Jessica K. Altman, MD, discussed the potential of agents poised to transform the landscape of acute myeloid leukemia.
Jessica K. Altman, MD
Several novel agents that have been moving through the pipeline in 2016 are poised to make a significant impact in the treatment of patients with acute myeloid leukemia (AML).
These include venetoclax (Venclexta), which received a breakthrough therapy designation in January for use in combination with hypomethylating agents in treatment-naïve patients, and midostaurin, which received a breakthrough therapy designation for newly diagnosed FLT3-mutated AML in February.
Jessica K. Altman, MD, an associate professor of Medicine (Hematology/Oncology), Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, discussed the potential of these and other agents in a lecture at the 2016 NCCN Annual Congress on Hematologic Malignancies, held September 30 to October 1 in New York City.
“There are a number of novel agents—those that depend on a specific mutation like IDH and FLT3 inhibitors, and those that may not require a specific mutation such as BCL-2 inhibitors, CD33 [antibodies], and different formulations of anthracycline- and cytarabine-based chemotherapy,” said Altman in an interview with OncLive. “There are a number of other pathways that are being studied that are earlier in investigation and of great interest.”FLT3 is overexpressed in the majority of AML cases, with activating mutations present in 25% to 40% of AML. The mutation can often lead to a worse prognosis, resulting in increased relapse rates and lower overall survival (OS) rates. It is also associated with leukocytosis and a high percentage of bone marrow blasts in de‐novo AML.
One of the most promising agents targeting FLT3 in AML is midostaurin.
“We are at a point now where the presence of a FLT3 mutation not only impacts prognosis or trial candidacy, but is now impacting our upfront therapy,” said Altman.
Midostaurin’s breakthrough designation was based on the phase III RATIFY trial, where adding it to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone. After censoring for patients who received stem cell transplants, the OS benefit with midostaurin remained steady at 25%.1
Midostaurin is available through an expanded access program, but at this time not all patients have access. An FDA approval would bring the agent to a much broader audience.
“Midostaurin with 7+3 [daunorubicin] is now considered a standard of care by many people” she said. “I think there is a lot of hope that midostaurin will be FDA approved. Hopefully, this will maintain interest in development of inhibitors to FLT3 and other mutations.”“The data with ABT-199 [Venetoclax] combined with HMA or LDAC in older adults with newly diagnosed AML who were not considered candidates for standard intensive chemotherapy are very encouraging,” said Altman. “However, randomized data is desired before we can assess the true impact.”
The agent has demonstrated significant benefit in a phase Ib/II trial, results of which were presented at the 2015 ASH Annual Meeting. The study explored venetoclax in combination with the hypomethylating agents decitabine or azacitidine in 22 treatment-naïve patients with AML.2
Doses varied among patients in the trial. Among patients receiving decitabine plus venetoclax, 6 patients received venetoclax at 400 mg and 6 patients received the drug at 800 mg. In the azacitidine plus venetoclax arm, 4 patients received the 400 mg of venetoclax and 6 patients received 800-mg venetoclax doses.
Of the 19 patients evaluable for response, the overall response rate (ORR) was 75% (n = 9) among patients who received venetoclax plus decitabine. At the 400-mg venetoclax dose, 2 patients achieved complete remission (CR) and 1 patient had a CR with incomplete marrow recovery (CRi). There were 5 cases of CRi and 1 partial response with the 800-mg venetoclax dose.
In the venetoclax plus azacitidine arm, the ORR was 70% (n =7). There was 1 CR and 2 cases of CRi with 400 mg of venetoclax. At the higher dose, there were 2 CRs, 1 CRi, and 1 PR.If the FDA approves it, CPX-351 could be practice changing and may have potential across various settings of AML, said Altman.
“CPX-351, if available, may be adopted for secondary AML,” she said.
A randomized, controlled phase III trial presented at the 2016 ASCO Annual Meeting3 investigated the therapy compared with cytarabine and 7+3 in older patients with high-risk, secondary AML.
The trial included 309 patients across 39 sites throughout both the United States and Canada who were between the ages of 60 and 75. Patients enrolled in the study were split into age-based cohorts of ages 60 to 69 or 70 to 75.
The study showed a median OS of 9.56 months (95% CI, 6.60-11.86) with CPX-351 versus 5.95 months (95% CI, 4.99-7.75) with 7+3 (HR, 0.69; P = .005).
The median event-free survival was 2.53 months (95% CI, 2.07-4.99) with CPX-351 versus 1.31 months (1.08-1.64) with 7+3 (HR, 0.74; P = .021).
Induction response rates, which include CR plus Cri, were also higher with CPX-351 at 47.7% versus 33.3% with 7+3 (P = .016).
Grade 3/4 adverse events were equal in both arms (92% vs 91%) and were similar in frequency and severity in both arms. Similar numbers of patients were transplanted in both arms.
CPX‐351, a liposomal formulation of cytarabine and daunorubicin, also has significant promise for the disease, as it received a breakthrough designation in May 2016 as a treatment for patients with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).