User login
Statin may reduce vaso-occlusive pain in SCD
Photo courtesy of the CDC
ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.
There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.
Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.
The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.
Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*
“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”
Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.
With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.
The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.
This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.
The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.
Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.
Results
Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.
The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.
Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.
The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).
Creatinine kinase remained stable during treatment, as did hemoglobin levels.
Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.
The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).
There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.
“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.
She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC. 
*Data in the abstract differ from the data presented.
Photo courtesy of the CDC
ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.
There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.
Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.
The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.
Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*
“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”
Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.
With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.
The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.
This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.
The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.
Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.
Results
Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.
The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.
Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.
The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).
Creatinine kinase remained stable during treatment, as did hemoglobin levels.
Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.
The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).
There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.
“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.
She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC.
*Data in the abstract differ from the data presented.
Photo courtesy of the CDC
ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.
There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.
Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.
The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.
Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*
“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”
Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.
With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.
The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.
This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.
The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.
Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.
Results
Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.
The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.
Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.
The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).
Creatinine kinase remained stable during treatment, as did hemoglobin levels.
Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.
The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).
Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).
There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.
“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.
She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC.
*Data in the abstract differ from the data presented.
Graft source and timing of HSCT affect survival in SCD
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
Photo by Chad McNeeley
ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).
However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.
Patient age and stem cell source were both independently associated with event-free and overall survival.
These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.
Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).
The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).
About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.
The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.
Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.
A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).
Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).
Results
The median follow-up was 45 months (range, 1-325).
At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.
Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.
Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.
Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.
The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.
The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.
Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.
Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.
Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.
“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”
She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.
*Data in the abstract differ from the presentation.
CAR T-cell therapy dubbed ‘promising’ for MM
Photo courtesy of ASH
ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.
The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.
In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.
The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.
The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.
The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA
single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.
Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m2 daily for 3 days and fludarabine at 30 mg/m2 daily for 3 days.
Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 106, 1 x 106, 3 x 106, and 9 x 106 CAR-positive T cells/kg.
Response and toxicity
“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”
One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 106). This response is ongoing and has lasted longer than 12 weeks.
Patient 8, who received a CAR-BCMA T-cell dose of 3 x 106, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.
Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 106) and lasted 2 weeks.
The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.
The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.
Best responders
Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.
“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.
Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.
Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.
Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.
The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.
Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.
Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.
“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”
Photo courtesy of ASH
ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.
The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.
In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.
The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.
The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.
The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA
single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.
Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m2 daily for 3 days and fludarabine at 30 mg/m2 daily for 3 days.
Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 106, 1 x 106, 3 x 106, and 9 x 106 CAR-positive T cells/kg.
Response and toxicity
“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”
One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 106). This response is ongoing and has lasted longer than 12 weeks.
Patient 8, who received a CAR-BCMA T-cell dose of 3 x 106, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.
Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 106) and lasted 2 weeks.
The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.
The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.
Best responders
Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.
“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.
Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.
Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.
Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.
The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.
Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.
Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.
“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”
Photo courtesy of ASH
ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.
The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.
In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.
The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.
The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.
The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA
single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.
Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m2 daily for 3 days and fludarabine at 30 mg/m2 daily for 3 days.
Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 106, 1 x 106, 3 x 106, and 9 x 106 CAR-positive T cells/kg.
Response and toxicity
“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”
One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 106). This response is ongoing and has lasted longer than 12 weeks.
Patient 8, who received a CAR-BCMA T-cell dose of 3 x 106, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.
Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 106) and lasted 2 weeks.
The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.
The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.
Best responders
Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.
“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.
Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.
Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.
Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.
The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.
Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.
Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.
“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”
HU noninferior to transfusion for stroke prevention in SCD
Photo courtesy of ASH
ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.
The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.
Because of these findings, the trial was terminated early, in November of last year.
Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.
“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”
Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.
Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.
Study design
For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.
All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.
In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.
In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.
The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.
Results
In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.
“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.
In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.
In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 109/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.
“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.
“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”
Early termination and noninferiority
Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.
At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.
The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10-16. By post-hoc analysis, the P value for superiority was 0.023.
Secondary endpoints
There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.
There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).
Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).
Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.
The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.
Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.
The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.
Because of these findings, the trial was terminated early, in November of last year.
Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.
“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”
Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.
Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.
Study design
For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.
All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.
In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.
In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.
The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.
Results
In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.
“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.
In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.
In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 109/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.
“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.
“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”
Early termination and noninferiority
Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.
At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.
The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10-16. By post-hoc analysis, the P value for superiority was 0.023.
Secondary endpoints
There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.
There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).
Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).
Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.
The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.
Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.
The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.
Because of these findings, the trial was terminated early, in November of last year.
Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.
“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”
Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.
Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.
Study design
For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.
All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.
In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.
In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.
The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.
Results
In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.
“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.
In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.
In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 109/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.
“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.
“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”
Early termination and noninferiority
Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.
At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.
The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10-16. By post-hoc analysis, the P value for superiority was 0.023.
Secondary endpoints
There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.
There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).
Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).
Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.
The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.
Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.
*Data in the abstract differ from data presented at the meeting.
Combination offers ‘important new option’ for CLL, team says
Photo courtesy of ASH
ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic
lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the
international research team that conducted the phase 3 study of this combination.
Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1
months versus 11.1 months, respectively.
“And the benefit was seen across risk groups,” Dr Zelenetz said.
He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.
Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.
Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.
“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”
The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.
Study 115 design and population
Study 115 was a double-blind, placebo-controlled phase 3 study.
The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m2 on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.
The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.
Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.
The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.
Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.
Patient disposition and demographics
One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.
Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).
The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.
A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.
Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.
Efficacy
Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said, at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).
In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.
Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.
ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.
Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.
Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.
Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.
There was no difference in survival benefit in patients with refractory disease.
Safety
All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.
Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.
Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.
The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.
Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.
Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).
The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.
Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.
Gilead Sciences developed idelalisib and funded Study 115.
*Data in the abstract differ slightly from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic
lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the
international research team that conducted the phase 3 study of this combination.
Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1
months versus 11.1 months, respectively.
“And the benefit was seen across risk groups,” Dr Zelenetz said.
He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.
Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.
Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.
“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”
The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.
Study 115 design and population
Study 115 was a double-blind, placebo-controlled phase 3 study.
The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m2 on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.
The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.
Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.
The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.
Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.
Patient disposition and demographics
One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.
Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).
The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.
A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.
Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.
Efficacy
Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said, at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).
In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.
Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.
ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.
Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.
Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.
Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.
There was no difference in survival benefit in patients with refractory disease.
Safety
All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.
Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.
Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.
The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.
Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.
Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).
The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.
Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.
Gilead Sciences developed idelalisib and funded Study 115.
*Data in the abstract differ slightly from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic
lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the
international research team that conducted the phase 3 study of this combination.
Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1
months versus 11.1 months, respectively.
“And the benefit was seen across risk groups,” Dr Zelenetz said.
He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.
Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.
Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.
“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”
The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.
Study 115 design and population
Study 115 was a double-blind, placebo-controlled phase 3 study.
The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m2 on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.
The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.
Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.
The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.
Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.
Patient disposition and demographics
One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.
Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).
The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.
A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.
Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.
Efficacy
Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said, at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).
In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.
Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.
ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.
Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.
Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.
Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.
There was no difference in survival benefit in patients with refractory disease.
Safety
All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.
Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.
Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.
The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.
Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.
Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).
The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.
Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.
Gilead Sciences developed idelalisib and funded Study 115.
*Data in the abstract differ slightly from data presented at the meeting.
Triplet disappoints in follicular lymphoma trial
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.
mAb could provide targeted approach to HLH treatment
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.
Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.
Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.
“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”
“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”
“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”
In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.
The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.
Patients and treatment
In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Response and survival
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.
Characteristics of response
For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.
Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.
Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m2. At the end of treatment, the median dose was 4.0 mg/m2 (P=0.023).
“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”
Adverse events and death
No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.
There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Infections
“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”
“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”
There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.
Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).
Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.
The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.
“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”
“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”
*Data in the abstract differ from data presented at the meeting.
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.
Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.
Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.
“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”
“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”
“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”
In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.
The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.
Patients and treatment
In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Response and survival
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.
Characteristics of response
For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.
Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.
Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m2. At the end of treatment, the median dose was 4.0 mg/m2 (P=0.023).
“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”
Adverse events and death
No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.
There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Infections
“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”
“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”
There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.
Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).
Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.
The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.
“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”
“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”
*Data in the abstract differ from data presented at the meeting.
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.
Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.
Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.
“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”
“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”
“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”
In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.
The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.
Patients and treatment
In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Response and survival
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.
Characteristics of response
For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.
Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.
Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m2. At the end of treatment, the median dose was 4.0 mg/m2 (P=0.023).
“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”
Adverse events and death
No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.
There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Infections
“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”
“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”
There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.
Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).
Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.
The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.
“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”
“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”
*Data in the abstract differ from data presented at the meeting.
Source of FVIII replacement matters, study shows
Photo courtesy of ASH
ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.
Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.
These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.
Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).
She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.
A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.
In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.
Study design
Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.
The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.
The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.
Patients were treated for 50 exposure days, 3 years, or until inhibitor development.
The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.
Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.
“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.
Results
In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.
Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.
Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.
The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.
More than 73% of all inhibitors were non-transient in both arms.
By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).
The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.
“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.
She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.
Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.
So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.
After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.
In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.
Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.
These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.
Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).
She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.
A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.
In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.
Study design
Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.
The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.
The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.
Patients were treated for 50 exposure days, 3 years, or until inhibitor development.
The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.
Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.
“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.
Results
In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.
Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.
Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.
The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.
More than 73% of all inhibitors were non-transient in both arms.
By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).
The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.
“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.
She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.
Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.
So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.
After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.
In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.
Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.
These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.
Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).
She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.
A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.
In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.
Study design
Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.
The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.
The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.
Patients were treated for 50 exposure days, 3 years, or until inhibitor development.
The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.
Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.
“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.
Results
In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.
Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.
Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.
The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.
More than 73% of all inhibitors were non-transient in both arms.
By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).
The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.
“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.
She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.
Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.
So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.
After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.
In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.
*Data in the abstract differ from data presented at the meeting.
CAR exhibits activity in resistant B-cell malignancies
Photo courtesy of ASH
ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.
Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”
Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).
Dr Kochenderfer presented these results at ASH as abstract 99.
For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.
The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.
All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.
The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).
All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 107 cells/kg.
Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.
Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.
One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.
Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).
In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).
Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.
Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.
There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.
“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.
None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.
Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.
Photo courtesy of ASH
ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.
Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”
Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).
Dr Kochenderfer presented these results at ASH as abstract 99.
For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.
The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.
All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.
The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).
All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 107 cells/kg.
Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.
Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.
One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.
Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).
In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).
Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.
Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.
There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.
“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.
None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.
Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.
Photo courtesy of ASH
ORLANDO, FL—Allogeneic chimeric antigen receptor (CAR) T cells directed against CD19 can have “significant” activity against resistant B-cell malignancies, even when given without prior chemotherapy, according to a presentation at the 2015 ASH Annual Meeting.
Nine of 20 patients responded to treatment with the CAR T cells, despite having failed prior allogeneic transplant. The best responses were observed in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
“Malignancies that were resistant to allogeneic transplants and standard donor lymphocyte infusions regressed after infusions of allogeneic anti-CD19 CAR T cells,” said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.
“Allogeneic anti-CD19 CAR T cells seem to be particularly effective against ALL and CLL, suggesting a possible antigenic stimulation that may be more pronounced in these malignancies.”
Adverse events associated with these CAR T cells included severe but reversible cytokine release syndrome, mild aphasia, and muscle damage. There were no cases of acute graft-vs-host disease (GVHD).
Dr Kochenderfer presented these results at ASH as abstract 99.
For this phase 1 study, researchers tested a CAR T-cell therapy that was originally developed by Dr Kochenderfer and his colleagues. The therapy is now known as KTE-C19 and is under development by Kite Pharmaceuticals. However, the company did not sponsor this trial.
The study was open to patients with any CD19+ B-cell malignancy that persisted after allogeneic transplant.
All patients except those with ALL were required to have received at least one standard donor lymphocyte infusion. In addition, patients were only eligible if they had minimal or no GVHD and were not receiving any systemic immunosuppressive drugs.
The trial included 20 patients—5 each with ALL, CLL, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).
All patients received a single infusion of CAR T cells derived from their original transplant donor. Production of these cells took 8 days. The highest dose of CAR T cells given was 107 cells/kg.
Four of the ALL patients obtained a minimal-residual disease-negative complete response (CR), but 2 of these patients subsequently relapsed. Of the other 2 patients, 1 remains in CR at 18 months of follow-up, and the other went on to receive a second allogeneic transplant. That patient remains in CR today.
Among the CLL patients, 1 achieved a CR, and 1 achieved a partial response (PR). One patient had stable disease (SD), and the other 2 progressed. Both the CR and the PR are ongoing at 36 and 18 months of follow-up, respectively.
One MCL patient achieved a CR, 1 had a PR, and 3 had SD. The CR is ongoing at 31 months. One DLBCL patient achieved a CR, 3 had SD, and 1 progressed.
Dr Kochenderfer noted that response was associated with higher blood CAR T-cell levels. There was a significant difference in CAR T-cell levels between responders and nonresponders (P=0.001).
In addition, the presence of blood B-cell levels before CAR T-cell infusion was associated with higher blood CAR T-cell levels. Patients with normal or high B lymphocytes had higher levels of CAR T cells in their blood (P=0.04).
Patients with high tumor burdens developed severe cytokine-release syndrome with fever, tachycardia, and hypotension. The ALL patients were particularly susceptible to cytokine-release syndrome.
Dr Kochenderfer said neurologic toxicity was rare and mild. There was 1 case of mild aphasia.
There were 2 patients with elevations in CPK, indicating muscle damage. Those patients also reported muscle pain, and 1 patient reported weakness.
“This is one of the first reports, I think, of muscle damage in CAR T-cell patients,” Dr Kochenderfer said.
None of the patients developed acute GVHD after CAR T-cell therapy. One patient had continued worsening of pre-existing chronic GVHD after treatment, and 1 patient developed mild chronic eye GVHD more than a year after CAR T-cell infusion.
Dr Kochenderfer said additional details from this trial will be published in an upcoming issue of the Journal of Clinical Oncology.
Ibrutinib ‘treatment of choice’ in rel/ref MCL
Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.
Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.
There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.
A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.
Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.
The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.
Study design
The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.
The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.
Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.
Patient characteristics
Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).
The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.
The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.
About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).
Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.
PFS
The study’s primary endpoint was PFS, as assessed by an independent review committee.
At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.
Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.
“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”
Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.
Secondary endpoints
The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.
This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.
The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.
The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).
And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.
Timing counts
Dr Rule also presented response and PFS data according to the number of prior therapies patients received.
He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.
In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.
Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.
At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.
“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”
Safety
“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.
Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.
Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.
Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.
Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).
The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).
The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).
The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).
Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.
At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.
Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.
Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.
There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.
A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.
Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.
The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.
Study design
The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.
The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.
Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.
Patient characteristics
Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).
The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.
The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.
About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).
Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.
PFS
The study’s primary endpoint was PFS, as assessed by an independent review committee.
At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.
Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.
“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”
Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.
Secondary endpoints
The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.
This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.
The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.
The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).
And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.
Timing counts
Dr Rule also presented response and PFS data according to the number of prior therapies patients received.
He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.
In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.
Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.
At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.
“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”
Safety
“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.
Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.
Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.
Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.
Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).
The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).
The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).
The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).
Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.
At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.
Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.
Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.
There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.
A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.
Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.
The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.
Study design
The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.
The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.
Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.
Patient characteristics
Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).
The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.
The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.
About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).
Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.
PFS
The study’s primary endpoint was PFS, as assessed by an independent review committee.
At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.
Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.
“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”
Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.
Secondary endpoints
The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.
This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.
The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.
The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).
And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.
Timing counts
Dr Rule also presented response and PFS data according to the number of prior therapies patients received.
He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.
In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.
Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.
At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.
“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”
Safety
“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.
Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.
Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.
Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.
Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).
The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).
The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).
The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).
Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.
At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.