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/R^pos) 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/R^pos 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/R^pos 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.

Figure 1.

Bone marrow morphology and phenotype of 3 patients with mast cell leukemia (MCL). Patients #25: MCL, #28: MCL, #20: MCL with an associated hematologic neoplasm (AHN). (A, C and E) Bone marrow (BM) smears show an abundance of pleomorphic mast cells (MCs) exhibiting metachromatic granules. Quantitative criteria for diagnosis of MCL are completely fulfilled since MC make up more than 90% of all nucleated cells. Note the bizarre giant metachromatic MCs in (A), the prominent hemophagocytic activity of MC in (C), and the marked cytological atypia of MCs with pronounced hypogranulation in (E). Case (E) also exhibits immature atypical eosinophils enabling the diagnosis of an AHN, probably myelodysplastic/myeloproliferative neoplasm with eosinophilia. (B, D and F) BM sections show extreme hypercellularity and packed MC infiltrates. Fat cells and normal blood cell precursors are subtotally depleted. The cytomorphological aspects are fully reflected by the histomorphological findings. Note the extreme siderosis in (D) and the clear-cell aspect of atypical MC in (F) with the possibility of a misdiagnosis (hairy cell leukemia, histiocytosis or even metastatic infiltrates of a renal cell carcinoma) unless appropriate immunohistochemistry is performed. (A–F) Wright-Giemsa staining.

Figure 2.

Mutational profile of 28 patients with mast cell leukemia (MCL). (A) Alignment of gene mutations in 28 patients with MCL. Each column represents an individual patient. Results of genetic analyses are depicted in different colors and (B) relative frequency distribution of KIT mutations, additional mutations and mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel.

Figure 3.

Overall survival (OS). Kaplan-Meier estimates of OS depending on comparisons between patients with mast cell leukemia (MCL, n=28) and a control group of patients with advanced systemic mastocytosis (without MCL) (n=124) enrolled within the ‘German Registry on Disorders of Eosinophils and Mast Cells’. CI: confidence interval; HR: hazard ratio.

Figure 4.

Kaplan-Meier estimates of overall survival (OS) depending on comparisons between multiple variables. (A) De novo mast cell leukemia (MCL) and secondary MCL (sMCL), (B) MCL with or without an associated hematologic neoplasm (AHN), (C) midostaurin treatment or cladribine (2-CDA) and/or midostaurin vice versa and (D) with mutations in the SRSF2/ASXL1/RUNX1 (S/A/R^pos) or without mutation in S/A/R (S/A/R^neg) gene panel. CI: confidence interval; HR: hazard ratio; NR: not reached.