Reactions 1704, p364 - 2 Jun 2018 Development of drug resistance due to KRAS and MEK1 mutations leading to relapse of hairy-cell leukaemia: case report A 73-year-old male developed drug resistance due to KRAS and MEK-1 mutations leading to relapse of hairy cell leukaemia (HCL) following treatment with vemurafenib [route not stated]. The man, who had HCL, had been receiving various treatments over the past 20 years. His past treatments included cladribine, pentostatin and splenectomy. In 2010, a BRAF mutation was identified. Consequently, he started receiving treatment with BRAF inhibitor vemurafenib 240mg twice daily. He experienced sustained haematological remission on vemurafenib treatment for over three years. However, in 2016, a gradual decline in his blood indices and bone marrow trephine was observed. Consequently, he was diagnosed with relapse of HCL [duration of treatment to reaction onset not clearly stated]. Vemurafenib treatment was continued with the addition of rituximab. Subsequently, this led to a transient improvement in blood indices. However no clearance of the bone marrow was observed. In 2017, the man required platelet and blood transfusion and was found to be refractory to further rituximab treatment. He was found to be systemically unwell and reported B symptoms. Subsequently, a whole genome sequencing was performed on DNA from purified CD19 tumour cells from samples taken prior to initiation of vemurafenib treatment and separately at relapse. The presence of underlying BRAF V600E mutation along with deletion of the other 7q was observed. Seven separate mutations in KRAS and two in MEK1 were identified, which had arisen during the course of vemurafenib treatment. The allele frequencies of each of the KRAS and MEK mutations were found to be consistent with parallel evolution of multiple resistance clones throughout the vemurafenib exposure. The KRAS and MEK1 mutations were considered as the likely mechanism of resistance to BRAF inhibition. Subsequent cloning of each mutation and expression in a lymphoma cell line confirmed that they all led to activation of ERK signalling that was not suppressed by BRAF inhibition. Consequently, purified tumour cells from the peripheral blood of the patient were tested for response to ex vivo inhibitors. Vemurafenib was found to be unable to abolish ERK activity in these cells. In contrast, a MEK inhibitor was found to be able to induce considerable apoptosis in tumour cells. Based on the results of this ex-vivo experiment, he was treated with cobimetinib combined with vemurafenib. Within one week, his B symptoms resolved. Within four weeks his blood counts normalised. However, a subsequent bone marrow biopsy revealed considerable persisting disease. Therefore, cobimetinib dose was increased. Within three months, substantial clearance of HCL from the bone marrow and return of normal haematopoiesis was observed. Author comment: "Remarkably, we also identified seven separate mutations in KRAS and two in MEK1 that had arisen during the course of his Vemurafenib. The allele frequencies of each of the KRAS and MEK mutations were consistent with parallel evolution of multiple resistance clones throughout the Vemurafenib exposure. We focused on the KRAS and MEK1 mutations as the likely mechanism of resistance to BRAF inhibition." Collord G, et al. Mechanism and targeted therapy of vemurafenib-resistant hairy- cell leukemia. British Journal of Haematology 181 (Suppl. 1): 82 abstr. BSH18-PO-071, Apr 2018. Available from: URL: http://doi.org/10.1111/bjh.15226 [abstract] - United Kingdom 803323617 0114-9954/18/1704-0001/$14.95 Adis © 2018 Springer International Publishing AG. All rights reserved Reactions 2 Jun 2018 No. 1704
Reactions Weekly – Springer Journals
Published: Jun 2, 2018
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