Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial.
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ABSTRACT:
SUBMITTER: Tiacci E
PROVIDER: S-EPMC8550943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).
| S-EPMC4811324 | biostudies-literature
Project description:The activating BRAF mutation p.V600E has been identified in many cancers, including colon and lung adenocarcinomas, papillary thyroid cancer, malignant melanoma, and hairy cell leukemia (HCL). Malignant melanoma and HCL are of particular interest because of both the high proportion of cases harboring the mutation and the dramatic responses to BRAF inhibitor therapy reported in the literature. This report presents a patient with HCL and malignant melanoma with the BRAF p.V600E mutation, and discusses the successful treatment of both cancers with the BRAF inhibitor dabrafenib.
| S-EPMC7250239 | biostudies-literature
Project description:This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ?2 prior systemic therapies, including ?1 purine nucleoside analog. Patients received moxetumomab pasudotox 40?µg/kg intravenously on days 1, 3, and 5 every 28 days for ?6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
| S-EPMC6087717 | biostudies-literature
Project description:PURPOSE:To determine tolerability and for the first time explore efficacy of bendamustine-rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine. EXPERIMENTAL DESIGN:Patients with HCL with ?2 prior therapies requiring treatment received rituximab 375 mg/m(2) days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m(2), days 1 and 2, for six cycles at 4-week intervals. RESULTS:At 70 and 90 mg/m(2)/dose of bendamustine, overall response rate was 100%, with three (50%) and four (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All six without MRD remain in CR at 30 to 35 (median, 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/mL at baseline to undetectable and 2 ng/mL after CR, respectively (P < 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%), and neutropenia (42%). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity. CONCLUSION:BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m(2)/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m(2)/dose was chosen for future testing.
| S-EPMC3861900 | biostudies-literature
Project description:AimsTo characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74).MethodsData from both studies were pooled (n = 123) to develop a population PK model. Covariates included demographics, disease state, liver and kidney function, prior treatment, and antidrug antibodies (ADAs). Exposure-response and exposure-safety were analysed separately by study. A 1-compartment model with linear elimination from the central compartment and 2 clearance (CL) rates was developed.ResultsMoxetumomab pasudotox was cleared more rapidly after cycle 1, day 1 (CL1 = 24.7 L/h) than subsequently (CL2 = 3.76 L/h), with high interindividual variability (116 and 109%, respectively). In Study 1053, patients with ADA titres >10 240 showed ~4-fold increase in CL. Higher exposures (≥median) were related to higher response rates, capillary leak syndrome and increased creatinine (Study 1053 only), or grade ≥3 adverse events (Study 1001 only). Clinical benefits were still observed in patients with lower exposure or high ADA titres.ConclusionDespite a high incidence of immunogenicity with increased clearance, moxetumomab pasudotox demonstrated efficacy in hairy cell leukaemia.
| S-EPMC7318999 | biostudies-literature
Project description:Abstract BACKGROUND Approximately 9%-18% of LGGs possess BRAF V600E mutations. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma, lung cancer, and anaplastic thyroid cancer. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) was evaluated as treatment for patients with recurrent/refractory BRAF V600E–mutated LGG. METHODS In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including LGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the LGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 1 or 2 glioma that was refractory to standard-of-care therapies. The primary endpoint was investigator-assessed overall response rate (ORR) by RANO criteria. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Nine patients with LGG had enrolled at data cutoff (3 January 2018). Eight of 9 patients were evaluable for response. Median age was 33 years. Eight of 9 patients had received prior surgery. Investigator-assessed confirmed ORR was 50% (4/8; 95% CI, 16%-84%), with 3 of 4 responses ongoing at data cutoff. Two of 4 patients had a DOR of ≥ 18 months. The PFS and OS Kaplan-Meier estimates at 18 months were 50% (95% CI, 15%-78%) and 86% (95% CI, 33%-98%), respectively. Adverse events (AEs) in patients with LGG included fatigue (67%), headache (67%), arthralgia, nausea, and pyrexia (56% each). Grade 3/4 AEs included fatigue (22%), arthralgia, headache, and diarrhea (11% each). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with recurrent/refractory BRAF V600E-mutated LGG, with manageable AEs and no new safety signals
| S-EPMC6217698 | biostudies-literature
Project description:Abstract BACKGROUND Current treatment outcomes for patients with recurrent HGG are poor, with median progression-free survival (PFS) and overall survival (OS) of 2.5 and 7.5 months, respectively. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) resulted in an intracranial overall response rate (ORR) of 58% in BRAF V600–mutated melanoma brain metastases. Dabrafenib + trametinib was evaluated as treatment for patients with BRAF V600E–mutated HGG. METHODS In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the HGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 3 or 4 glioma and had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. The primary endpoint was investigator-assessed ORR by RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Thirty-seven patients with HGG had enrolled at data cutoff (3 January 2018). Median age was 42 years, 31 of 37 patients were evaluable for response. Investigator-assessed confirmed ORR was 26% (8/31; 95% CI, 12%-45%), including 1 complete response (CR). Six of 8 responses were ongoing at data cutoff. Five of 8 responding patients had a DOR of ≥ 12 months. Median PFS was 1.9 months (95% CI, 1.7–18.5). Median OS was 11.7 months (95% CI, 6.4-not reached). Adverse events (AEs) in patients with HGG included fatigue (35%), headache (30%), and rash (24%). Grade 3/4 AEs included neutropenia (8%) and fatigue (5%). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with BRAF V600E-mutated recurrent/refractory HGG, as 1 patient had a CR, and most responders had a prolonged DOR.
| S-EPMC6217670 | biostudies-literature
Project description:BACKGROUND:Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients. METHODS:In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90?mg/m2 on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60?mg/m2 (10-day regimen). RESULTS:Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90?mg/m2 /d, respectively [5-day regimen] and 53 patients who were assigned to 60?mg/m2 /d [10-day regimen]). The 90?mg/m2 dose showed no benefit in clinical outcomes in comparison with 60?mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P?=?.1061; CR, 18.9% vs 8%; P?=?.15). Adverse events (grade???3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation. CONCLUSIONS:Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325-34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
| S-EPMC5814873 | biostudies-literature
Project description:Multiple myeloma (MM) is an incurable plasma cell neoplasia characterized by relapsed and/or refractory (R/R) disease course, which poses a major therapeutic challenge. New therapies, including BRAF V600E mutation targeting, may become a new treatment option for R/R MM. In combination with mitogen-activated protein kinase inhibitors (MEKi), BRAF inhibitors (BRAFi) could provide better tailored clinical management, although experience in this field is lacking. To this date, there is only one case describing R/R MM treatment with BRAFi vemurafenib and MEKi cobimetinib. This is the first case presenting a R/R MM patient treated with BRAFi dabrafenib and MEKi trametinib.
| S-EPMC7584966 | biostudies-literature
Project description:Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
| S-EPMC3689585 | biostudies-literature