Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia

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 transplantation 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 (hazard ratio 5.4; P=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique associations 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.

Figure 1

Clinical risk factors associated with relapse and overall mortality/survival in patients with chronic myelomonocytic leukemia following hematopoietic cell transplantation. Overall and relapse-free survival (RFS) and the probabilities of relapse and non-relapse mortality (NRM) are shown for all 129 patients. Tick marks indicate censored patients. (A) Survival, RFS, relapse and NRM for all patients. (B) Relapse by cytogenetic risk. (C) Relapse by measurable residual disease (MRD) at transplantation as indicated by cytogenetics. (D) Relapse by MD Anderson Prognostic Score (MDAPS) and (E) by CMML-specific Prognostic Scoring System (CPSS) risk group. (F) Overall survival dependent upon cytogenetic risk and (G) MRD by cytogenetics. (H) NRM and (I) overall survival by Hematopoietic Cell Transplantation-Comorbidyt Index (HCT-CI).

Figure 2

Molecular profiling and risk factors associated with hematopoietic cell transplantation outcomes in patients with chronic myelomonocytic leukemia. (A) Unsupervised hierarchical clustering of a correlation matrix between mutations and clinical parameters. Group 1 consists of mutations in mitotic signaling pathways, myeloproliferative type of chronic myelomonocytic leukemia (CMML) (Prolifer), mutations in TP53, and high-risk disease by cytogenetics and prognostic scoring systems. Group 2 consists of mutations in epigenetic pathways, methylation, and splicing regulation. (B) Increased relapse following hematopoietic cell transplantation in patients with high mutation burden, stratified by total number of mutations (≥10 vs. <10), and (C) stratified by number of mutations in epigenetic regulators (≥4 vs. <4; classified in Online Supplementary Table S1). (D) Unsupervised clustering of association (odds ratio, corresponding to the scaling bar) between groups of mutations (signaling pathways, epigenetic regulators, and tumor suppressors), high-risk cytogenetics (cyto), risk stratification systems (CPSS, MDAPS) and relapse. CMML with a high mutation burden in epigenetic regulators (epigene) was distinct from previously recognized high-risk diseases by cytogenetic abnormalities, blast count, and mutations in tumor suppressors (red boxes). (E) Time from diagnosis to transplant. High mutation burden (≥10), in particular, in epigenetic processes (≥4), was associated with a longer interval from diagnosis to transplant, consistent with the concept of disease evolution and acquisition of more mutations (in epigenetic but less so in signaling pathways) with disease duration *P<0.05 (individual values in Online Supplementary Table S3). **P=0.01, ***P=0.03.