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Cladribine-based debulking chemotherapy sequential with reduced intensity regimen and post-transplantation maintenance for refractory myeloid leukemia: a prospective phase II clinical trial

Bone Marrow Transplantation volume 57, pages 1004–1006 (2022)Cite this article

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was the only curative treatment for patients with relapsed/refractory acute myeloid leukemia (R/R-AML) [1]. However, the overall outcome of conventional allo-HSCT regimen with myeloablative (MAC) or reduced-intensity conditioning (RIC) was unsatisfactory [2]. The sequential conditioning regimen with combination of debulking chemotherapy followed by RIC conditioning was developed and the treatment outcome was encouraging for primary R/R AML [3,4,5,6]. Previously, we reported the result of a sequential regimen of fludarabine, cytosine arabinoside (Ara-C) and idarubicin (FLAG-IDA) followed by fludarabine and busulfan (Flu-Bu) conditioning without post-transplantation maintenance therapy in patients of R/R AML. Overall, the leukemia-free survival (LFS) and overall survival (OS) were improved to 40% [7, 8].

For further optimize the treatment protocol, we replaced fludarabine and idarubicin by cladribine and etoposide. It has been shown that the addition of cladribine improved the treatment outcome in newly diagnosed AML [9]. Replacing idarubicin was to avoid potential cardiac toxicity in heavily pre-treated R/R AML with multiple cycles of anthracyclines. More recently, maintenance therapy, such as FLT3 inhibitor or low-dose decitabine has been shown to reduce significantly the relapse after transplantation [10, 11]. Here we reported of the result of the prospective single arm phase II study to evaluate the feasibility and efficacy of new debulking chemotherapy with cladribine, Ara-C and etoposide (CLAGE) followed by reduced toxicity Flu-Bu conditioning regimen and maintenance therapy after allo-HSCT (NCT03882203). The RR-AML was defined as no remission after 2 cycles of induction therapy, no remission after re-induction therapy after first relapse or multiple relapse. For chronic myeloid leukemia (CML), refractory was defined as second blast crisis or beyond. The primary endpoint was the 1-year LFS with secondary endpoints including 1-year OS, 100-day and 1-year incidence of non-relapse mortality (NRM) and 1-year incidence of relapse (CIR). Based on the Simon’s Stage II optimal design with a targeted 1-year LFS at 50%, a total of 18 patients were enrolled while the rule of early stop by continuous monitoring for toxicity via Pocock-type boundary was carried out targeting a NRM not over 35%.

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Fig. 1: Transplantation outcomes.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Author notes

  1. These authors contributed equally: Ling Wang, Wenhui Gao.

  2. These authors share the senior authorship: Jieling Jiang, Jiong Hu.

Authors and Affiliations

  1. Shanghai Institute of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Ling Wang, Wenhui Gao, Lining Wang, Jieling Jiang & Jiong Hu

  2. Shanghai Clinical Research Center (SCRC), Feng Lin International Centre, Shanghai, China

    Min Wan

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  1. Ling Wang
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Contributions

LW and WHG conceived and planned the clinical trial, wrote the protocol, acquired data, analyzed the data, wrote the manuscript. LW and MW performed the statistics, and revised the manuscript. JJ contributed to patient enrollment, revised the manuscript. JH conceived and planned the clinical trial, wrote the protocol, analyzed the data, revised the manuscript.

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Correspondence to Jieling Jiang or Jiong Hu.

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Wang, L., Gao, W., Wang, L. et al. Cladribine-based debulking chemotherapy sequential with reduced intensity regimen and post-transplantation maintenance for refractory myeloid leukemia: a prospective phase II clinical trial. Bone Marrow Transplant 57, 1004–1006 (2022). https://doi.org/10.1038/s41409-022-01639-0

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