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Venetoclax plus hypomethylating agents as first salvage therapy for myeloid malignancies relapsing after allogeneic HSCT

Bone Marrow Transplantation volume 61, pages 101–103 (2026)Cite this article

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Relapse of Acute Myeloid Leukemia (AML) and Myelodisplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (HSCT) occurres in about 40% of patients and has a dismal prognosis [1]; DLI showed comparable results of second HSCT [2], and to date there is no evidence of the best salvage therapy. Venetoclax in combination with hypomethylating agents (HMA) has shown efficacy in both previously untreated unfit patients [3], and for relapsed/refractory AML [4]. Some studies investigated the efficacy of HMA-venetoclax in AML/MDS relapsing after HSCT [5,6,7,8]: response rate and 1-year survival among studies were comparable (30–50% and 40–50%, respectively) as confirmed by the metanalysis conducted by Du et al. [9]. We conducted a multicentric retrospective observational study involving nine Italian centers to investigate the safety and efficacy of HMA-venetoclax combination as first salvage therapy for AML/MDS relapsing after HSCT to evaluate safety and efficacy, and to identify determinants of response and survival. Hematological and extrahematological adverse events during treatment were graded as per CTCAEv5 [10]. Overall response rate (ORR) included all complete response and complete response with incomplete haematological recovery (CR/Cri) patients. Overall survival (OS) was calculated from the start of HMA-venetoclax treatment to the last follow up. Methods are detailed in supplemental material. All methods were performed in accordance with the relevant guidelines and regulations. The study was conducted according to the Declaration of Helsinki and was approved by the Ethic committee of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome as part of the TOHP (Transplant Outcome in Hematological Patients) study (Protocol number 3326). All the patients had given written informed consent to use their data for research purposes.

Myeloid neoplasms relapsing after allogeneic HSCT remain an unmet clinical need. We present the largest real-world experience on the use of HMA-venetoclax for myeloid neoplasms relapsing after HSCT. Safety profile was acceptable, in the context of heavily pretreated patients: febrile neutropenia was the most common adverse event and the first cause of treatment interruptions. Fatal infections occurred in 8 patients (9%). We found an ORR of 36%, with 33% of CR rate. Cytogenetic and molecular characteristics influenced response rate and survival: TP53 mutation and complex karyotype at diagnosis correlated with no response to HMA-venetoclax, while NPM1 mutated patients showed better CR rate. Patients who achieved CR/CRi had better survival compared to those who did not: indeed, patients harbouring TP53 mutation or complex karyotype had lower OS, and patients with NPM1 mutated AML had longer OS. Patients suffering from early relapse from HSCT show no response to HMA-venetoclax and lower survival. We also found that patients treated with DLI in addition to HMA-venetoclax showed better OS. Our study, despite the retrospective design, shows that HMA-venetoclax treatment is safe and effective in patients with AML or MDS relapsing after alloHSCT. In addition, patients with late relapses after HSCT and with NPM1 mutations can benefit particularly from HMA-venetoclax, and whenever possible, DLI should be administered. These patients can obtain durable responses and also undergo a second HSCT. In contrast, patients with complex karyotype or TP53 mutations or experiencing early relapses after HSCT should be candidate to experimental protocols; however, median survival was 6-9 months also in this high-risk subgroup, for which new options are needed. More prospective studies are needed to confirm our findings.

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Fig. 1: Overall survival curves.

Data availability

For original data, please contact via e-mail: simona.sica@unicatt.it.

References

  1. Arfons LM, Tomblyn M, Rocha V, Lazarus HM. Second hematopoietic stem cell transplantation in myeloid malignancies. Curr Opin Hematol. 2009;16:112–23.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kharfan-Dabaja MA, Labopin M, Polge E, Nishihori T, Bazarbachi A, Finke J, et al. Association of second allogeneic hematopoietic cell transplant vs donor lymphocyte infusion with overall survival in patients with acute myeloid leukemia relapse. JAMA Oncol. 2018;4:1245–53.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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;103:e404–7

    Article  PubMed  PubMed Central  Google Scholar 

  5. Byrne M, Danielson N, Sengsayadeth S, Rasche A, Culos K, Gatwood K, et al. The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia. Am J Hematol. 2020;95:1006–14.

    Article  CAS  PubMed  Google Scholar 

  6. Joshi M, Cook J, McCullough K, Nanaa A, Gangat N, Foran JM, et al. Salvage use of venetoclax-based therapy for relapsed AML post allogeneic hematopoietic cell transplantation. Blood Cancer J. 2021;11:49.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gao F, Gao Y, Luo Y, Yu J, Fu H, Lai X, et al. Venetoclax plus hypomethylating agent for the salvage treatment of relapsing myeloid malignancies after hematopoietic stem cell transplantation: A multicenter retrospective study on behalf of the Zhejiang Cooperative Group for Blood and Marrow Transplantation. Am J Hematol. 2022;97:E44–E47.

    Article  CAS  PubMed  Google Scholar 

  8. Zhao P, Ni M, Ma D, Fang Q, Zhang Y, Li Y, et al. Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2022;101:119–30.

    Article  CAS  PubMed  Google Scholar 

  9. Du Y, Li C, Zhao Z, Liu Y, Zhang C, Yan J. Efficacy and safety of venetoclax combined with hypomethylating agents for relapse of acute myeloid leukemia and myelodysplastic syndrome post allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. BMC Cancer. 2023;23:764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute.

  11. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345–77.

    Article  PubMed  Google Scholar 

  12. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. These authors contributed equally: Patrizia Chiusolo, Filippo Frioni.

  2. These authors jointly supervised this work: Simona Sica, Cristina Papayannidis.

Authors and Affiliations

  1. Section of Hematology, Department of Laboratory and Hematological Sciences, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Patrizia Chiusolo, Filippo Frioni, Roberto Maggi, Andrea Mattozzi, Sabrina Giammarco & Simona Sica

  2. University of Brescia, Adult Bone Marrow Transplant Unit, ASST Spedali Civili di Brescia, Brescia, Italy

    Michele Malagola

  3. IEO, Clinical Haemato-Oncology Division Via Ripamonti, Milano, Italy

    Fabio Giglio & Irene Maria Monella

  4. Division of Haematology, Department of Oncology, A.O.U. Città Della Salute e della Scienza di Torino, Turin, Italy

    Carolina Secreto & Alessandro Busca

  5. Ematologia Azienda Ospedale Padova, Padova, Italy

    Federica Lessi & Fabio D’Amore

  6. Ospedale Opera Padre Pio-San Giovanni Rotondo, San Giovanni Rotondo, Italy

    Mariachiara Abbenante

  7. Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy

    Giovanni Marconi

  8. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy

    Jacopo Nanni & Cristina Papayannidis

Authors
  1. Patrizia Chiusolo
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  2. Michele Malagola
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  3. Fabio Giglio
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  4. Filippo Frioni
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  5. Carolina Secreto
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  6. Federica Lessi
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  7. Fabio D’Amore
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  8. Irene Maria Monella
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  12. Roberto Maggi
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  14. Sabrina Giammarco
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  15. Alessandro Busca
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  16. Simona Sica
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  17. Cristina Papayannidis
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Contributions

PC, FFr, SS and CP designed the study, MM, FG, CS, FL, FDA, IMM, MA, GM, JN, RM, AM, SG, AB, PC, CP treated the patients and collected the data. PC, FFr, CP, SS drafted the paper. All authors critically reviewed and approved the manuscript.

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Correspondence to Simona Sica.

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The authors declare no competing interests.

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Chiusolo, P., Malagola, M., Giglio, F. et al. Venetoclax plus hypomethylating agents as first salvage therapy for myeloid malignancies relapsing after allogeneic HSCT. Bone Marrow Transplant 61, 101–103 (2026). https://doi.org/10.1038/s41409-025-02723-x

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