Abstract Background: The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high risk groups (Blood 2025; blood.2024027170. doi: https://doi.org/10.1182/blood.2024027170). The objective of the current study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk category. Methods: CMML diagnosis and sub-categorization were according to the International Consensus Classification, which included CMML1 (bone marrow/peripheral blood blasts 10%/5%) vs CMML-2 (bone marrow/peripheral blood blasts ≥10%/≥5%) and CMML-MP (leukocytes ≥13 x 10⁹/L) vs. CMML-MDS (leukocytes 13 x 10⁹/L) Arber et al. Blood 2022;140:1200. The BLAST score is based on clinical risk factors including circulating blasts ≥2%, leukocytes ≥13 x 10⁹/L, and severe or moderate anemia whereas BLAST-Mol also accounts for mutations and karyotype. Comparative parameters and overall survival (OS) were calculated from the time of initial CMML diagnosis for both the transplant and non-transplant groups. Statistical analyses were performed using JMP Pro 17.1.0, (SAS Institute, Cary, NC, USA). Results: A total of 775 consecutive Mayo Clinic patients with CMML (68% males, median age 71 years) were included in the current retrospective study (1994-2024). At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Compared to those in the non-ASCT cohort (N=624), patients who underwent ASCT were younger (median age 61 vs. 73 years; p=0.01) and were more likely to have CMML-2 (22% vs 12%; p0.01) or high-risk BLAST-Mol (34% vs 21%; p=0.03) categories. Otherwise, BLAST clinical risk distribution and specific mutational frequencies were similar between the ASCT and non-ASCT cohorts. Overall, OS was longer in the ASCT (median 77 months; HR 0.3, 95% CI 0.28-0.46; p0.01), compared to the non-ASCT (median 28 months), cohort. The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; HR 0.19, 95% CI 0.1-0.3; p0.01), intermediate-risk (81 vs. 28 months; HR 0.2, 95% CI 0.1-0.4; p0.01), and low-risk (111 vs. 65 months; HR 0.6, 95% CI 0.3-0.99; p=0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of 0.01, 0.01, and 0.08. The survival benefit of ASCT was individually ascertained for most unfavorable (ASXL1 p0.01; SETBP1 p0.01; NRAS p=0.02; RUNX1 p=0.02; U2AF1 p=0.04; DNMT3A p=0.06) and favorable (TET2 p0.01; PHF6 p=0.07) mutations as well as unfavorable karyotype (p0.01). CMML patients who received transplant without history of blast transformation (BT) and with bone marrow blast percentage 5% at the time of ASCT had the best survival outcome with median survival that was not reached and with 5/10-year survival rate of 66%/60%. By comparison, median survival was 44 months for patients with pre-transplant history of BT (HR 0.4, 95% CI 0.2-0.6) and 74 months for transplanted patients without history of BT but bone marrow blast percentage of 5% or more at the time of ASCT (HR 0.5, 95% CI 0.2-0.9). For reference, median survival was 31 months for non-transplanted patients without history of BT (HR 0.2, 95% CI 0.1-0.3), and 21 months for their counterparts with history of BT (HR 0.2, 95% CI 0.1-0.2). In multivariable analysis (MVA), predictors of superior OS in the ASCT cohort included bone marrow blasts less than 5% at the time of ASCT (HR 0.4, 95% CI 0.2-0.8; p=0.02), absence of BT prior to ASCT (HR 0.4, 95% CI 0.2-0.7; p0.01), normal karyotype at time of diagnosis (HR 0.5, 95% CI 0.3-0.9; p=0.02), and CMML-1 vs. CMML-2 (HR 0.5, 95% CI 0.3-0.9; p=0.03). A similar analysis of parameters at diagnosis in the non-ASCT cohort identified CMML-MP (p0.01), CMML-2 (p0.01), ASXLMUT (p0.01), DNMT3AMUT (p0.01), TET2WT (p0.01), male gender (p=0.03), and unfavorable karyotype (p=0.02) as independent risk factors for OS. Conclusions: The current study highlights the benefit of ASCT for all three BLAST and BLAST-Mol risk groups in CMML and its potential to overcome the adverse impact of high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.
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