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MEC plus ixazomib looks promising in relapsed/refractory AML
ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.
The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.
Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.
The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.
Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.
They received one cycle of the therapy, which included 8mg/m2 of mitoxantrone, 80 mg/m2 of etoposide, and 1,000 mg/m2 of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.
The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.
Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.
“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”
Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.
“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.
Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.
The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.
Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.
ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.
The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.
Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.
The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.
Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.
They received one cycle of the therapy, which included 8mg/m2 of mitoxantrone, 80 mg/m2 of etoposide, and 1,000 mg/m2 of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.
The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.
Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.
“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”
Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.
“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.
Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.
The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.
Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.
ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.
The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.
Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.
The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.
Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.
They received one cycle of the therapy, which included 8mg/m2 of mitoxantrone, 80 mg/m2 of etoposide, and 1,000 mg/m2 of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.
The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.
Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.
“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”
Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.
“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.
Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.
The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.
Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.
REPORTING FROM ASH 2017
Key clinical point: Major finding: The overall response rate was 53%.
Study details: A phase 1 trial involving 30 patients.
Disclosures: Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.
Source: Advani A et al. ASH 2017, Abstract 150.
GCLAM therapy shows promise for relapsed/refractory AML
ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.
Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m2 per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.
“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.
Resistant disease occurred in 11 patients, she noted.
Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.
Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.
The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.
“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.
At the mitoxantrone maximum tolerated dose of 16 mg/m2 per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m2 per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.
“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.
The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.
A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m2 per day was associated with significantly better overall survival, compared with a dose of 10 mg/m2 per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m2 per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m2 dose, but the difference was not statistically significant (odds ratio, 1.87).
“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m2 compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.
The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.
The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.
The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.
Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.
The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m2 per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m2 of cladribine on days 1-5, and 2 mg/m2 of cytarabine on days 1-5.
“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.
If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.
In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m2 per day), as defined in phase 1.
“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”
A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.
Dr. Halpern reported having no relevant financial disclosures.
SOURCE: Halpern AB et al. ASH 2017, Abstract 149
ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.
Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m2 per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.
“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.
Resistant disease occurred in 11 patients, she noted.
Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.
Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.
The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.
“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.
At the mitoxantrone maximum tolerated dose of 16 mg/m2 per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m2 per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.
“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.
The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.
A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m2 per day was associated with significantly better overall survival, compared with a dose of 10 mg/m2 per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m2 per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m2 dose, but the difference was not statistically significant (odds ratio, 1.87).
“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m2 compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.
The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.
The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.
The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.
Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.
The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m2 per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m2 of cladribine on days 1-5, and 2 mg/m2 of cytarabine on days 1-5.
“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.
If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.
In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m2 per day), as defined in phase 1.
“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”
A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.
Dr. Halpern reported having no relevant financial disclosures.
SOURCE: Halpern AB et al. ASH 2017, Abstract 149
ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.
Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m2 per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.
“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.
Resistant disease occurred in 11 patients, she noted.
Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.
Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.
The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.
“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.
At the mitoxantrone maximum tolerated dose of 16 mg/m2 per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m2 per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.
“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.
The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.
A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m2 per day was associated with significantly better overall survival, compared with a dose of 10 mg/m2 per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m2 per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m2 dose, but the difference was not statistically significant (odds ratio, 1.87).
“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m2 compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.
The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.
The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.
The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.
Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.
The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m2 per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m2 of cladribine on days 1-5, and 2 mg/m2 of cytarabine on days 1-5.
“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.
If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.
In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m2 per day), as defined in phase 1.
“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”
A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.
Dr. Halpern reported having no relevant financial disclosures.
SOURCE: Halpern AB et al. ASH 2017, Abstract 149
REPORTING FROM ASH 2017
Key clinical point: GCLAM was well tolerated and had potent antileukemia activity in a phase 1/2 trial.
Major finding: The overall response rate was 60%.
Study details: A phase 1/2 study of 40 patients.
Disclosures: Dr. Halpern reported having no financial disclosures.
Source: Halpern AB et al. ASH 2017, Abstract 149.
Tamibarotene shows strong results in high-risk APL patients
ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.
The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.
“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.
Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.
The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).
Both treatments were generally well tolerated, Dr. Takeshita reported.
Study subjects received ATRA at a daily dose of 45 mg/m2 for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m2 divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m2 divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.
Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.
Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.
“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.
In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.
The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.
Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.
SOURCE: Takeshita A et al., ASH 2017, abstract 642.
ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.
The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.
“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.
Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.
The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).
Both treatments were generally well tolerated, Dr. Takeshita reported.
Study subjects received ATRA at a daily dose of 45 mg/m2 for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m2 divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m2 divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.
Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.
Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.
“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.
In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.
The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.
Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.
SOURCE: Takeshita A et al., ASH 2017, abstract 642.
ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.
The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.
“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.
Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.
The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).
Both treatments were generally well tolerated, Dr. Takeshita reported.
Study subjects received ATRA at a daily dose of 45 mg/m2 for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m2 divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m2 divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.
Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.
Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.
“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.
In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.
The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.
Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.
SOURCE: Takeshita A et al., ASH 2017, abstract 642.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The 7-year relapse-free survival was 62% vs. 89% with ATRA vs. tamibarotene in high-risk patients.
Study details: Long-term maintenance results in 344 patients from a randomized controlled trial.
Disclosures: Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.
Source: Takeshita A et al. ASH 2017, abstract 642.
VIDEO: Practice changers out of ASH 2017
ATLANTA – There were a lot of new data presented during the annual meeting of the American Society of Hematology. But what findings could actually change the way you practice?
Robert A. Brodsky, MD, director of the division of hematology at Johns Hopkins University in Baltimore and the moderator for the late-breaking abstract session at ASH, highlighted results from two studies.
Data from the MURANO trial showed robust results for a combination of venetoclax and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). At a median follow-up of 23.8 months, median progression-free survival -had not been reached in patients randomized to venetoclax/rituximab, while patients who received bendamustine plus rituximab had a median PFS of 17 months.
The based on the data presented, Dr. Brodsky said.
Another “enormously exciting and practice-changing” finding is that direct oral anticoagulants can be used safely in patients with cancer, Dr. Brodsky said in an interview.
In a randomized, open-label study, 12 months of daily treatment with edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in cancer patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – There were a lot of new data presented during the annual meeting of the American Society of Hematology. But what findings could actually change the way you practice?
Robert A. Brodsky, MD, director of the division of hematology at Johns Hopkins University in Baltimore and the moderator for the late-breaking abstract session at ASH, highlighted results from two studies.
Data from the MURANO trial showed robust results for a combination of venetoclax and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). At a median follow-up of 23.8 months, median progression-free survival -had not been reached in patients randomized to venetoclax/rituximab, while patients who received bendamustine plus rituximab had a median PFS of 17 months.
The based on the data presented, Dr. Brodsky said.
Another “enormously exciting and practice-changing” finding is that direct oral anticoagulants can be used safely in patients with cancer, Dr. Brodsky said in an interview.
In a randomized, open-label study, 12 months of daily treatment with edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in cancer patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – There were a lot of new data presented during the annual meeting of the American Society of Hematology. But what findings could actually change the way you practice?
Robert A. Brodsky, MD, director of the division of hematology at Johns Hopkins University in Baltimore and the moderator for the late-breaking abstract session at ASH, highlighted results from two studies.
Data from the MURANO trial showed robust results for a combination of venetoclax and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). At a median follow-up of 23.8 months, median progression-free survival -had not been reached in patients randomized to venetoclax/rituximab, while patients who received bendamustine plus rituximab had a median PFS of 17 months.
The based on the data presented, Dr. Brodsky said.
Another “enormously exciting and practice-changing” finding is that direct oral anticoagulants can be used safely in patients with cancer, Dr. Brodsky said in an interview.
In a randomized, open-label study, 12 months of daily treatment with edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in cancer patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ASH 2017
mIDH inhibitors could fill treatment gap in AML
ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.
Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.
The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,
Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.
The median duration of any response was 12.2 months, he said.
Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.
Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.
The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.
“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”
In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.
The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.
These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
Combination approach
Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.
Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.
In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.
The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.
The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.
In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.
Patients in this group had a median age of 76 years and the median number of treatment cycles was three.
The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.
One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.
The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.
Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.
Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.
The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”
These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.
Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.
SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639
ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.
Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.
The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,
Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.
The median duration of any response was 12.2 months, he said.
Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.
Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.
The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.
“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”
In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.
The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.
These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
Combination approach
Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.
Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.
In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.
The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.
The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.
In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.
Patients in this group had a median age of 76 years and the median number of treatment cycles was three.
The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.
One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.
The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.
Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.
Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.
The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”
These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.
Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.
SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639
ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.
Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.
The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,
Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.
The median duration of any response was 12.2 months, he said.
Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.
Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.
The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.
“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”
In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.
The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.
These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
Combination approach
Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.
Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.
In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.
The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.
The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.
In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.
Patients in this group had a median age of 76 years and the median number of treatment cycles was three.
The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.
One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.
The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.
Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.
Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.
The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”
These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.
Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.
SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The overall response rates were 32%, 67%, and 73% with enasidenib, enasidenib plus azacitidine, and ivosidenib plus azacitidine, respectively.
Study details: Two phase 1/2 studies of 38 and 17 patients.
Disclosures: Both studies were sponsored by Celgene. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.
Sources: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639.
New hematologic, cardiovascular system link may have therapeutic implications
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM ASH 2017
RELAZA2: MRD-guided azacitidine reduces relapse risk in MDS and AML
ATLANTA – in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.
Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.
Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.
The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.
“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.
Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m2 of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.
Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.
“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.
Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.
In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.
The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.
“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.
The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.
SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.
ATLANTA – in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.
Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.
Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.
The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.
“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.
Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m2 of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.
Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.
“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.
Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.
In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.
The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.
“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.
The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.
SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.
ATLANTA – in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.
Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.
Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.
The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.
“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.
Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m2 of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.
Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.
“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.
Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.
In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.
The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.
“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.
The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.
SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.
REPORTING FROM ASH 2017
Key clinical point: MRD-guided azacitidine therapy reduces hematological relapse in high-risk MDS/AML.
Major finding: The relapse-free survival rate at 6 months was 58%.
Study details: An analysis of 53 patients from the open-label RELAZA2 trial.
Disclosures: The RELAZA2 trial is sponsored by Technische Universität Dresden, Germany. Dr. Platzbecker reported serving as a consultant for and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron Pharma.
Source: Platzbecker U et al. ASH 2017 Abstract #565.
Novel JAK1 inhibitor shows promise for myeloid malignancies
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Overall response rates with INCB052793 plus azacitidine were 67% in AML and 56% in MDS or MDS/MPN.
Study details: A phase 1/2 study involving 58 initial patients.
Disclosures: This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
Source: Zeidan A et al. ASH 2017 Abstract 640.
AUDIO: Immunotherapy’s role in NHL
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
EXPERT ANALYSIS FROM ASH 2017
Update of gene therapy in hemophilia A
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported. 
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.