ASH 2014

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

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).

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

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.

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

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.”

Christoph Röllig, MD

Photo courtesy of ASH

SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia

(AML).

The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.

“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.

Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.

Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized

trials.

An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.

However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger

patient population.

They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.

The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.

Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.

All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.

The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.

Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.

The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.

After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.

Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).

Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”

Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).

The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).

An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.

“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”

Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).

Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.

Christoph Röllig, MD

Photo courtesy of ASH

SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia

(AML).

The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.

“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.

Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.

Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized

trials.

An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.

However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger

patient population.

They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.

The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.

Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.

All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.

The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.

Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.

The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.

After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.

Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).

Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”

Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).

The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).

An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.

“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”

Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).

Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.

Christoph Röllig, MD

Photo courtesy of ASH

SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia

(AML).

The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.

“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.

Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.

Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized

trials.

An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.

However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger

patient population.

They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.

The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.

Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.

All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.

The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.

Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.

The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.

After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.

Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).

Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”

Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).

The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).

An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.

“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”

Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).

Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.