AML

The Food and Drug Administration has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe, is used to detect the FLT3 mutation in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial, which enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835 or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit. Efficacy results are available for 138 patients, with a median follow-up of 4.6 months.

The complete response (CR) rate was 11.6% (16/138), the CR rate with partial hematologic recovery (CRh) was 9.4% (13/138), and the CR/CRh rate was 21% (29/138). The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion dependent at baseline, and 33 of these patients (31.1%) became transfusion independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion independent at baseline remained transfusion independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months.

The most common adverse events were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, constipation, stomatitis, cough, headache, hypotension, dizziness, and vomiting.

A total of 8% of patients (n = 22) discontinued gilteritinib because of adverse events, the most common of which were pneumonia (2%), sepsis (2%), and dyspnea (1%).
 

[email protected]

The Food and Drug Administration has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe, is used to detect the FLT3 mutation in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial, which enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835 or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit. Efficacy results are available for 138 patients, with a median follow-up of 4.6 months.

The complete response (CR) rate was 11.6% (16/138), the CR rate with partial hematologic recovery (CRh) was 9.4% (13/138), and the CR/CRh rate was 21% (29/138). The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion dependent at baseline, and 33 of these patients (31.1%) became transfusion independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion independent at baseline remained transfusion independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months.

The most common adverse events were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, constipation, stomatitis, cough, headache, hypotension, dizziness, and vomiting.

A total of 8% of patients (n = 22) discontinued gilteritinib because of adverse events, the most common of which were pneumonia (2%), sepsis (2%), and dyspnea (1%).
 

[email protected]

The Food and Drug Administration has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe, is used to detect the FLT3 mutation in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial, which enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835 or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit. Efficacy results are available for 138 patients, with a median follow-up of 4.6 months.

The complete response (CR) rate was 11.6% (16/138), the CR rate with partial hematologic recovery (CRh) was 9.4% (13/138), and the CR/CRh rate was 21% (29/138). The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion dependent at baseline, and 33 of these patients (31.1%) became transfusion independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion independent at baseline remained transfusion independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months.

The most common adverse events were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, constipation, stomatitis, cough, headache, hypotension, dizziness, and vomiting.

A total of 8% of patients (n = 22) discontinued gilteritinib because of adverse events, the most common of which were pneumonia (2%), sepsis (2%), and dyspnea (1%).
 

[email protected]

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

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

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

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

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

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

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

The U.S. Food and Drug Administration has approved the hedgehog pathway inhibitor glasdegib (Daurismo) for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed acute myeloid leukemia who are aged 75 years and older or who are ineligible for intensive chemotherapy.

[email protected]

The U.S. Food and Drug Administration has approved the hedgehog pathway inhibitor glasdegib (Daurismo) for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed acute myeloid leukemia who are aged 75 years and older or who are ineligible for intensive chemotherapy.

[email protected]

The U.S. Food and Drug Administration has approved the hedgehog pathway inhibitor glasdegib (Daurismo) for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed acute myeloid leukemia who are aged 75 years and older or who are ineligible for intensive chemotherapy.

[email protected]

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

The Food and Drug Administration has granted accelerated approval to venetoclax for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat newly diagnosed adults with AML who are aged 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies – the phase 1b M14-358 trial ( NCT02203773 ) and the phase 1/2 M14-387 trial ( NCT02287233 ).

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m ² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m ² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively. The most common adverse events (AEs) – occurring in at least 30% of patients in both arms – were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia. The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome. The incidence of fatal AEs was 1.5% within 30 days of treatment initiation. The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m ² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea. The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection. The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche.

[email protected]

The Food and Drug Administration has granted accelerated approval to venetoclax for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat newly diagnosed adults with AML who are aged 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies – the phase 1b M14-358 trial ( NCT02203773 ) and the phase 1/2 M14-387 trial ( NCT02287233 ).

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m ² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m ² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively. The most common adverse events (AEs) – occurring in at least 30% of patients in both arms – were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia. The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome. The incidence of fatal AEs was 1.5% within 30 days of treatment initiation. The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m ² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea. The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection. The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche.

[email protected]

The Food and Drug Administration has granted accelerated approval to venetoclax for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat newly diagnosed adults with AML who are aged 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies – the phase 1b M14-358 trial ( NCT02203773 ) and the phase 1/2 M14-387 trial ( NCT02287233 ).

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m ² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m ² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively. The most common adverse events (AEs) – occurring in at least 30% of patients in both arms – were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia. The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome. The incidence of fatal AEs was 1.5% within 30 days of treatment initiation. The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were aged 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m ² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea. The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection. The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche.

[email protected]

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has now approved three generic arsenic trioxide products for use in patients with acute promyelocytic leukemia (APL).

Two of the products—from Zydus Cadila and Amring Pharmaceuticals—were approved on November 13.

The third—from Fresenius Kabi—was approved in August and launched in the United States last month.

All three injectable arsenic trioxide products (1 mg/mL) are generic versions of Teva’s Trisenox.

Since 2000, Trisenox has been FDA-approved to induce remission and as consolidation therapy for patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy, and whose APL is characterized by presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

In January, the FDA approved Trisenox for use in combination with tretinoin to treat adults with newly diagnosed, low-risk APL with the t(15;17) translocation or PML/RAR-alpha gene expression.

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has now approved three generic arsenic trioxide products for use in patients with acute promyelocytic leukemia (APL).

Two of the products—from Zydus Cadila and Amring Pharmaceuticals—were approved on November 13.

The third—from Fresenius Kabi—was approved in August and launched in the United States last month.

All three injectable arsenic trioxide products (1 mg/mL) are generic versions of Teva’s Trisenox.

Since 2000, Trisenox has been FDA-approved to induce remission and as consolidation therapy for patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy, and whose APL is characterized by presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

In January, the FDA approved Trisenox for use in combination with tretinoin to treat adults with newly diagnosed, low-risk APL with the t(15;17) translocation or PML/RAR-alpha gene expression.

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has now approved three generic arsenic trioxide products for use in patients with acute promyelocytic leukemia (APL).

Two of the products—from Zydus Cadila and Amring Pharmaceuticals—were approved on November 13.

The third—from Fresenius Kabi—was approved in August and launched in the United States last month.

All three injectable arsenic trioxide products (1 mg/mL) are generic versions of Teva’s Trisenox.

Since 2000, Trisenox has been FDA-approved to induce remission and as consolidation therapy for patients with APL who are refractory to, or have relapsed after, retinoid and anthracycline chemotherapy, and whose APL is characterized by presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

In January, the FDA approved Trisenox for use in combination with tretinoin to treat adults with newly diagnosed, low-risk APL with the t(15;17) translocation or PML/RAR-alpha gene expression.

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.

The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.

The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.

At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.

“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.

This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.

[email protected]

SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.

The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.

The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.

At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.

“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.

This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.

[email protected]

SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.

The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.

The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.

At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.

“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.

This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.

[email protected]

SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.

The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.

©GunarsB/Thinkstock

This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.

“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.

Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.

Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.

“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.

Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.

For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.

“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.

They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.

SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.

The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.

©GunarsB/Thinkstock

This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.

“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.

Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.

Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.

“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.

Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.

For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.

“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.

They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.

SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.

The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.

©GunarsB/Thinkstock

This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.

“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.

Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.

Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.

“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.

Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.

For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.

“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.

They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.

SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.