Jen Smith

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

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

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

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

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

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

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Bone marrow harvest

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.

Bone marrow harvest

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.

Bone marrow harvest

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.

PBSC collection

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.

PBSC collection

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.

PBSC collection

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.

Prescription medications

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.

Prescription medications

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.

Prescription medications

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.

Preparing HSCs for transplant

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.

Preparing HSCs for transplant

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.

Preparing HSCs for transplant

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.

Umbilical cord blood donation

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.

Umbilical cord blood donation

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.

Umbilical cord blood donation

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.

Patient receives chemotherapy

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.

Patient receives chemotherapy

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.

Patient receives chemotherapy

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.

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”