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NK-cell therapy in resistant MDS, AML
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Results of a phase 1/2 trial suggest treatment with haploidentical natural killer (NK) cells can be effective against relapsed/refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
NK-cell therapy elicited responses in 6 of the 16 patients studied and provided a bridge to transplant for 5 patients.
Three responders were still alive at more than 3 years of follow-up.
There were 4 grade 3 adverse events (AEs) and 2 grade 5 AEs considered possibly or probably related to NK-cell therapy.
Investigators reported these results in Clinical Cancer Research.
The trial enrolled 16 patients. Eight had MDS/AML, 3 had de novo AML, and 5 had high-risk MDS, including refractory anemia with excess blasts (RAEB) type 1 progressing toward type 2, RAEB-2, and chronic myelomonocytic leukemia type 2.
The patients’ median age was 64 (range, 40-70), and they had received a median of 3 prior therapies (range, 1-6). Six patients had received an allogeneic hematopoietic stem cell transplant (HSCT).
For this study, all patients received fludarabine, cyclophosphamide, and total lymphoid irradiation prior to receiving haploidentical NK cells.
The median follow-up was 8 months for all patients and 28 months for responders.
Efficacy
Six patients responded to treatment. One patient with de novo AML had a complete response (CR). Two high-risk MDS patients had a marrow CR (mCR), as did 2 MDS/AML patients. One MDS/AML patient had a partial response (PR).
Two patients had stable disease (SD)—1 with MDS and 1 with MDS/AML. One patient with de novo AML had a morphologic leukemia-free state after NK-cell therapy.
Five patients proceeded to HSCT—3 in mCR, 1 in PR, and 1 with SD.
Three patients were still alive at last follow-up—1 with MDS who achieved an mCR and went on to HSCT, 1 with MDS/AML who achieved an mCR and went on to HSCT, and 1 with MDS/AML who achieved an mCR and went on to receive chemotherapy and donor lymphocyte infusion.
One survivor has more than 5 years of follow-up (the MDS patient), and the other 2 have more than 3 years of follow-up.
“Our study shows that patients with MDS, AML, and MDS/AML can be treated with NK cell-based immunotherapy and that the therapy can be highly efficacious,” said study author Hans-Gustaf Ljunggren, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
Safety
The most common AEs of any grade considered possibly or probably related to NK-cell therapy were chills (n=13) and nausea (n=4).
Two patients had cytokine release syndrome (CRS) likely associated with hemophagocytic lymphohistiocytosis (HLH).
Each of the following potentially related AEs were reported once: headache, vomiting, encephalitis infection, sinus tachycardia, bone pain, pain in extremity, and maculopapular rash.
There were 4 grade 3 AEs—CRS/HLH (n=1), chills (n=1), and nausea (n=2)—but no grade 4 AEs.
There were 2 grade 5 AEs—CRS/HLH and encephalitis infection. These occurred in a single patient who died with HLH, human herpes virus-6 encephalitis, and AML relapse.
Two investigators involved in this study serve on the scientific advisory board of Fate Therapeutics. Dr Ljunggren serves on the scientific advisory board of CellProtect, Nordic Pharmaceuticals, and HOPE Bio-Sciences. He is also on the board of directors of Vycellix and is a collaborator with Fate Therapeutics.
Azacitidine now available in China
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%). 
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).
Azacitidine for injection (Vidaza®) is now available in China.
The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).
Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.
“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.
“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”
Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.
Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).
Azacitidine was given subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.
The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.
There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.
In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.
Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.
Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).
AML immune profiles correlate with relapse-free survival
SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.
The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.
The investigators identified two distinct immune gene expression profiles (GEPs) that were largely age-differentiated: Cluster A (myeloid-enriched specimens) included 26 children and 8 adults, and cluster B (myeloid-depleted specimens) included 9 children and 18 adults. These GEPs predicted clinical outcome; relapse free survival was 2.2 months in cluster A versus 18.3 months in cluster B (hazard ratio, 2.58) and overall survival was 6.3 months in cluster A, compared with 22.4 months in cluster B (HR, 2.39), Dr. Vadakekolathu reported.
The findings could have implications for the development of new treatment strategies, he said, noting that AML is a highly heterogeneous disease in terms of genetics, clinical manifestations, and outcome.
“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.
The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.
“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.
In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.
Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.
Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.
Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.
The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.
This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.
SOURCE: Rutella S et al. ASCO-SITC Abstract 50
SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.
The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.
The investigators identified two distinct immune gene expression profiles (GEPs) that were largely age-differentiated: Cluster A (myeloid-enriched specimens) included 26 children and 8 adults, and cluster B (myeloid-depleted specimens) included 9 children and 18 adults. These GEPs predicted clinical outcome; relapse free survival was 2.2 months in cluster A versus 18.3 months in cluster B (hazard ratio, 2.58) and overall survival was 6.3 months in cluster A, compared with 22.4 months in cluster B (HR, 2.39), Dr. Vadakekolathu reported.
The findings could have implications for the development of new treatment strategies, he said, noting that AML is a highly heterogeneous disease in terms of genetics, clinical manifestations, and outcome.
“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.
The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.
“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.
In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.
Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.
Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.
Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.
The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.
This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.
SOURCE: Rutella S et al. ASCO-SITC Abstract 50
SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.
The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.
The investigators identified two distinct immune gene expression profiles (GEPs) that were largely age-differentiated: Cluster A (myeloid-enriched specimens) included 26 children and 8 adults, and cluster B (myeloid-depleted specimens) included 9 children and 18 adults. These GEPs predicted clinical outcome; relapse free survival was 2.2 months in cluster A versus 18.3 months in cluster B (hazard ratio, 2.58) and overall survival was 6.3 months in cluster A, compared with 22.4 months in cluster B (HR, 2.39), Dr. Vadakekolathu reported.
The findings could have implications for the development of new treatment strategies, he said, noting that AML is a highly heterogeneous disease in terms of genetics, clinical manifestations, and outcome.
“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.
The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.
“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.
In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.
Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.
Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.
Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.
The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.
This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.
SOURCE: Rutella S et al. ASCO-SITC Abstract 50
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point:
Major finding: Relapse-free survival was 2.2 months in a cluster of myeloid-enriched specimens, compared with 18.3 months in a cluster of myeloid-depleted specimens (hazard ratio, 2.58).
Study details: A pan-cancer analysis of bone marrow specimens from 74 patients.
Disclosures: This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment and other financial relationships with NanoString Technologies.
Source: Rutella S et al. ASCO-SITC Abstract 50.
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.
EC grants orphan designation to gilteritinib for AML
The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.
The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.
The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.
Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).
Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).
There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).
The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).
Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.
The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.
The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.
Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).
Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).
There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).
The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).
Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.
The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.
The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.
Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).
Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).
There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).
The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).
Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
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.
FDA approves injection treatment for low-risk APL
The Food and Drug Administration announced the approval of arsenic trioxide injection (Trisenox) in combination with tretinoin for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) characterized by t(15;17) translocation or PML/RAR-alpha gene expression.
The expanded indication was granted by the FDA on Jan. 12 after priority review. It is based on published studies and a review of Teva’s global safety database for arsenic trioxide.
A recent randomized, phase 3 trial compared tretinoin plus arsenic trioxide with tretinoin plus chemotherapy as first-line treatment for APL (J Clin Oncol. 2017 Feb 20;35[6]:605-12). It found that 100% of 127 patients in the tretinoin plus arsenic trioxide arm achieved complete remission, compared with 97% of 136 patients in the tretinoin plus chemotherapy arm. After a median follow-up of 40.6 months, the event-free survival at 50 months for patients in the tretinoin/arsenic trioxide arm was 97.3% vs. 80% for tretinoin/chemotherapy (P = .001).
The arsenic trioxide injection carries a boxed warning for differentiation syndrome and cardiac conduction abnormalities.
The Food and Drug Administration announced the approval of arsenic trioxide injection (Trisenox) in combination with tretinoin for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) characterized by t(15;17) translocation or PML/RAR-alpha gene expression.
The expanded indication was granted by the FDA on Jan. 12 after priority review. It is based on published studies and a review of Teva’s global safety database for arsenic trioxide.
A recent randomized, phase 3 trial compared tretinoin plus arsenic trioxide with tretinoin plus chemotherapy as first-line treatment for APL (J Clin Oncol. 2017 Feb 20;35[6]:605-12). It found that 100% of 127 patients in the tretinoin plus arsenic trioxide arm achieved complete remission, compared with 97% of 136 patients in the tretinoin plus chemotherapy arm. After a median follow-up of 40.6 months, the event-free survival at 50 months for patients in the tretinoin/arsenic trioxide arm was 97.3% vs. 80% for tretinoin/chemotherapy (P = .001).
The arsenic trioxide injection carries a boxed warning for differentiation syndrome and cardiac conduction abnormalities.
The Food and Drug Administration announced the approval of arsenic trioxide injection (Trisenox) in combination with tretinoin for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) characterized by t(15;17) translocation or PML/RAR-alpha gene expression.
The expanded indication was granted by the FDA on Jan. 12 after priority review. It is based on published studies and a review of Teva’s global safety database for arsenic trioxide.
A recent randomized, phase 3 trial compared tretinoin plus arsenic trioxide with tretinoin plus chemotherapy as first-line treatment for APL (J Clin Oncol. 2017 Feb 20;35[6]:605-12). It found that 100% of 127 patients in the tretinoin plus arsenic trioxide arm achieved complete remission, compared with 97% of 136 patients in the tretinoin plus chemotherapy arm. After a median follow-up of 40.6 months, the event-free survival at 50 months for patients in the tretinoin/arsenic trioxide arm was 97.3% vs. 80% for tretinoin/chemotherapy (P = .001).
The arsenic trioxide injection carries a boxed warning for differentiation syndrome and cardiac conduction abnormalities.
FDA expands approval for arsenic trioxide
The US Food and Drug Administration (FDA) has expanded the approved use of arsenic trioxide (TRISENOX®) injection.
The drug is now approved for use in combination with all-trans retinoic acid (ATRA) for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
Arsenic trioxide is also FDA-approved for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
“This label expansion represents an important benefit, as TRISENOX is now an FDA-approved, first-line treatment option for patients with acute promyelocytic leukemia,” said Paul Rittman, senior vice-president and general manager of Teva Oncology.
The expanded approval for arsenic trioxide was based on a priority review by the FDA of data from the scientific literature and a review of Teva’s global safety database for arsenic trioxide.
Data from this database were presented at the 2016 ASH Annual Meeting.
According to the presentation, the most common adverse events observed in patients receiving arsenic trioxide were QT prolongation, decrease in white blood cells, APL differentiation syndrome, febrile neutropenia, neutropenia, pyrexia, alanine aminotransferase increase, neutrophil decrease, platelet count decrease, aspartate aminotransferase increase, leukocytosis, and pancytopenia.
The combination of arsenic trioxide and ATRA was evaluated in a phase 3 trial of patients with APL. Results from this trial were published in the Journal of Clinical Oncology in February 2017.
The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.
A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).
After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).
At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).
After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.
In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.
The US Food and Drug Administration (FDA) has expanded the approved use of arsenic trioxide (TRISENOX®) injection.
The drug is now approved for use in combination with all-trans retinoic acid (ATRA) for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
Arsenic trioxide is also FDA-approved for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
“This label expansion represents an important benefit, as TRISENOX is now an FDA-approved, first-line treatment option for patients with acute promyelocytic leukemia,” said Paul Rittman, senior vice-president and general manager of Teva Oncology.
The expanded approval for arsenic trioxide was based on a priority review by the FDA of data from the scientific literature and a review of Teva’s global safety database for arsenic trioxide.
Data from this database were presented at the 2016 ASH Annual Meeting.
According to the presentation, the most common adverse events observed in patients receiving arsenic trioxide were QT prolongation, decrease in white blood cells, APL differentiation syndrome, febrile neutropenia, neutropenia, pyrexia, alanine aminotransferase increase, neutrophil decrease, platelet count decrease, aspartate aminotransferase increase, leukocytosis, and pancytopenia.
The combination of arsenic trioxide and ATRA was evaluated in a phase 3 trial of patients with APL. Results from this trial were published in the Journal of Clinical Oncology in February 2017.
The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.
A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).
After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).
At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).
After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.
In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.
The US Food and Drug Administration (FDA) has expanded the approved use of arsenic trioxide (TRISENOX®) injection.
The drug is now approved for use in combination with all-trans retinoic acid (ATRA) for the treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
Arsenic trioxide is also FDA-approved for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
“This label expansion represents an important benefit, as TRISENOX is now an FDA-approved, first-line treatment option for patients with acute promyelocytic leukemia,” said Paul Rittman, senior vice-president and general manager of Teva Oncology.
The expanded approval for arsenic trioxide was based on a priority review by the FDA of data from the scientific literature and a review of Teva’s global safety database for arsenic trioxide.
Data from this database were presented at the 2016 ASH Annual Meeting.
According to the presentation, the most common adverse events observed in patients receiving arsenic trioxide were QT prolongation, decrease in white blood cells, APL differentiation syndrome, febrile neutropenia, neutropenia, pyrexia, alanine aminotransferase increase, neutrophil decrease, platelet count decrease, aspartate aminotransferase increase, leukocytosis, and pancytopenia.
The combination of arsenic trioxide and ATRA was evaluated in a phase 3 trial of patients with APL. Results from this trial were published in the Journal of Clinical Oncology in February 2017.
The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.
A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).
After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).
At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).
After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.
In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.
EMA recommends orphan designation for pracinostat
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).