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The 2015 BMT Tandem Meetings took place February 11-15 in San Diego, California.
‘Biodegradable’ CAR may aid transplant in AML
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.” 
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”
Drug shows promise for treating VOD after HSCT
Photo by Chad McNeeley
SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).
Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.
The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.
Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.
T-IND study
Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).
The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.
Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).
At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.
Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.
NNT study
Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).
For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).
At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).
Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.
Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.
Compassionate use program
Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).
The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.
Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).
At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.
Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).
Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.
The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.
Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.
T-IND study
Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).
The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.
Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).
At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.
Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.
NNT study
Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).
For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).
At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).
Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.
Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.
Compassionate use program
Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).
The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.
Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).
At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.
Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).
Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.
The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.
Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.
T-IND study
Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).
The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.
Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).
At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.
Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.
NNT study
Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).
For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).
At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).
Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.
Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.
Compassionate use program
Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).
The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.
Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).
At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.
Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.
*Information in the abstract differs from that presented at the meeting.
Haplo-BMT feasible in high-risk malignancies
Photo by Chad McNeeley
SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.
Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.
Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.
Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.
“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”
So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.
For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.
All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.
Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.
‘Excellent’ outcomes
The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.
The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.
Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.
The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.
Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.
Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.
A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.
Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).
The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.
Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).
“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.
“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.
Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.
Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.
Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.
“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”
So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.
For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.
All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.
Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.
‘Excellent’ outcomes
The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.
The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.
Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.
The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.
Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.
Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.
A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.
Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).
The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.
Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).
“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.
“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.
Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.
Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.
Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.
“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”
So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.
For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.
All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.
Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.
‘Excellent’ outcomes
The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.
The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.
Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.
The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.
Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.
Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.
A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.
Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).
The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.
Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).
“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.
“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”
*Information in the abstract differs from that presented at the meeting.
Older age doesn’t decrease HRQOL among PBSC donors
Photo courtesy of Canterbury
District Health Board
SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.
In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.
Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).
“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”
With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).
The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.
A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).
Pre- and post-donation HRQOL
Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.
Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.
At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).
Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).
At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”
However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).
“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of Canterbury
District Health Board
SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.
In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.
Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).
“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”
With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).
The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.
A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).
Pre- and post-donation HRQOL
Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.
Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.
At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).
Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).
At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”
However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).
“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of Canterbury
District Health Board
SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.
In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.
Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).
“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”
With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).
The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.
A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).
Pre- and post-donation HRQOL
Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.
Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.
At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).
Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).
At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”
However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).
“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”
*Information in the abstract differs from that presented at the meeting.
Ibrutinib demonstrates efficacy in CLL after allo-HSCT
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of CDC
SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.
One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.
Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).
David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.
Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).
High response rate
The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.
All 16 patients analyzed had prior allogeneic
hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.
Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).
The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.
The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.
The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.
Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.
Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.
And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).
‘Promising’ donor immune modulation
Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.
Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.
Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.
The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.
Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.
And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.
Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.
*Information in the abstract differs from that presented at the meeting.
Predicting outcomes of allo-HSCT in ALL
Photo by Chad McNeeley
SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).
The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).
Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.
And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.
Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*
Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.
The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.
At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.
Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.
Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.
The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.
In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).
For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.
The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.
“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”
“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).
The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).
Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.
And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.
Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*
Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.
The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.
At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.
Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.
Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.
The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.
In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).
For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.
The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.
“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”
“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).
The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).
Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.
And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.
Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*
Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.
The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.
At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.
Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.
Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.
The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.
In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).
For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.
The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.
“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”
“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”
*Information in the abstract differs from that presented at the meeting.
Product ‘solves engraftment problem’ with UCBT
Photo courtesy of NHS
SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.
John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord
blood units in which CD34 cells were expanded using the aryl hydrocarbon
receptor antagonist StemRegenin 1.
Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.
Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*
The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.
In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.
Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.
Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.
Phase 1
Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).
The median TNC dose was 2.5 x 107/kg for the unmanipulated cord blood unit and 5.1 x 107/kg for the HSC835 unit. The median CD34 count was 0.4 x 106/kg and 17.4 x 106/kg, respectively. And the median CD3 count was 8.5 x 106/kg and 2.5 x 106/kg, respectively.
Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.
Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.
Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).
In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.
“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”
Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.
Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.
“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.
Phase 2
For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.
In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.
“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”
Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of NHS
SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.
John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord
blood units in which CD34 cells were expanded using the aryl hydrocarbon
receptor antagonist StemRegenin 1.
Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.
Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*
The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.
In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.
Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.
Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.
Phase 1
Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).
The median TNC dose was 2.5 x 107/kg for the unmanipulated cord blood unit and 5.1 x 107/kg for the HSC835 unit. The median CD34 count was 0.4 x 106/kg and 17.4 x 106/kg, respectively. And the median CD3 count was 8.5 x 106/kg and 2.5 x 106/kg, respectively.
Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.
Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.
Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).
In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.
“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”
Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.
Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.
“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.
Phase 2
For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.
In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.
“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”
Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of NHS
SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.
John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord
blood units in which CD34 cells were expanded using the aryl hydrocarbon
receptor antagonist StemRegenin 1.
Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.
Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*
The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.
In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.
Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.
Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.
Phase 1
Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).
The median TNC dose was 2.5 x 107/kg for the unmanipulated cord blood unit and 5.1 x 107/kg for the HSC835 unit. The median CD34 count was 0.4 x 106/kg and 17.4 x 106/kg, respectively. And the median CD3 count was 8.5 x 106/kg and 2.5 x 106/kg, respectively.
Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.
Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.
Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).
In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.
“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”
Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.
Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.
“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.
Phase 2
For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.
In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.
“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”
Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.
*Information in the abstract differs from that presented at the meeting.
Expanded MSCs can treat severe aGVHD
SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.
The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.
Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.
“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.
Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.
The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.
At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.
The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.
Treatment and outcomes
Patients received 8 bi-weekly, intravenous infusions of 2 × 106 MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.
The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.
Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.
Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.
At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.
Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).
The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.
*Information in the abstract differs from that presented at the meeting.
SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.
The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.
Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.
“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.
Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.
The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.
At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.
The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.
Treatment and outcomes
Patients received 8 bi-weekly, intravenous infusions of 2 × 106 MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.
The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.
Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.
Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.
At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.
Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).
The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.
*Information in the abstract differs from that presented at the meeting.
SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.
The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.
Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.
“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.
Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.
The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.
At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.
The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.
Treatment and outcomes
Patients received 8 bi-weekly, intravenous infusions of 2 × 106 MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.
The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.
Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.
Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.
At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.
Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).
The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.
*Information in the abstract differs from that presented at the meeting.
Day 90 CR not a good endpoint for auto-HSCT, doc says
Photo by Rhoda Baer
SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.
Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic
toxicity, compared to patients who received melphalan (mel) alone.
However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).
These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.
Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*
“High-dose melphalan at 200 mg/m2 is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”
A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to
investigate that possibility in a randomized, phase 3 trial.
The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.
Forty-nine patients received bu-mel—a 130 mg/m2 daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m2. All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m2.
Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.
Adverse events
At 100 days post-transplant, the transplant-related mortality was 0% in both arms.
“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”
Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).
There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.
Response
At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).
“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.
Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good
partial response were 69% and 86%, respectively (P=0.65).
Maintenance
A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.
The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.
Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.
Survival
At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.
Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.
“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.
He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary
endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.
Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory
board, honoraria) with Celgene, Millennium, and Onyx.
*Information in the abstract differs from that presented at the meeting.
Photo by Rhoda Baer
SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.
Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic
toxicity, compared to patients who received melphalan (mel) alone.
However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).
These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.
Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*
“High-dose melphalan at 200 mg/m2 is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”
A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to
investigate that possibility in a randomized, phase 3 trial.
The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.
Forty-nine patients received bu-mel—a 130 mg/m2 daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m2. All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m2.
Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.
Adverse events
At 100 days post-transplant, the transplant-related mortality was 0% in both arms.
“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”
Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).
There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.
Response
At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).
“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.
Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good
partial response were 69% and 86%, respectively (P=0.65).
Maintenance
A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.
The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.
Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.
Survival
At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.
Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.
“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.
He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary
endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.
Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory
board, honoraria) with Celgene, Millennium, and Onyx.
*Information in the abstract differs from that presented at the meeting.
Photo by Rhoda Baer
SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.
Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic
toxicity, compared to patients who received melphalan (mel) alone.
However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).
These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.
Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*
“High-dose melphalan at 200 mg/m2 is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”
A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to
investigate that possibility in a randomized, phase 3 trial.
The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.
Forty-nine patients received bu-mel—a 130 mg/m2 daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m2. All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m2.
Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.
Adverse events
At 100 days post-transplant, the transplant-related mortality was 0% in both arms.
“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”
Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).
There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.
Response
At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).
“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.
Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good
partial response were 69% and 86%, respectively (P=0.65).
Maintenance
A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.
The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.
Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.
Survival
At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.
Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.
“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.
He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary
endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.
Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory
board, honoraria) with Celgene, Millennium, and Onyx.
*Information in the abstract differs from that presented at the meeting.