To the editor,
Chronic neutrophilic leukemia (CNL) is a rare, frequently aggressive Philadelphia (Ph)-negative myeloproliferative neoplasm (MPN). Traditional cytoreductive therapies such as hydroxyurea 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) program (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 hematopoietic cell transplantation (allo-HCT)allo-HCT(1, 5–8). The allo-HCT outcomes were poor when patients were transplanted in accelerated or blast-phase of CNL compared to chronic-phase(9).
This was an observational, multicenter analysis using the datasets of the Center for International Blood in Marrow Transplant Research (CIBMTR®) and the European Society for Blood and Marrow Transplantation (EBMT®). 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 EBMT registry] who underwent first allo-HCT between 2000 and 2018 and reported to the CIBMTR and EBMT registries were included in the study. Cases with blast-phase or secondary 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 4 (14%) patients. This information was missing in 4 (14%) patients. Among the 25 patients with available information, splenomegaly was reported in 8(28%) patients and the use of hydroxyurea was reported in 19 (66%) patients. Other reported pre-transplant 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. 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 Supplementary table s2 for full details on genetic abnormalities. Most transplants were performed using a HLA-identical sibling (N=12, 41%) or 8/8 unrelated donor (N= 10, 34%) with peripheral blood stem cell graft (PBSC, N=27, 93%). MAC regimen was used in 14 (48%) patients and calcineurin-inhibitor-based GVHD prophylaxis was used in 22 (76%) patients. Table 1 shows detailed baseline characteristics.
Table 1:
Baseline characteristics
| Characteristic | N=29 (%) |
|---|---|
| Registry | |
| CIBMTR | 16 (55) |
| EBMT | 13 (45) |
| Patient related | |
| Age - Median (min-max) | 58 (33–72) |
| Karnofsky score | |
| 80–100 | 27 (93) |
| <80 | 2 (7) |
| HCT-CI - no. (%) | |
| 0 | 10 (34) |
| 1 | 2 (7) |
| 2 | 4 (14) |
| 3+ | 8 (28) |
| Missing | 5 (17) |
| Hb g/L count at HCT - median (min-max) | 93 (70–144) |
| ANC /μL count at HCT - median (min-max) | 5658 (0–111153) |
| WBC ×109/L count at HCT - median (min-max) | 9 (0–141) |
| Platelets ×109 median (min-max) | 111 (7–556) |
| Splenomegaly at HCT | |
| No | 16 (55) |
| Yes | 8 (28) |
| Splenectomy | 1 (3) |
| Missing | 4 (14) |
| Pre-treatment (HU) use | |
| No | 6 (21) |
| Yes | 19 (66) |
| Missing | 4 (14) |
| Pre-treatment (HMA) use | |
| No | 22 (76) |
| Yes | 4 (14) |
| Missing | 3 (10) |
| Pre-treatment (TKI) use | |
| No | 19 (66) |
| Yes | 7 (24) |
| Missing | 3 (10) |
| Pre-treatment (Ruxolitinib) use | |
| No | 19 (66) |
| Yes | 7 (24) |
| Missing | 3 (10) |
| Disease status at HCT | |
| Complete remission (CR) | 4 (14) |
| Hematologic improvement (HI) | 6 (21) |
| No response / stable disease (NR/SD) | 11 (38) |
| Progressive disease (PD) | 3 (10) |
| Relapse | 1 (3) |
| Missing | 4 (14) |
| Time from diagnosis to transplant - no. (%) | |
| Median (min-max) | 11 (3–65) |
| Transplant related | |
| Donor type | |
| HLA-identical sibling | 12 (41) |
| Other related | 1 (3) |
| Well-matched unrelated (8/8) | 10 (34) |
| Partially matched unrelated (7/8) | 4 (14) |
| Unrelated (matching unknown) | 2 (7) |
| Graft source | |
| Bone marrow | 2 (7) |
| Peripheral blood | 27 (93) |
| Donor/recipient sex match - no. (%) | |
| M-M | 8 (28) |
| M-F | 8 (28) |
| F-M | 8 (28) |
| F-F | 5 (17) |
| Donor/recipient CMV serostatus | |
| +/+ | 10 (34) |
| +/− | 2 (7) |
| −/+ | 6 (21) |
| −/− | 10 (34) |
| Missing | 1 (3) |
| Conditioning regimen intensity | |
| MAC | 14 (48) |
| RIC/NMA | 15 (52) |
Abbreviations: hematopoietic cell transplantation (HCT); HCT-CI, HCT comorbidity index; Hg, hemoglobin; ANC- absolute neutrophil count; HLA, human leukocyte antigen; CMV: cytomegalovirus; MAC- myeloablative conditioning; RIC- reduced-intensity conditioning; NMA- non-myeloablative; M-male; F-female; HU-hydroxyurea; TKI-tyrosine kinase inhibitor; HMA-hypomethylating agent
The outcomes were censored at 48 months from allo-HCT, based on median follow-up duration of CIBMTR cohort. The NRM was 10.3% (95% CI: 2–24.1) at 1 year and 13.8% (95% CI: 3.7–28.9) at 4 years after allo-HCT. Most relapses were seen within 1 year of allo-HCT with 1-year and 4-year RI being 31% (95% CI: 15.5–49.2) and 34.5% (95% CI: 18.2–52.9), respectively. Allo-HCT resulted in DFS of 58.6% (95% CI: 40.5–75.6) at 1 year and 51.7% (95% CI: 33.8–69.4) at 4 years after allo-HCT, respectively. The OS was 69% (95% CI: 51.3–84.2) at 1 year and 55.2% (95% CI: 37.1=72.5) at 4 years, respectively (Supplemental table s4). The most common cause of death was primary disease (57%), followed by infection (14%). (Supplemental table s3)
In the largest analysis of such kind, we reported 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 4 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 1/3 patients relapsing within a year of transplant. Our results are favorable compared to the previous retrospective cohort from Japan were 1-year OS was 40% in 5 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 related haploidentical donor marrow graft. Further studies are needed to explore the role of RIC regimens and alternative donor for allo-HCT in CNL. Impact of concurrent myeloid mutations such as ASXL1, SETBP1 in outcomes of allo-HCT also remains to be determined. There may be a role of 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 post-transplant 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 survival benefit of allo-HCT due to lack of non-HCT control in this analysis. A larger international collaborative effort may be required to achieve 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 post-transplant therapies to improve the outcomes of allo-HCT in chronic-phase CNL. The optimal allo-HCT platform remains to be defined for CNL. Comparative studied with non-transplant cohort are needed to determine relative benefit of allo-HCT in CNL.
Supplementary Material
Figure 1:
Non-relapse mortality (A, NRM), relapse incidence (B, RI), disease-free survival (C, DFS), and overall survival (D, OS)
Acknowledgements:
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 Defense, 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) centers 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.
Footnotes
Conflict of interest:
B.Dholaria- Institutional research funding: Takeda, Janssen, Angiocrine, Pfizer, Poseida, MEI, Consultancy/Advisor: 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
Rest of the authors have no relevant COI to disclose.
Publisher's Disclaimer: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bjh.18297
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