Rapid response of biallelic <i><scp>BRAF</scp></i><scp>V</scp>600<scp>E</scp> mutated hairy cell leukaemia to low dose vemurafenib

Follows, George; Sims, Hannah; Bloxham, David; Zenz, Thorsten; Hopper, Melanie A.; Liu, Hongxiang; Bench, Anthony J.; Wright, Penny; Veer, M. B. Van't; Scott, Mike

doi:10.1111/bjh.12201

Cited by 63 publications

(31 citation statements)

References 5 publications

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“…36,38,39 Demonstration of the BRAF V600E mutation could also be important for those who do not respond to standard therapy or have multiple relapses. [40][41][42][43][44][45] Inhibitors of BRAF V600E have provided responses in patients who are resistant to standard therapy. 46 Consequently, it is now recommended that all patients with HCL be evaluated for this mutation by using a sensitive molecular assay that can detect the often few (,10%) leukemic cells present in the peripheral blood or in bone marrow aspirates diluted with blood as a result of dry tap.…”

Section: Establishing the Diagnosismentioning

confidence: 99%

“…5,46 Complete remissions have been reported after using the BRAF inhibitor vemurafenib in relapsed and refractory disease. [42][43][44][45]69 The duration of these remissions is currently being defined in well-designed clinical trials. However, relapse is a frequent finding, and thus strategic combinations and/or alternative schedules of administration will need to be pursued.…”

Section: Consideration For Investigational Approachesmentioning

confidence: 99%

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Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

Grever

Abdel‐Wahab

Andritsos

et al. 2017

Blood

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219

290

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Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients

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Section: Establishing the Diagnosismentioning

confidence: 99%

Section: Consideration For Investigational Approachesmentioning

confidence: 99%

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

Grever

Abdel‐Wahab

Andritsos

et al. 2017

Blood

Self Cite

219

290

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“…Five patients have previously been reported and are included with updated follow-up. [12][13][14]20,21 Clinical data and follow-up information were collected by chart review. Bone marrow slides were centrally reviewed (n 5 11, by M.A.).…”

Section: Data Collection and Response Definitionmentioning

confidence: 99%

“…5,8 Data from trials in BRAFmutated melanomas 9,10 have inspired investigators to treat refractory HCL patients with the BRAF inhibitor (BRAFi) vemurafenib, which showed striking clinical activity. [11][12][13][14][15] Dosing of vemurafenib outside clinical trials has been significantly lower than standard melanoma dosing (240 mg twice daily vs 960 mg twice daily). 12,16 Two phase 2 trials (an Italian trial [n 5 26] and a US trial [n 5 24]) have explored the melanoma dose of 2 3 960 mg and demonstrated efficacy in all treated patients.…”

Section: Introductionmentioning

confidence: 99%

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib

Dietrich

Pircher

Endris

et al. 2016

Blood

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110

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Key Points• Low doses of the BRAF inhibitor vemurafenib are highly effective in refractory hairy cell leukemia.• Abrogation of BRAF V600E-induced signaling was consistently seen with 240 mg of vemurafenib twice daily.The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n 5 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care. (Blood. 2016;127(23):2847-2855

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“…Mutations in BRAF V600E have been observed and effectively targeted in other tumor types, including melanoma, 15,16 ameloblastoma, 20,27,42 hairy cell leukemia, 12,13,17,23,33,38 Erdheim-Chester disease, 21,23 and pleomorphic xanthoastrocytoma. 11,23,29,32 We recently achieved a clinically significant response in a patient with a recurrent BRAF V600E mutant PCP using targeted BRAF and MEK inhibitors 5 ( Fig.…”

Section: Targeted Therapy In Pcpmentioning

confidence: 99%

Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy

Martínez-Gutiérrez

D’Andrea²,

Cahill

et al. 2016

FOC

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Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute–sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.

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Rapid response of biallelic BRAFV600E mutated hairy cell leukaemia to low dose vemurafenib

Cited by 63 publications

References 5 publications

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib

Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy

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