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

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E 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 BRAFV600E 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 BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

[Retinoblastoma: recent advances]. / Le rétinoblastome: les avancées récentes.

Retinoblastoma is the most common intraocular malignancy of infancy with an incidence of 1/15,000 to 1/20,000 births. Sixty percent of retinoblastomas are unilateral, with a median age at diagnosis of two years, and in most cases are not hereditary. Retinoblastoma is bilateral in 40% of cases, with an earlier median age at diagnosis of one year. All bilateral and multifocal unilateral forms are hereditary and are part of a genetic cancer predisposition syndrome. All children with a bilateral or familial form, and 10 to 15% of children with an unilateral form, constitutionally carry an RB1 gene mutation. The two most frequent symptoms revealing retinoblastoma are leukocoria and strabismus. Diagnosis is made by fundoscopy, with ultrasound and magnetic resonance imaging (MRI) contributing both to diagnosis and assessment of the extension of the disease. Treatment of patients with retinoblastoma must take into account the various aspects of the disease (unilateral/bilateral, size, localization…), the risk to vision and the possible hereditary nature of the disease. The main prognostic aspects are still premature detection and adapted coverage by a multi-disciplinary specialized team. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is taken according to the histological risk factors. The most important recent therapeutic advances concern the conservative treatment which is proposed for at least one of the two eyes in most bilateral cases: laser alone or in combination with chemotherapy, cryotherapy or brachytherapy. Recently, the development of new conservative techniques of treatment, such as intra-arterial selective chemotherapy perfusion, aims at preserving visual function in these children and decreasing the number of enucleations and the need for external beam radiotherapy. The vital prognosis related to retinoblatoma is now excellent in industrialized countries, but long-term survival is still related to the development of secondary tumors, mainly secondary sarcoma. Retinoblastoma requires multi-disciplinary care as well as a long term specialized follow-up. Early counseling of patients and their family concerning the risk of transmission of the disease and the risk of development of secondary tumors is necessary.

Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma.

BACKGROUND: Carboplatin plays an important role in the conservative management of retinoblastoma, but is associated with risk of ototoxicity in these young children whose sensory prognosis may be also compromised by their loss of vision. This retrospective study analyzed the impact of carboplatin on hearing in the context of conservative management of children with retinoblastoma. METHODS: Data for 175 children treated at the Institut Curie between 1994 and 2002 were analyzed. RESULTS: Median age at diagnosis was 8 months (0-60). Carboplatin was administered on 3 days (200 mg/m(2)/day) or 5 days (160 mg/m(2)/day) with etoposide and with diode-laser therapy at the dose of 560 mg/m(2) (chemothermotherapy). Median cumulative dose of carboplatin was 2,880 mg/m(2) (560-6,160). Ototoxicity was investigated by pure-tone audiometry and scored by Brock's grading scale before and after treatment. The median follow-up of hearing assessment was 5 years (1.8-11). Ototoxicity was detected in 8 children: 3 grade 1, 1 grade 2, and 2 grade 4. The two patients with grade 4 hearing-loss required a hearing aid. Two children developed bilateral high frequency hearing-loss, considered to be secondary to carboplatin but with less than Brock grade 1. Ototoxicity was observed for a median cumulative dose of carboplatin of 3,120 mg/m(2) (1,200-5,830). Only one child developed ototoxicity during treatment. All other cases were discovered after the last dose of carboplatin with a median interval of 3.7 years (0-7.6). No other risk factor for ototoxicity was able to account for these lesions. CONCLUSION: Children receiving carboplatin require long-term audiometric follow-up.