Abstract
BACKGROUND: Acute myeloid leukemia (AML) with RAM immunophenotype is a newly recognized high-risk AML immunophenotypic subcategory characterized by blasts with bright expression of CD56 and weak to absent expression of CD45, HLA-DR, and CD38, as first described by the Children's Oncology Group (COG). The relationship between AML-RAM and other CD56-positive acute leukemias is unclear. The goal of this study is to characterize the clinicopathological characteristics of AML with RAM phenotype and compare them with other CD56 co-expressing acute leukemias. METHODS: From a multi-institutional search, we identified a total of 160 CD56+ acute leukemia cases, including AML-RAM (n = 28), CD56+ acute undifferentiated leukemia (AUL) (n = 11), CD56+ T-lymphoblastic leukemia (n = 39), and CD56+ AML (n = 81). We compared the clinical and pathologic findings of these groups. RESULTS: AML-RAM patients were significantly younger and presented with significantly higher platelet and white blood cell counts and bone marrow (BM) blast percentages when compared to AUL (p > 0.05) and had higher median BM blast percentages than T-ALL and CD56+ AML groups (both p < 0.05). Flow cytometry showed significantly brighter expression of CD56 on blasts as compared to other CD56+ AML cases, partial CD34 expression compared to AUL, and AML, weak-to-absent CD38 expression compared to all groups, and absent HLA-DR and terminal deoxynucleotidyl transferase as compared to AUL and T-ALL (all p < 0.05). The frequency of abnormal karyotypes was significantly higher among RAM when compared to all groups (p < 0.05). Next-generation sequencing profiles differed among the leukemia groups, with significant enrichment of CBFA2T3::GLIS2 fusions (p < 0.05) and TP53 mutations (p < 0.05) in RAM cases compared to other AML control groups, and U2AF1 (p < 0.05), serine and arginine-rich splicing factor 2 (p < 0.05), and BCL6 co-repressor (p < 0.05) mutations compared to AUL. Clinical outcome analysis demonstrated significantly lower 3-year overall survival of the RAM subgroup (36 months) compared to control groups (p = 0.002). CONCLUSION: We find that AML with RAM phenotype occurs primarily in younger ages, with distinct clinicopathological, immunophenotypic, and mutational presentations, and worse prognosis. This diagnosis should be considered in the clinical differential diagnosis of CD56-positive acute leukemias.