scholarly journals Case Report: Early Association of Vemurafenib to Standard Chemotherapy in Multisystem Langerhans Cell Histiocytosis in a Newborn: Taking a Chance for a Better Outcome?

2021 ◽  
Vol 11 ◽  
Author(s):  
Stefania Gaspari ◽  
Valentina Di Ruscio ◽  
Francesca Stocchi ◽  
Roberto Carta ◽  
Marco Becilli ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Laboratory Data ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Multisystem Disease ◽  
Response To Chemotherapy ◽  
First Line Treatment

Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients.

Adult Langerhans cell histiocytosis: A contemporary single-institution series of 186 patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7018-7018
Author(s):  
Gaurav Goyal ◽  
Marie Hu ◽  
Jason R Young ◽  
Robert Vassallo ◽  
Jay H Ryu ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Langerhans Cell Histiocytosis ◽  
Overall Response Rate ◽  
Langerhans Cell ◽  
Braf V600e ◽  
First Line ◽  
Multisystem Disease ◽  
Presenting Symptoms ◽  
Systemic Therapies

7018 Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm driven by MAPK-ERK mutations in majority of patients. Contemporary data on treatments and outcomes in adult LCH are lacking. Hence, we undertook this study to analyze a large cohort of adult LCH patients. Methods: This was a retrospective study of adult (≥18 years) LCH patients seen at our institution between 1998 and 2018. Results: We included 186 patients with adult LCH (median age 43; 19-88), and 54% were females. 70% of patients were diagnosed after 2007. Common presenting symptoms were cough/dyspnea (30%), rash (17%), pain/swelling in head (17%), and diabetes insipidus (10%). 70 (38%) patients had multisystem LCH, 62 (33%) had isolated pulmonary LCH, and 35 (19%) had unifocal LCH. Common sites of involvement included lung (59%), bone (37%), skin (21%), and nervous system (16%). 121 (65%) were smokers; 48% of these had lung disease, while 52% had multisystem disease. 18 of 31 tested (58%) patients had BRAF-V600E mutation. Most common first-line treatment was smoking cessation in 24 patients, and led to an overall response rate (ORR) of 83% in pulmonary lesions. Radiation therapy was used in 11 patients, and led to an ORR 82%. Surgical resection of lesion was done in 23 patients, with relapses in 24%. Systemic therapies were used in 78 (42%) patients (Table). Most common first-line systemic therapy was cladribine with ORR of 78%. Vemurafenib was used in 3 patients with BRAF-V600E, leading to an ORR of 67% . After a median follow-up of 23 months (0-261), 21 patients had died. Of these, 10 died of progressive LCH. Median OS was not reached, and mean OS was 196 months. Conclusions: This is the largest contemporary series of adult LCH. It shows that diverse clinical spectrum, ranging from benign course to a progressive multisystem disease. Although smoking cessation was an effective treatment for pulmonary LCH, a large subset required systemic chemotherapy. [Table: see text]

scholarly journals Pulmonary Langerhans Cell Histiocytosis: An Update From the Pathologists' Perspective

2016 ◽  
Vol 140 (3) ◽  
pp. 230-240 ◽  
Author(s):  
Anja C. Roden ◽  
Eunhee S. Yi
Keyword(s):  
Pulmonary Hypertension ◽  
Langerhans Cell Histiocytosis ◽  
Treatment Options ◽  
Additional Treatment ◽  
Langerhans Cell ◽  
Braf V600e ◽  
First Line ◽  
Clonal Proliferation ◽  
Pulmonary Langerhans Cell Histiocytosis ◽  
Appropriate Treatment

Context Pulmonary Langerhans cell histiocytosis (PLCH) is a rare histiocytic disorder that almost exclusively affects the lungs of smokers. PLCH is characterized by bronchiolocentric nodules and/or cysts in an upper and mid lung distribution with sparing of the costophrenic angles. The diagnosis can be challenging and often requires transbronchial biopsy or surgical lung biopsy. Pulmonary hypertension is a relatively common and sometimes severe complication of PLCH. The pathogenesis of PLCH is still debated. Recently, BRAF V600E mutation and BRAF expression have been identified in some patients with PLCH, suggesting that at least a subset of PLCH has a clonal proliferation. While smoking cessation is the first-line treatment of PLCH, some patients might require additional treatment and eventually transplant. Given that the lesional cells of PLCH express BRAF in some patients, MAPKinase pathway–targeted treatment might be useful for therapy-resistant patients. Objective —To present the more recently recognized clinical and pathologic aspects of PLCH, including pulmonary hypertension in PLCH, pathogenesis, and treatment, as well as the basic diagnostic approach to PLCH. Data Sources Authors' own research, and search of literature database (PubMed) and UpToDate. Conclusions —Despite the recent progress, more studies are needed to elucidate the biology of PLCH for identification of prognostic factors and appropriate treatment options, especially for therapy-refractory PLCH cases.

Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer

2020 ◽  
pp. 030089162096982
Author(s):  
Mustafa Gürbüz ◽  
Erman Akkuş ◽  
Abdullah Sakin ◽  
Semiha Urvay ◽  
Atike Gökçen Demiray ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Locally Advanced ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Her2 Positive ◽  
Intensified Chemotherapy ◽  
First Line Treatment

Purpose: Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. Methods: This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. Results: There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8–6.4) and 5.3 months (95% CI 2.6–8), respectively ( p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3–13.9) and 15.2 months (95% CI 12.7–17.7), respectively ( p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. Conclusion: Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

2019 ◽  
Vol 22 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Erdener Ozer ◽  
Akin Sevinc ◽  
Dilek Ince ◽  
Resmiye Yuzuguldu ◽  
Nur Olgun
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Disease Relapse ◽  
Multisystem Disease ◽  
Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4075-4075
Author(s):  
Tomohiro Nishina ◽  
Nozomu Fuse ◽  
Takeshi Kuwata ◽  
Shigenori Kadowaki ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Performance Status ◽  
Gastroesophageal Junction ◽  
Her2 Status ◽  
Prognostic Impact ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Ecog Performance Status ◽  
Significant Difference ◽  
First Line Treatment

4075 Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalin-fixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ≥20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2+ was defined as IHC 3+ or IHC 2+/FISH+. Results: Of 293 pts, 43 (15%) were HER2+. Baseline pt characteristics between HER2+ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p=0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p=0.003), No. of metastatic sites (≥2, 72% vs. 46%; p=0.003) and presence of liver metastasis (56% vs. 31%; p=0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2+ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79–1.55; log rank p=0.550). After adjusting other prognostic factors with Cox hazard model, HER2+ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p=0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.

Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with BRAF V600–mutant unresectable or metastatic melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9507-9507 ◽  
Author(s):  
Paul D. Nathan ◽  
Caroline Robert ◽  
Jean Jacques Grob ◽  
Daniil Stroyakovskiy ◽  
Boguslawa Karaszewska ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Line Treatment ◽  
Long Term Effects ◽  
First Line ◽  
Phase 3 ◽  
Term Benefit ◽  
First Line Treatment

9507 Background: First-line treatment with D+T demonstrated prolonged progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutant unresectable or metastatic melanoma. With 5 years of follow-up, we report survival and describe characteristics of patients in the phase 3 COMBI-d and COMBI-v trials with long-term benefit. Methods: Pooled 5-year landmark data for patients treated with D+T in the phase 3 COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials were analyzed. The trials enrolled patients with previously untreated BRAF V600E/K–mutant unresectable or metastatic melanoma. Patients received D 150 mg twice daily plus T 2 mg once daily vs either D + placebo (COMBI-d) or vemurafenib (COMBI-v). The primary endpoints were PFS in COMBI-d and OS in COMBI-v. Results: The pooled population included 563 patients who received D+T (COMBI-d, n = 211; COMBI-v, n = 352). Four- and 5-year PFS and OS rates were similar, suggesting a stabilization (4- and 5-year PFS, 21% [95% CI, 17%-24%] and 19% [95% CI, 15%-22%, respectively]; 4- and 5-year OS, 37% [95% CI, 33%-42%] and 34% [95% CI, 30%-38%], respectively). In patients with normal baseline lactate dehydrogenase (LDH) levels the 5-year PFS rate was 25% vs 8% in patients with elevated baseline LDH levels. Similarly, the 5-year OS rate was considerably higher in patients with normal baseline LDH levels vs those with elevated LDH levels at baseline (43% vs 16%). Among patients with normal baseline LDH levels and < 3 organ sites with metastases, the 5-year PFS and OS rates were 31% and 55%, respectively. In addition, exploratory analyses will be performed to characterize subgroup(s) of patients most likely to experience long-term benefit. Of 299 patients who received subsequent anticancer therapy following treatment with D+T, 151 (51%) received an anti–CTLA-4 therapy and 102 (34%) received an anti–PD-1 therapy. The safety profile of D+T was as previously reported, and no new safety signals were observed. No treatment-related deaths were reported. Conclusions: First-line treatment with D+T leads to durable long-term benefit in many patients with BRAF V600–mutant unresectable or metastatic melanoma. Clinical trial information: NCT01584648; NCT01597908.

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