Clinical Outcomes and Influence of Mutation Clonal Dominance in Oligomonocytic and Classical Chronic Myelomonocytic Leukemia
Authors: Montalban Bravo Guillermo , Kanagal-Shamanna Rashmi , Guerra Veronia , Ramos Perez Jorge M. , Hammond Danielle , Paul Shilpa , Naqvi Kiran , Sasaki Koji , Jabbour Elias , DiNardo Courtney D. , Takahashi Koichi , Konopleva Marina , Pemmaraju Naveen , Kadia Tapan M. , Ravandi Farhad , Daver Naval , Borthakur Gautam , Estrov Zeev E. , Khoury Joseph D. , Loghavi Sanam , Pierce Sherry A. , Bueso-Ramos Carlos E. , Patel Keyur , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: February 2021

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&lt;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&lt;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&lt;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.
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Disclosures
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.