Outcomes of Chronic Myelomonocytic Leukemia (CMML) after Hypomethylating Agent (HMA) Failure
Authors: Guerra Veronia , Ramos Perez Jorge M. , Hammond Danielle , Chien Kelly S. , Kanagal-Shamanna Rashmi , Naqvi Kiran , Sasaki Koji , Paul Shilpa , Kadia Tapan M. , DiNardo Courtney D. , Konopleva Marina , Daver Naval , Ravandi Farhad , Pemmaraju Naveen , Short Nicholas J. , Issa Ghayas C. , Takahashi Koichi , Estrov Zeev E. , Pierce Sherry A. , Kantarjian Hagop M. , Garcia-Manero Guillermo , Montalban Bravo Guillermo 
Published: February 2021

Introduction: Hypomethylating agents (HMA) are effective therapies in chronic myelomonocytic leukemia (CMML), with an overall and complete (CR) response rates that range from 40-75% and 19-40% between studies, respectively. HMA therapy is associated with an overall survival (OS) of 12-24 months. However, the rate of HMA failure is 50% and is associated with a poor prognosis with an OS of 4-7 months. Defining predictors of HMA failure and optimal management of these patients (pts) is essential.
Methods: We studied 157 pts with CMML treated with HMA between May 2010 and April 2020, whose bone marrow samples were analyzed by target next-generation sequencing. We performed chart review to obtain treatment responses and analyze correlations between clinical, cytogenetic and molecular characteristics and HMA failure. Primary objective was to determined risk factors associated with HMA failure. Secondary objectives include overall response rates (ORR) by 2015 IWG response criteria for MDS/MPN, overall survival (OS) and transformation-free survival (TFS) after HMA failure for CMML.
Results: A total of 95 pts had HMA failure (61%), 59 pts (38%) with primary failure and 36 pts (23%) with secondary failure, with median time to HMA failure of 11 months (mo) (9 mo primary failure vs. 21 mo for secondary failure). Seventy-one pts (75%) were &gt;65 years, and most pts were male (72%) with 16% having proliferative CMML (MP-CMML). Most patients had a normal karyotype (57%). Baseline characteristics are listed in Table 1. The most frequent mutations at diagnosis were TET2 (53%), SRSF2 (48%) and ASXL1 (46%). We analyzed the risk factors associated with HMA failure by logistic regression analysis. Univariate analysis (UVA) showed a significant association of ASXL1 mutation and HMA failure (Odds ratio OR 2.26, P value = 0.016). There was a tendency towards higher risk of failure in pts with MP-CMML (OR 1.57, p= 0.065) and SRSF2 mutation (OR 2.05, P=0.084) (Figure 1). The most common somatic mutations at HMA failure were ASXL1 (55%), SRSF2 (44%), TET2 (43%) and NRAS (32%) (Figure 2). Emergence of previously not detected mutations occurred in 59% of pts and included: NRAS (14%), ASXL1 (9%) and IDH1 (8%), with 18% of pts having cytogenetic evolution. IDH1 mutation was significantly associated with CMML blast transformation (Figure 2). The rate of CMML blast transformation after HMA failure was 14%. Of the 73 pts with CMML after HMA failure 45 received therapy and were eligible for response. Therapies included HMA single agent (47%), HMA combination therapy (ruxolitinib, rigosertib or ipilimumab) (24%), chemotherapy (13%) and other investigational therapies (16%). Pts with CMML blast transformation were included in AML protocols, with high-intensity chemotherapy (35%) or low-intensity therapies (65%). Among pts with CMML after HMA failure, the ORR was 16%, with 13% mCR and 2% HI and 13% progression to AML (Table 2). There was no difference in the ORR by therapy, or type of HMA failure with 16% with HMA single agent, 18% with HMA combination and 17% after chemotherapy, and ORR was 12% for primary failure and 21% for secondary failure. Of the 6 pts (13%) that underwent HSCT, no patient relapse and 1 pt died from infection 6 months after HSCT. A total of 40 pts died (55%), 12 pts from infections (30%), 4 pts progressive disease (10%), 3 pts due to other malignancies (8%) and 1 pt from bleeding (3%). With a median follow up of 20 months, the OS was 11 months for CMML and 5 mo for CMML blast transformation (p=0.002) (Figure 3 A). The OS after HMA failure was 23 mo for primary failure (23 mo for 1ry failure with lack of HI and 6 mo for 1ry failure with no response or progressive disease) and 6 mo for secondary failure (p= 0.120). Risk factors associated with worse OS by UVA included cytogenetic clonal evolution (Figure 3B), male gender, anemia, RUNX1 and TP53 mutations. Hematologic stem cell transplant was associated with improved OS (NR vs 6 months, HR 0.08, p=0.017).
Conclusions: HMA failure occurs in 60% of pts with CMML and is associated with ASXL1 mutations. Emergence of mutations at progression are common (59%) and more frequently involve the RAS pathway, IDH1 and ASXL1 mutations. The rate of AML transformation in CMML with HMA therapy is 14%. HMA failure is associated with poor prognosis, with an OS of 11 months. Cytogenetic evolution, anemia, RUNX1 and TP53 mutations are associated with worse OS in pts whose disease experiences HMA failure.

Disclosures
Sasaki: Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Kadia:Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Honoraria; Astellas: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding. DiNardo:Calithera: Research Funding; Novartis: Consultancy; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Konopleva:AstraZeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: 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; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Agios: Research Funding; Calithera: Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy. 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; Daiichi Sankyo: 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. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Pemmaraju:Plexxikon: Research Funding; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria. Short:Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Kantarjian:Aptitute Health: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; BMS: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Garcia-Manero:H3 Biomedicine: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Amphivena Therapeutics: Research Funding.