INTRODUCTION: The current WHO definition requires presence of persistent absolute monocytosis for the diagnosis of chronic myelomonocytic leukemia (CMML). Oligomonocytic CMML (O-CMML), defined by presence of clinical and pathological features of CMML in the presence of an absolute monocyte count (AMC) of 0.5-0.9x109/L and ³10% monocytes, has been proposed as a unique entity. To date, there is scarce data on the clonal architecture, optimal therapeutic management and survival outcomes of these patients (pts) compared to those with classical CMML.
METHODS: We evaluated all untreated pts who met proposed diagnostic criteria of O-CMML treated at the University of Texas MD Anderson Cancer Center from 2000 to 2020. Whole bone marrow DNA was subject to 81 gene targeted next-generation sequencing (NGS) analysis in a subset of patients. Variant allele frequency (VAF) estimates were used to evaluate clonal relationships within each individual sample using Pearson goodness-of-fit tests and VAF differences. Response to therapy was assessed following MDS/MPN IWG response criteria.
RESULTS: A total of 30 pts met criteria for O-CMML. Compared to a cohort of 271 pts with classical CMML, there were no significant differences in cytogenetic abnormalities based on CMML-specific prognostic scoring system (CPSS). NGS was available in 10 (33%) patients with O-CMML. Frequency of identified mutations and their VAFs are shown in Figure 1A and compared to that of the CMML cohort. Frequencies of mutations in ASXL1 (50% vs 49.1%, p=0.958), SRSF2 (60% vs 39.4%, p=0.198), TET2 (70% vs 49.1%, p=0.199) and RUNX1 (20% vs 19.4%, p=0.965) were similar in O-CMML and CMML with RAS pathway mutations (NRAS, KRAS, CBL, NF1, SETBP1, PTPN11) being more frequent in CMML compared to O-CMML (51.4% vs 20%, p=0.053). The median number of mutations was 4 (range 1-12), and 4 (range 0-8) in O-CMML and CMML (p=0.578), respectively. No significant differences in median VAFs for ASXL1 (28.2% vs 33.5%, p=0.503), SRSF2 (41.1% vs 45.7%, p=0.743), TET2 (30.4% vs 42.6%, p=0.342), RUNX1 (26.9% vs 32.7%, p=0.837), and RAS pathway mutations (21.6% vs 23%, p=0.197) were observed between both groups. Frequencies at which each mutation appeared as a dominant or minor clone are shown in Figure 1B. Mutations in RAS pathway were more likely to appear as minor clones in patients with O-CMML (71% vs 50%, p<0.001). Among O-CMML patients, therapy consisted of hypomethylating agents (HMA) in 17 (57%), intensive chemotherapy in 2 (9%) and other investigational agents in 4 (17%) pts. When evaluating pts treated with HMA, those with O-CMML had a higher complete response rate (53% vs 27%, p=0.032) and significantly longer median response durations compared to CMML (14.4 vs 6.6 months, p=0.046). A total of 6 (20%) patients underwent allogeneic stem-cell transplantation. Twelve (40%) pts progressed to CMML within a median of 13.5 months (range 3.8-102.8 months). Univariate analysis for survival revealed that diagnosis of O-CMML (HR 0.39, 95% CI 0.21-0.75, p=0.04), age (HR 1.06, 95% CI 1.00-1.13, p=0.039), and CPSS int-2/high (HR 2.59, 95% CI 1.72-3.89, p<0.001) predicted for OS. By multivariate analysis for OS, both age (HR 1.03, HR 1.01-1.51, p=0.003) and CPSS int-2/high (HR 2.63, 95% CI 1.73-3.98, p<0.001), but not O-CMML (HR 0.59, 95% CI 0.31-1.14, p=0.120) retained their significance. Pts with int-2/high CPSS O-CMML had similar outcomes to low/int-1 CMML (Figure 1C). Pts with low/int-1 O-CMML had a trend to improved outcomes and those with int-2/high CMML had significantly worse survival (Figure 1C).
CONCLUSIONS: This data supports the revision of AMC threshold for the diagnosis of CMML. This data also supports that clinical and mutational features should guide confirmation of the diagnosis of CMML.
Sasaki:Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Syros: Honoraria; Novartis: Consultancy. Konopleva:Genentech: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Calithera: Research Funding; Agios: Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; DAVA Oncology: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Samus Therapeutics: Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding. Kadia:Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Pulmotec: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding. Ravandi:Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Abbvie: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Adaptive biotechnologies: Honoraria; Jazz: Research Funding; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy.
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