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Study confirms IDH2 as therapeutic target in AML, MDS
in the Moscone Center
SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.
From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.
Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.
“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”
He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*
The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.
Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).
Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.
To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.
As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.
Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”
Safety
The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).
The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.
Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.
He also pointed out that there was no increase in AEs with increased dose of the drug.
Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.
Efficacy
Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).
“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”
Many of the durable responses are partial remissions, he noted.
Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.
“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”
This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.
Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration. 
*Data in the presentation were updated from the abstract.
in the Moscone Center
SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.
From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.
Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.
“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”
He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*
The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.
Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).
Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.
To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.
As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.
Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”
Safety
The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).
The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.
Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.
He also pointed out that there was no increase in AEs with increased dose of the drug.
Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.
Efficacy
Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).
“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”
Many of the durable responses are partial remissions, he noted.
Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.
“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”
This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.
Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.
*Data in the presentation were updated from the abstract.
in the Moscone Center
SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.
From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.
Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.
“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”
He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*
The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.
Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).
Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.
To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.
As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.
Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”
Safety
The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).
The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.
Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.
He also pointed out that there was no increase in AEs with increased dose of the drug.
Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.
Efficacy
Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).
“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”
Many of the durable responses are partial remissions, he noted.
Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.
“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”
This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.
Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.
*Data in the presentation were updated from the abstract.
Blinatumomab confirmed as treatment option in MRD+ ALL
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—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—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.
Researchers show CTL019 cells proliferate and persist
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.
Two activin receptor fusion proteins show promise in anemia
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.
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.
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.
First randomized evidence for kinase inhibitor use in AML
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.
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.
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.
More isn’t always better with daunorubicin induction in AML
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
New agents challenge role of transplant in high-risk CLL
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Panobinostat demonstrates ‘profound’ synergy with bortezomib
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
Chlorambucil’s role in untreated CLL debated
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
Armored CAR T cells next on the production line
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies.
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies.
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies.