The recently approved BCL2 inhibitor venetoclax (VEN) has achieved promising outcomes in new and relapsed/refractory (R/R) acute myeloid leukemia (AML). Although its use is not well established in R/R AML with extramedullary disease (EMD), some reports have shown promising outcomes. We retrospectively analyzed 11 patients of R/R AML with EMD (with (n = 4) or without (n = 7) concurrent marrow involvement), who were treated with VEN plus decitabine (n = 9) or low-dose cytarabine (n = 2) between May 2020 and October 2020 in Seoul St. Mary’s Hospital. The median number of prior treatment lines was 3 (1–6), and most (n = 9, 81.8%) had multiple sites of EMD. Nine patients (81.8%) received concurrent therapy for extramedullary (EM) involvement sites with radiotherapy (RT) (n = 4), surgery (n = 1), and both of them (n = 4). Among 11 patients, 4 patients (36.4%) had either marrow or EM responses to VEN combination; EM response was seen in 1 patient (9.1%, partial response) who had received concurrent RT (25 Gy, 10 fx) during the 1st cycle of VEN combination, and other 3 patients showed marrow response without EM response. After median follow-up of 27.0 months, the median overall survival was estimated to be 5.4 months. To conclude, VEN combination regimens have shown only modest efficacy in EM recurrence of AML with little impact on eliciting EM response.

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.
Brunstein CG, Pasquini MC, Kim S, Fei M, Adekola K, Ahmed I, et al. Effect of conditioning regimen dose reduction in obese patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019 Mar;25(3):480–7.
Brandwein JM, Saini L, Geddes MN, Yusuf D, Liu F, Schwann K, et al. Outcomes of patients with relapsed or refractory acute myeloid leukemia: a population-based real-world study. Am J Blood Res. 2020;10(4):124–33.
Maiti A, Rausch CR, Cortes JE, Pemmaraju N, Daver NG, Ravandi F, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 2021 Mar 1;106(3):894–8.
Ganzel C, Manola J, Douer D, Rowe JM, Fernandez HF, Paietta EM, et al. Extramedullary disease in adult acute myeloid leukemia is common but lacks independent significance: analysis of patients in ECOG-ACRIN cancer research group trials, 1980–2008. J Clin Oncol. 2016;34(29):3544–53.
Byrd JC, Weiss RB, Arthur DC, Lawrence D, Baer MR, Davey F, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol. 1997;15(2):466–75.
Chang H, Brandwein J, Yi QL, Chun K, Patterson B, Brien B. Extramedullary infiltrates of AML are associated with CD56 expression, 11q23 abnormalities and inferior clinical outcome. Leuk Res. 2004;28(10):1007–11.
Kobayashi R, Tawa A, Hanada R, Horibe K, Tsuchida M, Tsukimoto I, et al. Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia. Pediatr Blood Cancer. 2007;48(4):393–8.
Tsimberidou AM, Kantarjian HM, Wen S, Keating MJ, O’Brien S, Brandt M, et al. Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia. Cancer. 2008;113(6):1370–8.
Koc Y, Miller KB, Schenkein DP, Daoust P, Sprague K, Berkman E. Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation. Cancer. 1999;85(3):608–15.
Lee KH, Lee JH, Choi SJ, Lee JH, Kim S, Seol M, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant. 2003;32(8):835–42.
Harris AC, Kitko CL, Couriel DR, Braun TM, Choi SW, Magenau J, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica. 2013 Feb;98(2):179–84.
Sakellari I, Gavriilaki E, Batsis I, Mallouri D, Gavriilaki M, Apostolou C, et al. Isolated extramedullary relapse as a poor predictor of survival after allogeneic hematopoietic cell transplantation for acute leukemia. Biol Blood Marrow Transplant. 2019 Sep;25(9):1756–60.
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(1):7–17.
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(7):617–29.
Wei AH, Strickland SAJr, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277–84.
Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45.
Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091–6.
Karakas T, Miething CC, Maurer U, Weidmann E, Ackermann H, Hoelzer D, et al. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia. Leukemia. 2002;16(5):846–54.
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.
Maiti A, DiNardo CD, Qiao W, Kadia TM, Jabbour EJ, Rausch CR, et al. Ten-day decitabine with venetoclax versus intensive chemotherapy in relapsed or refractory acute myeloid leukemia: a propensity score-matched analysis. Cancer. 2021;127(22):4213–20.
Stahl M, Menghrajani K, Derkach A, Chan A, Xiao W, Glass J, et al. Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Blood Adv. 2021;5(5):1552–64.
Jan Philipp B, Smith G, Rong W, Robert TW, Martin ST, Amer MZ, et al. Venetoclax as monotherapy and in combination with hypomethylating agents or low dose cytarabine in relapsed and treatment refractory acute myeloid leukemia: a systematic review and meta-analysis. Haematologica. 2020;105(11):2659–63.
Park S, Kwag D, Kim TY, Lee JH, Lee J, Min GJ, et al. A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Ther Adv Hematol. 2022;13:20406207221081637.
Otoukesh S, Zhang J, Nakamura R, Stein AS, Forman SJ, Marcucci G, et al. The efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia with extramedullary involvement. Leuk Lymphoma. 2020;61(8):2020–3.
Park S, Kim TY, Lee JH, Lee J, Min GJ, Park SS, et al. Differential effects of donor lymphocyte infusion upon treatment response and GVHD according to relapse level and donor sources in patients with myelodysplastic syndrome. Ther Adv Hematol. 2021;12:20406207211043748.
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642–9.
Cribe AS, Steenhof M, Marcher CW, Petersen H, Frederiksen H, Friis LS. Extramedullary disease in patients with acute myeloid leukemia assessed by (18)F-FDG PET. Eur J Haematol. 2013;90(4):273–8.
Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. Recist 1.1 – update and clarification: from the RECIST committee. Eur J Cancer. 2016;62:132–7.
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.
Aldoss I, Yang D, Aribi A, Ali H, Sandhu K, Al Malki MM, et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018 Sep;103(9):e404–7.
DiNardo CD, Maiti A, Rausch CR, Pemmaraju N, Naqvi K, Daver NG, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020 Oct;7(10):e724–36.
Kwag D, Cho BS, Bang SY, Lee JH, Min GJ, Park SS, et al. Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Blood Cancer J. 2022;12(12):169.
Kanate AS, Vos J, Chargualaf MJ. Venetoclax for refractory myeloid sarcoma. J Oncol Pract. 2019;15(7):413–5.
Pan W, Zhao X, Shi W, Jiang Z, Xiao H. Venetoclax induced complete remission in extramedullary relapse of AML co-harboring NPM1, TET2, and NRAS mutations after haploidentical hematopoietic stem cell transplantation. Leuk Lymphoma. 2020;61(11):2756–9.
Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53.
Alfayez M, Ivan D, Pemmaraju N, Daver N, DiNardo CD. Systemic immunotherapy effective for refractory extramedullary acute myeloid leukemia. JCO Precis Oncol. 2019;3(3):1–6.
You do not currently have access to this content.