First Clinical Report of Tipifarnib for the Treatment of T-Large Granular Lymphocyte (LGL) Leukemia.
Notice bibliographique
Résumé
Abstract INTRODUCTION: Lymphoproliferative diseases of large granular lymphocytes (LGL leukemia) are clinical syndromes associated with increased circulating CD3+CD8+CD57+ T-LGL s. Chronic neutropenia, anemia, and arthritis are clinical manifestations mediated by autoimmune reactivity of this lymphocyte population. Previously, we found evidence that extracellular-regulated kinase (ERK) and Ras were constitutively active in the patient’s LGLs. Ablation of Ras activity by a dominant-negative form of Ras and pharmacologic inhibition with farnesyltransferase inhibitors FTI2153 and R115777 (tipifarnib, Zarnestra®, Johnson & Johnson) resulted in ERK inhibition and enhanced apoptosis of the leukemic LGLs. A multicenter phase 2 clinical trial using tipifarnib was initiated with a two-stage design. Here we provide the first report of the efficacy and safety of tipifarnib in patients with LGL leukemia. METHODS: Patients were to be treated in the first stage with four cycles of therapy at a dose of 300 mg twice daily for 21 days out of a 28- day intermittent cycle. Key patient entry criteria were neutrophil counts < 500 cells/μl, transfusion-dependent anemia, and clonal CD3+/CD57+ T-cells greater than 350 cells/μl in the peripheral blood. WBC, ALC, hemoglobin, platelet counts, and ANC were determined. Bone marrow biopsies were performed on all patients prior to therapy and then repeated when worsening cytopenias occurred. Tipifarnib was stopped when bone marrow cellularity was reduced by 50% compared to baseline. Bone marrow colony formation assessed using14-day CFU-GM and BFU-E assays in methycellulose (Stem Cell Separation Systems, Vancouver BC). Growth factor support with G-CSF was allowed during the 7 days off when ANCs were < 500 cells/μl. RESULTS: Five males and two females (mean 57 years old) received tipifarnib. Four patients failed to complete the study due to toxicity. Three patients were removed from study due to grade 3–4 bone marrow toxicity and/or infections requiring hospitalization and a tipifarnib-unrelated death occurred in one patient. Three patients completed four cycles and were evaluated for response with a dose reduction for bone marrow toxicity required in one of these evaluable patients. Leukemic LGL cells from the three evaluable patients displayed a dose-dependent increase in apoptosis in vitro and treatment was associated with reduced ALCs in two cases. None of the patients met the pre-determined criteria for response. However, one patient, shown to be growth factor unresponsive prior to therapy, had an increase in ANC from 0 at baseline to 8,600 cells/μl while receiving G-CSF on week 16. The number of bone marrow colonies also increased in this patient after therapy. All bone marrow biopsies, which were required in five cases, showed significantly improved erythroid or myeloid differentiation. CONCLUSIONS: Improvements in bone marrow differentiation suggest that tipifarnib may prove beneficial for the treatment of LGL leukemia if a safe dose and schedule is established and the treatment prolonged to allow for bone marrow recovery.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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