Outcomes of allogeneic haematopoietic cell transplantation for chronic neutrophilic leukaemia: A combined CIBMTR / CMWP of EBMT analysis
Year: 2022
Type: article
Abstract: Chronic neutrophilic leukaemia (CNL) is a rare, frequently aggressive Philadelphia (Ph)-negative myeloproliferative neoplasm (MPN). Traditional cytoreductive therapies such as hydroxyurea (hydroxycarbamide) and interferon have produced mixed results and disease responses are generally short-lived.1, 2 In a phase II study, treatment with the JAK1/2 inhibitor ruxolitinib resulted in overall response rates of 65% (n = 21) with significant reduction in CSF3R allele burden among responders.3 Despite these encouraging early results, disease progression was the main cause of death among patients treated with ruxolitinib. In a population-based analysis from the Surveillance, Epidemiology, and End Results (SEER) programme (n = 73) and the National Cancer Database (NCDB) (n = 121), the median overall survival (OS) was 1.8 and 2.2 years respectively.4 Previous retrospective studies have shown durable remission in a subset of patients who received allogeneic haematopoietic cell transplantation (allo-HCT).1, 5-8 The allo-HCT outcomes were poor when patients were transplanted in accelerated or blast-phase CNL compared to chronic-phase.9 This was an observational, multicentre analysis using the data sets of the Center for International Blood in Marrow Transplant Research (CIBMTR®) and the European Society for Blood and Marrow Transplantation (EBMT®). The protocol was approved by the institutional review boards of the National Institutes of Health Office for Human Research Protections, and the National Marrow Donor Program (NMDP) Institutional Review Board and Chronic Malignancies Working Party of the EBMT. All patients gave informed consent to use their anonymized personal information for research purposes. A total of 29 adult patients with CNL [16 (55%) from CIBMTR and 13 (45%) from the EBMT registry] who underwent their first allo-HCT between 2000 and 2018 and were reported to the CIBMTR and EBMT registries were included in the study. Cases with blast-phase or secondary acute myeloid lymphoma (AML) before transplant were not included in this analysis. The median follow-up from allo-HCT was 71 (range: 25–161) months for the entire cohort. The median patient age was 58 (range: 33–72) years and the median time from diagnosis of CNL to allo-HCT was 11 (range: 3–65) months. The disease status at allo-HCT was reported to be no response/stable disease in 11 (38%) patients and complete remission (CR) in four (14%) patients. This information was missing in four (14%) patients. Among the 25 patients with available information, splenomegaly was reported in eight (28%) patients and the use of hydroxyurea was reported in 19 (66%) patients. Other reported pretransplant therapies included hypomethylating agent (n = 4), tyrosine kinase inhibitor (n = 7) and ruxolitinib (n = 7). Data on somatic mutations was only available in a subset (n = 9) of patients. The following somatic mutations were reported in the database: CSF3R (n = 9), ASXL1 (n = 4), DNMT3A (n = 1), IDH2 (n = 1), SETBP1 (n = 4), SRSF2 (n = 2), CUX1 (n = 1), SF3B1 (n = 3) RUNX1 (n = 2). JAK2 was tested and negative in 17 (59%) patients. Please refer to Table S2 (Supporting information) for full details on genetic abnormalities. Most transplants were performed using a human leukocyte antigen (HLA)-identical sibling (n = 12, 41%) or 8/8 unrelated donor (n = 10, 34%) with a peripheral blood stem cell (PBSC) graft (n = 27, 93%). The myeloablative conditioning (MAC) regimen was used in 14 (48%) patients and calcineurin-inhibitor-based graft-versus-host disease (GVHD) prophylaxis was used in 22 (76%) patients. Table 1 shows the detailed baseline characteristics. The outcomes were censored at 48 months from allo-HCT, based on median follow-up duration of the CIBMTR cohort. The non-relapse mortality (NRM) was 10.3% [95% confidence interval (CI): 2–24.1] at one year and 13.8% (95% CI: 3.7–28.9) at four years after allo-HCT. Most relapses were seen within one year of allo-HCT with one- and four-year relapse incidence (RI) being 31% (95% CI: 15.5–49.2) and 34.5% (95% CI: 18.2–52.9) respectively. Allo-HCT resulted in a disease-free survival (DFS) of 58.6% (95% CI: 40.5–75.6) at one year and 51.7% (95% CI: 33.8–69.4) at four years after allo-HCT respectively. The OS was 69% (95% CI: 51.3–84.2) at one year and 55.2% (95% CI: 37.1 = 72.5) at four years respectively (Table S4; Figure 1). The most common cause of death was primary disease (57%), followed by infection (14%) (Table S3). In the largest analysis of this kind, we report the long-term outcomes of allo-HCT in CNL combing two large international registries (CIBMTR and EBMT). Allo-HCT resulted in durable DFS and OS with nearly half of patients surviving at four years after allo-HCT. The NRM rates are acceptable despite predominant use of MAC regimen and PBSC graft. Disease relapse was the main cause of transplant failure with around one third of patients relapsing within a year of transplant. Our results are favourable compared to the previous retrospective cohort from Japan where one-year OS was 40% in five patients with CNL. It is important to note that we excluded patients with blast-phase CNL, and most transplants were performed using a well HLA-matched sibling or unrelated donor (n = 22, 76%). In the case series from Japan, two patients received cord blood grafts and one patient received a related haploidentical donor marrow graft. Further studies are needed to explore the role of reduced-intensity conditioning (RIC) regimens and alternative donor for allo-HCT in CNL. The impact of concurrent myeloid mutations such as ASXL1 and SETBP1 in outcomes of allo-HCT also remains to be determined. There may be a role for monitoring CSF3R in marrow for detection of early relapse after allo-HCT although this requires validation.10 Being a registry-based study, our study had limitations including missing information on pre- and posttransplant therapies, details of conditioning regimen, molecular markers and measurable residual disease status. Information about GVHD was missing in most patients. We were not able to conduct a multivariate analysis given the small number of cases. It is difficult to ascertain the survival benefit of allo-HCT due to the lack of non-HCT control in this analysis. A larger international collaborative effort may be required to achieve an adequate sample size. In this collaborative study from two international transplant registries, we were able to demonstrate that allo-HCT is feasible for patients with CNL and may lead to long-term survival. Further studies are needed to define optimal timing and pre- and posttransplant therapies to improve the outcomes of allo-HCT in chronic-phase CNL. The optimal allo-HCT platform remains to be defined for CNL. Comparative studies with non-transplant cohorts are needed to determine the relative benefit of allo-HCT in CNL. Bhagirathbhai Dholaria, Aleksandar Radujkovic, Donal McLornan, Ibrahim Yakoub-Agha, Wael Saber and Noel Estrada-Merly contributed to the conception and design of the study; Noel Estrada-Merly, Tiarlan Sirait and Soyoung Kim analysed the data; Bhagirathbhai Dholaria, Donal McLornan, Wael Saber and Noel Estrada-Merly contributed to the writing of the manuscript; all authors critically reviewed the manuscript and approved the final version. The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Institutes of Health National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases. It is also supported by the Health Resources and Services Administration (HHSH250201700006C and HHSH250201700007C) and the Office of Naval Research (N00014-20-1-2705 and N00014-20-1-2832). Additional federal support is provided by the National Institutes of Health National Cancer Institute (R01CA215134), the National Institutes of Health National Institute of Allergy and Infectious Diseases (R01AI128775, U01AI126612), the National Institutes of Health National Heart, Lung, and Blood Institute (R01HL130388), the National Institutes of Health National Eye Institute (UG1HL06924), and the Biomedical Advanced Research and Development Authority. Support is also provided by Be the Match Foundation, Boston Children's Hospital, Dana Farber, St. Baldrick's Foundation, Stanford University, the Medical College of Wisconsin, the National Marrow Donor Program, and the following commercial entities: Actinium Pharmaceuticals, Inc., Adienne SA, AlloVir, Inc., Amgen, Inc., Angiocrine Bioscience, Astellas Pharma US, Bluebird Bio, Inc., Bristol Myers Squibb Co., Celgene Corp., CSL Behring, CytoSen Therapeutics, Inc., Daiichi Sankyo Co., Ltd., ExCellThera, Fate Therapeutics, Gamida Cell, Ltd., Genentech Inc., Incyte Corporation, Janssen/Johnson & Johnson, Jazz Pharmaceuticals, Inc., Kiadis Pharma, Kite, a Gilead Company, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Merck Sharp & Dohme Corp., Millennium, the Takeda Oncology Co., Miltenyi Biotec, Inc., Novartis Pharmaceuticals Corporation, Omeros Corporation, OncoImmune, Inc., Orca Biosystems, Inc., Pfizer, Inc., Pharmacyclics, LLC, Sanofi Genzyme, StemCyte, Takeda Pharma, Vor Biopharma and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defence, the Health Resources and Services Administration, or any other agency of the US government. We thank all the European Society for Blood and Marrow Transplantation (EBMT) centres and national registries for contributing patients to this study (Supplementary Appendix material). We also thank the data managers for their excellent work and the patients who contributed their data. B. Dholaria—Institutional research funding: Takeda, Janssen, Angiocrine, Pfizer, Poseida, MEI; consultancy/adviser: Jazz, Gamida Cell, MJH BioScience, Arivan Research, BEAM therapeutics. D. McLornan—Jazz: speaker bureau and advisory boards, Novartis: speaker bureau and research funding, AbbVie: speaker bureau, BMS-Celgene: research funding. The other authors have no relevant conflicts of interest to disclose. Patients and/or guardian(s) gave informed consent for research. No material from other sources was used for this manuscript. The final analysis dataset will be posted to the CIBMTR website at https://www.cibmtr.org/ReferenceCenter/PubList/PubDsDownload/Pages/default.aspx. Appendix S1 Table S1 Table S2 Table S3 Table S4 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Source: British Journal of Haematology
DOI: 10.1111/bjh.18297
Authors: Bhagirathbhai Dholaria, Aleksandar Radujkovic, Noel Estrada‐Merly, Tiarlan Sirait, Soyoung Kim, Juan Carlos Hernández‐Boluda, Tomasz Czerw, Patrick J. Hayden, Ankit Kansagra, Vincent T. Ho, Taiga Nishihori, Paul Shaughnessy, Bart Scott, Ryotaro Nakamura, Betul Oran, Mohamed Kharfan‐Dabaja, Bipin N. Savani, Donal McLornan, Ibrahim Yakoub‐Agha, Wael Saber
Institutions: Vanderbilt University Medical Center, University Hospital Heidelberg, Medical College of Wisconsin, European Society for Blood and Marrow Transplantation, Hospital Clínico Universitario de Valencia, The Maria Sklodowska-Curie National Research Institute of Oncology, Trinity College Dublin, St. James's Hospital, The University of Texas Southwestern Medical Center, Dana-Farber Cancer Institute, Moffitt Cancer Center, Methodist Healthcare, Fred Hutch Cancer Center, City Of Hope National Medical Center, The University of Texas MD Anderson Cancer Center, Mayo Clinic, Mayo Clinic in Florida, University College Hospital, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, Institute for Translational Research in Inflammation
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Be The Match Foundation, Bristol-Myers Squibb, Astellas Pharma US, Stanford University, St. Baldrick's Foundation, Boston Children's Hospital, Novartis Pharmaceuticals Corporation, StemCyte, Medical College of Wisconsin, Angiocrine Bioscience, bluebird bio, Incyte, Omeros Corporation, Daiichi-Sankyo, Kiadis Pharma, Kyowa Hakko Kirin, Miltenyi Biotec, Fonds de dotation CSL Behring pour la recherche, CytoSen Therapeutics, National Institutes of Health, Health Resources and Services Administration, Genentech, Johnson and Johnson, Merck Sharp and Dohme, Biomedical Advanced Research and Development Authority, Sanofi Genzyme, Pharmacyclics, National Heart, Lung, and Blood Institute, Office of Naval Research, National Eye Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: G1360182821, G3745029439, G5804481516, Improving the Availability of Younger Unrelated Hematopoietic Stem Cell Donors, G6787592842, G6979277618, Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency, Integrating health informatics in a scalable stepped care self-management program for survivors after hematopoietic cell transplantation, Integrated Exchange and Storage of Current- and Future-Generation Immunogenomic Data, A Data Resource for Blood and Marrow Transplants and Adoptive Cellular Therapy Research
OpenAlex ID: W4281646440