Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E–positive LCH

Abstract

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect "risk organs" (RO). The established role of BRAF V600E mutation in LCH led to a targeted approach. However, the targeted therapy can't cure the disease and the cessation leads to quick relapses. In our study, we combined cytarabine (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 RO+ and 6 RO-. Five patients received the therapy upfront, while the other 14 - as the second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg) which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2/every 12 h, 6 mg/m2/day, Days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median DAS decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on Day 28. All patients except one received complete protocol treatment, and 15 of them didn't have disease progression. The 2-year relapse-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary MDS (sMDS) after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.

Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis

“…One patient developed secondary myelodysplastic syndrome, but other toxicities were reportedly manageable. 19 The patients in our study were similar at the age of diagnosis (1.15 years vs. 10 months for RO+ and 24 months for RO−), but older and with longer treatment history compared to the Evseev series (6.8 years vs. 17 months for RO+ and 24 months for RO−; median 4 prior therapies vs. 2). In this study, ORR was comparable (90% vs. 100%) in a challenging population treated with less toxic therapy that can be administered outpatient in most cases.…”

Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study

“…Evseev, D found that combined cytarabine (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with vemurafenib achieved stable remission in LCH patients, but all patients experienced grade 3–4 hematological adverse reactions. One patient developed secondary myelodysplastic syndrome (sMDS) 14 months after vemurafenib therapy cessation (Evseev et al 2023 ). In our study, we administered vemurafenib in combination with low-toxicity chemotherapy for over 12 months to the majority of patients, and most of them achieved clinical and molecular remission.…”

From mutation to management: Advancing Langerhans cell histiocytosis treatment through combination therapies

“…COMMENTARY combination cladribine, cytarabine and vemurafenib in patients with BRAFV600E-positive LCH, achieving a 2-year event-free survival rate of 78.9%. 8 The vemurafenib was administered sequentially to avoid the risk of overlapping toxicities. Notably, none of the participants had previously received MAPK inhibition, and only one had been treated with cladribine.…”

“…Recently, Evseev et al. presented findings from a prospective phase II trial that investigated the efficacy of combination cladribine, cytarabine and vemurafenib in patients with BRAFV600E‐positive LCH, achieving a 2‐year event‐free survival rate of 78.9% 8 . The vemurafenib was administered sequentially to avoid the risk of overlapping toxicities.…”