Myelodysplastic Syndrome

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse 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.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse 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.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse 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.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

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.

Mitchel L. Zoler/Frontline Medical News

[email protected]

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.

Mitchel L. Zoler/Frontline Medical News

[email protected]

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.

Mitchel L. Zoler/Frontline Medical News

[email protected]

SOURCE: Zeidan A et al. ASH 2017 Abstract 640.

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

myelodysplastic syndrome

Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.

In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.

Overall survival (OS) was about a year longer for responders than for non-responders.

MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.

Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).

Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.

The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.

Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).

All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.

Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m²/day to 1700 mg/m²/day in 14-day cycles.

The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m²/day, and the recommended phase 2 dose was 1375 mg/m²/day.

Safety

All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).

The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).

Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.

Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.

Efficacy

Nineteen patients were evaluable for efficacy.

Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.

Five patients had stable disease, 3 with MDS and 2 with tAML.

The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).

“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.

He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.

myelodysplastic syndrome

Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.

In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.

Overall survival (OS) was about a year longer for responders than for non-responders.

MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.

Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).

Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.

The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.

Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).

All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.

Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m²/day to 1700 mg/m²/day in 14-day cycles.

The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m²/day, and the recommended phase 2 dose was 1375 mg/m²/day.

Safety

All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).

The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).

Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.

Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.

Efficacy

Nineteen patients were evaluable for efficacy.

Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.

Five patients had stable disease, 3 with MDS and 2 with tAML.

The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).

“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.

He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.

myelodysplastic syndrome

Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.

In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.

Overall survival (OS) was about a year longer for responders than for non-responders.

MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.

Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).

Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.

The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.

Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).

All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.

Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m²/day to 1700 mg/m²/day in 14-day cycles.

The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m²/day, and the recommended phase 2 dose was 1375 mg/m²/day.

Safety

All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).

The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).

Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.

Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.

Efficacy

Nineteen patients were evaluable for efficacy.

Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.

Five patients had stable disease, 3 with MDS and 2 with tAML.

The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).

“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.

He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.

acute myeloid leukemia

Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).

The generic drug is approved for the same indications as VIDAZA®.

This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.

It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.

“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.

“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”

acute myeloid leukemia

Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).

The generic drug is approved for the same indications as VIDAZA®.

This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.

It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.

“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.

“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”

acute myeloid leukemia

Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).

The generic drug is approved for the same indications as VIDAZA®.

This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.

It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.

“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.

“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”

The Food and Drug Administration has approved vemurafenib for adults with Erdheim-Chester disease (ECD) with the BRAF V600 mutation.

The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.

The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.

The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).

Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.

The full prescribing information is available at zelboraf.com.

[email protected]

On Twitter @maryellenny

The Food and Drug Administration has approved vemurafenib for adults with Erdheim-Chester disease (ECD) with the BRAF V600 mutation.

The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.

The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.

The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).

Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.

The full prescribing information is available at zelboraf.com.

[email protected]

On Twitter @maryellenny

The Food and Drug Administration has approved vemurafenib for adults with Erdheim-Chester disease (ECD) with the BRAF V600 mutation.

The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.

The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.

The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).

Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.

The full prescribing information is available at zelboraf.com.

[email protected]

On Twitter @maryellenny

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.