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Clinical Trial
. 2011 Mar 1;29(7):789-96.
doi: 10.1200/JCO.2010.32.8021. Epub 2011 Jan 10.

"V体育2025版" Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis

Animesh Pardanani  1 , Jason R Gotlib, Catriona Jamieson, Jorge E Cortes, Moshe Talpaz, Richard M Stone, Michael H Silverman, D Gary Gilliland, Jolene Shorr, Ayalew Tefferi
Affiliations
Clinical Trial

Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis

Animesh Pardanani et al. J Clin Oncol. .

Abstract

Purpose: Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor VSports手机版. .

Patients and methods: In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. V体育安卓版.

Results: Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days V体育ios版. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = . 04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < . 01); the decrease was durable at 12 months. .

Conclusion: TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis VSports最新版本. .

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

"V体育官网入口" Figures

Fig 1.
Fig 1.
Splenomegaly response to TG101348 therapy. Decrease in palpable spleen size from baseline by cycle for patients in the maximum-tolerated dose cohort (n = 37). The proportion of patients with 50% or greater and 100% decrease in palpable splenomegaly is displayed. For patients who completed six cycles of treatment, 90% had a 25% or greater reduction in palpable spleen size, 66% had a 50% or greater reduction, and the spleen became nonpalpable in 31%.
Fig 2.
Fig 2.
Effects of TG101348 on symptoms of myelofibrosis. (A) Proportion of patients in maximum-tolerated dose cohort with complete resolution of early satiety by cycle from a baseline symptom score of‘mild (score = 1 to 3), moderate (score = 4 to 7), or severe (score = 8 to 10). Twenty-seven patients (79%) and 19 patients (56%) were evaluable for improvement in early satiety at the end of 1 and 6 cycles, respectively. After two cycles of treatment, 56% reported complete resolution of this symptom with durable benefit. (B) Proportion of patients in maximum-tolerated dose cohort with complete resolution of fatigue by cycle from a baseline symptom score of mild (score = 1 to 3), or improvement in or complete resolution of fatigue from a baseline score of moderate (score = 4 to 7) or severe (score = 8 to 10). Twenty-four patients (71%) and 16 patients (47%) were evaluable for improvement in fatigue at the end of one and six cycles, respectively. After six cycles, 63% reported improvement, and 25% had complete resolution of this symptom. (C) Proportion of patients in maximum-tolerated dose cohort with complete resolution of night sweats by cycle from a baseline symptom score of mild (score = 1 to 3), moderate (score = 4 to 7), or severe (score = 8 to 10). Fourteen patients (40%) and nine patients (26%) were evaluable for improvement in night sweats at the end of one and six cycles, respectively. After one cycle, 64% of patients had complete resolution of this symptom; after six cycles, this proportion had increased to 89%.
Fig 3.
Fig 3.
Response of leukocytosis to TG101348 therapy. Changes in WBC after six cycles for patients who entered the study with leukocytosis (WBC > 11 × 109/L). After six cycles, 16 patients across doses (57%) and 13 patients in the MTD cohort (72%) achieved a normal WBC, with durable benefit.
Fig 4.
Fig 4.
Effect of TG101348 therapy on JAK2 V617F allele burden. Box plot representation of JAK2 V617F allele burden data (A,B) for all mutation-positive patients (n = 51) and (C,D) for the subgroup with baseline allele burden greater than 20% (n = 23). The y-axis represents the JAK2 V617F allele burden from 1.0 (100%) to 0.0 (0%).The change in JAK2 V617F allele burden per cycle of treatment (up to end of cycle 12; ie, C13D1) compared with prestudy baseline is shown (A,C) for the two groups. (B,D) The change at the end of cycle 6 (ie, C7D1) and cycle 12. A significant decrease in JAK2 V617F allele burden compared with prestudy baseline was observed at the end of cycle 6 (B) for the mutation-positive group (P = .04) and (D) for the subgroup with baseline allele burden greater than 20% (P = .002); a similar significant decrease was seen at the end of cycle 12 (B) for the former (P = .01) and (D) latter (P = .002) groups. The Wilcoxon matched-pair signed-rank test was used to compare the median JAK2 V617F allele burden for the comparisons.
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VSports注册入口 - References

    1. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342:1255–1265. - PubMed
    1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895–2901. - PubMed
    1. Hussein K, Pardanani AD, Van Dyke DL, et al. International Prognostic Scoring System– independent cytogenetic risk categorization in primary myelofibrosis. Blood. 2010;115:496–499. - "V体育安卓版" PubMed
    1. Patnaik MM, Caramazza D, Gangat N, et al. Age and platelet count are IPSS-independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival. Eur J Haematol. 2010;84:105–108. - PubMed
    1. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–1148. - PubMed

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