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Outcomes in patients with CRLF2 overexpressed acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation

Bone Marrow Transplantation volume 56, pages 1746–1749 (2021)Cite this article

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Acute lymphoblastic leukemia (ALL) of B-cell lineage affects ~75% of newly diagnosed adults with ALL [1]. Treatment outcomes in adults are inferior to children. One of the factors that was thought to drive this difference is intolerance to pediatric regimens. Stock et al. reported the results of a pediatric regimen used in an adolescent and young adult population with an overall survival (OS) of 73% at 3 years, which is less than the pediatric standard of >90%; they identified the presence of a Philadelphia-like (Ph-like) gene expression signature as a poor prognostic factor [2]. Other similar observations have led to efforts to understand the biological drivers of poor-risk disease, one of which is the Ph-like subtype of ALL [3, 4]. Ph-like ALL is a high-risk subtype of ALL with a similar gene expression profile to Ph+ ALL. However, these patients have a wide range of alterations in the activating tyrosine kinase pathway rather than expression of the single aberrant BCR-ABL fusion protein [3, 5]. And while Ph+ ALL patients have tyrosine kinase inhibitors that target BCR-ABL1 to help optimize their treatment, Ph-like ALL, to date, does not routinely have such treatment options [6,7,8]. Nearly half of Ph-like patients, especially in the adult subset, overexpress cytokine receptor-like factor 2 (CRLF2), and the remaining patients have fusions involving JAK2, ABL1, ABL2, and other tyrosine kinases [3]. Patients with Ph-like ALL, including CRLF2 overexpression, have poor outcomes with chemotherapy [3], and therefore hematopoietic stem cell transplant (HCT) is often recommended. However, the efficacy of HCT in these patients is unknown. Case reports have described HCT in this patient population [9], but here we are reporting the outcomes of HCT in a series of patients with only CRLF2 overexpressed B-ALL.

In this single center retrospective study, we identified 20 consecutive patients who had CRLF2 overexpression and received an HCT at MD Anderson between 2014 and 2019. This study was approved by the MD Anderson Institutional Review Board and carried out in accordance with the Declaration of Helsinki. The primary objective of the study was to describe the OS of these transplanted patients, with secondary endpoints of progression-free-survival (PFS), non-relapse mortality (NRM), graft-versus-host disease (GVHD), and graft-versus-host disease-free, relapse-free survival (GRFS). CRLF2 status was identified via FISH or multi-parameter flow cytometry, as previously described [3, 10]. FISH for CRLF2 rearrangement was performed with sequential hybridization for CRLF2, P2RY8, and IGH using probes prepared from clones RP13-167H21, RP11-309M23, and RP13-76L22 (CRLF2 3′), WI2-3390E22, WI2-2865K18, WI2-0735M13, and WI2-1570L13 (region between CRLF2 and P2RY8), RP13-297E16 and RP11-449L4 (P2RY8 5′), and RP5-998D24 and RP11-1065N8 (IGH enhancer). Multi-color flow cytometry was performed using phycoerythrin-conjugated anti-CRLF2 antibody (clone eBio1A6; eBioscience, San Diego, CA) with the concentration recommended by the manufacturer, and CRLF2 expression was directly assessed on B lymphoblasts identified by a combination of CD19, CD10, CD34, and CD45 markers (all antibodies purchased from BD Biosciences) [10]. Response assessment was based on <5% blasts and complete recovery of normal blood counts [11]. Measurable residual disease (MRD) was assessed before HCT by six-color flow cytometry, with a sensitivity of 0.01%, as previously described [11]. Acute GVHD was staged and graded according to the Glucksberg scale [12]. Chronic GVHD was reported as limited and/or extensive [13].

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Fig. 1: Primary transplant outcomes for the study group.

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Authors and Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA

    Paul Koller

  2. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rima M. Saliba, Celina Ledesma, Gabriela Rondon, Uday Popat, Amin Alousi, Rohtesh Mehta, Betul Oran, Amanda Olson, Chitra Hosing, Muzaffar Qazilbash, Issa Khouri, Elizabeth Shpall, Richard Champlin & Partow Kebriaei

  3. Division of Hematology/Oncology, Department of Medicine, University of California Irvine School of Medicine, Irvine, CA, USA

    Stefan Ciurea

  4. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jeffrey Jorgensen & Sa Wang

  5. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nitin Jain, Elias Jabbour, Hagop Kantarjian & Marina Konopleva

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Correspondence to Partow Kebriaei.

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Koller, P., Saliba, R.M., Ledesma, C. et al. Outcomes in patients with CRLF2 overexpressed acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 56, 1746–1749 (2021). https://doi.org/10.1038/s41409-021-01262-5

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