Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia
Authors: Hammond Danielle , Kadia Tapan M. , DiNardo Courtney D. , Konopleva Marina , Short Nicholas J. , Daver Naval , Ravandi Farhad , Pemmaraju Naveen , Jabbour Elias J. , Chien Kelly S. , Pierce Sherry A. , Kantarjian Hagop , Garcia-Manero Guillermo , Montalban-Bravo Guillermo 
Published: November 2021

Abstract
Background: Despite advances in the treatment of de novo acute myeloid leukemia (AML), AML arising from antecedent chronic myelomonocytic leukemia (herein simply AML-MRC) continues to have dismal outcomes. We sought to describe the clinical features and contemporary determinates of outcomes in AML-MRC, comparing different therapeutic strategies.
Methods: We retrospectively reviewed 141 patients (pts) with AML-MRC evolving from CMML who presented to our institution from 2000 to present. Mutation testing at baseline was performed using 28-gene (n = 30) or 81-gene (n = 26) amplicon-based next-generation sequencing panels. Responses were defined by ELN 2017 criteria. Cox proportional hazard regression and the Kaplan-Meir product limit method were used to study association of variables with relapse-free survival (RFS) and overall survival (OS). OS was defined as the time from institutional AML-MRC diagnosis to death or last follow up and was not censored at date of hematopoietic stem cell transplant (SCT).
Results: Baseline pt and disease characteristics are shown in Table 1. The median age was 70 years with a male preponderance. Forty-nine percent had FAB M4/M5 morphology at leukemic transformation (LT); 3 pts presented as myeloid sarcoma. Cytogenetics were diploid and complex ± -7/7q in 43% and 15% of pts, respectively. ELN cytomolecular risk was poor in 43%. Select mutation frequencies include: ASXL1 (45%), TET2 (43%), SRSF2 (42%), FLT3-ITD (19%), NRAS (14%), KRAS (7%), PTPN11 (6%), NPM1 (5%), IDH1/2 (4%), TP53 (3%), SETBP1 (2%), CBL (1%) and NF1 (1%). Sixty-three percent of pts had ≥1 RAS pathway mutation(s). Median number of therapies for CMML or AML-MRC received prior to presenting to our institution was 1 (range 0-5), and 78% of previously-treated pts had prior hypomethylating agent (HMA) exposure. Treatment details and outcomes are outlined in Table 2. Frontline treatment was HMA/low-dose cytarabine (LDAC)-, AML induction chemotherapy (ICT)- or investigational therapy-based in 34%, 52% and 14% of the 103 pts who received leukemia-directed therapy. Overall CR/CRi rate was 41%, 29% and 5% with frontline, second-line and third-line therapies with a median estimated RFS of 5.9, 1.8 and not estimable (NE) months, respectively. Despite the higher upfront response rate in the ICT-treated subset (CR/CRi 37% HMA/LDAC, 48% ICT, 21% investigational therapy), this did not translate to a statistically significant improvement in RFS (p = 0.424) nor OS (Figure 1, p = 0.882) by treatment strategy. Estimated median OS for the entire treated cohort was 6.7 months (95% CI 5.8, 9.2) whereas it was 21.2 months (95% CI 9.3, NE) for the 9 pts who were bridged to a consolidative SCT in the frontline setting. In univariate analysis, statistically significant predictors of OS &gt;1 year included: baseline PB blasts &lt;10%, higher hemoglobin level, lack of prior treatment for antecedent disease, CR/CRi response and receipt of SCT with initial treatment strategy. In multivariate analysis, only the lack of prior treatment for antecedent CMML/AML-MRC remained a significant predictor of OS (OR 3.4; 95% CI 1.2, 9.5).
Conclusion: These results suggest that regardless of the treatment strategy employed, there are no allograft-sparing therapies which currently improve outcomes in AML-MRC evolving from CMML. While cytomolecular features have demonstrated independent prognostic impact in CMML, they did not here following LT. This underscores the need to develop clinical trials dedicated to this entity, recognizing the unique biological drivers of LT in CMML.
Figure 1 Figure 1.

Disclosures
Kadia: BMS: Other: Grant/research support; Jazz: Consultancy; AstraZeneca: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Amgen: Other: Grant/research support; Liberum: Consultancy; Aglos: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; AbbVie: Consultancy, Other: Grant/research support. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Konopleva: Calithera: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ablynx: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding. Short: Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria. Daver: Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Novimmune: Research Funding; ImmunoGen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Astex: Honoraria, Research Funding. Pemmaraju: Roche Diagnostics: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Clearview Healthcare Partners: Consultancy; MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; Blueprint Medicines: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria.