All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia

Author(s): Gail J. Roboz, M.D.¹; Amer M. Zeidan, M.B., B.S., M.H.S.²; Gabriel N. Mannis, M.D.³; Pau Montesinos, M.D., Ph.D.⁴; Montserrat Arnan, M.D., Ph.D.⁵; Michael R. Savona, M.D.⁶; Olatoyosi Odenike, M.D.⁷; James K. McCloskey, M.D.⁸; Harshad V. Amin, M.D.⁹; Amir T. Fathi, M.D.¹⁰; Teresa Bernal del Castillo, M.D., Ph.D.¹¹; Gabriela Rodríguez-Macías, M.D., Ph.D.¹²; Jane L. Liesveld, M.D.¹³; Annie P. Im, M.D.¹⁴; Jan Cerny, M.D., Ph.D.¹⁵; Teresa C. Gentile, M.D., Ph.D.¹⁶; Aram Oganesian, Ph.D.¹⁷; Danna Chan, Pharm.D.¹⁷; Yubing Wan, Ph.D.¹⁷; Margit Dijkstra, M.D.¹⁷; Harold N. Keer, M.D., Ph.D.¹⁷; Elizabeth A. Griffiths, M.D.¹⁸; Courtney D. DiNardo, M.D.¹⁹;

Source: NEJMoa2510223

Dr. Maen Hussein's Thoughts

47% of the patients in this study had complete response (CR) on all oral regimen of decitabine–cedazuridine 5 days every 28 days plus venetoclax 400mg daily. Median overall survival (OS) was 15.5 months. This was in patients who are not candidate for induction therapy. Trial had 189 patients.

BACKGROUND

For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine–cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy.

METHODS

In this phase 1–2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine–cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine–cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1–2a) and complete response (phase 2a–b).

RESULTS

A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug–drug interactions were observed between decitabine–cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% 30 days and 10% 60 days.

CONCLUSIONS

Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine–cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.)

Author Affiliations

¹Weill Cornell Medicine, New York Presbyterian Hospital, New York; ²Yale University and Yale Comprehensive Cancer Center, New Haven, CT; ³Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA; ⁴Hospital Universitari i Politecnic La Fe, Valencia, Spain; ⁵Institut Català d’Oncologia, L’Hospitalet de Llobregat, Institut d’Investigació Biomèdica de Bellvitge, Universitat de Barcelona, Barcelona; ⁶Vanderbilt–Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville; ⁷University of Chicago Medicine and Comprehensive Cancer Center, Chicago; ⁸John Theurer Cancer Center, Hackensack Medical Center, Hackensack, NJ; ⁹Boca Raton Clinical Research, Boca Raton, FL; ¹⁰Massachusetts General Hospital Cancer Center–Harvard Medical School, Boston; ¹¹Hospital Universitario Central de Asturias–Instituto Universitario del Principado de Asturias–Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain; ¹²Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid; ¹³James P. Wilmot Cancer Institute, University of Rochester, Rochester, NY; ¹⁴University of Pittsburgh–UPMC Hillman Cancer Center, Pittsburgh; ¹⁵University of Massachusetts Chan Medical School–UMass Memorial Healthcare, Worcester; ¹⁶State University of New York Upstate Medical University, Syracuse; ¹⁷Taiho Oncology, Pleasanton, CA; ¹⁸Roswell Park Comprehensive Cancer Center, Buffalo, NY; ¹⁹University of Texas M.D. Anderson Cancer Center, Houston

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