Outcomes of Patients with Acute Myeloid Leukemia (AML) with Myelodysplasia Related Changes (AML-MRC) Are Dependent on Diagnostic Criteria and Therapy
Authors: Montalban Bravo Guillermo , Kanagal-Shamanna Rashmi , Sasaki Koji , Ravandi Farhad , Cortes Jorge E. , Daver Naval G. , Takahashi Koichi , DiNardo Courtney D. , Jabbour Elias , Borthakur Gautam M. , Naqvi Kiran , Konopleva Marina Y , Pierce Sherry A. , Bueso-Ramos Carlos E. , Patel Keyur P. , Kantarjian Hagop M. , Garcia-Manero Guillermo , Kadia Tapan M. 
Published: November 2019

INTRODUCTION: AML with myelodysplasia related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, presence of myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. Defining the outcomes within this heterogeneous subgroup of pts is necessary to select optimal therapy.
METHODS: We evaluated all pts with AML-MRC diagnosed and treated at our institution from 2013 to 2018. All cases where reviewed by 2 hematopathologists to establish diagnosis of AML-MRC following WHO 2017 criteria. Patients with therapy-related myeloid neoplasms were excluded. Sequencing data was obtained by use of an 81-gene targeted, next generation sequencing (NGS) platform. Pts were classified into 4 categories: 1) AML-MRC was based on cytogenetic abnormalities (AML-MRC-C) in pts with definitory cytogenetic abnormalities; 2) AML-MRC with history of prior MDS or MDS/myeloproliferative neoplasm (MDS/MPN) in 103 (25%) pts (AML-MRC-H); 3) AML-MRC with history of prior therapy for antecedent MDS or MDS/MPN (AML-MRC-S) and 4) AML-MRC with presence of &gt;50% dysplasia in 3 lineages (AML-MRC-M) in pts with compatible morphologic features but none of the prior. We reviewed response and survival outcomes based on subgroup, therapy, and clinic-pathologic factors.
RESULTS: A total of 415 pts with AML-MRC where identified. Median age at diagnosis was 70 years (range 18-94). A total of 243 (59%) pts had AML-MRC-C, 47 (11%) had AML-MRC-H, 28 (7%) had AML-MRC-S and 97 (23%) had AML-MRC-M. Among pts with a prior history of MDS or MDS/MPN, 23 (22%) had received therapy with hypomethylating agents, 1 (1%) with lenalidomide and 3 (3%) with ruxolitinib and 1 with 7+3 (1%) (these were categorized as AML-MRC-S). Median bone marrow blast percentage on aspirate was 35% (range 1-97%). Among pts with AML-MRC-C the defining cytogenetic abnormality included: complex karyotype in 186 (77%), monosomy 5 or del(5q) in 14 (6%), monosomy 7 or del(7q) in 38 (16%), concurrent chromosome 5 or 7 abnormalities in 2 (1%), del(13q) in 2 (1%) and i(17) in 1 (0.5%) pt. Data on NGS was available in 95 pts. Identified mutations are shown in Figure 1A. Mutations in TP53 where more commonly observed in pts with AML-MRC-C (p=0.001). Prior publications (Lindsley et al Blood 2015) have shown that secondary-type mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2) identify a subset of pts with AML with worse than expected outcomes. Among evaluable pts, a total of 37 (39%) pts had secondary-type mutations. Based on variant allele frequency of identified mutations, mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. A total of 73 (18%) pts received therapy with single agent hypomethylating agents (HMA), 67 (16%) with HMA in combination with investigational drugs, 86 (21%) with low-dose cytarabine (LDAC) based therapies and 119 (29%) with intensive chemotherapy. Response outcomes on evaluable pts are shown in Figure 1B. With a median follow up of 28.3 months (95% CI 25.7-30.9 months) the median overall survival (OS) was 10.5 months (95% CI 9.1-12.0 months). Pts with AML-MRC-M and AML-MRC-H had significantly better outcomes than those with AML-MRC-C or AML-MRC-S (overall p&lt;0.001, Figure 1C). Among pts with AML-MRC-C those with complex karyotype had significantly worse outcomes than those with other defining cytogenetic abnormalities (p&lt;0.001). Pts treated with intensive chemotherapy had improved OS compared to those treated with other forms of therapy (p=0.002, Figure 1D). However, when evaluating outcomes by AML-MRC subtype, use of intensive therapy was only associated with improved survival on AML-MRC-M (overall p=0.039, Figure 1E) but not in AML-MRC-C or AML-MRC-H (data not shown). No significant differences in OS were observed in pts with secondary-type mutations (p=0.568) but, among pts with AML-MRC-M presence of these mutations was associated with a trend to worse OS (median OS 3.8 months vs NR, p=0.228).
CONCLUSION: AML-MRC is a heterogeneous group of AML with diverse mutational abnormalities and outcomes. Selection of therapy should be based on cytogenetic abnormalities and AML-MRC subtype.
Figure 1

Disclosures
Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Borthakur:GSK: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding. Konopleva:Calithera: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Astex: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.