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Gene variants linked to survival after HSCT
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
Agent exhibits activity in leukemias, MDS
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
Amgen withdraws application for darbepoetin alfa
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.
Manufactured graft deemed safe in blood cancer patients
LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.
The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).
Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.
However, the remaining 5 patients were still alive and disease-free at last follow-up.
There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.
These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).
The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.
The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.
Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.
The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).
Results
The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).
None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).
Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.
All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.
None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.
AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).
Phase 2
The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.
Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.
The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.
*Some data in the abstract differ from the presentation.
LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.
The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).
Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.
However, the remaining 5 patients were still alive and disease-free at last follow-up.
There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.
These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).
The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.
The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.
Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.
The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).
Results
The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).
None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).
Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.
All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.
None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.
AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).
Phase 2
The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.
Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.
The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.
*Some data in the abstract differ from the presentation.
LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.
The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).
Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.
However, the remaining 5 patients were still alive and disease-free at last follow-up.
There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.
These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).
The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.
The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.
Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.
The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).
Results
The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).
None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).
Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.
All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.
None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.
AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).
Phase 2
The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.
Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.
The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.
*Some data in the abstract differ from the presentation.
HSCT approach provides ‘excellent’ survival in FA
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
Expanded UCB product can stand alone
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
‘Remarkable’ survival seen with pretransplant JAK inhibitor
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The 2-year overall survival rate was 89%.
Study details: Findings in 28 patients from an ongoing prospective phase 2 study.
Disclosures: Dr. Salit reported having no financial disclosures. The study was sponsored by the Fred Hutchinson Cancer Research Center in Seattle.
Source: Salit R et al. BMT Tandem Meetings, Abstract 17.
NK-cell therapy in resistant MDS, AML
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Azacitidine now available in China
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).
Sotatercept promising for treatment of anemia in MDS
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
FROM LANCET HAEMATOLOGY
Key clinical point:
Major finding: In all, 36 patients (49%) achieved hematologic improvement–erythroid and 20 patients (27%) achieved independence from transfusion for at least 56 days.
Data source: A phase 2 trial that included 74 patients with lower-risk myelodysplastic syndromes who did not respond to erythropoiesis-stimulating agents.
Disclosures: Celgene funded the study. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
Source: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.