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

Abstract

International audienceAn 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/m2 per day) plus cladribine (9 mg/m2 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 \textless .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 toxicit

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

“…The severe clinical form of the disease principally affects young children (age , 2 years) and tends to involve risk organs (RO), including the hematopoietic system, spleen, and/or the liver. Despite a low mortality rate, 3,4 long term, irreversible adverse effects are common. 5 In particular, endocrine dysfunction, secondary to pituitary involvement, and neurodegenerative disease are reported in approximately 20% and 5% of cases, respectively.…”

“…At the other end of the spectrum, more severe disease forms can be treated with effective second-line therapies, but these are reported to be highly toxic. 3 This toxicity is relevant, given that incidence of long-term adverse effects (PC) remains substantial for patients with LCH; more than one quarter of patients with BRAF V600E developed PC with LCH. Thus, anti-BRAF therapies represent a promising new line of inquiry.…”

Salvage treatment of relapsed/refractory LCH

“…There had been several reports showing the effectiveness of 2CdA/Ara-C combination as second line treatment for R/R MS RO+ high risk LCH patients [2]. …”

“…As the 2-CdA/Ara-C chemotherapy frequently develop WHO grade 4 hematologic toxicity and severe infection [2], the usage of this regimen should be restrictive to patients showing “AD intermediate or AD worse” in RO after week 6 or week 12 of standard chemotherapy with vinblastine and prednisone. Those MS RO+ patients who are regarded as “AD better” without achieving NAD state after 12 weeks' standard therapy need to be treated with less toxic vincristine/Ara-C/prednisone chemotherapy of Stratum II.…”

“…The poor survival rate of MS LCH patients with RO involvement (RO+) who are refractory to or relapsing after standard chemotherapy was much improved with the introduction of salvage chemotherapy using 2CdA and Ara-C [2], but still there are patients not responding and dying with R/R disease.…”