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2811 Predictors of Outcomes in Adult AML with MLL Rearrangements

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
AML, Adult, Diseases, Study Population, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Ghayas C. Issa, MD1, Jabra Zarka, MD1*, Koji Sasaki, MD1, Daewoo Pak, PhD2*, Jing Ning, PhD2*, Nicholas J. Short, MD1, Elias Jabbour, MD1, Tapan M. Kadia, MD3, Gautam Borthakur, MD3, Guillermo Garcia-Manero, MD3, Michael Andreeff, MD, PhD4, Hagop M. Kantarjian, MD5 and Farhad Ravandi, MBBS1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX
5University of Texas MD Anderson Cancer Center, Houston, TX

Background: Rearrangements of the mixed-lineage leukemia gene (MLLr) cause a unique group of acute leukemias with variable phenotypes but a universally adverse prognosis. Determinants of response in AML with rearrangements of the MLL gene are unknown.

Objective: To determine the mutational profile, phenotypic and clinical characteristics of MLLr AML.

Methods: We screened adult patients (pts) with AML treated at our center between 1990 and 2019. 393/9465 pts (4%) with MLLr AML were identified. Among them, 174 pts had newly diagnosed AML and are the focus of this analysis; we compared their outcomes to 522 age-matched pts (19%) with newly diagnosed AML and diploid karyotype (DK). From 2012, next-generation sequencing panels were used to detect genes recurrently mutated in myeloid neoplasms. Baseline characteristics were assessed and overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test.

Results: MLLr patients were younger than Pts with DK (median age: 51 vs 61 years, P<0.0001) and had higher baseline LDH (median: 1783 vs 1358 U/L for DK), and bone marrow blast % (median: 66% vs 53%), but lower platelet counts (median: 57 vs 71 x109/L, P< 0.02). Most common rearrangements were due to t(9;11) in 97 pts (56%), t(11;19) in 30 pts (17%), t(6;11) in 19 pts (11%), and (v;11q23.3) in 28 pts (16%). 65 (37%) MLLr patients had therapy-related (t-AML) (vs 9% of DK, P<0.0001). Pts with MLLr AML had fewer mutations than DK (median 0.5 vs 1.2 mutation/patient P<0.0001), most commonly affecting the RAS and TP53 genes. Notably, compared to DK, mutations in FLT3 (12% vs 34%, P<0.0001), IDH1/2 (7% vs 32%, P<0.0001) and DNMT3A (5% vs 30%, P<0.0001) were less frequent in MLLr. The majority of pts with MLLr had a monocytic/myelomonocytic phenotype (64% vs 28%, P=<0.0001). Blasts in MLLr had lower expression of CD7 (median: 6% vs 14%), CD13 (median: 58% vs 74%), and CD34 (median: 16% vs 38%), and higher CD33 (median: 94% vs 82%) (P<0.001).

Pts with MLLr had a similar response rate to age matched pts with DK (CR/CRi: 82 vs 80%, P=0.7) but worse OS (median: 0.9 vs 2 years, P<0.0001). Pts with t-AML and MLLr had significantly worse OS vs non-t-AML with MLLr (median OS of 0.5 vs 1.2 years, P<0.0001). In a landmark analysis, allogeneic hematopoietic stem cell transplant (HSCT) in first complete response (CR) was associated with markedly improved outcomes in MLLr AML (median OS of 10.7 vs 1.1 years, P<0.0001). In a multivariate analysis of factors predicting overall survival in MLLr AML, HSCT was associated with a lower risk of death with a HR of 0.38 (95% CI 0.24 - 0.58, P <0.0001). The only other predictors identified were elevated creatinine (HR of 1.43, 95% CI 1.12 - 1.83, P=0.004) and an elevated WBC (HR of 1.00, 95% CI 1.00 - 1.01, P<.0002).

Conclusion: MLLr is an uncommon subtype of AML with characteristic molecular and phenotypic features and dismal outcomes. Allogeneic HSCT in first CR is associated with a significantly improved survival. Given the limited progress made in treatment of this entity, novel approaches are needed.

Disclosures: Issa: Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Sasaki: Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Short: Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Jabbour: Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Kadia: Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Astellas: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding. Borthakur: Novartis: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; GSK: Research Funding; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding. Garcia-Manero: Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Andreeff: Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Kantarjian: Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Delta Fly: Honoraria; Jazz: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi: Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH