Page 138 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):652-660
Myelodysplastic/Myeloproliferative Neoplasms
Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplanta- tion in patients with chronic myelomonocytic leukemia
Janghee Woo,1,2 Dae Ro Choi,1 Barry E. Storer,1 Cecilia Yeung,1,2 Anna B. Halpern,1,2 Rachel B. Salit,1,2 Mohamed L. Sorror,1,2 David W. Woolston,1 Tim Monahan,1 Bart L. Scott1,2 and H. Joachim Deeg1,2 12
Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, WA, USA
ABSTRACT
Chronic myelomonocytic leukemia (CMML) is a heterogeneous group of clonal hematopoietic malignancies with variable clinical and molecular features. We analyzed long-term results of allogeneic hematopoietic cell transplantation in patients with CMML and determined clinical and molecular risk factors associated with outcomes. Data from 129 patients, aged 7-74 (median 55) years, at various stages of the disease and transplanted from related or unrelated donors were analyzed. Using a panel of 75 genes somatic mutations present before hematopoietic cell transplan- tation were identified In 52 patients. The progression-free survival rate at 10 years was 29%. The major cause of death was relapse (32%), which was significantly associated with adverse cytogenetics (hazard ratio, 3.77; P=0.0002), CMML Prognostic Scoring System (hazard ratio, 14.3, P=0.01), and MD Anderson prognostic scores (hazard ratio, 9.4; P=0.005). Mortality was associated with high-risk cytogenetics (hazard ratio, 1.88; P=0.01) and high Hematopoietic Cell Transplantation Comorbidity Index (score ≥4: hazard ratio, 1.99; P=0.01). High overall mutation burden (≥10 mutations: hazard ratio, 3.4; P=0.02), and ≥4 mutated epigenetic regulatory genes (haz- ard ratio 5.4; P=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique asso- ciations of mutations and clinical features. CMML with a high mutation burden appeared to be distinct from high-risk groups defined by complex cytogenetics. New transplant strategies must be developed to target specific disease subgroups, stratified by molecular profiling and clinical risk factors.
Introduction
Chronic myelomonocytic leukemia (CMML) can present either as a myeloprolif- erative type (MP-CMML) or a myelodysplastic type (MD-CMML), with leukocyte counts of ≥13 × 109/L and <13 × 109/L, respectively, and is therefore classified by the World Health Organization (WHO) as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).1 The clinical course in terms of survival and risk of evolu- tion into acute myeloid leukemia (AML) varies.2 Prognosis tends to be worse with MP-CMML than with MD-CMML.3 The blast percentage (in blood and bone mar- row) has clear prognostic implications.4,5 CMML-0 allows for <2% blasts in periph- eral blood or <5% blasts in the bone marrow or both; CMML-1 refers to cases with 2% to 4% blasts in the peripheral blood or 5% to 9% in bone marrow or both; and CMML-2 refers to cases with 5% to 19% blasts in peripheral blood, 10% to 19% in bone marrow, or the presence of Auer rods.
The highly heterogeneous nature of CMML has led to the development of vari- ous prognostic scoring systems in an attempt to assign individual patient risk.6-8 These systems have incorporated hematologic indices, cytogenetic abnormalities, and transfusion dependency. More recently, recurrent somatic mutations have been identified in genes associated with signaling pathways (RAS, CBL, CSF3R, and
Correspondence:
H. JOACHIM DEEG
jdeeg@fredhutch.org
Received: February 8, 2019. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2019.218677
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/652
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
652
haematologica | 2020; 105(3)
ARTICLE