Page 230 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
Characteristics and outcomes associated with CD2 and CD25 expression on bone marrow mast cells in patients with systemic mastocytosis
Mastocytosis corresponds to a heterogeneous group of hematologic disorders characterized by the accumulation of neoplastic mast cells (MC) in one or more organs. The World Health Organization (WHO) and the International Consensus Classification (ICC) described several variants of mastocytosis, including cutaneous mastocytosis (CM), MC sarcoma (MCS), and systemic mastocytosis (SM).1,2 SM has been subsequently divided into non-advanced SM (including bone marrow [BM] mastocytosis, indolent SM [ISM], and smoldering SM) and advanced SM (Adv-SM). The Adv-SM subgroup includes aggressive SM (ASM), MC leukemia (MCL), and SM with associated hematologic neoplasm (SM-AHN). In the majority of cases, adults with mastocytosis har- bor a D816V mutation in the KIT tyrosine kinase domain (TKD).3 Other KIT mutations have been described in the juxtamembrane domain, and some patients have wild- type (WT) KIT.4 Furthermore, an abnormal phenotype for CD2, CD25 or CD30 expression on BMMC (as assessed with immunohistochemistry or flow cytometry) is considered to be pathognomonic of atypical MC.5,6 The WHO and ICC classifications differentiate several morphological patterns, including well-differentiated SM (WDSM), which can occur in any type of SM.7 WDSM is morphologically character- ized by round mast cells with a well-granulated mature appearance, a low prevalence of the KIT mutation, and an almost complete lack of expression of CD2 and CD25, whereas CD30 is expressed. Apart from WDSM, few stud- ies have investigated the characteristics and outcomes associated with the expression of CD2 and CD25 in SM. One report found a higher frequency of CD2 expression in SM compared to CM, while another study observed a non-significant trend towards a lower frequency of CD2 expression in Adv-SM compared to ISM.8,9
Patients with Adv-SM have a worse prognosis than those with non-Adv-SM, and the main therapeutic goal is to pro- long survival. Until recently, cladribine was the standard treatment for patients with Adv-SM. Although the marketing authorization of tyrosine kinase inhibitors (TKI) targeting the D816V-mutated KIT receptor (midostaurin and avapri- tinib) has significantly prolonged survival times in Adv-SM, allogeneic hematopoietic stem cell transplantation remains the only curative therapy.10-12 Thus, the identification of prognostic factors for time to treatment failure (TTF) and overall survival (OS) is critical for the optimization of pa- tient care. The Mutation-Adjusted Risk Score for Adv-SM (MARS) has become the reference score in this population.13 However, the prognostic impact of abnormal phenotypes
has not been extensively characterized. The objective of the present study was to investigate the characteristics and outcomes of mastocytosis patients as a function of their BMMC expression of CD2 and CD25.
All diagnoses of mastocytosis were based on the WHO 2016 classification. The study data were collected by medical staff at the French National Referral Center for Mastocytosis (CEREMAST, France). All the patients were participating in a retrospective, cross-sectional study sponsored by the French Association for Research Initiatives on MCs and Mastocytosis (AFIRMM). The study was approved by the local investigational review board (CPP G.H. Pitié-Salpêtrière, Paris, France; reference: 93-00) and was conducted in com- pliance with the principles of the Declaration of Helsinki. The study included two cohorts of patients with masto- cytosis. The first cohort aimed to investigate the charac- teristics associated with the expression of CD2 and CD25 on MC (discovery cohort), while the second cohort aimed to study the prognostic significance associated with the expression of CD2 in a nationwide cohort of patients with Adv-SM treated with midostaurin (midostaurin cohort). The “discovery cohort” (N=81) included adult patients re- ferred to a CEREMAST reference center for the diagnosis of mastocytosis. Patients were prospectively enrolled over a 4-year period between January 2008 and December 2011. MCS patients were included in the Adv-SM group for analyses. Fresh BM aspirates were immunophenotyped at diagnosis. The midostaurin cohort (N=111) included adult patients retrospectively enrolled with the diagnosis of Adv-SM, available CD2/CD25 phenotyping data, and the presence of C finding(s). The cladribine cohort (N=17) in- cluded patients from the midostaurin cohort, who had been treated by cladribine prior to midostaurin therapy. Eighty-one consecutive adult patients with a diagnosis of mastocytosis were included in the discovery cohort (Online Supplementary Table S1); there were 54 patients with non- Adv-SM (including 54 ISM patients) and 27 patients with Adv-SM (including 15 ASM, 8 SM-AHN, 2 MCL, and 2 MCS). Sixty-six patients (81.5%) had a KIT D816 mutation, 2 had a juxtamembrane mutation, and 13 had a WT KIT gene. Of the 81 BM samples immunophenotyped, MC were detected in 73 (90.1%). Of the 73 samples with detectable BMMC, the phenotypes were as follows: CD2+/CD25+ (N=58, 79.5%), CD2-/CD25+ (N=10, 13.7%), CD2-/CD25- (N=5, 6.8%), CD2+/ CD25- (N=0, 0%). We next investigated the relationship between the phenotype and the KIT genotype. All the pa- tients with a KIT TKD mutation and an evaluable phenotype
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