Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis

Eder, Sarah; Schwentner, Raphaela; Soussia, Philipp Ben; Abagnale, Giulio; Attarbaschi, Andishe; Minkov, Milen; Halbritter, Florian; Hutter, Caroline

doi:10.1182/bloodadvances.2021005442

Cited by 22 publications

(17 citation statements)

References 27 publications

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“…To this end, (longitudinal) assessment of mutant alleles in cellular or cell-free DNA derived from peripheral blood and/or bone marrow represents an interesting opportunity for prognostic staging and monitoring response to therapy. 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 …”

Section: Discussionmentioning

confidence: 99%

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for approximately 80% of genetic driver alterations in neoplastic LCH-cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of SS-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival (EFS) in the overall cohort, neither BRAF nor MAP2K1 mutations associated with EFS when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH, but also question the independent prognostic value of lesional BRAFV600E status.

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Section: Discussionmentioning

confidence: 99%

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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“…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 ). The cytotoxicity of chemotherapeutic agents can compensate for this deficiency.…”

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

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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.

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“…However, targeted therapy can not eradicate the neoplastic clone and most of the patients relapsed after drug withdrawal [23]. In a recent study, a patient treated with the combination of the BRAF inhibitor and chemotherapy based on Ara-c and 2-CDA achieved molecular remission and not relapsed after stopping the treatment [27]. Therefore, the combination of chemotherapy and targeted therapy may obtain a sustained remission and needs further studies.…”

Section: Discussionmentioning

confidence: 99%

Treatment of children with refractory/relapse high risk Langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone

Wang

et al. 2023

Preprint

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Background: The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO+ LCH) have poor prognosis. The patients with MS-RO+ LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective in refractory/relapse MS-RO+ LCH, with low toxicity. Methods: We retrospectively analyzed pediatric refractory/relapse MS-RO+ LCH patients treated with the low-dose Ara-c (100mg/m2/d×5days) or high-dose Ara-c (500mg/m2/d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, long term outcomes and adverse events were analyzed. Results: From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were enrolled in the study. 11 (84.64%) of the 13 patients treated with the LAC regimen and 6 (85.71%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up, and the 5-year event-free survival rate (EFS) was 42.98% and 85.71% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.46% (5/13) and 42.86% (3/7) of patients who received the LAC and HAC regimen. Conclusions: A combination of Ara-c, VDS and prednisone might be effective as a salvage treatment in some patients with refractory/relapse MS-RO+ LCH , with low toxicity and 5-year overall survival rate of 100%. The high-dose Ara-c regimen was associated with numerically higher EFS rate.

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Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis

Cited by 22 publications

References 27 publications

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

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

Treatment of children with refractory/relapse high risk Langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone

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