BRAF Inhibition in Refractory Hairy-Cell Leukemia

Dietrich, Sascha; Glimm, Hanno; Andrulis, Mindaugas; Kalle, Christof von; Ho, Anthony D.; Zenz, Thorsten

doi:10.1056/nejmc1202124

Cited by 235 publications

(160 citation statements)

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“…Vemurafenib is an inhibitor of mutant BRAF, and has some efficacy against both BRAFV600E-associated melanoma and hairy-cell leukemia [55]. We conducted a pilot study of vemurafenib treatment for three patients who had multisystemic and refractory ECD and carried the BRAFV600E mutation.…”

Section: Braf Inhibition As An Alternative To Ifnα For Ecd Patients Cmentioning

confidence: 99%

Erdheim–Chester Disease

et al. 2014

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Erdheim-Chester disease (ECD) is a rare (approximately 500 known cases worldwide), non-inherited, nonLangerhans form of histiocytosis of unknown origin, first described in 1930. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by foamy histiocytes, "lipid-laden" macrophages, or histiocytes, surrounded by fibrosis. Diagnosis of ECD involves the analysis of histiocytes in tissue biopsies: these are typically foamy and CD68+ CD1a− in ECD, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. 99 Technetium bone scintigraphy revealing nearly constant tracer uptake by the long bones is highly suggestive of ECD, and a "hairy kidney" appearance on abdominal CT scan is observed in approximately half of ECD cases. Central nervous system involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimum initial therapy for ECD seems to be administration of interferon α (or pegylated interferon α), and prolonged treatment significantly improves survival; however, tolerance may be poor. Cases of ECD present with strong systemic immune activation, involving IFNα, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. More than half of ECD patients carry the BRAF V600E mutation, an activating mutation of the protooncogene BRAF. A small number of patients harboring this mutation and with severe multisystemic and refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which was proved very beneficial.

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Section: Braf Inhibition As An Alternative To Ifnα For Ecd Patients Cmentioning

confidence: 99%

Erdheim–Chester Disease

et al. 2014

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“…[7][8][9] Similarly, these targeted therapies might also have antitumor activity in various other BRAF-mutated neoplasias. [10][11][12][13][14] Accurate and rapid detection of BRAF mutations in metastatic melanoma is therefore essential for optimal patient care and may possibly be also required in other tumor entities in the near future.…”

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confidence: 99%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

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BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n ¼ 377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.

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“…In all cases, novel therapeutic agents will depend on the BRAF mutational status. In case of mutated BRAF , specific inhibitors of the BRAF pathway should represent the best option (see below) 16, 40. In unmutated BRAF cases, depending on the accessibility of the drug and of clinical trials, immunotoxins, BCR inhibitors or a combination of bendamustine with rituximab should be considered.…”

Section: Treatment Updates (Figures 2 and 3)mentioning

confidence: 99%

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

Troussard

Cornet

2017

American J Hematol

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Disease overviewHairy cell leukemia (HCL) and HCL‐like disorders, including HCL variant (HCL‐V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B‐cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.DiagnosisDiagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.Risk stratificationProgression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4‐34 positive HCL cases are associated with poor prognosisRisk adapted therapyPurine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option.Management of progressive or refractory diseaseIt is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.

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BRAF Inhibition in Refractory Hairy-Cell Leukemia

Cited by 235 publications

References 5 publications

Erdheim–Chester Disease

Erdheim–Chester Disease

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

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