LAUSR

To the Editor: Acute lymphoblastic leukemia (ALL) bearing the KMT2Arearrangement is a high-risk genomic subgroup, characterized by chemotherapy-resistance and a propensity for rapid relapse with reported 5-year overall survival of less than 20%. Unique in its involvement in early leukemogenesis, KMT2A gene rearrangement has been described to confer overlapping immunophenotypic features of both myeloblasts and lymphoblasts, hence previously known as the mixed-lineage leukemia (MLL) gene. This distinctive characteristic potentially drives lineage switch (LS) between lymphoid and myeloid leukemic cells during treatment, especially after highly lymphoid-targeted therapies. CD19-directed immunotherapies have revolutionized the treatment paradigm for relapsed/refractory ALL patients with the introduction of bispecific T-cell engaging antibody, blinatumomab, and novel chimeric antigen receptor T-cell (CAR-T) therapies. However, LS has been increasingly recognized as an emerging therapeutic challenge following these targeted treatments. Herein, we report the case of a Jehovah's Witness (JW) patient with relapsed KMT2A-rearranged ALL, who achieved an MRD (minimal/measurable residual disease)-negative, complete remission (CR) after one cycle of blinatumomab and subsequently presented with a LS to acute myeloid leukemia (AML). Moreover, we reviewed the literature and summarized all reported cases of ALL with LS following CD19-directed immunotherapy to help better characterize, identify the risk factors as well as potential genetic mechanisms driving this condition. A 60-year-old, JW female with Philadelphia chromosomenegative [Ph( )], B-cell ALL was transferred to our facility following relapse of her disease. Initial cytogenetic and fluorescence in situ hybridization (FISH) studies revealed the KMT2A/AFF1 fusion [t(4;11) (q21;q23)]. No significant findings on next generation sequencing (NGS) were reported by the outside hospital. At diagnosis, the patient was initiated on a non-intensive induction regimen of hydroxyurea, prednisone, and vincristine. This was followed by POMP maintenance (vincristine, methotrexate, 6-mercaptopurine, and prednisone) after an MRD-positive CR was attained. The patient relapsed 7 months after initial diagnosis with a WBC exceeding 250 10/L for which she underwent leukapheresis. Available treatment options were limited as the patient declined transfusion of any blood products. The patient was commenced on blinatumomab salvage therapy and achieved an MRD-negative CR after her first cycle. No occurrences of severe neutropenia, thrombocytopenia, or anemia were encountered during her treatment course. Three weeks into her second cycle, her peripheral blood showed emergence of circulating blasts. Bone marrow cytologic study revealed AML with monocytic differentiation involving 80%–90% of total nucleated cells. Blasts expressing CD31, CD33, CD34 (small subset), CD43, CD68, and lysozyme were reported by immunohistochemistry; CD19 expression was not present on relapse. Cytogenetic studies revealed numerous chromosomal abnormalities in addition to the previously found KMT2A/AFF1 rearrangement, suggesting a LS with clonal evolution of the original leukemic clone. NGS revealed newmutations in TP53 and in RUNX1. Her pathology studies are available as Table S1. Treatment with venetoclax and azacitidine was initiated followed by venetoclax and decitabine to target her TP53 mutation. With the inability to support her with transfusions, despite supplementation with B12, folate, iron and growth factors, the patient was transitioned to comfort care and died of profound anemia while having active AML. Even though uncommon, conversion of leukemia lineage during treatment has been described in both AML and ALL patients. For ALL, this condition has most frequently been reported in infants and with the KMT2A-rearrangement. Nevertheless, it remains a rare event with an estimated range between 0.6% to 6% at relapse. Blinatumomab has demonstrated high rates of response with a favorable toxicity profile in the treatment of relapsed/refractory or MRD-positive ALL. However, key observations found among case reports of LS following CD19-directed immunotherapy raises concerns for KMT2A-rearranged patients (Table 1). A review of the past 8 years since the FDA's initial approval of blinatumomab identified 33 reported cases, 17 with blinatumomab and 16 with an anti-CD19 CAR-T cell therapy (Table 1). The median [IQR] number of prior CRs was 1 [1, 2] (among those reported) with time to LS occurring within 12 months in 90.9% of patients. Of significance, the KMT2A-rearrangement was implicated in 81.8% of cases—88.2% with blinatumomab and 75% with a CAR-T immunotherapy. A multicenter, retrospective study of 420 CAR-T patients by Lamble, et al. reported that the KMT2A-rearrangement was the predominant cytogenetic abnormality seen with LS, being present in 75% and 4.9% of LS and non-LS patients, respectively (p < .001). Age, gender, prior blinatumomab exposure, hematopoietic stem cell transplantation (HSCT), and CAR-T response were not significant predictors for LS in the investigators' analysis. Received: 23 August 2022 Accepted: 26 August 2022