Cladribine as First-Line Therapy for Indolent and Advanced Systemic Mastocytosis

Conference Correspondent

Systemic mastocytosis (SM) is a rare cancer that results from hyperactivation of mast cells and their subsequent accumulation in various organs. SM can be categorized into advanced SM (AdvSM), smoldering SM (SSM), and indolent SM (ISM). AdvSM is characterized by the presence of at least a clinical presentation profile (C-findings) indicative of organ dysfunction and encompasses a collection of high-grade forms of SM, including aggressive SM (ASM), SM associated with a hematologic neoplasm (SM-AHN), and mast-cell leukemia. ISM typically presents with a relatively low burden of mast cells and shows evidence of systemic involvement but lacks C-findings. Although ISM is generally associated with a good prognosis for patients, progression of ISM can lead to the development of AdvSM. ISM and AdvSM may present with urticaria pigmentosa or mast-cell mediator symptoms (MC-MSs).

Current treatment options for SM include midostaurin, avapritinib, and cladribine. These therapies typically attempt to reduce symptoms and slow disease progression. Midostaurin and avapritinib have recently emerged in the SM treatment landscape to reverse the effects of KIT mutations, which are associated with approximately 95% of all cases of SM. Although both have demonstrated promise as effective options, they also carry a risk of adverse gastrointestinal and neurologic events. Cladribine is a chemotherapy drug that has been used to safely and effectively treat SM since 2001. Considering developing and emerging therapies, the current investigation reviewed the impact of cladribine on the treatment of SM. Diagnosis of SSM, ISM, and AdvSM in all patients was confirmed by bone marrow biopsy. Forty-two patients with SM (n = 22 AdvSM and n = 20 ISM) with a median age of 65 years (range, 48-80 years) were assessed for response to cladribine (defined as lasting ≥1 months).

Twenty patients with a median age of 56 (range, 36-73 years) were diagnosed with SSM (n = 3) or ISM (n = 17). Among 19 patients evaluated, KIT D816V mutations were observed in 95% of samples and 12% of 17 patients presented with abnormal karyotypes. All SSM/ISM patients assessed had MC-MSs and 46% had urticaria pigmentosa. Cladribine treatment began in SSM/ISM patients within a median time of 4 months (range, 0.1-17 months) post-biopsy with 85% of patients completing ≥3 treatment cycles. Of the 14 patients in which overall response was evaluated, 60% achieved major regression of MC-MSs with peak response reached at 8.5 months after initiation of cladribine therapy. Decreases by >50% in both bone marrow mast-cell infiltration (50% of 10) and serum tryptase (46% of 13) were also observed. Cladribine side effects were limited to grade 3 or 4 myeloid cytopenia (n = 3; 15%) and lymphopenia (n = 6; 30%).

In the AdvSM group, most patients were diagnosed with SM-AHN (n = 13), 8 with ASM and 1 patient had MCL. Eighty-six percent of the 19 patients with AdvSM were positive for KIT D816V mutations and 14% of 21 evaluated had abnormal karyotypes. The majority (87%) of patients presented with ≥1 C-findings, 14% with urticaria pigmentosa, and all with MC-MSs. In the AdvSM cohort, cladribine treatment began within a median time of 1.5 months (range, 0.1-17 months) from biopsy with 55% of patients completing ≥3 treatment cycles. Five patients did not respond to cladribine. For patients who achieved response, median time to response was 3.7 months (range, 0.4-9 months) and median duration of response was 6 months (range, 1-67 months). Comparable overall response to cladribine was observed in 17 patients, of which 45% achieved major response and 32% partial response. Forty-four percent of patients demonstrated a >50% decrease in bone marrow mast-cell infiltration and 19% reached complete resolution. In the 22 AdvSM patients in whom enlarged liver (50%) and spleen (59%) were observed, cladribine treatment response was partial in 27% and complete in 36% of cases. Side effects primarily included cytopenias, and 6 patients experienced disease progression to acute myeloid leukemia or mast-cell leukemia.

Taken together, the study provides additional support of cladribine as an effective first-line therapeutic option for ISM and AdvSM with minimal side effects.

Tefferi A, Kittur J, Farrukh F, et al. Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3647.

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