AML

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to 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 companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to 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 companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to 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 companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.

The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.

vinya@mskcc.org

On Twitter @thedoctorisvin

A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.

The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.

vinya@mskcc.org

On Twitter @thedoctorisvin

A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.

The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.

vinya@mskcc.org

On Twitter @thedoctorisvin

Mast cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application for midostaurin (PKC412) as a treatment for advanced systemic mastocytosis (SM) and newly diagnosed, FLT3-mutated acute myeloid leukemia (AML).

The FDA has also accepted for review the premarket approval application for the midostaurin FLT3 companion diagnostic, which is designed to help identify patients who may have a FLT3 mutation and could potentially benefit from treatment with midostaurin.

Midostaurin is being developed by Novartis. The companion diagnostic is being developed by Novartis and Invivoscribe Technologies, Inc.

About priority review

The FDA grants priority review to applications for therapies that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it. The goal in the standard review process is to take action within 10 months.

About midostaurin

Midostaurin is an oral, multi-targeted kinase inhibitor. The drug was granted breakthrough therapy designation by the FDA earlier this year for newly diagnosed, FLT3-mutated AML.

According to Novartis, the new drug application submission for midostaurin includes data from the largest clinical trials conducted to date in advanced SM and newly diagnosed, FLT3-mutated AML.

Midostaurin in AML

In the phase 3 RATIFY trial, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in adults younger than 60 with FLT3-mutated AML. Results from this trial were presented at the 2015 ASH Annual Meeting.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.0074).

There was no significant difference in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in midostaurin arm and the placebo arm. Similarly, there was no significant difference in treatment-related deaths between the arms.

Midostaurin in SM

Data from the phase 2 study of midostaurin in patients with advanced SM were published in NEJM in June.

The drug produced a 60% overall response rate, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose of midostaurin.

Access to midostaurin

Since midostaurin remains investigational, both within the US and globally, Novartis opened a Global Individual Patient Program (compassionate use program) and, in the US, an Expanded Treatment Protocol, to provide access to midostaurin for eligible patients with newly diagnosed AML and advanced SM.

Physicians who want to request midostaurin for eligible patients can contact a Novartis medical representative in their respective countries. In the US, physicians can call 1-888-NOW-NOVA (1-888-669-6682) for more information.

Mast cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application for midostaurin (PKC412) as a treatment for advanced systemic mastocytosis (SM) and newly diagnosed, FLT3-mutated acute myeloid leukemia (AML).

The FDA has also accepted for review the premarket approval application for the midostaurin FLT3 companion diagnostic, which is designed to help identify patients who may have a FLT3 mutation and could potentially benefit from treatment with midostaurin.

Midostaurin is being developed by Novartis. The companion diagnostic is being developed by Novartis and Invivoscribe Technologies, Inc.

About priority review

The FDA grants priority review to applications for therapies that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it. The goal in the standard review process is to take action within 10 months.

About midostaurin

Midostaurin is an oral, multi-targeted kinase inhibitor. The drug was granted breakthrough therapy designation by the FDA earlier this year for newly diagnosed, FLT3-mutated AML.

According to Novartis, the new drug application submission for midostaurin includes data from the largest clinical trials conducted to date in advanced SM and newly diagnosed, FLT3-mutated AML.

Midostaurin in AML

In the phase 3 RATIFY trial, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in adults younger than 60 with FLT3-mutated AML. Results from this trial were presented at the 2015 ASH Annual Meeting.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.0074).

There was no significant difference in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in midostaurin arm and the placebo arm. Similarly, there was no significant difference in treatment-related deaths between the arms.

Midostaurin in SM

Data from the phase 2 study of midostaurin in patients with advanced SM were published in NEJM in June.

The drug produced a 60% overall response rate, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose of midostaurin.

Access to midostaurin

Since midostaurin remains investigational, both within the US and globally, Novartis opened a Global Individual Patient Program (compassionate use program) and, in the US, an Expanded Treatment Protocol, to provide access to midostaurin for eligible patients with newly diagnosed AML and advanced SM.

Physicians who want to request midostaurin for eligible patients can contact a Novartis medical representative in their respective countries. In the US, physicians can call 1-888-NOW-NOVA (1-888-669-6682) for more information.

Mast cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application for midostaurin (PKC412) as a treatment for advanced systemic mastocytosis (SM) and newly diagnosed, FLT3-mutated acute myeloid leukemia (AML).

The FDA has also accepted for review the premarket approval application for the midostaurin FLT3 companion diagnostic, which is designed to help identify patients who may have a FLT3 mutation and could potentially benefit from treatment with midostaurin.

Midostaurin is being developed by Novartis. The companion diagnostic is being developed by Novartis and Invivoscribe Technologies, Inc.

About priority review

The FDA grants priority review to applications for therapies that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it. The goal in the standard review process is to take action within 10 months.

About midostaurin

Midostaurin is an oral, multi-targeted kinase inhibitor. The drug was granted breakthrough therapy designation by the FDA earlier this year for newly diagnosed, FLT3-mutated AML.

According to Novartis, the new drug application submission for midostaurin includes data from the largest clinical trials conducted to date in advanced SM and newly diagnosed, FLT3-mutated AML.

Midostaurin in AML

In the phase 3 RATIFY trial, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in adults younger than 60 with FLT3-mutated AML. Results from this trial were presented at the 2015 ASH Annual Meeting.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.0074).

There was no significant difference in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in midostaurin arm and the placebo arm. Similarly, there was no significant difference in treatment-related deaths between the arms.

Midostaurin in SM

Data from the phase 2 study of midostaurin in patients with advanced SM were published in NEJM in June.

The drug produced a 60% overall response rate, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose of midostaurin.

Access to midostaurin

Since midostaurin remains investigational, both within the US and globally, Novartis opened a Global Individual Patient Program (compassionate use program) and, in the US, an Expanded Treatment Protocol, to provide access to midostaurin for eligible patients with newly diagnosed AML and advanced SM.

Physicians who want to request midostaurin for eligible patients can contact a Novartis medical representative in their respective countries. In the US, physicians can call 1-888-NOW-NOVA (1-888-669-6682) for more information.

AML cells

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has recommended that BP1001 receive orphan designation as a treatment for acute myeloid leukemia (AML).

BP1001 (liposomal Grb2 antisense) is a neutral-charge, liposome-incorporated, antisense drug designed to inhibit protein synthesis of growth factor receptor bound protein 2 (Grb2).

BP1001 is being developed by Bio-Path Holdings, Inc.

According to Bio-Path, inhibition of Grb2 by BP1001 represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with small molecule inhibitors.

Research has suggested that Grb2 plays an essential role in cancer cell activation via the RAS pathway. Grb2 bridges signals between activated and mutated tyrosine kinases, such as Flt3, c-Kit, and Bcr-Abl, and the Ras pathway, leading to activation of the ERK and AKT proteins.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

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 EMA during the product development phase and direct access to the centralized authorization procedure.

Trials of BP1001

Bio-Path has completed a phase 1 trial of BP1001 in patients with relapsed/refractory AML, chronic myeloid leukemia, and myelodysplastic syndromes.

The company has also completed the safety segment of a phase 2 trial in which BP1001 is being investigated in combination with low-dose ara-C to treat AML.

Bio-Path recently released data from these studies.

The phase 1 study included patients who had received an average of 6 prior therapies.

The patients received 8 doses of BP1001 over 4 weeks, escalating to a maximum dose of 90 mg/m². There were no dose-limiting toxicities, and Bio-Path said the drug was well tolerated.

Of the 18 evaluable patients with circulating blasts, 83% responded to BP1001. The average reduction in circulating blasts was 67%.

The phase 2 trial included patients with relapsed/refractory AML. There were 3 evaluable patients in each of 2 dosing cohorts—60 mg/m² and 90 mg/m². Patients received BP1001 twice a week for 4 weeks.

Five of the patients responded—3 with a complete response and 2 with a partial response. There were no adverse events attributed to BP1001, and the maximum-tolerated dose was not reached.

AML cells

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has recommended that BP1001 receive orphan designation as a treatment for acute myeloid leukemia (AML).

BP1001 (liposomal Grb2 antisense) is a neutral-charge, liposome-incorporated, antisense drug designed to inhibit protein synthesis of growth factor receptor bound protein 2 (Grb2).

BP1001 is being developed by Bio-Path Holdings, Inc.

According to Bio-Path, inhibition of Grb2 by BP1001 represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with small molecule inhibitors.

Research has suggested that Grb2 plays an essential role in cancer cell activation via the RAS pathway. Grb2 bridges signals between activated and mutated tyrosine kinases, such as Flt3, c-Kit, and Bcr-Abl, and the Ras pathway, leading to activation of the ERK and AKT proteins.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

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 EMA during the product development phase and direct access to the centralized authorization procedure.

Trials of BP1001

Bio-Path has completed a phase 1 trial of BP1001 in patients with relapsed/refractory AML, chronic myeloid leukemia, and myelodysplastic syndromes.

The company has also completed the safety segment of a phase 2 trial in which BP1001 is being investigated in combination with low-dose ara-C to treat AML.

Bio-Path recently released data from these studies.

The phase 1 study included patients who had received an average of 6 prior therapies.

The patients received 8 doses of BP1001 over 4 weeks, escalating to a maximum dose of 90 mg/m². There were no dose-limiting toxicities, and Bio-Path said the drug was well tolerated.

Of the 18 evaluable patients with circulating blasts, 83% responded to BP1001. The average reduction in circulating blasts was 67%.

The phase 2 trial included patients with relapsed/refractory AML. There were 3 evaluable patients in each of 2 dosing cohorts—60 mg/m² and 90 mg/m². Patients received BP1001 twice a week for 4 weeks.

Five of the patients responded—3 with a complete response and 2 with a partial response. There were no adverse events attributed to BP1001, and the maximum-tolerated dose was not reached.

AML cells

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has recommended that BP1001 receive orphan designation as a treatment for acute myeloid leukemia (AML).

BP1001 (liposomal Grb2 antisense) is a neutral-charge, liposome-incorporated, antisense drug designed to inhibit protein synthesis of growth factor receptor bound protein 2 (Grb2).

BP1001 is being developed by Bio-Path Holdings, Inc.

According to Bio-Path, inhibition of Grb2 by BP1001 represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with small molecule inhibitors.

Research has suggested that Grb2 plays an essential role in cancer cell activation via the RAS pathway. Grb2 bridges signals between activated and mutated tyrosine kinases, such as Flt3, c-Kit, and Bcr-Abl, and the Ras pathway, leading to activation of the ERK and AKT proteins.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

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 EMA during the product development phase and direct access to the centralized authorization procedure.

Trials of BP1001

Bio-Path has completed a phase 1 trial of BP1001 in patients with relapsed/refractory AML, chronic myeloid leukemia, and myelodysplastic syndromes.

The company has also completed the safety segment of a phase 2 trial in which BP1001 is being investigated in combination with low-dose ara-C to treat AML.

Bio-Path recently released data from these studies.

The phase 1 study included patients who had received an average of 6 prior therapies.

The patients received 8 doses of BP1001 over 4 weeks, escalating to a maximum dose of 90 mg/m². There were no dose-limiting toxicities, and Bio-Path said the drug was well tolerated.

Of the 18 evaluable patients with circulating blasts, 83% responded to BP1001. The average reduction in circulating blasts was 67%.

The phase 2 trial included patients with relapsed/refractory AML. There were 3 evaluable patients in each of 2 dosing cohorts—60 mg/m² and 90 mg/m². Patients received BP1001 twice a week for 4 weeks.

Five of the patients responded—3 with a complete response and 2 with a partial response. There were no adverse events attributed to BP1001, and the maximum-tolerated dose was not reached.

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Mitochondria (red) colocalization

with autophagosomes (green),

a process that happens during

mitophagy in cancer cells

treated with FLT3 inhibitor

Image from Besim Ogretmen

and Mohammed Dany/MUSC

Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.

Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.

“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.

AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.

“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.

However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.

In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.

In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.

A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.

Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.

Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.

“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”

LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.

Mitochondria (red) colocalization

with autophagosomes (green),

a process that happens during

mitophagy in cancer cells

treated with FLT3 inhibitor

Image from Besim Ogretmen

and Mohammed Dany/MUSC

Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.

Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.

“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.

AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.

“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.

However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.

In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.

In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.

A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.

Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.

Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.

“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”

LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.

Mitochondria (red) colocalization

with autophagosomes (green),

a process that happens during

mitophagy in cancer cells

treated with FLT3 inhibitor

Image from Besim Ogretmen

and Mohammed Dany/MUSC

Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.

Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.

“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.

AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.

“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.

However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.

In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.

In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.

A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.

Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.

Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.

“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”

LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”