ASH 2014

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Blood collection

Credit: Charles Haymond

SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.

JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

JCAR015 was tested at a dose of 1 - 3 x 10⁶ CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.

Twenty-one patients were male, and the median age was 55 (range, 23 to 74).

Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).

Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.

Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.

The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).

The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.

Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.

At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.

Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.

The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.

For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.

Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.

The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.

Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.

The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.

Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.

He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research indicates that extending anticoagulant therapy to 2 years can reduce the risk of recurrent venous thromboembolism (VTE) without increasing major bleeding, but this benefit only lasts while patients are receiving the therapy.

In the PADIS-PE study, patients with a first episode of symptomatic, unprovoked pulmonary embolism (PE) received 6 months of treatment with a vitamin K antagonist (VKA), followed by 18 months of warfarin or placebo.

Patients who received warfarin had a 77% reduction in the relative risk of recurrent VTE or major bleeding while they received treatment. But an additional 2 years of follow-up showed that this benefit was lost once patients stopped anticoagulation.

Francis Couturaud, MD, PhD, of the Brest University Hospital Center in Brest, France, presented these data at the 2014 ASH Annual Meeting as LBA-3.*

He and his colleagues randomized patients to receive warfarin (n=184) or placebo (n=187) for 18 months after their intial VKA treatment. Patients were followed for an additional 24 months after treatment ended.

Most baseline characteristics were similar between the treatment arms, although there was a significantly higher percentage of females in the warfarin arm.

“[Overall,] the mean age was below 60, [and] the mean BMI [body mass index] was below 30,” Dr Couturaud noted. “About 4% of patients had previous cancer [that had been] resolved for more than 2 years, 8% had previous distal DVT [deep vein thrombosis] or superficial venous thrombosis, a quarter of women were on estrogen-containing pills, and about one-third had an associated proximal DVT at the time of PE diagnosis.”

“Before the randomization, the mean duration of VKA [therapy] was 6 months, and the mean percentage of time within the therapeutic range was 70. At inclusion, about one-third of patients had residual perfusion defect, about 15% had residual DVT, the mean D-dimer level was below 500 μg/L, and about 27% had thrombophilia.”

Results

The study’s primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Significantly fewer patients met this endpoint in the warfarin arm than in the placebo arm—6 (3.3%) and 25 (13.5%), respectively (hazard ratio [HR]=0.23, P=0.0004).

Likewise, the number of patients with recurrent VTE at 18 months was significantly lower in the warfarin arm than in the placebo arm—3 (1.7%) and 25 (13.5%), respectively (HR=0.11, P<0.0001).

On the other hand, there was no significant difference in the rate of major bleeding between the treatment arms at 18 months. Four patients (2.2%) had major bleeding in the warfarin arm, as did 1 (0.5%) in the placebo arm (HR=4.07, P=0.18).

At 42 months, there was no significant difference between the treatment arms with regard to the composite outcome, the rate of recurrent VTE, or the rate of major bleeding.

The composite outcome occurred in 33 (20.8%) patients in the warfarin arm and 42 (24%) in the placebo arm (HR=0.74, P=0.19). Recurrent VTE occurred in 28 (17.9%) and 39 patients (22.1%), respectively (HR=0.67, P=0.10). And major bleeding occurred in 6 (3.5%) and 5 patients (3%), respectively (HR=1.12, P=0.71).

“[E]xtending anticoagulation for 18 additional months was associated with a major relative risk reduction of 77% of recurrent VTE or major bleeding during the treatment period,” Dr Couturaud said in summary. “However, this benefit was lost during a long-term follow-up of 2 years after stopping anticoagulation.”

“In addition, recurrent VTE occurred in 80% of cases as recurrent PE and in 90% of cases as unprovoked VTE. So additional investigations are needed to identify subgroups of patients at lower risk who may not need indefinite anticoagulation.”

This study was sponsored by Brest University Hospital. Investigators received research funding from Actelion Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, LEO Pharma, and Bayer.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.

The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.

Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.

But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.

Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*

“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”

“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”

To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.

Patient characteristics

The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.

According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.

Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.

Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).

Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).

There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.

PFS and OS

In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.

When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.

“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”

For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.

For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.

In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10^-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).

Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10^-5), status at HDT/ASCT (HR=2.15, P<10^-5), and rituximab use (HR=0.67, P=0.003).

For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).

Secondary malignancies

Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.

The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.

“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.

“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.