Mast Cell Leukemia: Clinical Heterogeneity, Molecular Aberrations, Treatment Responses, Survival, and Prognostic Factors

Mast cell leukemia (MCL) is a rare variant of advanced systemic mastocytosis (advSM) characterized by ≥20% mast cells (MCs) in a bone marrow (BM) smear. Our current knowledge of MCL, including clinical and molecular characteristics, treatment options, survival, and prognostic factors is limited to case reports, small case-series and/or literature reviews. While the KIT D816V mutation is present in >80-90% of patients in other SM subtypes, it has only been reported in approximately 50% of patients with MCL. Of interest, recent data have highlighted that the molecular pathogenesis of advSM/MCL is complex. In particular, additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/R^pos), seen in 60-70% of advSM patients, have a significant adverse impact on disease phenotype and prognosis (Jawhar et al., Leukemia, 2016). Here, we sought to evaluate a) relevant clinical and molecular characteristics, b) treatment responses, and c) survival and prognostic factors in 28 MCL patients (median age 67 years; range, 45-82; male 57%), enrolled in the 'German Registry of Disorders on Eosinophils and Mast Cells'. The median percentages of MC in BM smears and trephine biopsies were 25% (range, 20-95) and 65% (range, 20-100; 82% ≥50%), respectively. MC in peripheral blood (PB) ≥10% (leukemic MCL) were seen in only 2/28 patients. Median serum tryptase level was 550 µg/L (range, 160-1850; 93% ≥200, normal value <11.4). An associated hematologic neoplasm (AHN), e.g. CMML (n=7), MDS/MPNu (n=6), MDS (n=5) or CEL (n=2), was diagnosed in 20/28 (71%) patients. Primary MCL was diagnosed in 16/28 (57%) patients and secondary MCL evolving from other advSM subtypes (SM-AHN, n=10; aggressive SM, n=2) in 12/28 (43%) patients with a median of 18 months (range, 4-71) to transformation. Hematologic C-findings such as hemoglobin <10 g/dL and/or platelets <100x10⁹/L were identified in 26/28 (93%) patients. Non-hematologic signs of organ dysfunction included elevated alkaline phosphatase (AP), seen in 20/28 patients (71%, median 181; range 59-548) and splenomegaly in 28/28 (100%) patients. Spleen volumetry results obtained by magnetic resonance imaging were available in 16 patients and showed marked splenomegaly (≥1200 mL) in 8/16 cases (50%). Mutations in KIT were identified in 25/28 (89%) patients (D816V, n=19; D816H, n=3; D816Y, n=2; F522C, n=1) with a median KIT D816V expressed allele burden of 43% (range 20-98) in peripheral blood as measured by quantitative RT-PCR (RT-qPCR). S/A/R^pos were identified in 13/25 (52%) patients (by NGS analyses of 18 myeloid genes). Median observation from the time of MCL diagnosis was 13 months (range, 2-86) and 18/28 patients (64%) died with a median OS of 17 months (95% confidence interval [CI], 10-24). Cytoreductive treatment included midostaurin (n=13), cladribine followed by midostaurin or vice versa (n=9), cladribine (n=3), midostaurin and/or cladribine followed by intensive chemotherapy (n=3) with (n=1) or without (n=2) allogeneic stem cell transplantation. The median overall survival (OS) was 17 months (95% confidence interval, CI [10-24]) with a 2-year OS probability of 24% for all patients. In univariate analyses of multiple clinical, laboratory and molecular variables only bicytopenia (hemoglobin <10 g/dL and platelets <100x10⁹/L, n=13 vs. hemoglobin ≥10 g/dL or platelets ≥100x10⁹/L, n=13, P=0.02, hazard ratio, HR 3.2 [1.2-8.9]), elevated AP (P=0.009, HR 3.3 [1.3-8.3]) and S/A/R^pos (P=0.007, HR 5.0 [1.8-18.1]) were significantly inferior regarding OS. In multivariate analyses, S/A/R^pos remained the only independent poor risk marker for OS (Figure). There was no significant difference regarding OS between primary vs. secondary MCL (Figure) or MCL with vs. without AHN. Of interest, no difference regarding OS was detected in comparison between patients treated with midostaurin (n=13) vs. patients treated with cladribine following midostaurin or vice versa (n=9). In summary, we have found that a) leukemic MCL and MCL without C-findings are rare, b) secondary MCL is frequent and evolves from other advSM subtypes but not ISM, c) KIT D816V mutations are more frequent than previously reported and KIT D816V negative patients should be tested for other KIT mutations d) the prognostically highly relevant mutations in the S/A/R gene panel are present in approximately 50% of patients with MCL, and e) median OS is approximately 1.5 years with significantly inferior survival in S/A/R^pos patients.

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