A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Phase II Study of Oral Fludarabine in Untreated B-Cell Chronic Lymphocytic Leukemia.
Notice bibliographique
Résumé
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defined therapy; 12 discontinued due to toxicity, 8 due to progressive disease and 13 for other reasons, including 1 pt withdrawn due to AIHA.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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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 | 0,003 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».