Reappraisal of Mast Cell Leukemia Based on a Single Institution Review of 16 Cases: Role of Mast Cell Morphology in Determining Clinical Outcome

Background: Mast cell leukemia (MCL) is the leukemic variant of systemic mastocytosis (SM); in addition to meeting conventional diagnostic criteria for SM, it is defined by presence of ≥20% mast cells (MC) in the bone marrow (BM) aspirate smear. Presence of circulating MC is not mandatory; MCL is subclassified into leukemic and aleukemic variants based on whether MC comprise ≥10% or <10% of circulating leukocytes, respectively. Given the rarity of MCL, important disease aspects remain incompletely defined, including frequency of evolution from antecedent SM, frequency of associated hematological neoplasm (AHN), prevalence of KITD816V/other mutations, and the prognostic relevance/reproducibility of MC morphology. Furthermore, MCL (as currently defined) has a variable clinical course, with acute and chronic disease variants being recognized; one pitfall is that the latter group may be clinically indistinguishable from other SM subtypes with high BM MC burden. The aim of the current project is to identify clinical, laboratory and pathology features that determine prognosis/survival outcome in MCL patients.

Methods: The Mayo Clinic clinical and hematopathology databases were interrogated to identify MCL cases. Patients were retrospectively recruited after confirming research authorization and institutional review board approval. The diagnosis of MCL was per conventional diagnostic criteria. Clinical and laboratory data were collected at the time of MCL diagnosis. BM slides were reviewed by 3 hematopathologists (KKR, KK, and DC), with each slide set being independently reviewed by at least 2 pathologists, using prespecified criteria. MC were classified as either mature (atypical MC type I) or immature (atypical MC type II [promastocytes] and metachromatic blasts) based on the predominant MC population identified. (Valent et al., Ann Oncol. 2014 Sep;25(9):1691-1700). Patient follow up was updated in July 2022; data were censored at last follow up or death.

Results: A total of 16 MCL patients were identified (8 females, median age 65 years, range 41-75). Six patients (37%) had de novo MCL; the remaining had antecedent mast cell disease (smoldering SM=4, aggressive SM=3, SM+AHN=2, cutaneous mastocytosis=1). The AHN in 2 patients was CMML and MDS/MPN-unclassifiable, respectively. Four patients (25%) had biopsy confirmed cutaneous involvement. Ten (63%) and 9 (64%) patients had hepatomegaly and splenomegaly, respectively. Median (range) hemoglobin was 9.7 g/dL (7.2-11.9), leukocytes 8.7 x 10⁹/L (0.7-43.9), platelets 123 x 10⁹/L (14-633), serum tryptase 614 ng/mL (69-1684), and serum albumin 3.7 g/dL (2.6-4.7). B- and C-findings were present in 15 (94%) and 12 (75%) patients, respectively. Seven (44%) and 5 (31%) patients had circulating MC and blood eosinophil count >500/µL, respectively. Nine of 13 (69%) and 3 of 14 (19%) evaluable patients harbored KITD816V and abnormal karyotype, respectively. Seven (44%) patients displayed a predominantly 'immature’ MC morphology. After a median follow up of 3.9 months, 12 deaths were recorded. The median OS was 15 months; 2 patients underwent allogeneic stem cell transplant (ASCT).

Factors associated with significantly inferior overall survival (OS) on univariate analysis were: immature MC morphology (median OS 0.5 vs 20 months; p<0.01), peripheral blood eosinophilia (p<0.01), and absence of KITD816V (p=0.03). No survival difference was seen in 4 patients treated with midostaurin and/or avapritinib. On multivariable analysis, immature MC morphology retained significance for OS (Figure); among 7 patients with immature MC morphology, 5 had died within a month of their diagnosis, while 2 remain alive at 0.2- and 1-months follow-up. By contrast, among 9 patients with mature MC morphology, 7 had died after a follow-up period of 2.5-59 months, including one receiving ASCT and died at 16 months follow-up, while 2 remain alive at 5.6- and 164.2-months follow-up, the latter post-ASCT. Treatment details and NGS data (7 patients) will be presented at the meeting.

Conclusions: The current study identifies immature MC morphology as the most important predictor of inferior survival in MCL. Our observations suggest the need to refine current diagnostic criteria for MCL, in order to distinguish a biologically distinct patient population with a uniformly poor clinical outcome (i.e., 'true’ MCL) from those with more favorable outcome, despite high MC burden.

Al-Kali:Astex: Other: research support to institution. Patnaik:Kura Oncology: Research Funding; Stem Line Pharmaceuticals: Research Funding. Khera:Incyte: Consultancy; Optum: Honoraria. Palmer:CTI BioPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy; Protagonist: Consultancy; PharmaEssentia: Consultancy, Research Funding.