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NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens. 
NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.
NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.