Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis

Mohapatra, Debabrata; Gupta, Aditya Kumar; Haldar, Partha; Meena, Jagdish Prasad; Tanwar, Pranay; Seth, Rachna

doi:10.1080/08880018.2022.2072986

Cited by 7 publications

(3 citation statements)

References 36 publications

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“…More generally, these results are consistent with the previous pediatric experience in which genomically complex and clinically aggressive tumor types such as HGG and RMS 13,17 are largely resistant to single-agent MAPK pathway inhibition. Previous studies of single agents targeting MAPK signaling have shown durable responses in several pediatric cancer types whose genomes harbor few additional driver mutations (single pathway diseases), including progressive LGG harboring alterations in BRAF or NF1 , 18,21 Langerhans cell histiocytosis with BRAF mutations, 33 and inoperable plexiform neurofibromas 20 (leading to US Food and Drug Administration approval of selumetinib for neurofibromatosis patients with these tumors). In this arm of Pediatric MATCH, the primary signal of single-agent ulixertinib activity noted was in patients with LGG or glioneuronal tumors, none of whom had additional alterations beyond BRAF detected by tumor screening.…”

Section: Discussionmentioning

confidence: 99%

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Vo,

Sabnis,

Williams

et al. 2024

JCO Precis Oncol

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PURPOSE The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

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Section: Discussionmentioning

confidence: 99%

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Vo,

Sabnis,

Williams

et al. 2024

JCO Precis Oncol

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“…Recently, a growing understanding of MAPK pathway gene mutations and their role in the development of LCH has further substantiated the use of BRAF and MEK inhibitors for the treatment of LCH [1,4,5].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, standard treatment for ND-LCH has not been established. Vemurafenib, a BRAF inhibitor, was found to be effective in the treatment of BRAF V600Emutated LCH [2,4,5]. In this case report, we described a case of refractory BRAF V600E-mutated LCH involving neurodegenerative manifestations, that was successfully treated using vemurafenib.…”

Section: Introductionmentioning

confidence: 94%

Improvement of Neurodegenerative Disease after Use of Vemurafenib in Refractory BRAF V600E-Mutated Langerhans Cell Histiocytosis: A Case Report

Koh

Yoon

Kang

et al. 2022

Clin Pediatr Hematol Oncol

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Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder characterized by heterogenous lesions infiltrated with CD1a+/CD207+ cells. Although LCH has a relatively good prognosis, the prognosis for patients with LCH refractory to standard chemotherapy is poor. Neurodegenerative LCH (ND-LCH) is a central nervous system complication of LCH that is characterized by progressive radiological and clinical abnormalities. Symptomatic ND-LCH is difficult to treat and therefore has a poor prognosis. A two-year-old boy presented with a scalp mass. Biopsy confirmed LCH. Whole-body imaging revealed LCH involvement in multiple bones of the skull, facial bones, and lungs. Prednisolone and vinblastine chemotherapy was initiated. One-year post-treatment, most of the lesions in the bones and lung nodules disappeared, and chemotherapy was discontinued. New neurodegenerative lesions appeared 4 months after chemotherapy was discontinued. Second-line chemotherapy using cytarabine, vincristine, and prednisolone was initiated. However, neurological manifestations of ND-LCH worsened post second-line treatment, and the treatment was switched to cytarabine and cladribine. Despite third-line chemotherapy, the lesions progressed, and neurological deficits worsened. After identifying BRAF V600E mutation in the tumor tissue using next-generation sequencing, cytotoxic chemotherapy was discontinued and vemurafenib treatment was initiated. One-year post-vemurafenib therapy, ND-LCH manifestations regressed, and the patient experienced neurological improvement.

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Targeted Therapy With Vemurafenib in Brazilian Children With Refractory Langerhans Cell Histiocytosis: Two Case Reports and Review of Literature

Silva,

Magalhães,

Benincasa

et al. 2024

Cancer Reports

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BackgroundLangerhans cell histiocytosis (LCH) is a clonal myeloid neoplasm with inflammatory component. Refractory disease is a challenge, but vemurafenib has emerged as a therapeutic option. We will delineate the cases of two Brazilian children suffering from refractory LCH with a positive response to vemurafenib.CasesBoth cases had a diagnosis of multisystem disease with involvement of organs at risk and had not responded to standard and second‐line treatment. After refractoriness to classic treatment regimens, the BRAF mutation was investigated and found to be positive in both patients, and target therapy with vemurafenib was sought. The first case has been using vemurafenib for about 2 years and the second case has been using it for about 3 years, having had an attempt to suspend the medication after concomitant use with maintenance therapy. However, the disease returned 4 months after stopping the medication. Fortunately, the disease returned to remission status after the medication was reintroduced.ConclusionThese cases represent the first reported instances of off‐label vemurafenib use in Brazil for the treatment of LCH and both patients have demonstrated excellent responses to the medication. However, the long‐term side effects are unknown in children, and prospective studies are needed. In addition, there is a lack of epidemiological data on histiocytosis in Brazil and studies evaluating the budgetary impact of incorporating BRAF mutation research and the use of vemurafenib into the public health system. These reports could be a starting point.

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Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis

Cited by 7 publications

References 36 publications

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Improvement of Neurodegenerative Disease after Use of Vemurafenib in Refractory BRAF V600E-Mutated Langerhans Cell Histiocytosis: A Case Report

Targeted Therapy With Vemurafenib in Brazilian Children With Refractory Langerhans Cell Histiocytosis: Two Case Reports and Review of Literature

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