A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Phase II Study of Oral Fludarabine in Untreated B-Cell Chronic Lymphocytic Leukemia.

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 IgV_H 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 IgV_H 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defined therapy; 12 discontinued due to toxicity, 8 due to progressive disease and 13 for other reasons, including 1 pt withdrawn due to AIHA.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). IgV_H sequencing completed on 102/126 samples at the time of this analysis, and 62% of cases had unmutated IgV_H (>98% homology to known IgV_H gene), whereas 39% expressed mutated IgV_H genes. Forty-three (68%) of 63 cases with unmutated IgV_H, but only 5 (14.6%) of 39 cases with mutated IgV_H 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 IgV_H 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 IgV_H genes and appeared unaltered following treatment in most cases studied. Patients with ZAP-70-negative/mutated IgV_H CLL had a better ORR although this did not reach statistical significance.