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Combination of Venetoclax, Lower Intensity CPX-351 Shows Positive Results in Early-Stage AML Study

January 30, 2025

February 2025

Anna Azvolinsky, PhD

Anna Azvolinsky is a science and health journalist based in New York City.

A new clinical trial combining lower-intensity CPX-351 therapy plus venetoclax as induction therapy has shown positive initial results among patients with acute myeloid leukemia (AML) who are deemed unfit for intensive chemotherapy. The phase I trial has identified a recommended phase II dose and shown that the therapy is safe and has an acceptable side effect profile. A complete remission with incomplete hematologic recovery (CRi) was achieved by 17 of 35 patients (49%) after one cycle of therapy. Of these 17 patients, 14 had no detectable measurable residual disease (MRD). The results were published in Blood Advances.1

“The lower-intensity CPX-351 plus venetoclax regimen only requires two days of intravenous infusion, compared with seven days of azacitidine plus venetoclax. [The trial] regimen is resource intensive and more convenient for patients and their caregivers,” said study author Geoffrey L. Uy, MD, professor in the Division of Oncology at Washington University School of Medicine in St. Louis.

“In contrast to patients treated with azacitidine and venetoclax in the VIALE-A study, in which there was a lower rate of CR and a much higher proportion of patients achieving CRi, nearly all observed responses in this study were true CRs,” Dr. Uy said. “Notably, most patients, 82%, who achieved a CR or CRi in this study also achieved MRD negativity, which was often reached after only one treatment cycle.”

CPX-351 is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio optimized to produce greater drug exposure to the bone marrow compared to conventional cytarabine and daunorubicin. The formulation was approved by the U.S. Food and Drug Administration for the treatment of newly diagnosed therapy-related AML or AML with myelodysplasia-related changes in adults and pediatric patients 1 year and older.

Given that venetoclax exhibits potent clinical activity in multiple hematologic malignancies when combined with various classes of agents, including cytotoxic chemotherapy, immunotherapy, and molecularly targeted agents, the researchers sought to combine it with lower doses of CPX-351 for older adults with AML. Based on the results of the VIALE-A trial,2,3 the combination of a hypomethylating agent (HMA) and a BCL2 inhibitor such as venetoclax is the preferred treatment regimen for patients with AML who are older and are not considered eligible for intensive chemotherapy. However, the treatment is not curative, and myelosuppression and cytopenias are common among patients receiving this regimen. Additionally, for those patients with TP53-mutated disease, this combination regimen provides no survival benefit.

Overall, 35 patients were enrolled in the study and received dose level 1 (n=4), dose level 2 (n=7), or dose level 1b (n=24). At each dose level, venetoclax was administered at a 400 mg oral dose on days 2 through 21 of each cycle, except for cycle one when the venetoclax dose was ramped up. The recommended phase II dose of CPX-351 was 30 units/m2, administered on days 1 and 3 of each cycle. “This dose is approximately 30% of the standard dose of CPX-351 administered for intensively treated AML,” Dr. Uy said.

The most frequently reported adverse events (AEs) among the 24 patients in the expansion cohort were nausea (n=13), thrombocytopenia (n=11), febrile neutropenia (n=8), anemia (n=8), and hypokalemia (n=8). Among patients who achieved a CR or CRi, three of 17 discontinued the therapy due to an AE.

Among the 26 patients on the trial with TP53 wild-type disease, 15 (57.7%) achieved a CR or CRi, with 14 (53.8%) achieving a CR. Among the eight patients with a mutated TP53 gene, one patient achieved a CR, and one patient had a partial response.

Among the entire study population, the overall survival (OS) rate estimate at one year was 40%, and the median OS was 9.1 months. Among patients who achieved CR or CRi, the estimated duration of remission rate at one year was 71%, and the median time in remission was not yet reached.

According to the study authors, a randomized trial of venetoclax plus CPX-351 compared with venetoclax plus HMA is needed to directly compare outcomes of the two regimens.

According to Dr. Uy, several studies are ongoing, investigating the combination of CPX-351 plus venetoclax in younger adults with AML, including studies for intermediate- and high-risk AML that are being conducted in myeloMATCH, the new National Cancer Institute precision medicine initiative in AML.

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Uy GL, Pullarkat, V, Baratam P. et al. Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy. Blood Adv. 2024;8(24):6248-6256.
  2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.
  3. Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99(4):615-624.

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