A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Phase II Study of Oral Fludarabine in Untreated B-Cell Chronic Lymphocytic Leukemia.
Bibliographic record
Abstract
Abstract Fludarabine is a key drug in the treatment of CLL, and the oral formulation has an efficacy and safety profile similar to the intravenous formulation in previously treated patients (pts). The NCIC CTG conducted a phase II study evaluating the overall response rate (ORR) to oral fludarabine in previously untreated pts. Leukemia cells were studied for common cytogenetic abnormalities by FISH, expression of ZAP-70, and IgVH mutational status, to assess whether these parameters influence response to therapy. Eligibility criteria included diagnosis of CLL confirmed by lymphocytosis of >5×109/L, leukemia-cell expression of CD5, CD19, and CD23 with light chain restriction, and indication for treatment. Pts were treated with oral fludarabine 40 mg/m2/day × 5 days every 28 days for a max of 6–8 cycles. Response evaluation was based on NCI-WG criteria. Interphase FISH was performed on PBMCs, evaluating for deletion of ATM at 11q22.3, D13S319 at 13q14.3, D12Z1 at 12p11.1-q11.1, and p53 at 17p13.1. ZAP-70 expression and IgVH mutation analysis of CLL cells were assessed before therapy in all patients, and in a subset, after therapy. Results: 126 eligible pts were enrolled between Aug2002–Jan2004 at 26 institutions. Median age was 60.9 years, male 62%, female 38%. Distribution by Rai stage was I 25%, II 43%, III 14%, and IV 18%. The ORR at the completion of therapy was 64%, with 18% CR, 3% unconfirmed CR, 43% PR, 13% SD, and 13% PD. At median follow-up of 23.2 months, median progression-free survival (PFS) was 15.3 months (95% CI 13.6–16.7). Median overall survival has not been reached. 92 pts completed protocol defined therapy; 12 discontinued due to toxicity, 8 due to progressive disease and 13 for other reasons, including 1 pt withdrawn due to AIHA. Hematologic toxicity (NCI-WG) included thrombocytopenia, grade 3/4 (14/126; 11%), and neutropenia, grade 3/4 (54/126; 51%). FISH analysis revealed abnormal cytogenetics in 79% of 122 evaluable cases, with del (13) in 58%, del (11) in 23%, +12 in 14%, and del (17) in 5%, with more than 20% of CLL cells having each abnormality. All 6 pts with del (17) had a significantly poorer PFS relative to pts without a del (17) (Hazard Ratio 7.4, 95% CI 3.06–17.98). IgVH sequencing completed on 102/126 samples at the time of this analysis, and 62% of cases had unmutated IgVH (>98% homology to known IgVH gene), whereas 39% expressed mutated IgVH genes. Forty-three (68%) of 63 cases with unmutated IgVH, but only 5 (14.6%) of 39 cases with mutated IgVH expressed ZAP-70, a concordance rate similar to that observed previously. Of total 125 cases examined, 55 were ZAP-70 positive and 70 were negative; leukemia-cell expression of ZAP-70 was unchanged after therapy in 47/52 (90%) of cases successfully examined. ORR in the pts with ZAP-70-positive/unmutated IgVH CLL cells was 63% versus 77% in the ZAP-70-negative/mutated IgVH group (P=0.22). Conclusions: Oral fludarabine as a single agent in untreated CLL is associated with response rates and toxicity profile comparable to that of intravenous fludarabine given on a similar schedule. Leukemia-cell expression of ZAP-70 generally correlated with the use of unmutated IgVH genes and appeared unaltered following treatment in most cases studied. Patients with ZAP-70-negative/mutated IgVH CLL had a better ORR although this did not reach statistical significance.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".