n = 14). Eleven patients had a CR, three had a partial response (PR), and nine had stable disease.
Responses according to subtype were as follows:
- 7 CRs and 1 PR in angioimmunoblastic T-cell lymphoma.
- 2 CRs in PTCL not otherwise specified.
- 1 CR in gamma-delta T-cell lymphoma.
- 1 PR in ALK-negative anaplastic large-cell lymphoma.
- 1 CR and 1 PR in adult T-cell leukemia/lymphoma.
Eight responders have remained on cerdulatinib for anywhere from 3 months to more than 12 months. Five patients have had a response lasting at least 6 months. One patient went on to SCT after achieving a CR.
The most common grade 3 or higher AEs observed in PTCL patients were amylase increase (n = 8), lipase increase (n = 6), pneumonia/lung infection (n = 5), neutropenia (n = 4), diarrhea (n = 4), febrile neutropenia (n = 4), abdominal pain (n = 4), sepsis/bacteremia (n = 3), anemia (n = 3), fatigue (n = 2), and pain (n = 1).
There were two grade 5 AEs – acute respiratory distress syndrome and pneumonia.
CTCL cohort
The 29 CTCL patients had a median age of 62 years (range, 24-79). They had received a median of 4 (range, 1-13) prior therapies, 55% were refractory to their last therapy, and 3% had undergone SCT.
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 27 were evaluable for response.
The overall response rate was 26% (n = 7). Two patients achieved a CR, five achieved a PR, and nine had stable disease. Responses occurred in mycosis fungoides and Sézary syndrome.
Eleven of 23 patients (48%) achieved at least a 50% reduction in skin lesions, and the researchers observed rapid improvements in pruritus.
“I saw patients who would take the first pill, and they would call me and say, ‘I no longer itch,’ ” Dr. Feldman said.
The most common grade 3 or higher AEs in CTCL patients were lipase increase (n = 11), amylase increase (n = 5), sepsis/bacteremia (n = 3), pain (n = 2), fatigue (n = 1), neutropenia (n = 1), and diarrhea (n = 1).
“It’s a very well-tolerated drug,” Dr. Feldman said, adding that there were “really no severe side effects which would prohibit the use of the drug.”
She noted that cerdulatinib’s “favorable” side effect profile might make it a promising candidate for use in combination regimens.
“I think it will be possible to combine it with other drugs in development in T-cell lymphoma. … immunological checkpoint inhibitors, epigenetic modulators such as HDAC [histone deacetylase] inhibitors, methylating agents, and PI3 kinase inhibitors,” Dr. Feldman said.
She reported having no disclosures relevant to this study. The trial is sponsored by Portola Pharmaceuticals.
The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The spleen tyrosine kinase/Janus kinase inhibitor cerdulatinib has demonstrated activity against relapsed and refractory T-cell lymphomas.
In a phase 2 trial, cerdulatinib produced responses in 34% of patients with peripheral T-cell lymphoma (PTCL) and 26% of those with cutaneous T-cell lymphoma (CTCL).
The best responders were patients with angioimmunoblastic T-cell lymphoma, half of whom achieved a complete response (CR).
The most common grade 3 or higher adverse events (AEs) were amylase increase and lipase increase. However, these increases resolved with dose reduction or interruption, and there were no cases of clinical pancreatitis.
“The data is very encouraging,” said Tatyana Feldman, MD, of the John Theurer Cancer Center in Hackensack, N.J.
Dr. Feldman and her colleagues previously presented results from the phase 2 trial of cerdulatinib (NCT01994382) at the 2018 annual congress of the European Hematology Association.
Dr. Feldman and her colleagues presented data from expansion cohorts of the ongoing trial at the annual T-cell Lymphoma Forum. The cohorts included patients with PTCL or CTCL who had received at least one prior systemic therapy.
PTCL cohort
The 45 PTCL patients had a median age of 65 years (range, 21-84). They had received a median of 3 (range, 1-12) prior therapeutic regimens, 51% were refractory to their last therapy, and 27% had undergone stem cell transplant (SCT).
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 41 patients were evaluable for response.
The overall response rate was 34% (n = 14). Eleven patients had a CR, three had a partial response (PR), and nine had stable disease.
Responses according to subtype were as follows:
- 7 CRs and 1 PR in angioimmunoblastic T-cell lymphoma.
- 2 CRs in PTCL not otherwise specified.
- 1 CR in gamma-delta T-cell lymphoma.
- 1 PR in ALK-negative anaplastic large-cell lymphoma.
- 1 CR and 1 PR in adult T-cell leukemia/lymphoma.
Eight responders have remained on cerdulatinib for anywhere from 3 months to more than 12 months. Five patients have had a response lasting at least 6 months. One patient went on to SCT after achieving a CR.
The most common grade 3 or higher AEs observed in PTCL patients were amylase increase (n = 8), lipase increase (n = 6), pneumonia/lung infection (n = 5), neutropenia (n = 4), diarrhea (n = 4), febrile neutropenia (n = 4), abdominal pain (n = 4), sepsis/bacteremia (n = 3), anemia (n = 3), fatigue (n = 2), and pain (n = 1).
There were two grade 5 AEs – acute respiratory distress syndrome and pneumonia.
CTCL cohort
The 29 CTCL patients had a median age of 62 years (range, 24-79). They had received a median of 4 (range, 1-13) prior therapies, 55% were refractory to their last therapy, and 3% had undergone SCT.
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 27 were evaluable for response.
The overall response rate was 26% (n = 7). Two patients achieved a CR, five achieved a PR, and nine had stable disease. Responses occurred in mycosis fungoides and Sézary syndrome.
Eleven of 23 patients (48%) achieved at least a 50% reduction in skin lesions, and the researchers observed rapid improvements in pruritus.
“I saw patients who would take the first pill, and they would call me and say, ‘I no longer itch,’ ” Dr. Feldman said.
The most common grade 3 or higher AEs in CTCL patients were lipase increase (n = 11), amylase increase (n = 5), sepsis/bacteremia (n = 3), pain (n = 2), fatigue (n = 1), neutropenia (n = 1), and diarrhea (n = 1).
“It’s a very well-tolerated drug,” Dr. Feldman said, adding that there were “really no severe side effects which would prohibit the use of the drug.”
She noted that cerdulatinib’s “favorable” side effect profile might make it a promising candidate for use in combination regimens.
“I think it will be possible to combine it with other drugs in development in T-cell lymphoma. … immunological checkpoint inhibitors, epigenetic modulators such as HDAC [histone deacetylase] inhibitors, methylating agents, and PI3 kinase inhibitors,” Dr. Feldman said.
She reported having no disclosures relevant to this study. The trial is sponsored by Portola Pharmaceuticals.
The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The spleen tyrosine kinase/Janus kinase inhibitor cerdulatinib has demonstrated activity against relapsed and refractory T-cell lymphomas.
In a phase 2 trial, cerdulatinib produced responses in 34% of patients with peripheral T-cell lymphoma (PTCL) and 26% of those with cutaneous T-cell lymphoma (CTCL).
The best responders were patients with angioimmunoblastic T-cell lymphoma, half of whom achieved a complete response (CR).
The most common grade 3 or higher adverse events (AEs) were amylase increase and lipase increase. However, these increases resolved with dose reduction or interruption, and there were no cases of clinical pancreatitis.
“The data is very encouraging,” said Tatyana Feldman, MD, of the John Theurer Cancer Center in Hackensack, N.J.
Dr. Feldman and her colleagues previously presented results from the phase 2 trial of cerdulatinib (NCT01994382) at the 2018 annual congress of the European Hematology Association.
Dr. Feldman and her colleagues presented data from expansion cohorts of the ongoing trial at the annual T-cell Lymphoma Forum. The cohorts included patients with PTCL or CTCL who had received at least one prior systemic therapy.
PTCL cohort
The 45 PTCL patients had a median age of 65 years (range, 21-84). They had received a median of 3 (range, 1-12) prior therapeutic regimens, 51% were refractory to their last therapy, and 27% had undergone stem cell transplant (SCT).
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 41 patients were evaluable for response.
The overall response rate was 34% (n = 14). Eleven patients had a CR, three had a partial response (PR), and nine had stable disease.
Responses according to subtype were as follows:
- 7 CRs and 1 PR in angioimmunoblastic T-cell lymphoma.
- 2 CRs in PTCL not otherwise specified.
- 1 CR in gamma-delta T-cell lymphoma.
- 1 PR in ALK-negative anaplastic large-cell lymphoma.
- 1 CR and 1 PR in adult T-cell leukemia/lymphoma.
Eight responders have remained on cerdulatinib for anywhere from 3 months to more than 12 months. Five patients have had a response lasting at least 6 months. One patient went on to SCT after achieving a CR.
The most common grade 3 or higher AEs observed in PTCL patients were amylase increase (n = 8), lipase increase (n = 6), pneumonia/lung infection (n = 5), neutropenia (n = 4), diarrhea (n = 4), febrile neutropenia (n = 4), abdominal pain (n = 4), sepsis/bacteremia (n = 3), anemia (n = 3), fatigue (n = 2), and pain (n = 1).
There were two grade 5 AEs – acute respiratory distress syndrome and pneumonia.
CTCL cohort
The 29 CTCL patients had a median age of 62 years (range, 24-79). They had received a median of 4 (range, 1-13) prior therapies, 55% were refractory to their last therapy, and 3% had undergone SCT.
The patients received cerdulatinib at 30 mg orally twice a day until progression or intolerance, and 27 were evaluable for response.
The overall response rate was 26% (n = 7). Two patients achieved a CR, five achieved a PR, and nine had stable disease. Responses occurred in mycosis fungoides and Sézary syndrome.
Eleven of 23 patients (48%) achieved at least a 50% reduction in skin lesions, and the researchers observed rapid improvements in pruritus.
“I saw patients who would take the first pill, and they would call me and say, ‘I no longer itch,’ ” Dr. Feldman said.
The most common grade 3 or higher AEs in CTCL patients were lipase increase (n = 11), amylase increase (n = 5), sepsis/bacteremia (n = 3), pain (n = 2), fatigue (n = 1), neutropenia (n = 1), and diarrhea (n = 1).
“It’s a very well-tolerated drug,” Dr. Feldman said, adding that there were “really no severe side effects which would prohibit the use of the drug.”
She noted that cerdulatinib’s “favorable” side effect profile might make it a promising candidate for use in combination regimens.
“I think it will be possible to combine it with other drugs in development in T-cell lymphoma. … immunological checkpoint inhibitors, epigenetic modulators such as HDAC [histone deacetylase] inhibitors, methylating agents, and PI3 kinase inhibitors,” Dr. Feldman said.
She reported having no disclosures relevant to this study. The trial is sponsored by Portola Pharmaceuticals.
The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
REPORTING FROM TCLF 2019
Key clinical point:
Major finding: The overall response rate was 34% in patients with peripheral T-cell lymphoma (PTCL) and 26% in patients with cutaneous T-cell lymphoma (CTCL).
Study details: Expansion cohorts of a phase 2 trial including 45 PTCL patients and 29 CTCL patients
Disclosures: The study was funded by Portola Pharmaceuticals. The investigator reported having no relevant conflicts.
Meta-analysis: IVIG bests anti-D on platelet count in pediatric ITP
For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.
Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.
“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.
Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.
The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.
In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.
Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 109/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 109/L.
Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.
Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.
“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”
The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.
SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.
For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.
Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.
“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.
Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.
The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.
In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.
Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 109/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 109/L.
Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.
Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.
“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”
The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.
SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.
For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.
Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.
“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.
Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.
The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.
In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.
Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 109/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 109/L.
Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.
Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.
“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”
The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.
SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.
FROM THE JOURNAL OF PEDIATRICS
Key clinical point:
Major finding: Treatment with IVIG was 15% more likely than anti-D immunoglobulin to raise platelet counts higher than 20 × 109/L within 24-72 hours.
Study details: A systematic review and meta-analysis of 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP.
Disclosures: The meta-analysis did not have outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.
Source: Lioger B et al. J Pediatr. 2019; 204:225-33.
Immunotherapy’s cardiac effects require early monitoring, management
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Monitor for cardiac symptoms and treat or interrupt immunotherapy as needed.
Major finding: Immune checkpoint inhibitors and CAR T-cell therapies are associated with distinct cardiovascular adverse events.
Study details: Review of strategies for managing the cardiovascular consequences of cancer immunotherapies.
Disclosures: Dr. Cornell reported having nothing to disclose.
Combo emerges as bridge to transplant in rel/ref PTCL
LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.
In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.
“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).
Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.
She reported results in 80 patients – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
Treatment
Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.
Patients in the romidepsin arm received romidepsin at 10 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m2 on days 1, 4, 8, and 11 of each cycle.
Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.
In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.
The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
Lead-in phase
The study also had a lead-in phase during which patients could receive single-agent duvelisib.
“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.
Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.
There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.
There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
Efficacy with romidepsin
Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).
Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.
CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.
Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.
The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.
Efficacy with bortezomib
Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).
Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.
Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.
The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
Safety
Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.
Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).
Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).
Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.
Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.
Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.
This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.
In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.
“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).
Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.
She reported results in 80 patients – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
Treatment
Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.
Patients in the romidepsin arm received romidepsin at 10 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m2 on days 1, 4, 8, and 11 of each cycle.
Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.
In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.
The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
Lead-in phase
The study also had a lead-in phase during which patients could receive single-agent duvelisib.
“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.
Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.
There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.
There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
Efficacy with romidepsin
Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).
Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.
CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.
Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.
The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.
Efficacy with bortezomib
Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).
Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.
Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.
The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
Safety
Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.
Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).
Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).
Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.
Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.
Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.
This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.
In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.
“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).
Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.
She reported results in 80 patients – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
Treatment
Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.
Patients in the romidepsin arm received romidepsin at 10 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m2 on days 1, 4, 8, and 11 of each cycle.
Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.
In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.
The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
Lead-in phase
The study also had a lead-in phase during which patients could receive single-agent duvelisib.
“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.
Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.
There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.
There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
Efficacy with romidepsin
Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).
Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.
CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.
Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.
The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.
Efficacy with bortezomib
Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).
Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.
Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.
The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
Safety
Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.
Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).
Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).
Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.
Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.
Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.
This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.
The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
REPORTING FROM TCLF 2019
Key clinical point:
Major finding: The overall response rate was 59%, and six of nine complete responders went on to transplant.
Study details: Phase 1 trial of 80 patients that included 27 evaluable PTCL patients who received romidepsin and duvelisib.
Disclosures: The study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.
FDA grants BI-1206 orphan designation for MCL
The Food and Drug Administration has granted orphan designation to BI-1206 for the treatment of mantle cell lymphoma (MCL).
BI-1206 is a monoclonal antibody being developed by BioInvent International.
The company says BI-1206 works by inhibiting FcgRIIB (CD32B), which is associated with poor prognosis in MCL and other non-Hodgkin lymphomas. By inhibiting FcgRIIB, BI-1206 is expected to enhance the activity of rituximab or other anti-CD20 monoclonal antibodies.
BioInvent is conducting a phase 1/2a study (NCT03571568) of BI-1206 in combination with rituximab in patients with indolent, relapsed/refractory B-cell non-Hodgkin lymphomas, including MCL. The first patient began receiving treatment with BI-1206 in September 2018.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases or disorders that affect fewer than 200,000 people in the United States. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The Food and Drug Administration has granted orphan designation to BI-1206 for the treatment of mantle cell lymphoma (MCL).
BI-1206 is a monoclonal antibody being developed by BioInvent International.
The company says BI-1206 works by inhibiting FcgRIIB (CD32B), which is associated with poor prognosis in MCL and other non-Hodgkin lymphomas. By inhibiting FcgRIIB, BI-1206 is expected to enhance the activity of rituximab or other anti-CD20 monoclonal antibodies.
BioInvent is conducting a phase 1/2a study (NCT03571568) of BI-1206 in combination with rituximab in patients with indolent, relapsed/refractory B-cell non-Hodgkin lymphomas, including MCL. The first patient began receiving treatment with BI-1206 in September 2018.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases or disorders that affect fewer than 200,000 people in the United States. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The Food and Drug Administration has granted orphan designation to BI-1206 for the treatment of mantle cell lymphoma (MCL).
BI-1206 is a monoclonal antibody being developed by BioInvent International.
The company says BI-1206 works by inhibiting FcgRIIB (CD32B), which is associated with poor prognosis in MCL and other non-Hodgkin lymphomas. By inhibiting FcgRIIB, BI-1206 is expected to enhance the activity of rituximab or other anti-CD20 monoclonal antibodies.
BioInvent is conducting a phase 1/2a study (NCT03571568) of BI-1206 in combination with rituximab in patients with indolent, relapsed/refractory B-cell non-Hodgkin lymphomas, including MCL. The first patient began receiving treatment with BI-1206 in September 2018.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases or disorders that affect fewer than 200,000 people in the United States. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
GALLIUM: MRD response correlates with outcomes in follicular lymphoma
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Progression-free survival (PFS) probability was about 80% in patients who were MRD negative at the end of induction, compared with about 50% in patients who were MRD positive (hazard ratio, 0.38).
Study details: An analysis of data from 634 patients in the phase 3 GALLIUM study.
Disclosures: The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
Source: Pott C et al. ASH 2018, Abstract 396.
Applying ECHELON-2 results to clinical practice
LA JOLLA, CALIF. – Results from the ECHELON-2 trial led to the U.S. approval of brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (CHP), but there are still questions about how to apply the trial results to practice.
At the annual T-cell Lymphoma Forum, trial investigators and other physicians debated the best use of this combination.
BV-CHP is approved to treat patients with previously untreated systemic anaplastic large-cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS).
Patients who received BV-CHP in ECHELON-2 had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
These results were initially presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in The Lancet (2019 Jan 19;393[10168]:229-40).
ECHELON-2 investigator Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, also presented details on the trial at the T-cell Lymphoma Forum. His presentation was followed by a discussion with meeting attendees about applying the trial results to clinical practice.
CD30 expression
One of the issues discussed was the importance of CD30 expression in deciding which patients should receive BV.
For a patient to be eligible for ECHELON-2, the diagnostic biopsy had to show at least 10% of the neoplastic cells were CD30-positive. However, the Food and Drug Administration (FDA) has not made a similar requirement for prescribing BV. PTCL patients with any level of CD30 expression are eligible for treatment with BV-CHP, according to the FDA.
“[I]t’s still a matter of great debate and controversy as to whether we have good enough data to suggest that there’s a threshold effect with regard to the expression of CD30 and responsiveness or sensitivity to brentuximab vedotin,” Dr. O’Connor said.
“This has been an issue from the very first day with this drug, which is, ‘Just how much CD30 do you need to get a response?’ I can’t speak on behalf of the FDA, but I think they are not absolutely convinced that there’s a threshold. They take [CD30-] positive as ‘good enough’ across the board.”
“The FDA has said, ‘The data we’ve seen says there’s a lot of heterogeneity [with biopsies].’ You may do a biopsy and find 30% [of cells are CD30-positive], and you may do another biopsy [in the same patient] and find less than 10%. I don’t think the regulatory agencies are convinced that a single biopsy looking at CD30 ... is representative of the entire tumor burden.”
Andrei Shustov, MD, an ECHELON-2 investigator from the University of Washington in Seattle, questioned whether CD30 expression should be considered when deciding on the use of BV in PTCL.
“Is CD30 staining relevant at all, or should we default back to studies, say, in colon cancer where we didn’t even care about EGFR because we might be missing it by current techniques?” Dr. Shustov asked. “Should we even worry about CD30 expression ... because we cannot reliably detect low levels of CD30?”
Some attendees echoed this sentiment, questioning the utility of assessing CD30 expression. Other attendees said they would defer to the trial data and only treat patients with BV-CHP if they had at least 10% CD30.
PTCL subtypes
Meeting attendees also discussed the value of BV in different PTCL subtypes.
At the request of European regulatory agencies, ECHELON-2 was largely focused on patients with sALCL. They made up 70% of the total trial population, while 16% of patients had PTCL-NOS, 12% had AITL, and a small number of patients had other subtypes. These numbers meant ECHELON-2 was not powered to determine differences in OS or PFS in non-sALCL subtypes.
As a result, some attendees expressed concerns about using BV-CHP to treat PTCL-NOS or AITL. They argued that it wasn’t clear whether patients with these subtypes would derive more benefit from BV-CHP, CHOP, or CHOP plus etoposide (CHOEP).
Other attendees said they would feel comfortable using BV-CHP in patients with PTCL-NOS or AITL based on ECHELON-2 results.
CHOP vs. CHOEP
The use of CHOP in ECHELON-2 was another point of discussion. Some attendees said CHOEP should have been used as the comparator instead.
A few individuals mentioned retrospective data suggesting CHOEP may confer a benefit over CHOP in PTCL (Blood. 2010 Nov 4;116[18]:3418-25).
Marek Trneny, MD, of Charles University General Hospital in Prague, referenced new data from the Czech National Lymphoma Registry, which showed that patients newly diagnosed with PTCL had superior PFS and OS when they received CHOEP rather than CHOP.
Based on these findings, Dr. Trneny said he would consider treating CD30-positive PTCL patients with CHOEP plus BV rather than BV-CHP.
However, most other attendees said they would not consider adding BV to CHOEP due to the absence of clinical trial data supporting this approach.
Some attendees did say they would use CHOEP instead of BV-CHP, particularly in patients with PTCL-NOS or AITL and in patients with CD30 expression below 10%.
ECHELON-2 was funded by Seattle Genetics and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
Dr. O’Connor and Dr. Shustov were investigators on ECHELON-2. Dr. O’Connor is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – Results from the ECHELON-2 trial led to the U.S. approval of brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (CHP), but there are still questions about how to apply the trial results to practice.
At the annual T-cell Lymphoma Forum, trial investigators and other physicians debated the best use of this combination.
BV-CHP is approved to treat patients with previously untreated systemic anaplastic large-cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS).
Patients who received BV-CHP in ECHELON-2 had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
These results were initially presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in The Lancet (2019 Jan 19;393[10168]:229-40).
ECHELON-2 investigator Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, also presented details on the trial at the T-cell Lymphoma Forum. His presentation was followed by a discussion with meeting attendees about applying the trial results to clinical practice.
CD30 expression
One of the issues discussed was the importance of CD30 expression in deciding which patients should receive BV.
For a patient to be eligible for ECHELON-2, the diagnostic biopsy had to show at least 10% of the neoplastic cells were CD30-positive. However, the Food and Drug Administration (FDA) has not made a similar requirement for prescribing BV. PTCL patients with any level of CD30 expression are eligible for treatment with BV-CHP, according to the FDA.
“[I]t’s still a matter of great debate and controversy as to whether we have good enough data to suggest that there’s a threshold effect with regard to the expression of CD30 and responsiveness or sensitivity to brentuximab vedotin,” Dr. O’Connor said.
“This has been an issue from the very first day with this drug, which is, ‘Just how much CD30 do you need to get a response?’ I can’t speak on behalf of the FDA, but I think they are not absolutely convinced that there’s a threshold. They take [CD30-] positive as ‘good enough’ across the board.”
“The FDA has said, ‘The data we’ve seen says there’s a lot of heterogeneity [with biopsies].’ You may do a biopsy and find 30% [of cells are CD30-positive], and you may do another biopsy [in the same patient] and find less than 10%. I don’t think the regulatory agencies are convinced that a single biopsy looking at CD30 ... is representative of the entire tumor burden.”
Andrei Shustov, MD, an ECHELON-2 investigator from the University of Washington in Seattle, questioned whether CD30 expression should be considered when deciding on the use of BV in PTCL.
“Is CD30 staining relevant at all, or should we default back to studies, say, in colon cancer where we didn’t even care about EGFR because we might be missing it by current techniques?” Dr. Shustov asked. “Should we even worry about CD30 expression ... because we cannot reliably detect low levels of CD30?”
Some attendees echoed this sentiment, questioning the utility of assessing CD30 expression. Other attendees said they would defer to the trial data and only treat patients with BV-CHP if they had at least 10% CD30.
PTCL subtypes
Meeting attendees also discussed the value of BV in different PTCL subtypes.
At the request of European regulatory agencies, ECHELON-2 was largely focused on patients with sALCL. They made up 70% of the total trial population, while 16% of patients had PTCL-NOS, 12% had AITL, and a small number of patients had other subtypes. These numbers meant ECHELON-2 was not powered to determine differences in OS or PFS in non-sALCL subtypes.
As a result, some attendees expressed concerns about using BV-CHP to treat PTCL-NOS or AITL. They argued that it wasn’t clear whether patients with these subtypes would derive more benefit from BV-CHP, CHOP, or CHOP plus etoposide (CHOEP).
Other attendees said they would feel comfortable using BV-CHP in patients with PTCL-NOS or AITL based on ECHELON-2 results.
CHOP vs. CHOEP
The use of CHOP in ECHELON-2 was another point of discussion. Some attendees said CHOEP should have been used as the comparator instead.
A few individuals mentioned retrospective data suggesting CHOEP may confer a benefit over CHOP in PTCL (Blood. 2010 Nov 4;116[18]:3418-25).
Marek Trneny, MD, of Charles University General Hospital in Prague, referenced new data from the Czech National Lymphoma Registry, which showed that patients newly diagnosed with PTCL had superior PFS and OS when they received CHOEP rather than CHOP.
Based on these findings, Dr. Trneny said he would consider treating CD30-positive PTCL patients with CHOEP plus BV rather than BV-CHP.
However, most other attendees said they would not consider adding BV to CHOEP due to the absence of clinical trial data supporting this approach.
Some attendees did say they would use CHOEP instead of BV-CHP, particularly in patients with PTCL-NOS or AITL and in patients with CD30 expression below 10%.
ECHELON-2 was funded by Seattle Genetics and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
Dr. O’Connor and Dr. Shustov were investigators on ECHELON-2. Dr. O’Connor is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – Results from the ECHELON-2 trial led to the U.S. approval of brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (CHP), but there are still questions about how to apply the trial results to practice.
At the annual T-cell Lymphoma Forum, trial investigators and other physicians debated the best use of this combination.
BV-CHP is approved to treat patients with previously untreated systemic anaplastic large-cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS).
Patients who received BV-CHP in ECHELON-2 had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
These results were initially presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in The Lancet (2019 Jan 19;393[10168]:229-40).
ECHELON-2 investigator Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, also presented details on the trial at the T-cell Lymphoma Forum. His presentation was followed by a discussion with meeting attendees about applying the trial results to clinical practice.
CD30 expression
One of the issues discussed was the importance of CD30 expression in deciding which patients should receive BV.
For a patient to be eligible for ECHELON-2, the diagnostic biopsy had to show at least 10% of the neoplastic cells were CD30-positive. However, the Food and Drug Administration (FDA) has not made a similar requirement for prescribing BV. PTCL patients with any level of CD30 expression are eligible for treatment with BV-CHP, according to the FDA.
“[I]t’s still a matter of great debate and controversy as to whether we have good enough data to suggest that there’s a threshold effect with regard to the expression of CD30 and responsiveness or sensitivity to brentuximab vedotin,” Dr. O’Connor said.
“This has been an issue from the very first day with this drug, which is, ‘Just how much CD30 do you need to get a response?’ I can’t speak on behalf of the FDA, but I think they are not absolutely convinced that there’s a threshold. They take [CD30-] positive as ‘good enough’ across the board.”
“The FDA has said, ‘The data we’ve seen says there’s a lot of heterogeneity [with biopsies].’ You may do a biopsy and find 30% [of cells are CD30-positive], and you may do another biopsy [in the same patient] and find less than 10%. I don’t think the regulatory agencies are convinced that a single biopsy looking at CD30 ... is representative of the entire tumor burden.”
Andrei Shustov, MD, an ECHELON-2 investigator from the University of Washington in Seattle, questioned whether CD30 expression should be considered when deciding on the use of BV in PTCL.
“Is CD30 staining relevant at all, or should we default back to studies, say, in colon cancer where we didn’t even care about EGFR because we might be missing it by current techniques?” Dr. Shustov asked. “Should we even worry about CD30 expression ... because we cannot reliably detect low levels of CD30?”
Some attendees echoed this sentiment, questioning the utility of assessing CD30 expression. Other attendees said they would defer to the trial data and only treat patients with BV-CHP if they had at least 10% CD30.
PTCL subtypes
Meeting attendees also discussed the value of BV in different PTCL subtypes.
At the request of European regulatory agencies, ECHELON-2 was largely focused on patients with sALCL. They made up 70% of the total trial population, while 16% of patients had PTCL-NOS, 12% had AITL, and a small number of patients had other subtypes. These numbers meant ECHELON-2 was not powered to determine differences in OS or PFS in non-sALCL subtypes.
As a result, some attendees expressed concerns about using BV-CHP to treat PTCL-NOS or AITL. They argued that it wasn’t clear whether patients with these subtypes would derive more benefit from BV-CHP, CHOP, or CHOP plus etoposide (CHOEP).
Other attendees said they would feel comfortable using BV-CHP in patients with PTCL-NOS or AITL based on ECHELON-2 results.
CHOP vs. CHOEP
The use of CHOP in ECHELON-2 was another point of discussion. Some attendees said CHOEP should have been used as the comparator instead.
A few individuals mentioned retrospective data suggesting CHOEP may confer a benefit over CHOP in PTCL (Blood. 2010 Nov 4;116[18]:3418-25).
Marek Trneny, MD, of Charles University General Hospital in Prague, referenced new data from the Czech National Lymphoma Registry, which showed that patients newly diagnosed with PTCL had superior PFS and OS when they received CHOEP rather than CHOP.
Based on these findings, Dr. Trneny said he would consider treating CD30-positive PTCL patients with CHOEP plus BV rather than BV-CHP.
However, most other attendees said they would not consider adding BV to CHOEP due to the absence of clinical trial data supporting this approach.
Some attendees did say they would use CHOEP instead of BV-CHP, particularly in patients with PTCL-NOS or AITL and in patients with CD30 expression below 10%.
ECHELON-2 was funded by Seattle Genetics and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
Dr. O’Connor and Dr. Shustov were investigators on ECHELON-2. Dr. O’Connor is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2019
Turoctocog alfa appears safe, effective in reducing bleeds
Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.
The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).
In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.
“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”
Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.
The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.
“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.
For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.
There were no Factor VIII inhibitors reported in the extension trial.
In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.
The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.
The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.
SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.
Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.
The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).
In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.
“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”
Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.
The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.
“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.
For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.
There were no Factor VIII inhibitors reported in the extension trial.
In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.
The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.
The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.
SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.
Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.
The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).
In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.
“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”
Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.
The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.
“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.
For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.
There were no Factor VIII inhibitors reported in the extension trial.
In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.
The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.
The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.
SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.
FROM HAEMOPHILIA
Key clinical point:
Major finding: No Factor VIII inhibitors were reported. Among 207 patients who received prophylaxis, the median annualized bleeding rate was 1.37.
Study details: A phase 3b open label extension trial in which 213 males with hemophilia A were exposed to prophylaxis or on-demand treatment.
Disclosures: The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.
Source: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-e394.
Thrombin generation looks promising as a hemophilia biomarker
SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.
Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.
Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.
In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.
One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.
Nearly three-quarters of patients in the study had a low bleeding score.
Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.
However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).
“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.
The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.
SOURCE: Nossair F et al. ASH 2018, Poster 3788.
SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.
Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.
Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.
In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.
One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.
Nearly three-quarters of patients in the study had a low bleeding score.
Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.
However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).
“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.
The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.
SOURCE: Nossair F et al. ASH 2018, Poster 3788.
SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.
Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.
Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.
In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.
One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.
Nearly three-quarters of patients in the study had a low bleeding score.
Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.
However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).
“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.
The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.
SOURCE: Nossair F et al. ASH 2018, Poster 3788.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Compared with baseline factor level, all thrombin generation values had a higher sensitivity to predict bleeding severity (57%-62% versus 29%).
Study details: The study included 81 patients with mild or moderate hemophilia A or B and compared biomarkers for differentiating between bleeding phenotype severities.
Disclosures: The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.
Source: Nossair F et al. ASH 2018, Poster 3788.
IPH4102 on fast track for Sézary syndrome
The who have received at least two prior systemic therapies.
IPH4102 is an anti-KIR3DL2 antibody being developed by Innate Pharma as a treatment for T-cell lymphomas.
The FDA’s fast track program is designed to expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
The fast track designation for IPH4102 is based on preliminary results from a phase 1 study (NCT02593045) of patients with advanced cutaneous T-cell lymphoma.
Data on 35 Sézary patients in this trial were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:684). The patients had a median age of 70 (range, 31-90), and they had received a median of 2 (range, 1-9) prior systemic therapies.
As of Oct. 15, 2018, the overall response rate was 42.9%, with 2 complete responses and 13 partial responses. The median duration of response was 13.8 months, and the median progression-free survival was 11.7 months.
Treatment-related adverse events (AEs) included asthenia (n = 5), lymphopenia (n = 5), fatigue (n = 3), pyrexia (n = 3), arthralgia (n = 2), and diarrhea (n = 1). The only grade 3/4 treatment-related AE was lymphopenia (n = 2).
Four patients experienced six grade 3 or higher AEs that were possibly related to treatment—grade 5 hepatitis (n = 1), grade 4 sepsis (n = 1), grade 3 lymphopenia (n = 3), and grade 3 hypotension (n = 1).
Based on these results, Innate Pharma is planning a phase 2 trial of IPH4102, which is expected to begin in the first half of this year.
The who have received at least two prior systemic therapies.
IPH4102 is an anti-KIR3DL2 antibody being developed by Innate Pharma as a treatment for T-cell lymphomas.
The FDA’s fast track program is designed to expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
The fast track designation for IPH4102 is based on preliminary results from a phase 1 study (NCT02593045) of patients with advanced cutaneous T-cell lymphoma.
Data on 35 Sézary patients in this trial were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:684). The patients had a median age of 70 (range, 31-90), and they had received a median of 2 (range, 1-9) prior systemic therapies.
As of Oct. 15, 2018, the overall response rate was 42.9%, with 2 complete responses and 13 partial responses. The median duration of response was 13.8 months, and the median progression-free survival was 11.7 months.
Treatment-related adverse events (AEs) included asthenia (n = 5), lymphopenia (n = 5), fatigue (n = 3), pyrexia (n = 3), arthralgia (n = 2), and diarrhea (n = 1). The only grade 3/4 treatment-related AE was lymphopenia (n = 2).
Four patients experienced six grade 3 or higher AEs that were possibly related to treatment—grade 5 hepatitis (n = 1), grade 4 sepsis (n = 1), grade 3 lymphopenia (n = 3), and grade 3 hypotension (n = 1).
Based on these results, Innate Pharma is planning a phase 2 trial of IPH4102, which is expected to begin in the first half of this year.
The who have received at least two prior systemic therapies.
IPH4102 is an anti-KIR3DL2 antibody being developed by Innate Pharma as a treatment for T-cell lymphomas.
The FDA’s fast track program is designed to expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
The fast track designation for IPH4102 is based on preliminary results from a phase 1 study (NCT02593045) of patients with advanced cutaneous T-cell lymphoma.
Data on 35 Sézary patients in this trial were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:684). The patients had a median age of 70 (range, 31-90), and they had received a median of 2 (range, 1-9) prior systemic therapies.
As of Oct. 15, 2018, the overall response rate was 42.9%, with 2 complete responses and 13 partial responses. The median duration of response was 13.8 months, and the median progression-free survival was 11.7 months.
Treatment-related adverse events (AEs) included asthenia (n = 5), lymphopenia (n = 5), fatigue (n = 3), pyrexia (n = 3), arthralgia (n = 2), and diarrhea (n = 1). The only grade 3/4 treatment-related AE was lymphopenia (n = 2).
Four patients experienced six grade 3 or higher AEs that were possibly related to treatment—grade 5 hepatitis (n = 1), grade 4 sepsis (n = 1), grade 3 lymphopenia (n = 3), and grade 3 hypotension (n = 1).
Based on these results, Innate Pharma is planning a phase 2 trial of IPH4102, which is expected to begin in the first half of this year.