Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study

Abstract

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.

© 2015 by The American Society of Hematology.

Figures

Figure 1

Study flowchart showing decision points after the first 2 therapeutic courses. The cumulative dose of cladribine in this protocol was 120 mg/m2 if the patient had a good response to the initial course.

Figure 2

The response after 2 courses of cladribine/Ara-C. At inclusion, the disease activity was active disease (AD) worse in 23 patients and AD stable in 4 patients. The disease score was similar in AD worse and AD stable patients. After 2 courses, disease activity was nonactive disease, AD stable in 2 patients, and AD better in 23 patients. The median score dropped from 12 at the start of therapy to 3 after 2 courses.

Figure 3

Survival since the start of the protocol (D1 cladribine/Ara-C). (A) Overall survival. (B) Survival according to DAS evolution. Good responders (DAS decrease >4 points) appeared to have a better outcome than poor responders (DAS decrease ≤4 points) (P < .04).