Lineage switching of the cellular distribution of <i>BRAF</i>
                  <i>V600E</i> in multisystem Langerhans cell histiocytosis

Milne, Paul; Bomken, Simon; Slater, Olga; Kumar, Ashish; Nelson, Adam; Velázquez, Jessica María Angélica Vargas; Mankad, Kshitij; Nicholson, James C.; Yeomanson, Daniel; Grundy, Richard G.; Kamal, Ähmed; Penn, Anthony; Pears, Jane; Millen, Gerard Cathal; Morland, Bruce; Hayden, James; Lam, Chun Ho; Madkhali, Maymoon; Macdonald, Jamie Liam; Singh, Preeti; Pagan, Sarah; Rodríguez‐Galindo, Carlos; Minkov, Milen; Donadieu, Jean; Picarsic, Jennifer; Allen, Carl E.; Bigley, Venetia; Collin, Matthew

doi:10.1182/bloodadvances.2021006732

Cited by 10 publications

(9 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Somatic BRAF V600E mutations in hematopoietic precursors increase the risk of developing multiple organ involvement in LCH (Rodriguez-Galindo and Allen 2020 ; Poch et al 2021 ). Moreover, the burden of these mutant clones correlates with the probability of relapse (Wang et al 2021 ; Milne et al 2023 ), emphasizing the importance of eliminating precursor cells for a cure. However, the persistence of BRAF V600E -positive mononuclear cells in both the blood and bone marrow, along with a high recurrence rate following drug withdrawal, suggests that vemurafenib monotherapy may be ineffective in completely eradicating LCH precursor cells (Eder et al 2022 ; Donadieu et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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

Lei,

Wang,

Lin

et al. 2024

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Background Langerhans cell histiocytosis (LCH) is a myeloid neoplasia with potentially fatal consequences, and about 2/3 of cases involve the BRAFV600E kinase-activated mutation. Vemurafenib, a BRAF inhibitor, has demonstrated significant clinical improvements in LCH. However, the high relapse rate of LCH following cessation of vemurafenib therapy remains a major challenge, and alternative treatment strategies require further investigation. Methods In this retrospective multi-center study, we evaluated the efficacy and safety of vemurafenib combined with conventional chemotherapy in patients with severe or refractory LCH. Results Seventeen patients were enrolled in the study, with eleven classified as risk organ involvement (RO +). Six received the combination therapy as the primary treatment, and eleven after being refractory to prior chemotherapy. The overall response rate was 94.1%. Progression-free survival among all 17 patients was 70.6% (12/17) at a median follow-up of 32 months, and relapse-free survival among the 15 patients with discontinuation after a response was 73.3%(11/15) at a median follow-up of 34 months. Five of six patients (83.3%) with myeloid BRAFV600E mutations demonstrated molecular remission. The overall survival rate was 100%. Adverse events were mostly classified as grades 1 or 2. Conclusion Our data suggest that the combination of vemurafenib and chemotherapy can achieve sustained clinical and molecular level relief in children with LCH, and side effects are tolerable.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Lei,

Wang,

Lin

et al. 2024

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

“…Meanwhile, concerns are growing about the future of patients with LCH receiving vemurafenib therapy for a long time. There are scattered reports on the clonal and biological evolution of the disease, 30 , 31 which are the first signs of the problems we might face in the future. Clonal proliferation, lineage switching, or secondary transformation still seem possible during prolonged BRAF inhibition.…”

Section: Discussionmentioning

confidence: 99%

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

Evseev,

Osipova,

Kalinina

et al. 2023

Blood Advances

View full text Add to dashboard Cite

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.

show abstract

“…The effect of these treatments is only suspensive, since the disease recurred after treatment cessation in most cases, although it remained sensitive when resuming the drug. Thus, targeting MAPK alterations does not eradicate the pathological cell clones at the origin of the disease [44 ▪ ].…”

Section: Mitogen-activated Protein Kinase Targeted Therapies In Lange...mentioning

confidence: 99%

Pulmonary Langerhans cell histiocytosis – an update on pathogenesis and treatment

Jouenne

Benattia

Tazi

2023

Current Opinion in Pulmonary Medicine

View full text Add to dashboard Cite

Purpose of review Pulmonary Langerhans cell histiocytosis (PLCH) is a rare diffuse cystic lung disease that affects young to middle-aged smoking adults of both genders. The identification of molecular alterations in the canonical mitogen-activated protein kinase (MAPK) signalling pathway in most specific lesions has demonstrated the clonal/neoplastic nature of PLCH. We will summarize the progress made in the understanding of the pathogenesis of adult PLCH, and briefly highlight the recent findings useful for the management of the patients. Recent findings The MAPK pathway is constantly activated in PLCH lesions. Apart from the BRAF V600E mutation, other driver somatic genomic alterations in this pathway (mainly MAP2K1 mutations/deletions and BRAF deletions) have been identified in the lesions, paving the way for targeted treatment. Smoking appears to promote the recruitment of MAPK-activated circulating myeloid precursors to the lung. The long-term survival of PLCH is more favourable with a 10-year survival >90%. Lung cancer and chronic respiratory failure are the main causes of death. Few patients develop severe pulmonary complications within the 5 years after diagnosis, justifying a close longitudinal follow-up of the patients. Summary PLCH is a MAPK driven neoplasia with inflammatory properties. The place of targeted therapies in severe forms of PLCH warrants further evaluation.

show abstract

Lineage switching of the cellular distribution of BRAF V600E in multisystem Langerhans cell histiocytosis

Cited by 10 publications

References 20 publications

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

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

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

Pulmonary Langerhans cell histiocytosis – an update on pathogenesis and treatment

Contact Info

Product

Resources

About