Acute myeloid leukemia with RAM immunophenotype: A new underdiagnosed entity

Abstract

Introduction: Acute myeloid leukemia (AML) with RAM immunophenotype is a distinct subtype of AML, as described by the Children's Oncology Group (COG), with characteristic morphological and immunophenotypic properties. It is characterized by strong CD56 expression with dim to negative CD45, HLA-DR, and CD38 expression.It is an aggressive leukemia with a poor response to induction chemotherapy and/or frequent relapses.Methods: Seven cases with the characteristic RAM immunophenotype were identified in this retrospective analysis of newly diagnosed pediatric AML cases from January 2019 to December 2021. Herein, we have critically analyzed their clinical, morphological, cytochemical, immunophenotyping, cytogenetic, and molecular profiles. The patients were traced and followed for their current disease and treatment status.Results: Of 302 cases of pediatric AML (age <18 years), seven cases (2.3%) with the distinct RAM phenotype were observed, with age ranging from 9 months to 5 years.Two patients were misdiagnosed earlier as small round cell tumor because of the strong CD56 positivity and the absence of leukocyte common antigen (LCA), but they were later correctly identified as granulocytic sarcoma. The bone marrow aspirate showed blasts with unusual cohesiveness and clumping with nuclear moulding, mimicking non-hematologic malignancies. Flow cytometry revealed blasts with low side scatter, dim to negative CD45 and CD38, negative cMPO, CD36, and CD11b; moderate to bright CD33, CD117, and bright CD56. The Mean fluorescence intensity (MFI) of CD13 expression was significantly lower as compared to the internal controls. Cytogenetic and molecular studies did not show any recurrent abnormalities.Reverse transcription polymerase chain reaction for CBFA2T3-GLIS2 fusion was performed in 5/7 cases, with one positive result. On clinical follow-up, two patients were refractory to chemotherapy. Six of the seven cases had succumbed to death (duration of survival: 3-343 days after initial diagnosis).Smeeta Gajendra and Shilpa Anupurba contributed equally.

Immunophenotypic clustering in paediatric acute myeloid leukaemia

“…And the prognosis was extremely unfavourable as well (Figure 4C). [23][24][25] This group of cases may be an extension of the RAM phenotype. On the other hand, we found cases of the same molecular subtype may have different outcomes, if the immunophenotype is different, such as KMT2A rearrangements (Figure 4D).…”

“…Both CBFA2T3::GLIS2 and FUS::ERG were positively associated with CD56, while negatively associated with CD38 and HLA-DR, similar to the reported RAM phenotype (RAM phenotype: bright CD56, with negative HLA-DR and dimto-negative CD45 and CD38). [23][24][25] We further conducted unsupervised immunophenotypic clustering and found cases with CBFB::MYH11, KMT2A-r and AML1::ETO fusions were basically mutually exclusively concentrated into separated groups. While NUP98r, RBM15::MKL1 and XPO1::TNRC18 fusions were clustered into one group (Figure 4A).…”