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Venetoclax-based salvage for management of relapsed acute leukaemia after allogeneic haematopoetic stem cell transplant: durable remissions only seen following consolidation with donor lymphocyte infusion or second transplant

Bone Marrow Transplantation volume 58, pages 1152–1156 (2023)Cite this article

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Venetoclax, used in combination with hypomethylating agents or low-dose cytarabine, is a well-established first-line treatment for patients with acute myeloid leukaemia (AML) unfit for intensive chemotherapy [1, 2]. There are limited data regarding efficacy in relapsed acute leukaemia after allogeneic stem cell transplant (allo-SCT). AML patients with early relapse post-transplant have a poor prognosis with a 2-year survival of <5% seen in those relapsing within 6 months after allo-SCT and 12% for relapse 6–24 months after allo-SCT [3]. Reinduction with intensive chemotherapy can lead to remission in 30–40% [4, 5] but durable remissions are rarely seen unless consolidated with donor lymphocyte infusion (DLI) or second allo-SCT. Schmid et al. demonstrated 2-year overall survival (OS) of 21% for those whose salvage treatment included DLI but only 9% in those not given DLI [6]. Hypomethylating agents in combination with DLI only lead to remission in <15% in frank relapse [7], although they may be more effective in setting of molecular relapse. Relapsed acute lymphoblastic leukaemia (ALL) after allo-HSCT has <10% long-term disease-free survival [8]. Whilst novel CD19 and CD22 targeting therapies have improved outcomes for relapsed B-ALL, there are less effective options for relapsed T-ALL.

We performed a retrospective analysis of 25 patients with relapsed myeloid malignancies or T-ALL after allo-SCT treated with venetoclax-based salvage between 2019 and 2022 at two UK centres. Twenty-three relapsed AML patients received venetoclax 300 mg day 1–28 (dose reduction to 100 mg OD for those on azoles) in combination with hypomethylating agent or low-dose cytarabine (azacitidine:75 mg/m2 subcutaneously (SC) day 1–7). Decitabine:20 mg/m2 intravenously day 1–5, cytarabine: 20 mg BD SC day 1–10). Two relapsed T-ALL patients received venetoclax 300 mg day 1–28 plus UKALL60+ regimen D Induction (dexamethasone 3 mg/m2 D1–3; idarubicin 10 mg/m2 PO day 1, vincristine 1 mg/m2 day 1, methotrexate 5 mg/m2 PO day 1,8,15,22, 6-mercaptopurine PO D1-28 and methotrexate 12.5 mg IT day 4). To minimise treatment-related adverse events, dose reductions/delays were made and/or GCSF was used in patients with G4 Neutropaenia/thrombocytopaenia who had achieved complete remission (CR)/CR with incomplete haematology recovery(CRi). Medical records were retrospectively reviewed for patient co-morbidities, disease subtype, cytogenetic/molecular risk, prior lines of therapy, donor type, conditioning regimen, use of DLI, response, relapse and survival. Response was assessed using 2022 ELN response criteria for AML [9] or NCCN 2019 response assessment guidelines for ALL. Adverse events were graded by CTCAE criteria. Survival estimates were calculated using Kaplan–Meier method. Leukaemia-free survival (LFS) was defined as the date of initiation of venetoclax to date of relapse, lack of response, death or date of last follow-up. OS was calculated from date of initiation of venetoclax to date of death or last follow-up. For patients who had DLI or HSCT consolidation, OS and LFS were calculated from the date of the first DLI or the date of the second HSCT.

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Fig. 1: Overall Survival and Leukaemia Free Survival.

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Authors and Affiliations

  1. Royal Marsden Hospital, London, UK

    Katy Smith, Dina Fathoala, Chloe Anthias, Sandra Easdale, Mark Ethell, Farheen Mir, Mike Potter, David Taussig & Emma Nicholson

  2. The London Clinic, London, UK

    Lucy Pickard

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  1. Katy Smith
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Contributions

KS led project design, data collection and analysis and manuscript writing. EN contributed to project design, data analysis, study management and manuscript writing. DF and LP contributed to data collection, study management and manuscript writing. CA, SE, ME, FM, MP and DT contributed to study management and manuscript writing. All authors accepted the final version of the manuscript.

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Correspondence to Emma Nicholson.

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Smith, K., Fathoala, D., Anthias, C. et al. Venetoclax-based salvage for management of relapsed acute leukaemia after allogeneic haematopoetic stem cell transplant: durable remissions only seen following consolidation with donor lymphocyte infusion or second transplant. Bone Marrow Transplant 58, 1152–1156 (2023). https://doi.org/10.1038/s41409-023-02029-w

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