Mark L. Fuerst

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

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

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

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

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

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

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

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

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

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

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

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

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Inside Moscone Center, site of

the 2014 ASH Annual Meeting

SAN FRANCISCO—A recombinant factor VIII (FVIII) Fc fusion protein is effective for routine prophylaxis and control of bleeding in previously treated children with severe hemophilia A, according to the first phase 3 study of a long-acting FVIII in very young patients.

Prophylactic treatment of hemophilia A with recombinant FVIII requires frequent infusions, up to 3 to 4 per week.

Conventional FVIII replacement therapies have circulating half-lives of 8 to 12 hours.

And children exhibit faster clearance than adults, which may necessitate even more frequent infusions.

Recombinant FVIII Fc fusion protein (Eloctate) has been shown to have a 1.5-fold longer half-life when compared with recombinant FVIII (Advate) in a phase 3 study of adults and adolescents.

“In a pediatric population, we demonstrated similar pharmacokinetic safety and efficacy in terms of annualized bleeding rate, with no inhibitors and no adverse events related to the drug,” said Guy Young, MD, of the University of Southern California in Los Angeles.

At the 2014 ASH Annual Meeting, Dr Young and his colleagues reported results observed with recombinant FVIII Fc fusion protein in the KIDS A-LONG study (abstract 1494). This phase 3 trial was sponsored by Biogen Idec and Sobi, the companies developing recombinant FVIII Fc fusion protein.

The study enrolled 71 males under the age of 12 with severe hemophilia A (< 1 IU/dL endogenous FVIII activity), who had at least 50 prior exposure days to FVIII and no history of FVIII inhibitors.

The patients received twice-weekly prophylactic infusions of the drug, 25 IU/kg on day 1 and 50 IU/kg on day 4. Adjustments to dosing frequency up to once every 2 days and dose to ≤ 80 IU/kg were made as needed.

A subset of 25 patients under age 6 and 35 patients ages 6 to 11 underwent sequential pharmacokinetic evaluations with their prior FVIII therapy (50 IU/kg), followed by the recombinant FVIII Fc fusion protein (50 IU/kg).

“The recombinant factor VIII Fc fusion protein was effective for routine prophylaxis and for control of bleeding,” Dr Young said. “A low annualized bleeding rate was observed in both age cohorts.”

About three-quarters of the patients had a longer dosing interval with recombinant FVIII Fc fusion protein compared with their prior FVIII prophylactic dosing interval.

About 90% of the patients were on twice-weekly dosing at the end of the study compared with about 75% infusing at least 3 times a week pre-study, Dr Young said. Some 93% of bleeding episodes were controlled with 1 or 2 injections.

“The recombinant FVIII Fc fusion protein had a prolonged half-life and reduced clearance compared with conventional FVIII,” Dr Young noted.

Half-life extension was comparable to that observed in adults and adolescents.

Adverse events were generally similar to those expected for the pediatric hemophilia population.

Some 85.5% of subjects reported at least one adverse event, but no patient discontinued treatment due to an adverse event. Two non-serious events (myalgia and erythematous rash) were related to recombinant FVIII Fc fusion protein.

Five patients (7.2%) experienced a total of 7 serious adverse events, which were not related to treatment. There were no reports of anaphylaxis, vascular thrombotic events, or death.

Dr Young said the next step is to test the recombinant FVIII Fc fusion protein in previously untreated young hemophilia A patients to determine the rate of immunogenicity.

“We don’t expect to see antibodies in these patients,” he said.

Inside Moscone Center, site of

the 2014 ASH Annual Meeting

SAN FRANCISCO—A recombinant factor VIII (FVIII) Fc fusion protein is effective for routine prophylaxis and control of bleeding in previously treated children with severe hemophilia A, according to the first phase 3 study of a long-acting FVIII in very young patients.

Prophylactic treatment of hemophilia A with recombinant FVIII requires frequent infusions, up to 3 to 4 per week.

Conventional FVIII replacement therapies have circulating half-lives of 8 to 12 hours.

And children exhibit faster clearance than adults, which may necessitate even more frequent infusions.

Recombinant FVIII Fc fusion protein (Eloctate) has been shown to have a 1.5-fold longer half-life when compared with recombinant FVIII (Advate) in a phase 3 study of adults and adolescents.

“In a pediatric population, we demonstrated similar pharmacokinetic safety and efficacy in terms of annualized bleeding rate, with no inhibitors and no adverse events related to the drug,” said Guy Young, MD, of the University of Southern California in Los Angeles.

At the 2014 ASH Annual Meeting, Dr Young and his colleagues reported results observed with recombinant FVIII Fc fusion protein in the KIDS A-LONG study (abstract 1494). This phase 3 trial was sponsored by Biogen Idec and Sobi, the companies developing recombinant FVIII Fc fusion protein.

The study enrolled 71 males under the age of 12 with severe hemophilia A (< 1 IU/dL endogenous FVIII activity), who had at least 50 prior exposure days to FVIII and no history of FVIII inhibitors.

The patients received twice-weekly prophylactic infusions of the drug, 25 IU/kg on day 1 and 50 IU/kg on day 4. Adjustments to dosing frequency up to once every 2 days and dose to ≤ 80 IU/kg were made as needed.

A subset of 25 patients under age 6 and 35 patients ages 6 to 11 underwent sequential pharmacokinetic evaluations with their prior FVIII therapy (50 IU/kg), followed by the recombinant FVIII Fc fusion protein (50 IU/kg).

“The recombinant factor VIII Fc fusion protein was effective for routine prophylaxis and for control of bleeding,” Dr Young said. “A low annualized bleeding rate was observed in both age cohorts.”

About three-quarters of the patients had a longer dosing interval with recombinant FVIII Fc fusion protein compared with their prior FVIII prophylactic dosing interval.

About 90% of the patients were on twice-weekly dosing at the end of the study compared with about 75% infusing at least 3 times a week pre-study, Dr Young said. Some 93% of bleeding episodes were controlled with 1 or 2 injections.

“The recombinant FVIII Fc fusion protein had a prolonged half-life and reduced clearance compared with conventional FVIII,” Dr Young noted.

Half-life extension was comparable to that observed in adults and adolescents.

Adverse events were generally similar to those expected for the pediatric hemophilia population.

Some 85.5% of subjects reported at least one adverse event, but no patient discontinued treatment due to an adverse event. Two non-serious events (myalgia and erythematous rash) were related to recombinant FVIII Fc fusion protein.

Five patients (7.2%) experienced a total of 7 serious adverse events, which were not related to treatment. There were no reports of anaphylaxis, vascular thrombotic events, or death.

Dr Young said the next step is to test the recombinant FVIII Fc fusion protein in previously untreated young hemophilia A patients to determine the rate of immunogenicity.

“We don’t expect to see antibodies in these patients,” he said.

Inside Moscone Center, site of

the 2014 ASH Annual Meeting

SAN FRANCISCO—A recombinant factor VIII (FVIII) Fc fusion protein is effective for routine prophylaxis and control of bleeding in previously treated children with severe hemophilia A, according to the first phase 3 study of a long-acting FVIII in very young patients.

Prophylactic treatment of hemophilia A with recombinant FVIII requires frequent infusions, up to 3 to 4 per week.

Conventional FVIII replacement therapies have circulating half-lives of 8 to 12 hours.

And children exhibit faster clearance than adults, which may necessitate even more frequent infusions.

Recombinant FVIII Fc fusion protein (Eloctate) has been shown to have a 1.5-fold longer half-life when compared with recombinant FVIII (Advate) in a phase 3 study of adults and adolescents.

“In a pediatric population, we demonstrated similar pharmacokinetic safety and efficacy in terms of annualized bleeding rate, with no inhibitors and no adverse events related to the drug,” said Guy Young, MD, of the University of Southern California in Los Angeles.

At the 2014 ASH Annual Meeting, Dr Young and his colleagues reported results observed with recombinant FVIII Fc fusion protein in the KIDS A-LONG study (abstract 1494). This phase 3 trial was sponsored by Biogen Idec and Sobi, the companies developing recombinant FVIII Fc fusion protein.

The study enrolled 71 males under the age of 12 with severe hemophilia A (< 1 IU/dL endogenous FVIII activity), who had at least 50 prior exposure days to FVIII and no history of FVIII inhibitors.

The patients received twice-weekly prophylactic infusions of the drug, 25 IU/kg on day 1 and 50 IU/kg on day 4. Adjustments to dosing frequency up to once every 2 days and dose to ≤ 80 IU/kg were made as needed.

A subset of 25 patients under age 6 and 35 patients ages 6 to 11 underwent sequential pharmacokinetic evaluations with their prior FVIII therapy (50 IU/kg), followed by the recombinant FVIII Fc fusion protein (50 IU/kg).

“The recombinant factor VIII Fc fusion protein was effective for routine prophylaxis and for control of bleeding,” Dr Young said. “A low annualized bleeding rate was observed in both age cohorts.”

About three-quarters of the patients had a longer dosing interval with recombinant FVIII Fc fusion protein compared with their prior FVIII prophylactic dosing interval.

About 90% of the patients were on twice-weekly dosing at the end of the study compared with about 75% infusing at least 3 times a week pre-study, Dr Young said. Some 93% of bleeding episodes were controlled with 1 or 2 injections.

“The recombinant FVIII Fc fusion protein had a prolonged half-life and reduced clearance compared with conventional FVIII,” Dr Young noted.

Half-life extension was comparable to that observed in adults and adolescents.

Adverse events were generally similar to those expected for the pediatric hemophilia population.

Some 85.5% of subjects reported at least one adverse event, but no patient discontinued treatment due to an adverse event. Two non-serious events (myalgia and erythematous rash) were related to recombinant FVIII Fc fusion protein.

Five patients (7.2%) experienced a total of 7 serious adverse events, which were not related to treatment. There were no reports of anaphylaxis, vascular thrombotic events, or death.

Dr Young said the next step is to test the recombinant FVIII Fc fusion protein in previously untreated young hemophilia A patients to determine the rate of immunogenicity.

“We don’t expect to see antibodies in these patients,” he said.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—The oral proteasome inhibitor ixazomib induces high-quality hematologic responses in patients with relapsed/refractory systemic light-chain (AL) amyloidosis, with generally manageable side effects, a phase 1 study suggests.

Preliminary results from this study indicated that ixazomib had promise for treating AL amyloidosis.

Now, researchers have reported updated safety data and figures for hematologic and organ responses, progression-free survival, and overall survival.

The study was presented at the 2014 ASH Annual Meeting (abstract 3450) 5 days after the US Food and Drug Administration granted ixazomib breakthrough status for the treatment of relapsed/refractory AL amyloidosis.

“To have an oral drug that is well-tolerated and extremely effective in patients exposed to all lines of other therapy is remarkable in this disease,” said study investigator Giampaolo Merlini, MD, of the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, at the University of Pavia in Italy.

He and his colleagues evaluated ixazomib in 22 patients with a median age of 65 years. They were heavily pretreated, with 95% exposed to melphalan and 73% to bortezomib.

The patients received 4 mg of ixazomib on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Those who did not achieve a hematologic partial response after 3 cycles received added dexamethasone.

In 21 evaluable patients, the overall response rate was 52%, including a complete response and very good partial response in 43% of patients.

Dr Merlini noted that responses were deep and durable. And the high response rates translated into high organ response rates.

“End-organ damage is what kills patients,” he said. “In 18 evaluable patients, both the heart and kidney response rate was 45%.”

At 1 year, progression-free survival was 60%. At 2 years, overall survival was 63%.

The drug was well-tolerated as well. The 3 most common side effects—nausea, diarrhea, and fatigue—were mild and seen in about 30% of patients.

Severe grade 3 or higher side effects included thrombocytopenia, diarrhea, and rash, occurring in about 10% of patients.

The development program for ixazomib in AL amyloidosis progressed directly from this phase 1 trial to a phase 3 study, TOURMALINE-AL1. The trial is already underway, with 80 patients enrolled thus far.

TOURMALINE-AL1 investigators are comparing ixazomib plus dexamethasone to physician’s choice of treatment in patients with relapsed/refractory AL amyloidosis. Data from this trial are expected by the end of 2015.

“For the first time, we have evidence of an oral drug that is extremely effective,” Dr Merlini said. “We need to see the phase 3 data, but it could be a breakthrough.”

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—The oral proteasome inhibitor ixazomib induces high-quality hematologic responses in patients with relapsed/refractory systemic light-chain (AL) amyloidosis, with generally manageable side effects, a phase 1 study suggests.

Preliminary results from this study indicated that ixazomib had promise for treating AL amyloidosis.

Now, researchers have reported updated safety data and figures for hematologic and organ responses, progression-free survival, and overall survival.

The study was presented at the 2014 ASH Annual Meeting (abstract 3450) 5 days after the US Food and Drug Administration granted ixazomib breakthrough status for the treatment of relapsed/refractory AL amyloidosis.

“To have an oral drug that is well-tolerated and extremely effective in patients exposed to all lines of other therapy is remarkable in this disease,” said study investigator Giampaolo Merlini, MD, of the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, at the University of Pavia in Italy.

He and his colleagues evaluated ixazomib in 22 patients with a median age of 65 years. They were heavily pretreated, with 95% exposed to melphalan and 73% to bortezomib.

The patients received 4 mg of ixazomib on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Those who did not achieve a hematologic partial response after 3 cycles received added dexamethasone.

In 21 evaluable patients, the overall response rate was 52%, including a complete response and very good partial response in 43% of patients.

Dr Merlini noted that responses were deep and durable. And the high response rates translated into high organ response rates.

“End-organ damage is what kills patients,” he said. “In 18 evaluable patients, both the heart and kidney response rate was 45%.”

At 1 year, progression-free survival was 60%. At 2 years, overall survival was 63%.

The drug was well-tolerated as well. The 3 most common side effects—nausea, diarrhea, and fatigue—were mild and seen in about 30% of patients.

Severe grade 3 or higher side effects included thrombocytopenia, diarrhea, and rash, occurring in about 10% of patients.

The development program for ixazomib in AL amyloidosis progressed directly from this phase 1 trial to a phase 3 study, TOURMALINE-AL1. The trial is already underway, with 80 patients enrolled thus far.

TOURMALINE-AL1 investigators are comparing ixazomib plus dexamethasone to physician’s choice of treatment in patients with relapsed/refractory AL amyloidosis. Data from this trial are expected by the end of 2015.

“For the first time, we have evidence of an oral drug that is extremely effective,” Dr Merlini said. “We need to see the phase 3 data, but it could be a breakthrough.”

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—The oral proteasome inhibitor ixazomib induces high-quality hematologic responses in patients with relapsed/refractory systemic light-chain (AL) amyloidosis, with generally manageable side effects, a phase 1 study suggests.

Preliminary results from this study indicated that ixazomib had promise for treating AL amyloidosis.

Now, researchers have reported updated safety data and figures for hematologic and organ responses, progression-free survival, and overall survival.

The study was presented at the 2014 ASH Annual Meeting (abstract 3450) 5 days after the US Food and Drug Administration granted ixazomib breakthrough status for the treatment of relapsed/refractory AL amyloidosis.

“To have an oral drug that is well-tolerated and extremely effective in patients exposed to all lines of other therapy is remarkable in this disease,” said study investigator Giampaolo Merlini, MD, of the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, at the University of Pavia in Italy.

He and his colleagues evaluated ixazomib in 22 patients with a median age of 65 years. They were heavily pretreated, with 95% exposed to melphalan and 73% to bortezomib.

The patients received 4 mg of ixazomib on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Those who did not achieve a hematologic partial response after 3 cycles received added dexamethasone.

In 21 evaluable patients, the overall response rate was 52%, including a complete response and very good partial response in 43% of patients.

Dr Merlini noted that responses were deep and durable. And the high response rates translated into high organ response rates.

“End-organ damage is what kills patients,” he said. “In 18 evaluable patients, both the heart and kidney response rate was 45%.”

At 1 year, progression-free survival was 60%. At 2 years, overall survival was 63%.

The drug was well-tolerated as well. The 3 most common side effects—nausea, diarrhea, and fatigue—were mild and seen in about 30% of patients.

Severe grade 3 or higher side effects included thrombocytopenia, diarrhea, and rash, occurring in about 10% of patients.

The development program for ixazomib in AL amyloidosis progressed directly from this phase 1 trial to a phase 3 study, TOURMALINE-AL1. The trial is already underway, with 80 patients enrolled thus far.

TOURMALINE-AL1 investigators are comparing ixazomib plus dexamethasone to physician’s choice of treatment in patients with relapsed/refractory AL amyloidosis. Data from this trial are expected by the end of 2015.

“For the first time, we have evidence of an oral drug that is extremely effective,” Dr Merlini said. “We need to see the phase 3 data, but it could be a breakthrough.”

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”