Patient with mixed-phenotype acute leukemia with CBFB rearrangement

Abstract

The patient is a 52-year-old man who presented to our institution with a 3 months history of fevers, gingival swelling, and tender skin lesions on his face, chest, and lower extremities. Complete blood count revealed leukocytosis of 20 10/L with 65% circulating blasts. Bone marrow evaluation confirmed an acute leukemia with 64% blasts and abnormal eosinophilic precursors with coarse basophilic granules. The majority of blasts were myeloperoxidase (MPO)-positive. A bone marrow biopsy showed sheets of immature cells, extensively replacing normal hematopoietic elements. Scattered eosinophils were associated with the leukemic infiltrate. Tissue biopsy of a skin lesion showed involvement by myeloid blasts. Flow cytometric immunophenotyping of the bone marrow aspirate showed two distinct aberrant cell populations. The larger population (90%) showed evidence of myeloid differentiation while a smaller population of cells showed evidence of B-cell differentiation (Figure 1(A,B)) established by the presence of CD19, CD20, and cytoplasmic CD79a expression. Fluorescence in situ hybridization (FISH) performed on the bone marrow aspirate, revealed rearrangement of the CBFB (core binding factor B) gene in 74% of analyzed interphases (Figure 1(C)). Conventional cytogenetic studies showed an abnormal male karyotype with inversion 16, trisomy 8, trisomy 9, and trisomy 22 (48, XY, þ8, þ9, inv (16) (p13.1q22) [1]/ 49, idem, þ22[19]). Gene sequencing studies showed the presence of a FLT3 internal tandem duplication and four distinct RAS mutations [KRAS (G13D) and NRAS (G12C, G12D, and G12S)]. The NRAS mutations were present in mutually exclusive alleles, based on visualization of sequencing data in integrated genomic viewer (IGV). A diagnosis of mixed phenotype acute leukemia (MPAL) (B/myeloid) with CBFB rearrangement was established. Since the majority of blasts showed myeloid differentiation, treatment was initiated with FLAG-IDA regimen for AML with CBFB rearrangement and one dose of gemtuzumab ozogamicin 3mg/m on day 1. Days 21 and 28 bone marrow examinations confirmed achievement of morphologic remission, and flow cytometric immunophenotyping was negative for minimal residual disease (MRD) for both the myeloid and B-lymphoid components. Cytogenetic analysis confirmed response with achievement of diploid cytogenetics. CBFB-MYH11 transcript, however, remained detectable by quantitative real-time PCR (3.18%). The patient subsequently received six cycles of FLAG consolidation with idarubicin added to the fourth consolidation cycle. He remained in MRD-negative remission by flow cytometry. Cytogenetic analysis remained diploid. CBFB-MYH11 transcript decreased significantly by the end of consolidation cycles but remained detectable at a very low level (<0.01%). Therefore, decitabine (20mg/m IV daily for 5 d every 4–6 weeks) was recently started in order to achieve complete molecular response. MPAL is an uncommon entity, representing less than 4% of all acute leukemias [1]. MPAL is defined by an acute leukemia harboring blasts that express antigens of more than one lineage. These can contain distinct blast populations of different lineages (bi-lineal) or a uniform population with expression of multiple lineage-defining antigens. The majority of MPALs exhibit myeloid differentiation with either Bor T-lymphoid differentiation. The two most frequently occurring chromosomal aberrations associated with MPAL are t (9; 22)/BCR-ABL1 (Philadelphia [Ph] chromosome) and KMT2A (MLL) rearrangements. Cases that harbor these translocations are recognized as distinct MPAL entities under the WHO 2016 classification system [1–5]. While co-occurrence of CBFB rearrangement and BCR-ABL1 has been previously described in cases of acute myeloid leukemia, either de novo or arising from chronic myeloid leukemia [6], MPAL with CBFB rearrangement has not been previously reported. Here, we present a unique and previously unreported case of mixed-phenotype acute leukemia, B-myeloid, with CBFB rearrangement. While a bilineal immunophenotype