Venetoclax-based lower-intensity regimens for acute myeloid leukemia
Clinical pearls for a new standard of care
Acute myeloid leukemia (AML) is a heterogeneous disease with variable genetic features and clinical outcomes. The main curative option for AML remains intensive chemotherapy and allogeneic hematopoietic stem cell transplant (HSCT) in selected patients. However, with a median age at diagnosis of 67 years old and frequent comorbidities, a large proportion of patients diagnosed with AML are not eligible for intensive chemotherapy. Until recently, the only treatments available for patients with AML ineligible for intensive chemotherapy were single-agent hypomethylating agents (HMAs) such as azacitidine and decitabine, or low-dose cytarabine (LDAC). In older patients with AML, these treatments have been reported to improve outcomes over best supportive care (BSC) alone. However, in clinical studies the expected median overall survival (OS) remained less than 12 months. Fortunately, our increasing knowledge of AML biology has accelerated the development of novel targeted drugs for AML. Among these, the anti-apoptotic protein B-cell lymphoma 2 (BCL2) inhibitor venetoclax has completely changed the therapeutic landscape of AML, especially for patients who are ineligible for intensive chemotherapy. Venetoclax is approved by Health Canada for use in combination with azacitidine or LDAC for the treatment of newly diagnosed untreated AML in patients who are 75 years or older or have comorbidities precluding the use of intensive chemotherapy. This approval is based on the two pivotal randomized, Phase 3 trials VIALE-A (azacitidine plus venetoclax) and VIALE-C (cytarabine plus venetoclax). Although seemingly easier to administer than intensive chemotherapy, venetoclax-based regimens are not as “non-intensive” as they are sometimes considered to be. They require the implementation of specific precautionary measures and monitoring to avoid excessive toxicity and optimize patients’ outcomes. We will review here practical points to safely administer venetoclax-based regimens to patients with AML who are ineligible for intensive chemotherapy.
Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-77.
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with> 30% blasts. Blood. 2015 Jul 16;126(3):291-9.
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 7;30(21):2670.
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114-24.
Richard-Carpentier G, DiNardo CD. Single-agent and combination biologics in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):548-56.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020 Aug 13;383(7):617-29.
Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137-45.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK, National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010 Jul 22;116(3):354-65.
Granfeldt Østgård LS, Medeiros BC, Sengeløv H, Nørgaard M, Andersen MK, Dufva IH, Friis LS, Kjeldsen E, Marcher CW, Preiss B, Severinsen M. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study. J Clin Oncol. 2015 Nov 1;33(31):3641-9.
Montalban-Bravo G, Kanagal-Shamanna R, Class CA, Sasaki K, Ravandi F, Cortes JE, Daver N, Takahashi K, Short NJ, DiNardo CD, Jabbour E. Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy. Am J Hematol. 2020 Jun;95(6):612-22.
Ball BJ, Famulare CA, Stein EM, Tallman MS, Derkach A, Roshal M, Gill SI, Manning BM, Koprivnikar J, McCloskey J, Testi R. Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure. Blood Adv. 2020 Jul 14;4(13):2866-70.
Nanni J, Papayannidis C, Cristiano G, Marconi G, Sartor C, Parisi S, Saed R, Zannoni L, Ottaviani E, Bandini L, Testoni N. An Outpatient Management for First Cycle of Venetoclax and Hypomethylating Agents Results in Reduced Infection Rate and Hospitalizations in Acute Myeloid Leukemia Patients. Blood. 2021 Nov 23;138:2340.
Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston KV, Strasfeld L. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct 20;36(30):3043-54.
Aldoss I, Dadwal S, Zhang J, Tegtmeier B, Mei M, Arslan S, Al Malki MM, Salhotra A, Ali H, Aribi A, Sandhu K. Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents. Blood Adv. 2019 Dec 10;3(23):4043-9.
Patterson TF, Thompson III GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clinical Infect Dis. 2016 Aug 15;63(4):e1-60.
Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH. Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther. 2017 Feb 1;39(2):359-67.