ASH 2015

Bone marrow harvest

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.

Bone marrow harvest

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.

Bone marrow harvest

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.

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Five-year results from the COMFORT-II trial appear to confirm that treatment with ruxolitinib can improve spleen size and survival in patients with myelofibrosis (MF).

“These results pave the way to use ruxolitinib earlier in the course of the disease,” said lead study author Claire Harrison, MD, a consultant hematologist at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

Dr Harrison presented the results at the 2015 ASH Annual Meeting (abstract 59).

Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated rapid, durable improvements in splenomegaly and MF symptoms, as well as improved survival in the phase 3 COMFORT-I and COMFORT-II studies.

In COMFORT-II, significantly more patients achieved the primary endpoint—a 35% or greater decrease in spleen volume from baseline at week 48—with ruxolitinib than with best available therapy (BAT).

The 3-year follow-up confirmed that spleen volume reductions were sustained, and ruxolitinib treatment remained tolerable with long-term use.

The randomized, open-label, multicenter study included 219 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Two-thirds of patients received ruxolitinib twice daily, and one-third of patients received BAT, which was administered at doses and schedules determined by the investigator.

Almost two-thirds of the patients on the BAT arm crossed over to receive ruxolitinib upon protocol-defined progression following the primary analysis after week 48. All patients randomized to BAT have crossed over or discontinued, Dr Harrison said.

She presented the 5-year final study results, which showed that more than half of the patients (53.4%) experienced significant reductions in spleen size with ruxolitinib therapy and sustained this benefit over a median duration of 3.2 years.

“There was a 33% improvement in overall survival with ruxolitinib as compared to BAT,” she said.

Using a statistical model of survival if patients had not crossed-over to ruxolitinib, the survival benefit was 56% in favor of ruxolitinib.

“The plateau in spleen responses correlates well with the survival advantage,” Dr Harrison said.

She noted that the JAK allele burden was also reduced in the majority of patients who crossed over during the study. A recent bone marrow analysis shows a 20% improvement in fibrosis as well.

Nearly one-quarter of patients from both the ruxolitinib arm and those who crossed over from the BAT arm remained on treatment with ruxolitinib for 5 years.

All adverse events were consistent with previous analyses of treatment with ruxolitinib in MF, Dr Harrison said. The most common adverse events in ruxolitinib-treated patients were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33%).

The most common grade 3/4 adverse events included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and shortness of breath (4.2%).

“This long-term analysis after a vast number of patient-years shows the ongoing benefit, with no new safety signals and a strong survival message,” Dr Harrison said.

“Hematologists can be confident treating patients with ruxolitinib. It is safe, effective, and leads to significant long-term benefit. Myelofibrosis patients feel better, their spleens are smaller, and they may survive longer.”

COMFORT-II was sponsored by Novartis, which licensed ruxolitinib from Incyte Corporation for development and commercialization outside the US. COMFORT-I was sponsored by Incyte.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Five-year results from the COMFORT-II trial appear to confirm that treatment with ruxolitinib can improve spleen size and survival in patients with myelofibrosis (MF).

“These results pave the way to use ruxolitinib earlier in the course of the disease,” said lead study author Claire Harrison, MD, a consultant hematologist at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

Dr Harrison presented the results at the 2015 ASH Annual Meeting (abstract 59).

Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated rapid, durable improvements in splenomegaly and MF symptoms, as well as improved survival in the phase 3 COMFORT-I and COMFORT-II studies.

In COMFORT-II, significantly more patients achieved the primary endpoint—a 35% or greater decrease in spleen volume from baseline at week 48—with ruxolitinib than with best available therapy (BAT).

The 3-year follow-up confirmed that spleen volume reductions were sustained, and ruxolitinib treatment remained tolerable with long-term use.

The randomized, open-label, multicenter study included 219 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Two-thirds of patients received ruxolitinib twice daily, and one-third of patients received BAT, which was administered at doses and schedules determined by the investigator.

Almost two-thirds of the patients on the BAT arm crossed over to receive ruxolitinib upon protocol-defined progression following the primary analysis after week 48. All patients randomized to BAT have crossed over or discontinued, Dr Harrison said.

She presented the 5-year final study results, which showed that more than half of the patients (53.4%) experienced significant reductions in spleen size with ruxolitinib therapy and sustained this benefit over a median duration of 3.2 years.

“There was a 33% improvement in overall survival with ruxolitinib as compared to BAT,” she said.

Using a statistical model of survival if patients had not crossed-over to ruxolitinib, the survival benefit was 56% in favor of ruxolitinib.

“The plateau in spleen responses correlates well with the survival advantage,” Dr Harrison said.

She noted that the JAK allele burden was also reduced in the majority of patients who crossed over during the study. A recent bone marrow analysis shows a 20% improvement in fibrosis as well.

Nearly one-quarter of patients from both the ruxolitinib arm and those who crossed over from the BAT arm remained on treatment with ruxolitinib for 5 years.

All adverse events were consistent with previous analyses of treatment with ruxolitinib in MF, Dr Harrison said. The most common adverse events in ruxolitinib-treated patients were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33%).

The most common grade 3/4 adverse events included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and shortness of breath (4.2%).

“This long-term analysis after a vast number of patient-years shows the ongoing benefit, with no new safety signals and a strong survival message,” Dr Harrison said.

“Hematologists can be confident treating patients with ruxolitinib. It is safe, effective, and leads to significant long-term benefit. Myelofibrosis patients feel better, their spleens are smaller, and they may survive longer.”

COMFORT-II was sponsored by Novartis, which licensed ruxolitinib from Incyte Corporation for development and commercialization outside the US. COMFORT-I was sponsored by Incyte.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Five-year results from the COMFORT-II trial appear to confirm that treatment with ruxolitinib can improve spleen size and survival in patients with myelofibrosis (MF).

“These results pave the way to use ruxolitinib earlier in the course of the disease,” said lead study author Claire Harrison, MD, a consultant hematologist at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

Dr Harrison presented the results at the 2015 ASH Annual Meeting (abstract 59).

Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated rapid, durable improvements in splenomegaly and MF symptoms, as well as improved survival in the phase 3 COMFORT-I and COMFORT-II studies.

In COMFORT-II, significantly more patients achieved the primary endpoint—a 35% or greater decrease in spleen volume from baseline at week 48—with ruxolitinib than with best available therapy (BAT).

The 3-year follow-up confirmed that spleen volume reductions were sustained, and ruxolitinib treatment remained tolerable with long-term use.

The randomized, open-label, multicenter study included 219 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Two-thirds of patients received ruxolitinib twice daily, and one-third of patients received BAT, which was administered at doses and schedules determined by the investigator.

Almost two-thirds of the patients on the BAT arm crossed over to receive ruxolitinib upon protocol-defined progression following the primary analysis after week 48. All patients randomized to BAT have crossed over or discontinued, Dr Harrison said.

She presented the 5-year final study results, which showed that more than half of the patients (53.4%) experienced significant reductions in spleen size with ruxolitinib therapy and sustained this benefit over a median duration of 3.2 years.

“There was a 33% improvement in overall survival with ruxolitinib as compared to BAT,” she said.

Using a statistical model of survival if patients had not crossed-over to ruxolitinib, the survival benefit was 56% in favor of ruxolitinib.

“The plateau in spleen responses correlates well with the survival advantage,” Dr Harrison said.

She noted that the JAK allele burden was also reduced in the majority of patients who crossed over during the study. A recent bone marrow analysis shows a 20% improvement in fibrosis as well.

Nearly one-quarter of patients from both the ruxolitinib arm and those who crossed over from the BAT arm remained on treatment with ruxolitinib for 5 years.

All adverse events were consistent with previous analyses of treatment with ruxolitinib in MF, Dr Harrison said. The most common adverse events in ruxolitinib-treated patients were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33%).

The most common grade 3/4 adverse events included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and shortness of breath (4.2%).

“This long-term analysis after a vast number of patient-years shows the ongoing benefit, with no new safety signals and a strong survival message,” Dr Harrison said.

“Hematologists can be confident treating patients with ruxolitinib. It is safe, effective, and leads to significant long-term benefit. Myelofibrosis patients feel better, their spleens are smaller, and they may survive longer.”

COMFORT-II was sponsored by Novartis, which licensed ruxolitinib from Incyte Corporation for development and commercialization outside the US. COMFORT-I was sponsored by Incyte.

Crowd at the 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Results of a DFCI ALL Consortium trial have shown that adults with acute lymphoblastic leukemia (ALL) can be successfully and safely treated with a pediatric regimen using intensified pegylated asparaginase (PEG-ASP).

Investigators recently reported that young adults treated with native E coli asparaginase as part of their regimen had improved 4-year disease-free survival and overall survival (OS) rates.

Now, the team has shown it is possible to use PEG-ASP to improve young adult outcomes as well.

The investigators also described the toxicities with PEG-ASP and compared them to the prior DFCI ALL Consortium trial with native E coli asparaginase.

“[Wendy] Stock, years ago, analyzed young adult patients 16 to 20 based on whether or not they were treated on Children’s Cancer Group trials or CALGB trials,” said Daniel J. DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“And what she reported was that there was a dramatic improvement in the disease- and event-free survival . . . . And since that publication and presentation at ASH several years ago, there’ve been a large number of us who’ve tried to adapt pediatric trials or pediatric-inspired trials for the treatment of young adults with acute lymphoblastic leukemia.”

The PEG-ASP DFCI ALL trial is one such effort. Dr DeAngelo discussed the results of this trial at the 2015 ASH Annual Meeting (abstract 80).

Patient population

Investigators enrolled 110 patients on the trial.

Patients had to be between 18 and 50 years of age, with untreated ALL and no history of secondary ALL. Patients with Burkitt’s lymphoma were excluded.

The patients’ median age was 32 (range, 18–50), 62% were male, 80% were white, and 85% were non-Hispanic. Eleven percent had central nervous system (CNS) status 2 or 3 prior to the initiation of chemotherapy.

Most (87%) had a performance status of 0 or 1, 82% had the B-cell and 18% the T-cell phenotype, 19% were Ph-positive, 6% had an MLL translocation (11q23), and 18% had other translocations.

Study design

Induction chemotherapy consisted of doxorubicin, prednisone, vincristine, PEG-ASP, and intrathecal therapy.

The first consolidation consisted of high-dose methotrexate followed by a BFM-like intensification and high-dose cytarabine, etoposide, and dexamethasone.

CNS prophylaxis included intrathecal chemotherapy and cranial irradiation.

The second consolidation consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine, and 30 weeks of PEG-ASP.

The PEG-ASP was initially dosed at the pediatric level of 2500 IU/m² every 2 weeks.

“But due to some toxicity concerns in this treatment strategy—with specific emphasis on liver function abnormalities with hyperbilirubinemia, elevations of AST/ALT—we decided to amend the protocol and decrease the PEG dose from 2500 to 2000 and increase the interval from every 2 weeks to every 3 weeks,” Dr DeAngelo said.

Therefore, during this 30-week course, patients received 10 doses of PEG ASP as opposed to 15.

“We also went back and swapped out the PEG asparaginase during induction and reinserted native E coli to really ascertain comparative properties,” he said.

Maintenance therapy consisted of 3-week courses of vincristine, dexamethasone, methotrexate, and 6-mercaptopurine for 2 years from achievement of complete remission (CR).

During PEG-ASP therapy, patients received anticoagulation prophylaxis, preferably with low-molecular-weight heparin, as long as patients had a platelet count greater than 30,000/μL.

Results

Of the 110 patients enrolled, 65 received the higher dose of asparaginase, and 45 received the amended lower dose.

Ninety-one patients (89%) achieved a CR, 57 of whom received the higher dose of asparaginase and 34 the lower dose.

There were 2 induction deaths, both in the higher-dose group.

Twenty-one patients went on to transplant in CR1, 15 in the higher-dose group and 6 in the lower-dose group.

Twenty-three patients relapsed, 17 in the higher-dose group and 6 in the lower-dose group. Two of the relapses were CNS only.

Three patients died in remission, 2 in the higher-dose asparaginase group and 1 in the lower. And 3 patients died after stem cell transplant in CR, 2 in the higher-dose group and 1 in the lower.

At a median follow-up of 42.2 months, the 3-year disease-free survival for the entire cohort was 73%, and overall survival was 75%.

Subset analyses

The investigators performed subgroup analyses and came up with some “interesting observations,” Dr DeAngelo said.

Younger patients, ages 18 to 19 and 20 to 29, had a better OS than the older patients. The OS for younger patients is in the 80% to 85% range, “which is significantly better than the other patients in the 30 to 40 or 40 to 50 age groups,” Dr DeAngelo said.

Patients with T-cell ALL had a better OS than those with B-cell ALL and Ph-positive ALL, who had the worst OS of approximately 50%. The vast majority of Ph-negative patients were transplanted, and all received imatinib in addition to chemotherapy.

“[Patients with the T-cell phenotype] seemed to do particularly well on this strategy, which is something we showed in the last study as well, with an overall survival of 80%, compared to 70% for the B-cell Philadelphia-negative [patients],” Dr DeAngelo said.

He and his colleagues also found an association between OS and body mass index (BMI).

Obese or morbidly obese patients with a BMI of 30 or over had an OS of around 40%, while underweight or normal-weight patients had an OS of almost 90%, a “profound overall survival in the less-than-obese patients,” Dr DeAngelo said.

“And I think one of the things that is bringing down the curves is the obese,” he added, “which is a concern as the body mass index of the American population increases.”

Another discovery was that patients with minimal residual disease (MRD) of less than 10^-4 had better OS than those with a high MRD level.

After a single dose of PEG ASP during induction on day 4, asparagine was depleted for a median of 3 weeks. With a single dose of E coli asparaginase, on the other hand, asparagine is depleted for about a week.

Asparaginase levels during consolidation were “extraordinarily elevated” with the 2500 dose level of PEG-ASP compared to the lower dose level. Toxicity was much more manageable, however, as the dose was reduced, Dr DeAngelo said. And asparagine was still depleted throughout the 30 weeks, as per protocol.

Toxicity

The higher asparaginase dose group “surprisingly, had a very low rate of clinical pancreatitis,” Dr DeAngelo said.

At the higher asparaginase dose—2500 IU/m² every 2 weeks—66 patients experienced grade 3-5 adverse events: 30 (46%) febrile neutropenia, 1 (1%) pancreatitis, 19 (29%) AST, 34 (52%) ALT, 24 (36%) bilirubin, 19 (29%) thrombosis, 2 (3%) CNS hemorrhage, 3 (4%) hypersensitivity, and 4 (6%) osteonecrosis.

After the protocol amendment, “we saw a marked reduction in hyperbilirubinemia,” Dr DeAngelo said.

Grade 3–4 hyperbilirubinemia decreased from 36% to 7%, grade 3–4 ALT elevation decreased from 52% to 29%, and the rate of thrombosis decreased from 29% to 16%.

“Whether the latter decrease [thrombosis] was reflective of the decreased dose of asparaginase or the addition of anticoagulation, I can’t determine,”  Dr DeAngelo said, “but it seemed to reflect other studies.”

The investigators concluded that a dose-intensified pediatric regimen in adults is feasible, with an acceptable toxicity profile.

The team said this approach may translate to better survival for adults with ALL, with the exception of older adults and patients with a high BMI. PEG-ASP has increased toxicity in these patients.

The investigators recommend addressing the challenges that remain—psychosocial issues, practice patterns, and biology—with a unified approach and more cooperative group trials in young adults.

Crowd at the 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Results of a DFCI ALL Consortium trial have shown that adults with acute lymphoblastic leukemia (ALL) can be successfully and safely treated with a pediatric regimen using intensified pegylated asparaginase (PEG-ASP).

Investigators recently reported that young adults treated with native E coli asparaginase as part of their regimen had improved 4-year disease-free survival and overall survival (OS) rates.

Now, the team has shown it is possible to use PEG-ASP to improve young adult outcomes as well.

The investigators also described the toxicities with PEG-ASP and compared them to the prior DFCI ALL Consortium trial with native E coli asparaginase.

“[Wendy] Stock, years ago, analyzed young adult patients 16 to 20 based on whether or not they were treated on Children’s Cancer Group trials or CALGB trials,” said Daniel J. DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“And what she reported was that there was a dramatic improvement in the disease- and event-free survival . . . . And since that publication and presentation at ASH several years ago, there’ve been a large number of us who’ve tried to adapt pediatric trials or pediatric-inspired trials for the treatment of young adults with acute lymphoblastic leukemia.”

The PEG-ASP DFCI ALL trial is one such effort. Dr DeAngelo discussed the results of this trial at the 2015 ASH Annual Meeting (abstract 80).

Patient population

Investigators enrolled 110 patients on the trial.

Patients had to be between 18 and 50 years of age, with untreated ALL and no history of secondary ALL. Patients with Burkitt’s lymphoma were excluded.

The patients’ median age was 32 (range, 18–50), 62% were male, 80% were white, and 85% were non-Hispanic. Eleven percent had central nervous system (CNS) status 2 or 3 prior to the initiation of chemotherapy.

Most (87%) had a performance status of 0 or 1, 82% had the B-cell and 18% the T-cell phenotype, 19% were Ph-positive, 6% had an MLL translocation (11q23), and 18% had other translocations.

Study design

Induction chemotherapy consisted of doxorubicin, prednisone, vincristine, PEG-ASP, and intrathecal therapy.

The first consolidation consisted of high-dose methotrexate followed by a BFM-like intensification and high-dose cytarabine, etoposide, and dexamethasone.

CNS prophylaxis included intrathecal chemotherapy and cranial irradiation.

The second consolidation consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine, and 30 weeks of PEG-ASP.

The PEG-ASP was initially dosed at the pediatric level of 2500 IU/m² every 2 weeks.

“But due to some toxicity concerns in this treatment strategy—with specific emphasis on liver function abnormalities with hyperbilirubinemia, elevations of AST/ALT—we decided to amend the protocol and decrease the PEG dose from 2500 to 2000 and increase the interval from every 2 weeks to every 3 weeks,” Dr DeAngelo said.

Therefore, during this 30-week course, patients received 10 doses of PEG ASP as opposed to 15.

“We also went back and swapped out the PEG asparaginase during induction and reinserted native E coli to really ascertain comparative properties,” he said.

Maintenance therapy consisted of 3-week courses of vincristine, dexamethasone, methotrexate, and 6-mercaptopurine for 2 years from achievement of complete remission (CR).

During PEG-ASP therapy, patients received anticoagulation prophylaxis, preferably with low-molecular-weight heparin, as long as patients had a platelet count greater than 30,000/μL.

Results

Of the 110 patients enrolled, 65 received the higher dose of asparaginase, and 45 received the amended lower dose.

Ninety-one patients (89%) achieved a CR, 57 of whom received the higher dose of asparaginase and 34 the lower dose.

There were 2 induction deaths, both in the higher-dose group.

Twenty-one patients went on to transplant in CR1, 15 in the higher-dose group and 6 in the lower-dose group.

Twenty-three patients relapsed, 17 in the higher-dose group and 6 in the lower-dose group. Two of the relapses were CNS only.

Three patients died in remission, 2 in the higher-dose asparaginase group and 1 in the lower. And 3 patients died after stem cell transplant in CR, 2 in the higher-dose group and 1 in the lower.

At a median follow-up of 42.2 months, the 3-year disease-free survival for the entire cohort was 73%, and overall survival was 75%.

Subset analyses

The investigators performed subgroup analyses and came up with some “interesting observations,” Dr DeAngelo said.

Younger patients, ages 18 to 19 and 20 to 29, had a better OS than the older patients. The OS for younger patients is in the 80% to 85% range, “which is significantly better than the other patients in the 30 to 40 or 40 to 50 age groups,” Dr DeAngelo said.

Patients with T-cell ALL had a better OS than those with B-cell ALL and Ph-positive ALL, who had the worst OS of approximately 50%. The vast majority of Ph-negative patients were transplanted, and all received imatinib in addition to chemotherapy.

“[Patients with the T-cell phenotype] seemed to do particularly well on this strategy, which is something we showed in the last study as well, with an overall survival of 80%, compared to 70% for the B-cell Philadelphia-negative [patients],” Dr DeAngelo said.

He and his colleagues also found an association between OS and body mass index (BMI).

Obese or morbidly obese patients with a BMI of 30 or over had an OS of around 40%, while underweight or normal-weight patients had an OS of almost 90%, a “profound overall survival in the less-than-obese patients,” Dr DeAngelo said.

“And I think one of the things that is bringing down the curves is the obese,” he added, “which is a concern as the body mass index of the American population increases.”

Another discovery was that patients with minimal residual disease (MRD) of less than 10^-4 had better OS than those with a high MRD level.

After a single dose of PEG ASP during induction on day 4, asparagine was depleted for a median of 3 weeks. With a single dose of E coli asparaginase, on the other hand, asparagine is depleted for about a week.

Asparaginase levels during consolidation were “extraordinarily elevated” with the 2500 dose level of PEG-ASP compared to the lower dose level. Toxicity was much more manageable, however, as the dose was reduced, Dr DeAngelo said. And asparagine was still depleted throughout the 30 weeks, as per protocol.

Toxicity

The higher asparaginase dose group “surprisingly, had a very low rate of clinical pancreatitis,” Dr DeAngelo said.

At the higher asparaginase dose—2500 IU/m² every 2 weeks—66 patients experienced grade 3-5 adverse events: 30 (46%) febrile neutropenia, 1 (1%) pancreatitis, 19 (29%) AST, 34 (52%) ALT, 24 (36%) bilirubin, 19 (29%) thrombosis, 2 (3%) CNS hemorrhage, 3 (4%) hypersensitivity, and 4 (6%) osteonecrosis.

After the protocol amendment, “we saw a marked reduction in hyperbilirubinemia,” Dr DeAngelo said.

Grade 3–4 hyperbilirubinemia decreased from 36% to 7%, grade 3–4 ALT elevation decreased from 52% to 29%, and the rate of thrombosis decreased from 29% to 16%.

“Whether the latter decrease [thrombosis] was reflective of the decreased dose of asparaginase or the addition of anticoagulation, I can’t determine,”  Dr DeAngelo said, “but it seemed to reflect other studies.”

The investigators concluded that a dose-intensified pediatric regimen in adults is feasible, with an acceptable toxicity profile.

The team said this approach may translate to better survival for adults with ALL, with the exception of older adults and patients with a high BMI. PEG-ASP has increased toxicity in these patients.

The investigators recommend addressing the challenges that remain—psychosocial issues, practice patterns, and biology—with a unified approach and more cooperative group trials in young adults.

Crowd at the 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—Results of a DFCI ALL Consortium trial have shown that adults with acute lymphoblastic leukemia (ALL) can be successfully and safely treated with a pediatric regimen using intensified pegylated asparaginase (PEG-ASP).

Investigators recently reported that young adults treated with native E coli asparaginase as part of their regimen had improved 4-year disease-free survival and overall survival (OS) rates.

Now, the team has shown it is possible to use PEG-ASP to improve young adult outcomes as well.

The investigators also described the toxicities with PEG-ASP and compared them to the prior DFCI ALL Consortium trial with native E coli asparaginase.

“[Wendy] Stock, years ago, analyzed young adult patients 16 to 20 based on whether or not they were treated on Children’s Cancer Group trials or CALGB trials,” said Daniel J. DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“And what she reported was that there was a dramatic improvement in the disease- and event-free survival . . . . And since that publication and presentation at ASH several years ago, there’ve been a large number of us who’ve tried to adapt pediatric trials or pediatric-inspired trials for the treatment of young adults with acute lymphoblastic leukemia.”

The PEG-ASP DFCI ALL trial is one such effort. Dr DeAngelo discussed the results of this trial at the 2015 ASH Annual Meeting (abstract 80).

Patient population

Investigators enrolled 110 patients on the trial.

Patients had to be between 18 and 50 years of age, with untreated ALL and no history of secondary ALL. Patients with Burkitt’s lymphoma were excluded.

The patients’ median age was 32 (range, 18–50), 62% were male, 80% were white, and 85% were non-Hispanic. Eleven percent had central nervous system (CNS) status 2 or 3 prior to the initiation of chemotherapy.

Most (87%) had a performance status of 0 or 1, 82% had the B-cell and 18% the T-cell phenotype, 19% were Ph-positive, 6% had an MLL translocation (11q23), and 18% had other translocations.

Study design

Induction chemotherapy consisted of doxorubicin, prednisone, vincristine, PEG-ASP, and intrathecal therapy.

The first consolidation consisted of high-dose methotrexate followed by a BFM-like intensification and high-dose cytarabine, etoposide, and dexamethasone.

CNS prophylaxis included intrathecal chemotherapy and cranial irradiation.

The second consolidation consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine, and 30 weeks of PEG-ASP.

The PEG-ASP was initially dosed at the pediatric level of 2500 IU/m² every 2 weeks.

“But due to some toxicity concerns in this treatment strategy—with specific emphasis on liver function abnormalities with hyperbilirubinemia, elevations of AST/ALT—we decided to amend the protocol and decrease the PEG dose from 2500 to 2000 and increase the interval from every 2 weeks to every 3 weeks,” Dr DeAngelo said.

Therefore, during this 30-week course, patients received 10 doses of PEG ASP as opposed to 15.

“We also went back and swapped out the PEG asparaginase during induction and reinserted native E coli to really ascertain comparative properties,” he said.

Maintenance therapy consisted of 3-week courses of vincristine, dexamethasone, methotrexate, and 6-mercaptopurine for 2 years from achievement of complete remission (CR).

During PEG-ASP therapy, patients received anticoagulation prophylaxis, preferably with low-molecular-weight heparin, as long as patients had a platelet count greater than 30,000/μL.

Results

Of the 110 patients enrolled, 65 received the higher dose of asparaginase, and 45 received the amended lower dose.

Ninety-one patients (89%) achieved a CR, 57 of whom received the higher dose of asparaginase and 34 the lower dose.

There were 2 induction deaths, both in the higher-dose group.

Twenty-one patients went on to transplant in CR1, 15 in the higher-dose group and 6 in the lower-dose group.

Twenty-three patients relapsed, 17 in the higher-dose group and 6 in the lower-dose group. Two of the relapses were CNS only.

Three patients died in remission, 2 in the higher-dose asparaginase group and 1 in the lower. And 3 patients died after stem cell transplant in CR, 2 in the higher-dose group and 1 in the lower.

At a median follow-up of 42.2 months, the 3-year disease-free survival for the entire cohort was 73%, and overall survival was 75%.

Subset analyses

The investigators performed subgroup analyses and came up with some “interesting observations,” Dr DeAngelo said.

Younger patients, ages 18 to 19 and 20 to 29, had a better OS than the older patients. The OS for younger patients is in the 80% to 85% range, “which is significantly better than the other patients in the 30 to 40 or 40 to 50 age groups,” Dr DeAngelo said.

Patients with T-cell ALL had a better OS than those with B-cell ALL and Ph-positive ALL, who had the worst OS of approximately 50%. The vast majority of Ph-negative patients were transplanted, and all received imatinib in addition to chemotherapy.

“[Patients with the T-cell phenotype] seemed to do particularly well on this strategy, which is something we showed in the last study as well, with an overall survival of 80%, compared to 70% for the B-cell Philadelphia-negative [patients],” Dr DeAngelo said.

He and his colleagues also found an association between OS and body mass index (BMI).

Obese or morbidly obese patients with a BMI of 30 or over had an OS of around 40%, while underweight or normal-weight patients had an OS of almost 90%, a “profound overall survival in the less-than-obese patients,” Dr DeAngelo said.

“And I think one of the things that is bringing down the curves is the obese,” he added, “which is a concern as the body mass index of the American population increases.”

Another discovery was that patients with minimal residual disease (MRD) of less than 10^-4 had better OS than those with a high MRD level.

After a single dose of PEG ASP during induction on day 4, asparagine was depleted for a median of 3 weeks. With a single dose of E coli asparaginase, on the other hand, asparagine is depleted for about a week.

Asparaginase levels during consolidation were “extraordinarily elevated” with the 2500 dose level of PEG-ASP compared to the lower dose level. Toxicity was much more manageable, however, as the dose was reduced, Dr DeAngelo said. And asparagine was still depleted throughout the 30 weeks, as per protocol.

Toxicity

The higher asparaginase dose group “surprisingly, had a very low rate of clinical pancreatitis,” Dr DeAngelo said.

At the higher asparaginase dose—2500 IU/m² every 2 weeks—66 patients experienced grade 3-5 adverse events: 30 (46%) febrile neutropenia, 1 (1%) pancreatitis, 19 (29%) AST, 34 (52%) ALT, 24 (36%) bilirubin, 19 (29%) thrombosis, 2 (3%) CNS hemorrhage, 3 (4%) hypersensitivity, and 4 (6%) osteonecrosis.

After the protocol amendment, “we saw a marked reduction in hyperbilirubinemia,” Dr DeAngelo said.

Grade 3–4 hyperbilirubinemia decreased from 36% to 7%, grade 3–4 ALT elevation decreased from 52% to 29%, and the rate of thrombosis decreased from 29% to 16%.

“Whether the latter decrease [thrombosis] was reflective of the decreased dose of asparaginase or the addition of anticoagulation, I can’t determine,”  Dr DeAngelo said, “but it seemed to reflect other studies.”

The investigators concluded that a dose-intensified pediatric regimen in adults is feasible, with an acceptable toxicity profile.

The team said this approach may translate to better survival for adults with ALL, with the exception of older adults and patients with a high BMI. PEG-ASP has increased toxicity in these patients.

The investigators recommend addressing the challenges that remain—psychosocial issues, practice patterns, and biology—with a unified approach and more cooperative group trials in young adults.

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

pwendling@frontlinemedcom.com

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

pwendling@frontlinemedcom.com

ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.

Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).

One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).

Patrice Wendling/Frontline Medical News

The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.

“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.

Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.

Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).

Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.

Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).

Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.

In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).

The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.

During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.

pwendling@frontlinemedcom.com

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

James Kochenderfer, MD

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.”

James Kochenderfer, MD

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.”

James Kochenderfer, MD

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.”

Russel Ware, MD, PhD

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.

Russel Ware, MD, PhD

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.

Russel Ware, MD, PhD

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.

Attendees meet in Orlando

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.

Attendees meet in Orlando

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.

Attendees meet in Orlando

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.

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

pwendling@frontlinemedcom.com

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

pwendling@frontlinemedcom.com

ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.

This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.

Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.

“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.

The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).

The primary goal of the ongoing study is to establish the safety of the combination therapy.

In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.

At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.

Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.

Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].

The median number of cycles was six and median follow-up short at 7.4 months.

The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.

The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.

“We reported a lot, actually, of immune-related adverse events,” he said.

In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.

The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.

Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.

A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.

Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.

The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.

Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.

pwendling@frontlinemedcom.com