Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Abstract

Purpose: Off-label use of vemurafenib (VMF) to treat BRAF^V600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.

Patients and methods: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score.

Results: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAF^V600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAF^V600E clone.

Conclusion: VMF seemed safe and effective in children with refractory BRAF^V600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

FIG 1.

Langerhans cell histiocytosis (LCH) evolution on vemurafenib (VMF) according to various criteria. (A) Waterfall figure of the Disease Activity Score (DAS) change between day 1 and week 8 after starting VMF. (B) DAS evolution between VMF day 1 and week 8 according to the LCH extent of risk organ (RO) involvement (RO positive, RO negative). The differences were significant for the two groups (P < .001), but the amplitude was much more pronounced for the RO-positive group. (C) Female patient #1509231 with massive cervical lymph nodes viewed from the back on day –1 (DAS = 3; left) and after their disappearance on day 14 (right) of VMF administration. Her multisystemic RO-positive LCH was initially treated with two cycles of vinblastine plus corticosteroids (VBL + CS) that obtained good responses before reactivation, which was then retreated unsuccessfully with VBL + CS and then cladribine before further worsening. (D) Imaging of left-side temporal bone lesion in male patient #1509707. After an initial good response to standard VBL + CS induction, his initially RO-positive LCH reactivated locally on the first maintenance regimen. VBL + CS was prescribed again, but disease progression led to left-sided facial palsy. The first computed tomography scan (left) shows left-side temporal bone destruction and soft tissue involvement, whereas the computed tomography scan at week 6 on VMF (right) shows that almost all the initial lesions had disappeared and bone was partially remodeled.

FIG 2.

Kaplan-Meier plots of Langerhans cell histiocytosis (LCH) reactivation and survival rates. (A) Thirty assessable patients after vemurafenib (VMF) withdrawal with 95% CIs. (B) According to initial LCH risk organ (RO) involvement (RO positive, RO negative). The probability of reactivation was significantly higher for patients with RO-positive LCH (P = .0041). (C) According to circulating cell-free BRAF^V600E loads in plasma of 13 assessable patients after stopping VMF as determined by polymerase chain reaction. Despite the small number of available values, the probability of reactivation was significantly higher when the cell-free BRAF^V600E load was positive (P < .001) on VMF (P = .0124). (D) Survival rate with 95% CI since VMF onset for the 54 children with LCH.

FIG 3.

Circulating cell-free BRAF^V600E kinetics according to time on vemurafenib and Langerhans cell histiocytosis risk organ extent (18 positive for risk organ involvement [black lines, blue diamonds]; four negative for risk organ involvement [red lines and squares]). The BRAF^V600E allele load (expressed as the percentage of mutant alleles relative to the total number of alleles) is shown for each patient before vemurafenib onset (day 0), at weeks 6 to 8, and during months 3 to 6 and 9 to 12.