Predictors of Blast Transformation (BT) and Post-BT Survival in Chronic Myelomonocytic Leukemia (CMML)

Introduction

Chronic myelomonocytic leukemia (CMML) is associated with a 15-30% risk for blast transformation (BT) over 3-5 years. Post-BT survival remains dismal with a median overall survival (mOS) of ~6 months (mo), even with intensive therapies. Although genetic drivers are identified in >40% of BT-CMML cases (Carr, 2021), mechanisms of BT remain to be elucidated. This multicenter study examines risk factors for BT in CMML and predictors of post-BT survival.

Methods

CMML patients at Mayo Clinic (n = 400, 47%) and MD Anderson Cancer Center (n = 449, 53%) were included with IRB approval. Analyses used clinical and molecular data at diagnosis or first referral in chronic phase (CP) and again at BT. Categorical variables were compared by Chi squared and continuous by Mann-Whitney U or Kruskal-Wallis tests. Multivariate analyses used Cox proportional hazards models with binarization via receiver operator curves. Kaplan-Meier analyses were censored at hematopoietic cell transplantation (HCT). P < 0.05 was considered significant. Calculations used BlueSky (v10.3.1) or Prism (v10.2.3).

Results

Of 849 CMML patients (median age 71 years, 32% female, 90% white) included in the study, 133 (16%) underwent BT. In comparison to CP-CMML without BT, those with BT were more likely (p < 0.05) to have had higher WBC counts (15.1 vs 11.4 x10⁹/L), higher absolute monocyte counts (2.9 vs 2.2 x10⁹/L), lower platelet counts (84 vs 102 x10⁹/L), have circulating immature myeloid cells (52% vs 37%), and be classified as myeloproliferative (MP)-CMML (58% vs 44%) or CMML-2 (33% vs 17%) at diagnosis/first referral in CP.

More mutations were detected in BT-CMML than in CP-CMML (mean 3.2 vs 2.8, p = 0.002). Mutations in RAS (NRAS, KRAS, BRAF, CBL, PTPN11; 51% vs 40%, p = 0.02) and signaling (CSF3R, FLT3, JAK2, SH2B3; 15% vs 7%, p = 0.004) pathway genes were more frequent in BT-CMML. Conversely, there were fewer BT-CMML patients with the favorable ASXL1^WT/TET2^MT genotype compared to CP-CMML (22% vs 33%, p = 0.004).

Multivariate analysis identified MP-CMML (hazard ratio [HR] 1.5, p = 0.04), CMML-2 (HR 2.4, p < 0.001), and the presence of ≥4 somatic gene mutations (HR 1.8, p = 0.002) as risk factors for BT whereas the ASXL1^WT/TET2^MTgenotype was protective (HR 0.45, p = 0.002). The ASXL1^WT/TET2^MT genotype was also protective in the MP-CMML (HR 0.49, p = 0.04) and RAS-mutated (HR 0.35, p = 0.005) subgroups. Amongst BT-CMML cases, the median time to BT was 10 mo from diagnosis/referral.

Compared to their CP assessment, patients in an overlapping Mayo Clinic BT-CMML cohort (n = 156, median age 69 years, 35% female) were more likely to have NPM1 (24% vs 3%, p < 0.001) and IDH2 (14% vs 1%, p = 0.01) mutations at BT. Amongst cases with paired molecular evaluations (n = 44), 7 (16%) acquired new mutations, including FLT3-ITD (n = 2) and NPM1 (n = 2). Conversely, 6 (14%) lost mutations, including TET2 (n = 3), SRSF2 (n = 2), CBL, NRAS, or PTPN11 (n = 1 each). There were no differences in variant allele fractions in driver genes present at CP and BT. Abnormal karyotypes were more prevalent at BT than in CP (60% vs 34%, p < 0.001), and 26 (25%) patients with a normal karyotype in CP acquired structural (65%) and/or numerical (69%) changes at BT, including 6 (23%) that acquired a complex karyotype. Acute myeloid leukemia defining translocations were seen in 4 (4%) cases: 2 with t(8;21) and 1 each with inv(3) and t(10;11)(KMT2A::TET1).

After considering mutation and karyotype changes, only bone marrow blasts ≥30% (HR 1.7, p = 0.04) were independently prognostic for OS after BT (mOS 4 mo). Compared to supportive care (n = 50, mOS 1.3 mo), OS was improved by hypomethylating agents (HMA, n = 14, mOS 16 mo, HR 0.3, p < 0.001) or induction chemotherapy (n = 56, mOS 8 mo, HR 0.3, p < 0.001), but not by HMA + venetoclax (n = 11, mOS 6 mo, HR 0.7, p = 0.4). Allogeneic HCT (n = 28) improved mOS to 46 vs 3 mo (p < 0.001).

Amongst 4 patients with paired whole genome sequencing before and after BT, 3 had increased copy number alterations (including 2 with loss of heterozygosity, 2 with gains, and 3 with deletions) while the 4^th acquired novel likely pathogenic somatic mutations (MUC4, BAX, WNK2).

Conclusions

Survival in CMML after BT remains exceptionally poor. In this multicenter cohort, MP-CMML, CMML-2, and the presence of ≥4 somatic gene mutations were identified as risk factors for BT, with the ASXL1^WT/TET2^MT genotype being protective. Following BT, bone marrow blast burden ≥30% was an independent adverse predictor of survival.

Loghavi:Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Gangat:DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board. Mangaonkar:BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Garcia-Manero:Curis: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Astex: Other: Personal fees; Novartis: Research Funding; Amphivena: Research Funding; Helsinn: Research Funding; Genentech: Other: Personal fees; Genentech: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Astex: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Janssen: Research Funding; Aprea: Research Funding; Helsinn: Other: Personal fees; Forty Seven: Research Funding. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Patnaik:StemLine: Research Funding; Polaris: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Solu therapeutics: Research Funding; Kura Oncology: Research Funding; Epigenetix: Research Funding.