Allogenic Hematopoietic Cell Transplantation (HCT) for Chronic Myelomonocytic Leukemia: Clinical, Cytogenetic, and Mutational Risk Factors Associated with Survival

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by persistent monocytosis, combined with myeloid proliferation and dysplasia. Here, we report HCT outcomes in 129 patients (pts) with CMML, 7-74 (median 55) years of age, with follow-up extending to 25 years. Patients were conditioned with various intensity regimens and transplanted from related (N=45) or unrelated donors (N= 84). The source of stem cells was marrow in 34, "mobilized" peripheral blood cells in 93, and cord blood in 2 patients. The HCT-CI was 0-11 (median 3). Somatic mutations present pre-HCT were analyzed with a mutation panel sequencing for 75 genes. Fig. 1A and 1B show overall survival by WHO disease criteria and the Spanish cytogenetic classification, respectively. Acute graft-versus-host disease (GVHD) grades II-IV occurred in 74% and chronic GVHD in 43%. Relapse incidence was 32%. Overall and progression-free survival at 10 years was 28% and 29%, respectively. Multivariate regression models showed the following: Blast count >20% at HCT (CMML-T: HR 1.67, CI 0.9-3.2, p=0.13, Fig. 1A), high-risk cytogenetics (HR 1.88, CI 1.2-3.0, p=0.01, Fig. 1B) and high HCT comorbidity index (HCT-CI≥4: HR 1.99, CI 1.2-3.4, p=0.01, Fig. 1 C) negatively impacted survival. There were 52% and 42% of patients who carried mutations in ASXL1 and TET2 and they were not significantly associated with inferior survival (ASXL1: HR=1.6, CI 0.3-7.6, p=0.54, TET2: HR=1.3, CI 0.4-3.9, p=0.63). Mutations in ATRX (HR=17.3, CI 4.1-73, p=0.0005) and WT1 (HR=6.3 CI 1.6-24, p=0.01), however, were associated with inferior survival. The total number of mutations (> 10 mutations, HR=3.5, CI 1.4-7.3, p=0.02) and more mutations in genes regulating epigenetic processes (HR 1.8, CI 1.1-2.8, p=0.01) were associated with relapse. The molecular CMML-specific prognostic scoring system (CPSS-Mol, Elena et al. 2016) was not correlated with relapse or survival. Unsupervised clustering of the correlation matrix revealed distinct associations between mutations and clinical features (Fig. 2), Group 1, proliferative type (mutations in mitotic signaling pathways associated with high WBC/blast counts and high risk disease by prognostic scoring systems), and Group 2, dysplastic type (mutations in genes regulating epigenetic processes including ATRX and WT), which was associated with unfavorable outcome. In summary, a proportion of patients with CMML achieve lasting remissions following HCT. However, relapse and overall mortality remain high. Molecular annotation uncovered distinct subgroups of CMML, and higher number of mutations, in particular, of epigenetic regulators, may confer unfavorable transplant outcomes. Incorporation of mutations in addition to cytogenetics and comorbidity scores should improve transplant prognostication.