Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases

Abstract

We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/ SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT) D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0Á01). Treatmentemergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KIT D816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.

Response and resistance to cladribine in patients with advanced systemic mastocytosis: a registry-based analysis

“…In historical cohorts of up to a maximum of 32 AdvSM patients [18,19,21], the ORR on cladribine according to (modified) Valent criteria [21,36] ranged between 50 and 100%. [20] Further interpretation on the impact of treatment with cladribine on progression-free (PFS), relapsefree (RFS), event-free (EFS), leukemia-free (LFS) and overall survival is limited because (i) most reports did not clearly differentiate between ISM and AdvSM, (ii) no report separated between 1L-and 2L-treatment and (iii) the definitions of PFS/RFS/EFS/LFS were not consistent between studies.…”

“…inhibitor avapritinib [16,17], has extended the therapeutic options for patients with AdvSM, which were previously based on the off-label use of the purine analogue cladribine [18][19][20][21][22]. However, recent data on response rates and variably on leukemia-free (LFS), event-free-(EFS) and overall survival (OS) meanwhile favor the use of midostaurin and avapritinib [23][24][25][26].…”

“…Notwithstanding, cladribine will remain a relevant treatment option beyond first-line treatment due to intolerance, resistance and progression on KIT inhibitors [23,27,28]. No predictive markers have yet been established for response, resistance and survival in cladribine-treated AdvSM patients [18][19][20][21][22], a gap which we aimed to fill by analysis of a comprehensive cohort of 79 cladribine-treated patients enrolled within the 'German Registry on Disorders of Eosinophils and Mast Cells' (GREM).…”

Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update

“…Another registry-based data analysis of patients with advanced SM, based on the MARS parameters and KIT D618V VAF, demonstrated the superiority of midostaurin versus cladribine regarding OS and leukemia-free survival [ 92 ]. Other studies showed that cytoreduction with cladribine successfully reduced the bone marrow mast cell burden and serum tryptase levels [ 93 , 94 , 95 , 96 , 97 , 98 ], particularly in patients with KIT D816V. A single institution study of 42 patients with advanced SM recently demonstrated that lack of KIT D816V mutation was an indication of cladribine resistance [ 93 ].…”

“…Other studies showed that cytoreduction with cladribine successfully reduced the bone marrow mast cell burden and serum tryptase levels [ 93 , 94 , 95 , 96 , 97 , 98 ], particularly in patients with KIT D816V. A single institution study of 42 patients with advanced SM recently demonstrated that lack of KIT D816V mutation was an indication of cladribine resistance [ 93 ].…”