A rare presentation of BCR-ABL1 and RUNX1-MECOM rearrangement in a pediatric patient with acute myeloid leukemia.

Key Clinical Message: In a patient with de novo AML, co-existing BCR::ABL1 p190 isoform and RUNX1::MECOM rearrangement is accompanied by a very poor prognosis including limited response to treatment and no molecular remission. It is essential to develop a consensus on the therapeutic modalities different from the current regimen. Abstract: Acquisition of BCR::ABL1 fusion as a primary or secondary event and RUNX1::MECOM fusion independently is reported in de novo and therapy-related MDS/AML, albeit with low frequency (<0.5%). Coexistence of BCR::ABL1 and MECOM translocation is known to cause leukemogenesis in animal models and progression towards blast crisis CML but not AML. Here we report a unique case of pediatric AML with concomitant BCR::ABL1 and RUNX1::MECOM fusion.Routine diagnostic work-up included WBC manual differential, immunophenotype, morphology, qPCR, FISH, and NGS-based CNV analyses. The patient presented with history of fever, dizziness, fatigue, gingival bleeding, and epistaxis associated with ecchymosis in right hand and heavy, prolonged menstrual period. At presentation, her hemoglobin was 5.3 g/dL, WBC 52.1(10*9/L), PLT 10(10*9/L), ESR 5 mm/h and LDH 2658 U/L. Bone marrow was hypercellular with 71% blasts, and flow cytometry showed myeloid markers including CD11c, CD33, CD34, and CD45 among others indicating AML with monocytic differentiation. FISH analyses showed variant t(9;22) (q34.1;q11.1), one additional copy each of chromosome 8 and Runx1 gene, while NGS-based CNV analyses revealed a terminal and proximal pathogenic gain within 9q34.12q34.3 and 22q11.1q11.23, respectively, and gain of entire chromosome 8 and 12 in mosaic state. qPCR confirmed the presence of p190 and also revealed RUNX1::MECOM fusion. Patient received ADE (cytarabine, daunorubicin, and etoposide) induction regimen but required multiple ICU admissions due to sepsis, cardiac shock, acute myocarditis, and thyroiditis. Coexisting BCR::ABL1 and RUNX1::MECOM fusion is suggestive of poor prognosis, and a need for consensus on the treatment modalities other than the current regimen is warranted.

De novo lymphoid blastic phase chronic myeloid leukemia: report and contemporary discussion.

OBJECTIVE: We herein describe two cases of de novo lymphoid blastic transformation in patients with no history of chronic-phase chronic myeloid leukemia (CP-CML), both of whom were labeled initially as Philadelphia positive B-Acute Lymphoblastic Leukemia (B-ALL). METHODS: The first patient was an 18-year-old male who presented with subjective fever, intentional weight loss, generalized fatigue, and headache. Investigations showed leukocytosis (312 × 10^3/ul), thrombocytopenia and anemia. Flowcytometry was consistent with B-ALL, with aberrant expression of CD13 and CD33. He was found to be positive for BCR::ABL by FISH, and karyotype confirmed the presence of the Philadelphia chromosome. He received a pediatric-inspired regimen and achieved remission with negative measurable residual disease (MRD) by flowcytometry, however with persistent cytogenetic abnormality using FISH for BCR::ABL. FISH abnormality was confirmed to be in the myeloid compartment using myeloid segregated FISH, reclassifying the disease to de novo lymphoid blastic phase CML. The second patient was a 52-year-old male who presented with fever and shortness of breath. Bilateral cervical lymphadenopathy and hepatosplenomegaly were identified on examination, and investigations showed leukocytosis (371 × 10^3/ul), anemia, and thrombocytopenia. BCR::ABL rearrangement was identified by FISH, molecular testing, and confirmed with karyotype. He was treated with Mini-CVD and Ponatinib, achieved complete remission with negative MRD by flow cytometry, however molecular studies showed BCR-ABL1 level at 58% IS indicating a persistent cytogenetic abnormality. RESULTS: De novo lymphoid blastic-phase CML can therefore be difficult to differentiate from Philadelphia positive B-ALL due to their overlapping clinical and laboratory picture, implying the need to do myeloid compartment evaluation at the time of diagnosis. CONCLUSION: With recent progress in the treatment of Philadelphia positive B-ALL, including the role of transplant with the use of novel agents, a better characterization of this disease entity in retrospective and prospective trials is warranted.

An Intriguing Case of Eosinophilia with FIP1L1/PDGFRA Rearrangement Who Presented as Thrombotic Thrombocytopenic Purpura.

Myeloid neoplasm with eosinophilia and FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) rearrangement is a multi-organ disease with diverse clinical presentation. Thrombotic thrombocytopenic purpura (TTP) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic organ damage. To our knowledge, only one case of eosinophilia with FIP1L1-PDGFRA rearrangement presented as a case of thrombotic thrombocytopenic purpura reported in the literature. We herein report a case of a young male patient with hypereosinophilic syndrome and FIP1L1-PDGFRA rearrangement who presented with asthma, transient ischemic attacks (TIA), and confusion. He had an acquired TTP that was successfully treated with plasma exchanges (PLEX), corticosteroids, rituximab, and later with the addition of imatinib mesylate (Gleevec, Novartis). He remains in complete remission on imatinib 100 mg daily for more than 28 months of follow-up.