Long Term Efficacy and Safety of Cladribine In Adult Systemic mastocytosis: a French Multicenter Study of 44 Patients

Systemic mastocytosis (SM) is a myeloproliferative disabling disorder for which no consensual curative therapy is currently available. Preliminary experiences in small groups of patients using cladribine (2-CdA) were encouraging, but no long term follow-up to evaluate its efficacy and safety have been reported.

We studied the efficacy and safety of 2-CdA in 44 patients with mastocytosis enrolled in a compassionate program in France. Characteristics of patients were as follows: 22 male, 22 female, mean age 54y (18-83y), mean duration of disease 13 y (6m-39y). Symptoms of the disease included pigmentosa urticaria (31), Fatigue (35), flushs (24), prurit (24), abdominal pain (21), Ascite (9), diarrhea (23), weight loss (16), Headache (14), Cough (10), splenomegaly (20), Lymph nodes (6), Bone fractures (6), pleural effusions (2), Neuropsychological symptoms (19). Blood cell count showed eosinophils >0.5g/l (10), Hb<10 gr/dl (10), Platelets<100 (9), neutrophils <1g/l (1), and high liver enzyme>2N (1/44). Patients were classified as having cutaneous mastocytosis (CM) (n=3) indolent SM (n=19), smoldering (SSM) (n=3), aggressive SM (ASM) (n=12) or SM with an associated clonal hematologic non-MC-lineage (AHNMD) (n=6), mast cell leukemia (n=1). Mean tryptase level was 158 (2.7-1240). All failed previous symptomatic therapy and/or recombinant interferon-a(n=10) or kinase inhibitors (n=7). Treatment consisted in intravenous 2-CdA (1 to 6 cycles of 0.15 mg/kg/d administered in a 2-hour infusion or subcutaneously for 5 d, repeated at 4–12 weeks), the mean number of infusion was 4.1 (1-15) to treat severe SM-related infiltration or symptoms.

After a median follow up of 35m (0-96m) 28 pts were alive, 14 were dead (all with ASM/ASM-AHNMD/MCL of mastocytosis progression n=5, Solid neoplasia n=2, hematological malignancy n= 3, septic shok n=4) and 2 were lost of follow up. Safety anlalysis showed 18 acute (pneumonia n=3) but no opportunistic infections except two zoster infections, and one renal tubulopathy. Five solid neoplasia were reported and one AML. Responses were observed for most of the symptoms with improvement of pigmentosa urticaria (n=24/31), fatigue (n=17/35), flushs (14/24), prurit (9/24), abdominal pain (9/21), Ascite (1/9), diarrhea (11/23), weight loss (8/16), Headache (4/14), Cough (5/10), splenomegaly (7/20), Lymph nodes (2/6), pleural effusions (0/2), Neuropsychological symptoms (5/19). Eosinophils count was normalized in 7/10 cases, Hb<10 gr/dl (1/12), Platelets<100 (0/9), neutrophils <1g/l (1). Tryptase levels decrease to 95 (1-867). Overall according to WHO criteria, major and partial response were observed in 7/12 ASM, none of ASM with AHNMD, 3/3 SSM, 17/19 ISM, 2/3 CM. Responses were in most of the cases transient with a median duration of 19.5m (0-72).

As a single agent, cladribine is an effective and safe treatment in symptomatic and aggressive SM. Cladribine improves significantly symptoms associated with the disease and may induce regression of mast cell tumoral burden. Its tolerability and efficacy argues for the possibility to use it even in ISM and symptomatic CM. Cladribine is ineffective to improve AHNMD. Further work is warranted to define the optimal regimen with respect to dose and schedule, and the usefulness of maintenance cladribine therapy.

Hermine:Lipomed: Research Funding. Off Label Use: Cladribine.