The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age > 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481–5. https://doi.org/10.1182/blood-2005-09-3724. e-pub ahead of print 2006/02/04.
Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute myeloid leukemia: An analysis of SEER data over 3 decades. Cancer. 2013;119:2720–7. https://doi.org/10.1002/cncr.28129. e-pub ahead of print 2013/05/02.
Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235–48. https://doi.org/10.1056/NEJMoa0901409. e-pub ahead of print 2009/09/25.
Vasu S, Kohlschmidt J, Mrozek K, Eisfeld AK, Nicolet D, Sterling LJ, et al. Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission. Blood Adv. 2018;2:1645–50. https://doi.org/10.1182/bloodadvances.2017015222. e-pub ahead of print 2018/07/12.
Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Disco. 2014;4:362–75. https://doi.org/10.1158/2159-8290.CD-13-0609. e-pub ahead of print 2013/12/19.
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41. https://doi.org/10.1016/j.stem.2012.12.013. e-pub ahead of print 2013/01/22.
Pollyea DA, Stevens BM, Jones CL, Winters A, Pei SS, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24:1859–+. https://doi.org/10.1038/s41591-018-0233-1.
Jones CL, Stevens BM, D’Alessandro A, Reisz JA, Culp-Hill R, Nemkov T, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2018;34:724–40. https://doi.org/10.1016/j.ccell.2018.10.005. e-pub ahead of print 2018/11/14.
Winters AC, Gutman JA, Purev E, Nakic M, Tobin J, Chase S, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3:2911–19. 0.1182/bloodadvances.2019000243.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383:617–29. https://doi.org/10.1056/NEJMoa2012971. e-pub ahead of print 2020/08/14.
Pollyea DA, Pratz K, Letai A, Jonas BA, Wei AH, Pullarkat V, 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. 2020. e-pub ahead of print 2020/10/30; https://doi.org/10.1002/ajh.26039.
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17. https://doi.org/10.1182/blood-2018-08-868752. e-pub ahead of print 2018/10/27.
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19:216–28. https://doi.org/10.1016/S1470-2045(18)30010-X. e-pub ahead of print 2018/01/18.
Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, et al. Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia. Cancer Disco. 2020;10:536–51. https://doi.org/10.1158/2159-8290.CD-19-0710. e-pub ahead of print 2020/01/25.
Aldoss I, Zhang J, Mei M, Al Malki MM, Arslan S, Ngo D, et al. Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia. Am J Hematol. 2020. e-pub ahead of print 2020/07/07; https://doi.org/10.1002/ajh.25929.
Arslan S, Zhang J, Dhakal P, Moran J, Naidoo N, Lombardi J, et al. Outcomes of therapy with venetoclax combined with a hypomethylating agent in favorable-risk acute myeloid leukemia. Am J Hematol. 2020. e-pub ahead of print 2020/11/24; https://doi.org/10.1002/ajh.26057.
DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135:791–803. https://doi.org/10.1182/blood.2019003988. e-pub ahead of print 2020/01/15.
Tiong IS, Dillon R, Ivey A, Teh TC, Nguyen P, Cummings N, et al. Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low-intensity chemotherapy in acute myeloid leukaemia. Br J Haematol. 2020. e-pub ahead of print 2020/05/28; https://doi.org/10.1111/bjh.16722.
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. https://doi.org/10.1182/blood-2016-08-733196. e-pub ahead of print 2016/11/30.
Sievers EL, Lange BJ, Buckley JD, Smith FO, Wells DA, DaigneaultCreech CA, et al. Prediction of relapse of pediatric acute myeloid leukemia by use of multidimensional flow cytometry. Jnci-J Natl Cancer I. 1996;88:1483–8. https://doi.org/10.1093/jnci/88.20.1483.
Loken MRB, L E, Wells DA. Monitoring AML Response Using “Difference from Normal” Flow Cytometry. In: Druley TE, (ed). Minimal Residual Disease Testing, Current Innovations and Future Directions. Cham, Switzerland: Springer International Publishing AG; 2019. pp. 101–37.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8. e-pub ahead of print 1995/06/01.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transpl. 2005;11:945–56. https://doi.org/10.1016/j.bbmt.2005.09.004. e-pub ahead of print 2005/12/13.
Sorror ML, Storer BE, Fathi AT, Gerds AT, Medeiros BC, Shami P, et al. Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol. 2017;3:1675–82. https://doi.org/10.1001/jamaoncol.2017.2714. e-pub ahead of print 2017/09/08.
Sorror ML, Storer BE, Nyland J, Estey EH. Revised acute myeloid leukemia composite model using the 2017 European leukemianet risk classification. JAMA Oncol. 2019;5:1062–4. https://doi.org/10.1001/jamaoncol.2019.0902. e-pub ahead of print 2019/05/17.
Sorror ML, Logan BR, Zhu X, Rizzo JD, Cooke KR, McCarthy PL, et al. Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a center for international blood and marrow transplant research study. Biol Blood Marrow Transpl. 2015;21:1479–87. https://doi.org/10.1016/j.bbmt.2015.04.004. e-pub ahead of print 2015/04/12.
Gutman JA, Ross K, Smith C, Myint H, Lee CK, Salit R, et al. Chronic graft versus host disease burden and late transplant complications are lower following adult double cord blood versus matched unrelated donor peripheral blood transplantation. Bone Marrow Transpl. 2016;51:1588–93. https://doi.org/10.1038/bmt.2016.186. e-pub ahead of print 2016/07/12.
Sharma P, Purev E, Haverkos B, Pollyea DA, Cherry E, Kamdar M, et al. Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant. Blood Adv. 2020;4:2227–35. https://doi.org/10.1182/bloodadvances.2020001554. e-pub ahead of print 2020/05/23.
Kim HT. Cumulative incidence in competing risks data and competing risks regression analysis. Clin Cancer Res. 2007;13:559–65. https://doi.org/10.1158/1078-0432.CCR-06-1210. e-pub ahead of print 2007/01/27.
Sandhu KS, Dadwal S, Yang D, Mei M, Palmer J, Salhotra A, et al. Outcome of allogeneic hematopoietic cell transplantation after venetoclax and hypomethylating agent therapy for acute myelogenous leukemia. Biol Blood Marrow Transpl. 2020;26:e322–7. https://doi.org/10.1016/j.bbmt.2020.08.027. e-pub ahead of print 2020/09/01.
Zappasodi P, Brociner M, Merati G, Nizzoli ME, Roncoroni E, Boveri E, et al. Venetoclax and azacytidine combination is an effective bridge to transplant strategy in relapsed/refractory acute myeloid leukemia patients. Ann. Hematol. 2020. e-pub ahead of print 2020/11/12; https://doi.org/10.1007/s00277-020-04333-7.
Pratz K, CD D, ML A, AG L, M T, VA P, et al. Outcomes after stem cell transplant in older patients with acute myeloid leukemia treated with venetoclax based therapies. Blood. 2019;134:264.
Salvatore D, Labopin M, Ruggeri A, Battipaglia G, Ghavamzadeh A, Ciceri F, et al. Outcomes of hematopoietic stem cell transplantation from unmanipulated haploidentical versus matched sibling donor in patients with acute myeloid leukemia in first complete remission with intermediate or high-risk cytogenetics: a study from the acute leukemia working party of the European society for blood and marrow transplantation. Haematologica. 2018;103:1317–28. https://doi.org/10.3324/haematol.2018.189258. e-pub ahead of print 2018/05/12.
Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375:944–53. https://doi.org/10.1056/NEJMoa1602074. e-pub ahead of print 2016/09/08.
Eapen M, Brazauskas R, Hemmer M, Perez WS, Steinert P, Horowitz MM, et al. Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity. Blood Adv. 2018;2:2095–103. https://doi.org/10.1182/bloodadvances.2018021980. e-pub ahead of print 2018/08/24.
Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35:1154–61. https://doi.org/10.1200/JCO.2016.70.7091. e-pub ahead of print 2017/04/06.
Wong TN, Miller CA, Klco JM, Petti A, Demeter R, Helton NM, et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood. 2016;127:893–7. https://doi.org/10.1182/blood-2015-10-677021. e-pub ahead of print 2015/12/04.
Lamba JK, Pounds S, Cao X, Crews KR, Cogle CR, Bhise N, et al. Clinical significance of in vivo cytarabine-induced gene expression signature in AML. Leuk Lymphoma. 2016;57:909–20. https://doi.org/10.3109/10428194.2015.1086918. e-pub ahead of print 2015/09/15.
Ho TC, LaMere M, Stevens BM, Ashton JM, Myers JR, O’Dwyer KM, et al. Evolution of acute myelogenous leukemia stem cell properties after treatment and progression. Blood. 2016;128:1671–8. https://doi.org/10.1182/blood-2016-02-695312. e-pub ahead of print 2016/07/17.
Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38:1273–83. https://doi.org/10.1200/JCO.19.03011. e-pub ahead of print 2019/12/21.
The authors thank all of the patients and the outstanding team at the Blood Disorders Center at the University of Colorado.
D.P. has received research funding and served as a consultant to Abbvie.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Pollyea, D.A., Winters, A., McMahon, C. et al. Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60. Bone Marrow Transplant (2021). https://doi.org/10.1038/s41409-021-01476-7