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687 Clinical and Genomic Characterization of Secondary Acute Myeloid Leukemia with Mixed Phenotype

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical and Epidemiological: Outcomes and Omics Potpourri
Hematology Disease Topics & Pathways:
Epidemiology, AML, Clinical Research, Clinically Relevant, Diseases, Myeloid Malignancies
Monday, December 13, 2021: 3:15 PM

Pallavi Galera1*, Alexander Chan2*, Andriy Derkach, PhD3*, Ying Liu1*, Jeeyeon Baik4*, Christopher Famulare, MS5*, Allison Sigler1*, Maria E. Arcila, MD6*, Douglas A Mata1*, Ahmet Dogan, MD, PhD7, Martin S. Tallman, MD8, Ross L. Levine, MD9, Yanming Zhang, MD10, Mikhail Roshal, MD, PhD4, Jacob L Glass, MD, PhD9 and Wenbin Xiao4

1Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Pathology, Memorial Sloan Kettering Cancer Center, NEW YORK, NY
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
4Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
5Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
6Molecular Diagnostic Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
7Department of Pathology, Hematopathology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
8Memorial Sloan-Kettering Cancer Center, New York, NY
9Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
10Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

INTRODUCTION

Mixed phenotype (MP) is characteristic for de novo mixed phenotype acute leukemia (dnMPAL) but can also be seen in blast phase of myeloproliferative neoplasms (MPN-BP), myeloid/lymphoid neoplasms with eosinophilia & rearrangements, acute myeloid leukemia (AML) with recurrent cytogenetic abnormalities (AML-RCA) and secondary AML (sAML) including AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML). Although WHO classification excludes sAML with MP (sAML-MP) from dnMPAL, the significance of MP in the setting of sAML and their genetic landscape has not been studied.

METHODS

The MSKCC pathology data base was searched from 01/2014 to 09/2020 and a cohort of 125 patients with MP as defined per WHO 2016 classification was obtained. The clinical, morphologic, immunophenotypic, and cytogenetic/molecular results were reviewed. Patients with a diagnosis of AML-RCA, myeloid/lymphoid neoplasms with eosinophilia & rearrangements, MPN-BP, B-ALL with isolated MPO and myelodysplastic syndrome (MDS) were excluded (Fig 1).

RESULTS

50 cases of sAML-MP (14 t-AML and 36 AML-MRC) were retrieved and compared to 42 dnMPAL cases and 100 sAML without MP (37 t-AML and 63 AML-MRC) (Table 1). The median age at diagnosis was 66 years which was higher than dnMPALs (44.5 yrs, p value <0.0001) and similar to sAML without MP. sAML-MP showed slight male preponderance (M:F=1.6). Out of the 50 cases; 26, 19 and 5 revealed B/Myeloid(B/M), T/M and B/T/M phenotype, respectively. The WBC, platelet and peripheral blood blast counts were all higher in the dnMPAL cohort. 37 cases of sAML-MP and 65 sAML without MP revealed MDS defining cytogenetic abnormalities. In comparison in the dnMPAL cohort, 5 revealed complex karyotype (CK) but with balanced translocations, 1 showed a hyperdiploid clone and 1 T/B phenotype case revealed CK.

Molecular studies (Table 2) revealed that the most commonly mutated genes in sAML-MP were RUNX1, DNMT3A, TP53 which were all present in a significantly higher frequency in comparison to dnMPAL. The frequency of RUNX1 mutation was higher in sAML-MP even in comparison to sAML without MP. Conversely, mutations in PHF6 frequently noted in dnMPALs were uncommon in sAML cohorts. Cluster analysis based on immunophenotyping of the 3 cohorts revealed 6 clusters (Fig 2) with separation between the 3 cohorts. Most of the dnMPAL with B/M phenotype formed a distinct tight cluster (cluster 3). Most of the sAML-MP were seen clustering together in cluster 4 whereas sAML without MP predominated in cluster 5 and 6. Cluster 1 revealed a mixture of dnMPAL and sAML-MP with predominantly T/M phenotype.

The overall survival (OS) was inferior in the sAML-MP cohort in comparison to dnMPAL cohort (median survival: 6.77 vs 36.99 mths, p value 0.00005; Fig 3A) and was similar to the sAML without MP cohort (median survival: 6.77 vs 4.96 mths, p value 0.33; Fig 3A). In a multivariate analysis, model adjusted for the age and allotransplant did not explain difference in OS between these groups. Comparison of OS between the 6 clusters (Fig 3B) revealed better OS in clusters 2 and 3 that were enriched for dnMPAL. Cluster1 in spite of having a mixture of dnMPAL and sAML-MP did poorly. This could be driven by enrichment in DNMT3A mutations in the dnMPAL with T/M phenotype.

Immunophenotypically distinct blast populations were flow cytometrically sorted in 4 cases of sAML-MP (2 each with T/M and B/M phenotype). While the majority of the genetic abnormalities were shared between populations with different lineages, a case with multiple mutations showed divergent KRAS/NRAS mutations showing clonal divergence as possible late event driving distinct lineage maturation (Table 3).

CONCLUSION

sAML-MP and sAML without MP are clinically similar and have biological overlaps with frequent somatic mutations in TP53, chromatin modifying genes and spliceosome-complex genes, which is different from dnMPAL. However, the frequency of RUNX1 mutation is higher in sAML-MP than sAML without MP suggesting its role in lineage infidelity. Though, cluster analysis based on immunophenotype separates the 3 cohorts into enriched clusters, there are still overlaps between sAML-MP and dnMPAL especially with a T/M phenotype as well as between sAML-MP and sAML without MP especially in TP53 mutated cases. Additional RNA seq and ATAC seq are currently being performed on flow cytometrically sorted distinct blast populations of the sAML-MP cases.

Disclosures: Galera: Paige.AI: Research Funding. Dogan: Physicians’ Education Resource: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; EUSA Pharma: Consultancy; Roche: Consultancy, Research Funding; Peer View: Honoraria. Tallman: Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Levine: Celgene: Research Funding; Incyte: Consultancy; Roche: Honoraria, Research Funding; Morphosys: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Amgen: Honoraria; Gilead: Honoraria; Zentalis: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees. Roshal: Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services. Glass: GLG: Consultancy. Xiao: Stemline Therapeutics: Research Funding.

*signifies non-member of ASH