The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm

Abstract

Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.

Mast cell leukemia (MCL): Clinico-pathologic and molecular features and survival outcome

“…Presence of AHN may further aggravate survival. Overall, our analysis largely confirms the findings recently reported by the German group (5). Shorter OS in their patients (17 vs. 31 months) could possibly be explained by much higher proportion (70 vs 30%) of patients with AHN in that study, with lower hemoglobin and platelet counts, indicating more aggressive disease.…”

“…Shorter OS in their patients (17 vs. 31 months) could possibly be explained by much higher proportion (70 vs 30%) of patients with AHN in that study, with lower hemoglobin and platelet counts, indicating more aggressive disease. Another important explanation could be a difference in the mutation profile of patients in the two studies: we found SRSF2 and ASXL1 co-mutated genes in only one patient (number 4 in Figure 1I) in contrast to 13 patients who had SRSF2/ASXL1/RUNX1 co-mutated genes in the German study(5). Our patient 4 had concurrent poor prognostic mutations (8) in SRSF2, CBL and ASXL1 genes, and lived only 1.4 months.…”

“…Till date, only two reports from European colleagues have systematically characterized MCL. One report reviewed 51 cases of MCL collected from various centers in France(1) and another report(5) reviewed 28 cases of MCL from Germany. The outcome of MCL was significantly inferior as compared to other subtypes of SM, with median survival of <2 years.…”

“…Infrequently, durable partial remissions were observed with single agent cladribine and more recently with midostaurin (a multi tyrosine kinase inhibitor, including abnormal KITD816V kinase, present in SM), now approved new therapy in the US for patients with ASM, SM-AHD, and MCL. (5, 6) Survival outcomes do not appear to improve after allogeneic stem cell transplantation. (7) Recently, the mutation profiles of ASM and MCL patients were reported.…”

“…In addition, presence of SRSF2/ASXL2/RUNX1 mutations (S/A/R) in patients with MCL was proposed to be an independent predictor for poor survival. (5)…”