Are We Making Progress in Acute Myeloid Leukemia?

November 2016, Vol 7, No 10

New York, NY—Acute myeloid leukemia (AML) was a hot topic at the 2016 National Comprehensive Cancer Network (NCCN) Congress on Hematologic Malignancies. Jessica K. Altman, MD, Associate Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, assured attendees that time was not standing still for patients with AML.

“I believe we are making progress in AML. We have a better understanding of cytogenetics and molecular abnormalities. We’ve made strides in improving allogeneic stem-cell transplantation by understanding the disease characteristics that warrant transplantation. We’ve also refined standard therapies, and novel agents for the efficacious treatment of AML are starting to emerge,” said Dr Altman.

Dr Altman focused on the 2 distinct types of emerging therapies for AML. The first group is not conditional on mutational complexities, and the second group of therapeutics is specifically designed for AML cytogenetics and molecular interactions.

Emerging Therapies Independent of Mutations in AML

The first strategy Dr Altman commented on was anthracycline dose intensification. In 3 of 4 studies, the dose of daunorubicin was increased from the standard 45 mg/m2 to 90 mg/m2, which resulted in improved complete response (CR) and overall survival (OS) rates.

CPX-351 is a liposomal formulation of cytarabine and daunorubicin being studied for AML. A study presented at the 2016 American Society of Clinical Oncology meeting randomized 309 patients with high-risk AML to treatment with CPX-351 or to the standard 7+3 induction therapy with cytarabine and daunorubicin.

The OS was 9.56 months in the CPX-351 arm compared with 5.95 months in the 7+3 induction therapy arm. The CR and CR with incomplete hematologic recovery (CRi) rates were 47.7% with CPX-351 versus 33.3% with the 7+3 induction therapy.

Another agent in development is SGN-CD33A, an anti-CD33–directed antibody. In a phase 1 study presented, 24 patients received SGN-CD33A and hypomethylating agents. Overall, 23 patients had treatment-naïve AML, and 42% had adverse cytogenetics. Remissions were typically achieved after 2 cycles of treatment, and the combined CR plus CRi rate was 65%.

Another emerging treatment for AML is venetoclax (Venclexta) that is not dependent on mutational complexities.

“Venetoclax is a small-molecule BCL-2 inhibitor, and it was combined with low-dose cytarabine in a phase 1b/2 trial that included 18 patients with treatment-naive AML who were 65 years of age or older. The patients had a combined CR and CRi rate of 54%. The 1-year OS was 70.5% in patients who did not have myeloproliferative neoplasms and 57.6% in patients who had myeloproliferative neoplasms,” she told attendees.

Emerging Therapies Targeting Mutations in AML

The FLT3 gene is one of the most common genetic mutations in AML, and one of the most important negative prognostic factors for the treatment of patients with AML. A very effective FLT3 inhibitor is the “holy grail” of AML therapies, but developing such inhibitors has been problematic. However, FLT3 inhibitors are evolving, Dr Altman said.

She discussed the FLT3 inhibitor midostaurin. A phase 3 clinical trial examined 717 adults with AML and mutation FLT3. Patients were randomized to midostaurin plus standard induction therapy or to placebo plus standard induction therapy. The midostaurin group also received maintenance therapy with midostaurin for 1 year. Patients who received midostaurin, standard chemotherapy, and 1-year maintenance therapy had a median OS of 74.7 months versus 26 months with standard chemotherapy.

Another study included 80 patients with AML plus FLT3 mutations who underwent hematopoietic-cell transplantation and achieved CR. A total of 26 patients were then given the FLT3 inhibitor sorafenib (Nexavar), and 54 patients who did not receive sorafenib acted as the control group. Patients who received sorafenib had a 2-year OS of 83% versus 58% in the control group. The relapse incidence was 9.5% in the sorafenib group versus 41% in the control group.

Gilteritinib is another FLT3 inhibitor being investigated for AML. A phase 1/2 clinical trial that Dr Altman conducted included 169 patients with refractory or relapsed AML with FLT3 mutations who received gilteritinib. Patients had an overall response rate of 53%, and the median OS was approximately 31 weeks.

“In the 1970s, we had allogeneic transplant and 7+3 induction therapy. In the 1980s, we incorporated cytarabine into our armamentarium. Now we have a variety of emerging therapies that include FLT3 inhibitors. So we are, indeed, making progress in AML,” said Dr Altman.

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