Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step

AUTOIMMUNE THROMBOCYTOPENIA

MA Granatkin1,2, EA Nikitin1,2, ES Mikhailov1, VA Doronin1, SV Minenko1, MM Okuneva1,2, NV Degtyareva1, ME Pochtar1,2, SA Lugovskaya1,2, YuN Kobzev1, OYu Vinogradova1, VV Ptushkin1,2

1 SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993

For correspondence: Prof. Evgenii Aleksandrovich Nikitin, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)572-06-44; e-mail: eugene_nikitin@mail.ru

For citation: Granatkin MA, Nikitin EA, Mikhailov ES, et al. Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step. Clinical oncohematology. 2022;15(3):282–8. (In Russ).

DOI: 10.21320/2500-2139-2022-15-3-282-288

ABSTRACT

Background. The treatment of elderly patients with acute myeloid leukemias (AML) is one of the most formidable challenges in oncohematology. Hypomethylating drugs combined with venetoclax show relatively high efficacy and lower toxicity in elderly AML patients.

Aim. To retrospectively analyze the efficacy and tolerability of the combined azacitidine/venetoclax therapy in AML primary patients of older age as well as to determine a spectrum of issues related to the implementation of this regimen in real-world clinical practice.

Materials & Methods. The retrospective analysis enrolled a cohort of patients followed-up at the Botkin City Clinical Hospital (n = 35). The median age was 73 years (range 60–90 years), 57 % of patients were over 70 years of age. The median follow-up duration was 5.2 months (range 1.6–42.6 months). By the time of final analysis 15 patients were still receiving the therapy. The median of overall survival was 11.1 months (95% confidence interval [95% CI] 8.1–14.1 months). The causes of death in 20 patients were AML progression (n = 3), non-COVID-19 infectious complications (n = 3), and COVID-19 (n = 10). In 4 patients the cause of death remained unidentified.

Results. Complete remission (CR) was documented in 17 (48.5 %) patients; CR with incomplete hematologic recovery was identified in 9 (26 %) patients. The median time before achieving remission was 67 days (range 27–120 days). In 96 % of patients CR was achieved after 3 azacitidine/venetoclax cycles. The mean CR duration was 9.2 months (95% CI 5.7–12.6 months); the median time before loss of response was 19 months. Relapses were diagnosed in 5 patients. Neutropenia > grade 3 was identified in patients who achieved remission on subsequent therapy cycles in 100 % of cases (n = 26), anemia > grade 2 was reported in 9 (34 %) patients, and thrombocytopenia > grade 3 was detected in 13 (50 %) patients. Despite frequent neutropenia, patients with remission did not show any severe infectious complications.

Conclusion. The combined azacitidine/venetoclax therapy in elderly patients yields remission in more than 70 % of cases and is not marked by any severe infectious complications, despite developing neutropenia. Due to its ease of administration and low toxicity, this regimen can be performed in outpatient units.

Keywords: acute myeloid leukemias, efficacy of therapy, venetoclax, hypomethylating drugs.

Received: January 31, 2022

Accepted: May 5, 2022

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Статистика Plumx английский

REFERENCES

  1. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5. doi: 10.1182/blood-2005-09-3724.
  2. Creutzig U, Zimmermann M, Reinhardt D, et al. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups. Cancer. 2016;122(24):3821–30. doi: 10.1002/cncr.30220.
  3. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422–9. doi: 10.1182/blood-2010-03-276485.
  4. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood. 2015;126(3):291–9. doi: 10.1182/blood-2015-01-621664.
  5. Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375(21):2023–36. doi: 10.1056/NEJMoa1605949.
  6. Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28(4):556–61. doi: 10.1200/jco.2009.23.9178.
  7. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53–61. doi: 10.1182/blood-2015-08-604520.
  8. Guerra VA, DiNardo C, Konopleva M. Venetoclax-based therapies for acute myeloid leukemia. Best Pract Res Clin Haematol. 2019;32(2):145–53. doi: 10.1016/j.beha.2019.05.008.
  9. Серегин Г.З., Лифшиц А.В., Валиев Т.Т. Таргетные препараты в лечении острых миелоидных лейкозов у детей. Российский журнал детской гематологии и онкологии. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85.
    [Seregin GZ, Lifshits AV, Valiev TT. Targeted drugs in the treatment of acute myeloid leukemia in children. Russian Journal of Pediatric Hematology and Oncology. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85. (In Russ)]
  10. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617–29. doi: 10.1056/NEJMoa2012971.
  11. Pollyea DA, Pratz K, Letai A, et al. Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study. Am J Hematol. 2021;96(2):208–17. doi: 10.1002/ajh.26039.
  12. Pollyea DA, Bixby D, Perl A, et al. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2021;19(1):16–27. doi: 10.6004/jnccn.2021.0002.
  13. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41. doi: 10.1016/j.stem.2012.12.013.
  14. Pan R, Ruvolo VR, Wei J, et al. Inhibition of Mcl-1 with the pan–Bcl-2 family inhibitor (–)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015;126(3):363–72. doi: 10.1182/blood-2014-10-604975.
  15. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75. doi: 10.1158/2159-8290.Cd-13-0609.
  16. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016;6(10):1106–17. doi: 10.1158/2159-8290.Cd-16-0313.
  17. Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9. doi: 10.3109/10428194.2014.910657.
  18. Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70. doi: 10.1007/s00277-012-1537-8.
  19. Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58(9):1–17. doi: 10.1080/10428194.2017.1283032.
  20. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182/blood-2018-08-868752.
  21. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019;33(12):2795–804. doi: 10.1038/s41375-019-0612-8.