Dabrafenib, Alone or in Combination with Trametinib, in Pediatric Patients with BRAF V600 Mutation-Positive Langerhans Cell Histiocytosis

Abstract Introduction: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder associated with varied clinical presentations. Patients (pts) with advanced disease have frequent recurrences despite standard chemotherapy and a significant proportion experience long-term complications, including orthopaedic, endocrine, auditory, or neurodegenerative complications. BRAF V600 mutations have been reported in over 50% of LCH cases. The BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is approved for BRAF V600-mutation positive melanoma, NSCLC, and anaplastic thyroid cancer. Here we describe the pooled analysis of pts with LCH from two open-label phase I/II studies in pediatric pts with recurrent/refractory malignancies, treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). Results: At the data cut-off date of January 19, 2021, 13 pts with LCH had received dabrafenib monotherapy (n=2, escalation; n=11, expansion). Median age was 3 years (range, 1-11) and all pts had received prior chemotherapy (100%); one patient received prior immunoglobulin and prior anti-CD52 monoclonal antibody (8%). Median duration of exposure to dabrafenib was 51 months (range, 7-65); 7 pts continued treatment on a rollover study and 6 discontinued, due to adverse events (AE; n=2), investigator decision (n=3), or switch to combination therapy via compassionate use (n=1). All pts experienced AEs, regardless of relationship to treatment; 11 pts (85%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly vomiting (46%), increased creatinine (38%), dry skin, rash, and melanocytic naevus (each 30%). AEs led to treatment discontinuation in 2 pts (increased blood creatinine; Epstein-Barr virus associated lymphoma, not related to treatment); there were no on-treatment deaths. The overall response rate (ORR) was 77% (6 complete response [CR]; 4 regressive disease [RD]); median duration of response (DOR) was not reached (NR), the estimated 24-month DOR rate was 90% (95% CI, 40-100). Median PFS was NR; the estimated 24-month PFS rate was 90% (95% CI, 50-100). At the data cut-off date of February 10, 2021, 12 pts with LCH had received dabrafenib + trametinib combination (2, escalation; 10, expansion). Median age was 4 years (range, 2-13) and all pts had received prior chemotherapy (100%). Median duration of exposure to treatment was 22 months (range 1.8-35.9); 8 patients continued therapy on a rollover study and 4 discontinued, due to AEs (n=2), lack of efficacy (n=1), or long term CR (n=1). All pts experienced AEs; 9 pts (75%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly pyrexia (58%), diarrhoea, dry skin, decreased neutrophil count, and vomiting (each 42%). AEs led to treatment discontinuation in 2 pts (AST increased; ALT increased); there were no on-treatment deaths. The ORR was 58% (4 CR; 3 RD); median DOR was NR, the estimated 24-month DOR rate was 100% (95% CI, NR-NR). Median PFS was NR; the estimated 24-month PFS rate was 100% (95% CI, NR-NR). Conclusions: Dabrafenib, with or without trametinib, demonstrated durable efficacy in pediatric pts with relapsed/refractory BRAF V600E mutation-positive LCH, with 90-100% of responses ongoing at 24 months. Treatment was associated with acceptable tolerability and manageable toxicities; the safety profile was consistent with what has been seen in other pediatric indications and in adult studies. Disclosures Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Roughton: Novartis Pharma AG: Current Employment. Choi: Novartis Pharmaceuticals: Current Employment. Osterloh: Novartis Farmacéutica S.A. Spain: Current Employment. Russo: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hargrave: AstraZeneca; Bayer; DayOne; Janssen; Novartis; Roche: Consultancy; AstraZeneca: Research Funding; AstraZeneca; Bayer; Novartis; Roche: Honoraria; Bayer: Speakers Bureau. OffLabel Disclosure: Trametinib in combination with dabrafenib is approved for the treatment of unresectable/metastatic melanoma with BRAF V600E or V600K mutations; adjuvant treatment for melanoma with BRAF V600E or V600K mutations; metastatic non-small cell lung cancer with BRAF V600E mutation; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E mutation.

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Vemurafenib provides a rapid and robust clinical response in paediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease based on ddPCR using cell-free circulating DNA

10.22541/au.160700442.27526762/v1 ◽

2020 ◽

Author(s):

Dmitry Evseev ◽

Irina Kalinina ◽

Elena Raykina ◽

Daria Osipova ◽

Zalina Abashidze ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Residual Disease ◽

Braf V600e Mutation ◽

Langerhans Cell ◽

Braf V600e ◽

Circulating Dna ◽

Neutropenic Sepsis ◽

Day Range ◽

Droplet Pcr ◽

Free Circulating Dna

Background Langerhans cell histiocytosis (LCH) involves abnormal proliferation of Langerhans cells (LC), which is typically driven by the BRAF V600E mutation. High-risk LCH has a poor prognosis. Procedure Fifteen children (5 girls, 10 boys) with BRAF V600E+ LCH received vemurafenib (initial dose median 40 mg/kg/day, range: 11–51.6 mg/kg/day) between March 2016 and February 2020. All patients had previous received LCH-directed chemotherapy. The median age at LCH onset was 2 months (range: 1–28 months) and the median age at the start of vemurafenib treatment was 22 months (range: 13–62 months). The median disease activity score (DAS) at the start of vemurafenib treatment was 12 points (range: 2–22 points). Results The median duration of vemurafenib therapy was 29 months (range: 2.4–45 months). All patients responded to treatment, with median DAS values of 4 points (range: 0–14 points) at week 4 and 1 point (range: 0–3 points) at week 26. Toxicities included skin/hair changes (93%) and non-significant QT prolongation (73%). Two patients died, including 1 patient who experienced hepatic failure after NSAID overdose and 1 patient who developed neutropenic sepsis. Electively stopping vemurafenib treatment resulted in relapse in 5 patients, and complete cessation was only possible for 1 patient. Digital droplet PCR for BRAF V600E using cell-free circulating DNA revealed that 7 patients had mutation statuses that fluctuated over time. Conclusion Our study confirms that vemurafenib treatment is safe and effective for young children with BRAF V600E+ multisystem LCH. However, treatment using vemurafenib does not completely eliminate the disease.

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Detection of BRAF V600E Mutation in Langerhans Cell Histiocytosis Using High-resolution Melting Analysis in Decalcified, Paraffin-embedded Tissue

Journal of Leukemia ◽

10.4172/2329-6917.1000101 ◽

2013 ◽

Vol 01 (01) ◽

Cited By ~ 1

Author(s):

Bin Fu

Keyword(s):

High Resolution ◽

Langerhans Cell Histiocytosis ◽

High Resolution Melting ◽

Braf V600e Mutation ◽

High Resolution Melting Analysis ◽

Langerhans Cell ◽

Braf V600e ◽

Melting Analysis

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Long-Term Outcomes and Safety of Continuous Lenalidomide Plus Dexamethasone (Len+Dex) Treatment in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v118.21.2929.2929 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2929-2929 ◽

Cited By ~ 1

Author(s):

Meletios Athanasios Dimopoulos ◽

Mohamad Hussein ◽

Arlene S Swern ◽

Donna M. Weber

Keyword(s):

Dose Reduction ◽

Median Duration ◽

Cox Regression ◽

Incidence Rates ◽

Long Term Outcomes ◽

Cox Regression Analysis ◽

Β2 Microglobulin ◽

Grade 3

Abstract Abstract 2929 Background: Two pivotal phase 3 trials (MM-009 and MM-010) randomized 704 pts to assess Len+Dex vs placebo plus dexamethasone (Dex) in RRMM. The results demonstrated the significant overall survival (OS) benefit of Len+Dex vs Dex (38.0 vs 31.6 mos; p =.045) despite crossover of 48% of Dex pts to the Len+Dex arm at unblinding or progression (Dimopoulos MA et al. Leukemia 2009;23 :2147-52). This is an analysis of the long-term outcomes and safety of continuous Len+Dex treatment. Methods: This retrospective analysis pooled pts treated with Len+Dex in MM-009 and MM-010, with a median follow-up of 48 mos for surviving pts. A subset of pts with progression-free survival (PFS) of ≥ 2 yrs was selected. Prognostic factors for PFS within this subgroup of pts were identified by incorporating all baseline covariates with a univariate p <.15 into multivariate Cox regression analyses, and all possible models were fitted using SAS 9.2. Adverse event (AE) management and dosing for pts with PFS ≥ 2 yrs was compared with that for all pts treated with Len+Dex in order to evaluate if differences in pt management could contribute to better clinical outcomes. Incidence rates for AEs were calculated using person-yrs of follow-up. Data from pts who received Len+Dex in MM-009 (up to July 23, 2008) and MM-010 (up to March 2, 2008) were included in this analysis. Results: Among all pts treated with Len+Dex (N = 353), a total of 64 pts (18%) achieved PFS ≥ 2 yrs. For these 64 pts, median age was 61 yrs (range 33–81 yrs), 48% received > 1 prior therapy, and 57% had β2-microglobulin levels of ≥ 2.5mg/L. All these pts achieved a ≥ partial response (PR), including 67% with a ≥ very good PR and 50% with a complete response. Median time to first response was 2.8 mos (range 1.9–18.2 mos) which is comparable to that of all pts treated with Len+Dex. Median duration of response was not reached vs 15.5 mos, respectively. With median follow-up of 49 mos, the 3-yr OS is 94% (95% confidence interval [CI] 88.06–99.94). In a multivariate Cox regression analysis, shorter PFS was predicted with higher baseline β2-microglobulin level (hazard ratio [HR] 1.07; 95% CI 1.02–1.12) and lower hemoglobin (HR 0.91; 95% CI 0.84–0.99), as well as a higher number of prior therapies (HR 1.18; 95% CI 1.02–1.37). The median duration of treatment was longer among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (46.2 mos [range 11.3–58.3] vs 9.8 mos [range 3.8–24], respectively). A higher proportion of these pts had a dose reduction within 12 mos after start of therapy vs all pts treated with Len+Dex (57% vs 24%, respectively). Dex dose was reduced in 27% of pts with PFS ≥ 2 yrs. Among pts without Len dose reduction, 31% had Dex dose reduction within the first 4 cycles. Granulocyte colony-stimulating factor was administered for the management of neutropenia in 39% of pts with PFS ≥ 2 yrs vs 25% of all pts treated with Len+Dex. Low discontinuation rates due to AEs were observed in both groups (12.5% vs 18.7%, respectively). The incidence rates per 100 person-yrs for grade 3–4 AEs among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (N = 353) were, respectively: neutropenia (14.9 vs 29), febrile neutropenia (0.9 vs 2.3), thrombocytopenia (2.6 vs 10.2), anemia (4.4 vs 9.5), infection (11.8 vs 20.9), deep vein thrombosis/pulmonary embolism (2.2 vs 8.9), fatigue (2.2 vs 5.5), neuropathy (1.8 vs 3.4), and gastrointestinal disorders (5.3 vs 9.7). The incidence rates per 100 person-yrs for second primary malignancies (SPMs) were similar to that of all pts treated with Len+Dex, respectively: myelodysplastic syndromes (0 vs 0.4), solid tumor (1.8 vs 1.3), and non-melanoma skin cancer (2.3 vs 2.4). These rates are comparable to those expected in people aged > 50 yrs generally (1.4 per 100 person-yrs) (Altekruse SF et al. SEER Cancer Statistics Review, 1975–2007). Conclusions: Long-term continuous therapy with Len+Dex has demonstrated efficacy and is generally well tolerated in pts with RRMM. Overall, 18% of patients treated with Len+Dex achieve a PFS of > 2 yrs. No increase in SPMs was observed with long term Len+Dex therapy. With appropriate AE management, the incidence rates of grade 3–4 AEs remain low. This analysis demonstrates the value of AE management and the need for appropriate dose-adjustment to maintain tolerability, allowing pts to remain on therapy for maximal benefit. Disclosures: Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Hussein:Celgene Corporation: Employment. Swern:Celgene Corporation: Employment. Weber:Celgene Corporation: Honoraria, Research Funding.

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A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10504 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10504-10504 ◽

Cited By ~ 7

Author(s):

Jason R. Fangusaro ◽

Arzu Onar-Thomas ◽

Tina Young-Poussaint ◽

Shengjie Wu ◽

Azra H Ligon ◽

...

Keyword(s):

Phase Ii ◽

Pediatric Brain Tumor ◽

Braf V600e Mutation ◽

Low Grade Glioma ◽

Braf V600e ◽

Low Grade ◽

Optic Pathway ◽

Grade 3 ◽

Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

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The BRAF-V600E mutation in hematological malignancies: a new player in hairy cell leukemia and Langerhans cell histiocytosis

Leukemia & Lymphoma ◽

10.3109/10428194.2012.706289 ◽

2012 ◽

Vol 53 (12) ◽

pp. 2339-2340 ◽

Cited By ~ 8

Author(s):

Tamar Tadmor ◽

Enrico Tiacci ◽

Brunangelo Falini ◽

Aaron Polliack

Keyword(s):

Hairy Cell Leukemia ◽

Langerhans Cell Histiocytosis ◽

Hematological Malignancies ◽

Braf V600e Mutation ◽

Langerhans Cell ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia

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

Pediatric and Developmental Pathology ◽

10.1177/1093526619847859 ◽

2019 ◽

Vol 22 (5) ◽

pp. 449-455 ◽

Cited By ~ 7

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.

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ddPCR Analysis Reveals BRAF V600E Mutations Are Infrequent in Isolated Pituitary Langerhans Cell Histiocytosis Patients

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa091 ◽

2020 ◽

Vol 79 (12) ◽

pp. 1313-1319

Author(s):

Anandani Nellan ◽

Avery Bodlak ◽

David M Mirsky ◽

Jean Mulcahy Levy ◽

Timothy P Garrington ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Pediatric Patients ◽

Braf V600e Mutation ◽

Langerhans Cell ◽

Braf V600e ◽

Pituitary Stalk ◽

Molecular Alteration ◽

Polymerase Chain ◽

Myeloid Neoplasia ◽

Pituitary Stalk Thickening

Abstract Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a highly variable clinical presentation affecting people of all ages. Mutations in BRAF V600E are the most identifiable molecular alteration in LCH although its incidence in pediatric patients with isolated pituitary stalk involvement is not well described. Pediatric patients with LCH and isolated pituitary stalk involvement typically present with central diabetes insipidus. Diagnosis requires a transcranial biopsy which often yields scant tissue. We sought to determine the prevalence of BRAF V600E mutations in patients with isolated pituitary stalk LCH using digital droplet polymerase chain reaction because this method requires minimal tumor DNA. We identified 8 patients with isolated pituitary stalk thickening who underwent a biopsy at Children’s Hospital Colorado from January 2001 to December 2019, as well as 6 patients with systemic LCH diagnosed by biopsy in the same period as a comparison. Only one out of the 8 patients with isolated thickened pituitary stalk was found to have a detectable BRAF V600E mutation. Five out of the 6 patients with systemic LCH had a detectable BRAF V600E mutation. In our series, BRAF V600E mutations are rare in pediatric patients with LCH and isolated pituitary stalk involvement.

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