First Clinical Report of Tipifarnib for the Treatment of T-Large Granular Lymphocyte (LGL) Leukemia.
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".