Cladribine for mastocytosis: benefits and risks

In this issue of Blood, Barete et al report the safety and efficacy of cladribine in 68 adult patients with mastocytosis.¹  Cladribine (2-chlorodeoxyadenosine) is a purine analog that causes apoptosis in cells after phosphorylation intracellularly to 2-chlorodeoxyadenosine-5′-triphosphate, which incorporates to DNA and causes DNA strand breaks. It does not require active cell division for this effect and therefore is ideal for a disorder like mastocytosis in which neoplastic mast cells often do not show a high rate of mitosis except in the most advanced and rare forms of the disease. This property of cladribine is also responsible for its major toxicity because it causes T- and B-cell lymphopenia, immunosuppression, and opportunistic infections along with overall bone marrow suppression. There has been also some concern that it may be associated with secondary malignancies, although conclusive data are lacking about this point.

The effect of cladribine as a cytoreductive agent in advanced mastocytosis (aggressive systemic mastocytosis, mastocytosis with an associated hematologic non–mast-cell disorder, and mast-cell leukemia) has been well recognized. It is often advocated as the first line of therapy in these disorders. Cladribine causes apoptosis in mast cells independent of the presence of the common D816V KIT mutation (which confers resistance to imatinib) because its mechanism of action does not involve tyrosine kinase inhibition.²  Currently available tyrosine kinase inhibitors do not show significant cytoreductive responses in KIT D816V⁺ mastocytosis.

The most important decision in using cladribine for systemic mastocytosis lies in the determination of the risk-vs-benefit ratio. This decision is easy to reach in patients with advanced mastocytosis who have a shortened life expectancy. Patients with indolent mastocytosis, however, have a life expectancy comparable with that of the age-matched general population, with an overall low rate of progression to advanced disease (currently estimated to be ∼3%). Therefore, the risk and benefit analysis in patients with indolent systemic mastocytosis (ISM) should consider not only the risk of progression into advanced disease but also the symptomatic status of the patient. Patients with mastocytosis often have symptoms of mast-cell mediator release including flushing, itching, abdominal cramps, nausea, vomiting, diarrhea, tachycardia, and hypotension, which may lead to syncopal or presyncopal episodes. Disabling fatigue and musculoskeletal pain are reported by some patients, although it is not clear whether these latter symptoms are directly related to mast-cell mediator release. Approximately 80% of patients with systemic mastocytosis have urticaria pigmentosa, a fixed hyperpigmented rash that involves the trunk and extremities. Because there is no curative treatment for mastocytosis, these symptoms are treated with antimediator drugs such as H1 and H2 antihistamines, antileukotriene drugs, cromolyn, glucocorticoids, and epinephrine. Although most patients see at least a partial improvement with antimediator therapy, some remain symptomatic and may require repeated emergency department evaluations for recurrent anaphylaxislike episodes. This population may be candidates for cladribine therapy, after careful consideration and a full discussion with the patient of the risks and benefits of the drug. I would not recommend its administration to patients with purely cutaneous disease.

The current study by Barete et al included, in addition to 32 patients with advanced variants, 28 patients with ISM, 2 with smoldering systemic mastocytosis, and 6 with cutaneous mastocytosis, although one cannot rule out the presence of systemic mastocytosis in the latter 6 patients because it is very unusual to have disease limited to the skin in an adult population. Although it is the largest series reported thus far, the current study is not the first to report the use of cladribine in indolent or smoldering mastocytosis. The first report of cladribine in a patient with mastocytosis by Tefferi et al appears to be of a patient with ISM with frequent anaphylactic episodes that resolved after therapy.³  Kluin-Nelemans et al reported a series of 10 patients, 3 of whom had indolent disease refractory to symptomatic treatment.⁴  Wimazal et al reported 2 patients with smoldering mastocytosis who had recurrent life-threatening anaphylaxis and saw a positive symptomatic response to cladribine.⁵  The Mayo Clinic reported 10 patients with ISM, with an overall response rate of 56% in evaluable patients.⁶  Interestingly, all published reports also confirm a significant reduction in the intensity of urticaria pigmentosa skin lesions.

The immunosuppressive and myelosuppressive effects of cladribine are of major concern. The current study reports that 47% of patients developed grade 3 or 4 neutropenia, and 82% had prolonged lymphopenia, including 1 patient with indolent disease who required stem cell transplantation because of persistent pancytopenia after cladribine. Twenty-two percent had infectious complications and 1 died of septic shock. There were 2 solid tumors observed during the observation period. None of the patients with ISM progressed to having aggressive mastocytosis.

The mechanism of action of cladribine in inducing symptomatic improvement in these patients remains to be elucidated. Although cladribine use is associated with a significant decrease in tryptase level and a reduction in bone marrow mast-cell infiltrates, it does not cause complete remission. Given the observation that mast-cell burden poorly correlates with mast-cell activation, there may be additional mechanisms through which cladribine may induce symptomatic improvement. Optimum dosing regimens, routes (IV, subcutaneous, or oral) and the value of combination therapies (eg, with tyrosine kinase inhibitors) need to be investigated in future clinical trials.