scholarly journals Early association of Vemurafenib to standard chemotherapy in multisystemic Langerhans cell histiocytosis in a newborn: take the chance for a better outcome?

2021 ◽  
Author(s):  
stefania gaspari ◽  
Valentina Di Ruscio ◽  
Francesca Stocchi ◽  
Roberto Carta ◽  
Marco Becilli ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Target Therapy ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Erk Signaling ◽  
Standard Chemotherapy ◽  
Disease Remission ◽  
Multisystemic Disease ◽  
Life Threatening

LCH is an aberrant monoclonal proliferation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystemic disease. Pathogenic cells expressed, in almost 70% of cases, an activation of the MAPK/ERK signaling pathway, in particular BRAF V600E mutation. We report on a newborn with multisystemic disease diagnosed in life-threatening medical conditions, who was successfully treated with the early association of BRAF inhibitor Vemurafenib to chemotherapy. After 12 months, Vemurafenib was discontinued, without any signs of relapse. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission.

scholarly journals The BRAF V600E Mutation Detection by quasa Sensitive Real-Time PCR Assay in Northeast Romania Melanoma Patients

2021 ◽  
Vol 11 (20) ◽  
pp. 9511
Author(s):  
Elena Porumb-Andrese ◽  
Ramona Gabriela Ursu ◽  
Iuliu Ivanov ◽  
Irina-Draga Caruntu ◽  
Vlad Porumb ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Target Therapy ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinical Samples ◽  
Primary Cutaneous Melanoma ◽  
Purification Method ◽  
Detection Of Mutations ◽  
National Reporting System

Background: The prevalence of melanoma in Romanian patients is underestimated. There is a need to identify the BRAF V600E mutation to accurately treat patients with the newest approved BRAF inhibitor therapy. This is a pilot study in which we first aimed to choose the optimal DNA purification method from formalin fixation and paraffin embedding (FFPE) malignant melanoma skin samples to assess the BRAF mutation prevalence and correlate it with clinical pathological parameters. Methods: 30 FFPE samples were purified in parallel with two DNA extraction kits, a manual and a semi-automated kit. The extracted DNA in pure and optimum quantity was tested for the BRAF V600E mutation using the quantitative allele-specific amplification (quasa) method. quasa is a method for the sensitive detection of mutations that may be present in clinical samples at low levels. Results: The BRAF V600E mutation was detected in 60% (18/30) samples in patients with primary cutaneous melanoma of the skin. BRAFV600E mutation was equally distributed by gender and was associated with age >60, nodular melanoma, and trunk localization. Conclusions: The high prevalence of BRAF V600E mutations in our study group raises awareness for improvements to the national reporting system and initiation of the target therapy for patients with malignant melanoma of the skin.

Multimodiale Therapie von Hirnmetastasen

2020 ◽  
Vol 46 (05) ◽  
pp. 228-231
Author(s):  
M. Ahmed ◽  
F. Meier ◽  
S. Beissert
Keyword(s):  
Zielgerichtete Therapie ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Epileptischer Anfall ◽  
Neurologische Defizite ◽  
Ca 50

ZusammenfassungDas Langzeitüberleben hat sich für Patienten mit metastasiertem Melanom durch die Etablierung der zielgerichteten Therapien sowie Immuntherapien mit 5-Jahres-Überlebensraten von ca. 50 % deutlich verbessert. Hirnmetastasen stellen jedoch weiterhin eine therapeutische Herausforderung dar. In der Vergangenheit lag das mediane Überleben für Patienten mit neu diagnostizierten Hirnmetastasen bei 2 – 6 Monaten 1. Retrospektive Analysen sprechen für einen Überlebensbenefit unter multimodaler Therapie mit einer 5-Jahres-Überlebensrate von über 20 % 1.Wir berichten über einen 50-jährigen Patienten mit multiplen symptomatischen Hirnmetastasen bei Erstdiagnose. Nach Exstirpation einer symptomatischen Metastase wurde bei BRAF-V600E-Mutation eine Systemtherapie mit dem BRAF-Inhibitor Dabrafenib in Kombination mit dem MEK-Inhibitor Trametinib eingeleitet. Hierunter zeigte sich ein rascher deutlicher Regress der zerebralen und extrazerebralen Metastasen. Nach 8 Wochen wurde die Systemtherapie auf eine Immuntherapie mit Nivolumab plus Ipilimumab umgesetzt. Kurz nach Therapieeinleitung trat ein epileptischer Anfall auf und die Hirnmetastasen zeigten sich wieder progredient. Zwei symptomatische Hirnmetastasen wurden reseziert, eine Ganzhirnradiatio mit Hippocampusschonung wurde eingeleitet und die Immuntherapie fortgesetzt. Aktuell erfolgt eine zielgerichtete Therapie mit Encorafenib und Binimetinib. 17 Monate nach Erstdiagnose befindet sich der Patient in gutem Allgemeinzustand ohne neurologische Defizite. Dieser Fallbericht bestätigt den retrospektiv beobachteten Überlebensbenefit für Patienten mit Hirnmetastasen unter multimodaler Therapie.

Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 571-578 ◽  
Author(s):  
Julien Haroche ◽  
Oussama Abla
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Juvenile Myelomonocytic Leukemia ◽  
Juvenile Xanthogranuloma ◽  
Poor Prognostic Factor ◽  
Erdheim Chester Disease ◽  
Recurrent Mutations ◽  
Life Threatening ◽  
Erdheim Chester ◽  
Chester Disease

Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

scholarly journals Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 571-578 ◽  
Author(s):  
Julien Haroche ◽  
Oussama Abla
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Juvenile Myelomonocytic Leukemia ◽  
Juvenile Xanthogranuloma ◽  
Poor Prognostic Factor ◽  
Erdheim Chester Disease ◽  
Recurrent Mutations ◽  
Life Threatening ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

scholarly journals Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5895-5895
Author(s):  
Gordon Ruan ◽  
Gaurav Goyal ◽  
Jithma P. Abeykoon ◽  
N. Nora Bennani ◽  
Karen Rech ◽  
...  
Keyword(s):  
Median Time ◽  
Low Dose ◽  
Braf Inhibitor ◽  
Brain Parenchyma ◽  
Advisory Board ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Starting Dose ◽  
Dose Reductions

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9074-9074
Author(s):  
Miguel F. Sanmamed ◽  
Sara Fernandez-Landazuri ◽  
Eduardo Castanon ◽  
Jose Echeveste ◽  
Maria D. Lozano ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Markers ◽  
Direct Sequencing ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Best Response ◽  
Response Table ◽  
S 100 ◽  
Melanoma Patients

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]

Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
David Planchard ◽  
Julien Mazieres ◽  
Gregory J. Riely ◽  
Charles M. Rudin ◽  
Fabrice Barlesi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Safety Data ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinical Activity ◽  
Duration Of Response ◽  
Nsclc Patients

8009 Background: Activating BRAF V600E mutations in NSCLC are present in < 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation–positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E–mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928. Methods: Single-arm, 2-stage, phase II study in stage IV BRAF V600E mutation–positive NSCLC pts who failed at least 1 line of chemotherapy. Dabrafenib dosed at 150 mg orally twice daily. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria. Results: The median age of the 17 pts was 69 years (range, 51-77 years). Most pts (12/17) were male, all were white with adenocarcinoma, and 13 were former smokers. All pts had failed at least 1 line of prior anticancer therapy, and 5 subjects had failed ≥ 2. At the time of reporting, 11 pts remain on therapy, and 6 have stopped therapy (5 with PD and 1 due to an AE). Thirteen pts were evaluable for efficacy. The best response for these pts included 7 PRs (5 confirmed PRs), 1 SD, and 4 PD; 1 pt discontinued due to an SAE (hypersensitivity reaction) prior to response assessment (ORR, 54%). The median duration of treatment for all 17 pts is approximately 9 weeks (range, 1-69 weeks). Among the 5 pts with confirmed PRs, duration of response was 29 and 49 weeks for the 2 pts who progressed, while the remaining 3 pts were responding for 6+ to 24+ weeks. The safety of dabrafenib in NSCLC pts appears to be generally consistent with what has been previously observed. The most common AEs were decreased appetite, fatigue, asthenia, dyspnea, and nausea, mostly grade 1 or 2. Five pts (29%) had a grade 3 AE, and 1 pt (6%) had a grade 4 SAE (hemorrhage). Conclusions: Dabrafenib shows early antitumor activity in BRAF V600E mutation–positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (≥ 3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC. Clinical trial information: NCT01336634.

scholarly journals Aggressive childhood-onset papillary craniopharyngioma managed with vemurafenib, a BRAF inhibitor

2021 ◽  
Author(s):  
Constance L Chik ◽  
Frank K H van Landeghem ◽  
Jacob C Easaw ◽  
Vivek Mehta
Keyword(s):  
Radiation Therapy ◽  
Tumor Recurrence ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Tumor Control ◽  
Tumor Shrinkage ◽  
Childhood Onset ◽  
Elevated Liver Enzymes ◽  
Tumor Regrowth

Abstract The papillary subtype of craniopharyngioma rarely occurs in children and commonly presents as a suprasellar lesion. Patients with papillary craniopharyngiomas frequently harbor the BRAF-V600E mutation and treatment with a BRAF inhibitor results in tumor shrinkage in several patients. Herein, we report a patient with childhood-onset papillary craniopharyngioma treated with vemurafenib for 40 months after multiple surgeries. At age 10, he presented with growth failure secondary to an intrasellar cystic lesions. He had three transsphenoidal surgeries before age 12 and a fourth surgery 25 years later for massive tumor recurrence. Pathology showed a papillary craniopharyngioma with positive BRAF-V600E mutation. Rapid tumor regrowth 4 months after surgery led to treatment with vemurafenib that resulted in tumor reduction within 6 weeks. Gradual tumor regrowth occurred after a dose reduction of vemurafenib because of elevated liver enzymes. He had further surgeries and within 7 weeks after stopping vemurafenib, there was massive tumor recurrence. He resumed treatment with vemurafenib before radiation therapy and similar tumor shrinkage occurred within 16 days. In this patient with childhood-onset papillary craniopharyngioma that was refractory to multiple surgeries, the use of vemurafenib resulted in significant tumor shrinkage that allowed for completion of radiation therapy and tumor control.

scholarly journals Newly diagnosed papillary craniopharyngioma with BRAF V600E mutation treated with single-agent selective BRAF inhibitor dabrafenib: a case report

Oncotarget ◽  
2019 ◽  
Vol 10 (57) ◽  
pp. 6038-6042 ◽  
Author(s):  
Mayank Rao ◽  
Meenakshi Bhattacharjee ◽  
Scott Shepard ◽  
Sigmund Hsu
Keyword(s):  
Case Report ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Newly Diagnosed

scholarly journals Relevant Imaging Presentation of Erdheim-Chester Disease: A case-report

2018 ◽  
Vol 13 (2) ◽  
Author(s):  
Philippe Jacob
Keyword(s):  
Bone Pain ◽  
Clinical Manifestations ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Bone Lesions ◽  
Erdheim Chester Disease ◽  
Promising Treatment ◽  
Erdheim Chester ◽  
Chester Disease

Erdheim-Chester disease (ECD) is a rare non-Langerhans multisystemic histiocytosis. This disorder is characterised by CD68+/CDa1- foamy histiocytes infiltration in tissues, especially bones, retroperitoneum, heart, lung and brain. Clinical manifestations may range from asymptomatic bone lesions to multiorganic symptoms. Bone pain in lower extremities are however the most common symptoms. Typical imaging findings include symmetric dyaphyseal osteosclerosis of long bones, periaortic sheathing (“coated aorta”) and retroperitoneal infiltration (“hairy kidney”). Lung and brain radiological abnormalities may also be seen on imaging screening. BRAF-V600E mutation is associated with around half of ECD patients. Vemurafenib, a mutated BRAF inhibitor, is a promising treatment for patients with this mutation. We present the case of a 60 years old man who arrived with a pathological right humerus fracture, and who was first admitted for a tuberculosis suspicion. ECD was first suspected with imaging screening.

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