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Imawan, Jensen (2009): Early and risk adapted therapy with Fludarabine in high risk binet stage a chronic lymphocytic leukemia patients. Dissertation, LMU München: Faculty of Medicine
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Abstract

Background Fludarabine, a nucleoside analogue, has established itself as a very potent and effective substance for treating CLL. It induces (as a mono therapy in comparison with other drugs used also in a mono therapy strategy) superior response rates and progression free survival. Particular information, however, concerning the efficacy of Fludarabine in CLL stage Binet A patients with high progression risk still unfortunately lacks. To find out whether an early Fludarabine mono therapy would bring clinical benefits, particularly regarding response rates and survival rates for this group of CLL patients, the German CLL Study Group (GCLLSG) conducted the CLL-1 study; a multicentre and randomized trial with 877 patients with previously untreated Binet stage A CLL. Methods The patients were assessed in terms of their progression risk through bone marrow histology (infiltration type), lymphocyte doubling time (LDT), serum thymidine kinase level and the serum-ß2-microglobulin level. The combination of a non-nodular bone marrow infiltration type or a LDT <12 months and a serum thymidine kinase level >7 U/l or a serum-ß2-microglobulin >3.5 mg/l indicates a high progression risk. Patients with high progression risk would be randomized into the treatment arm or the “watch and wait” arm. Patients in the treatment arm (cohort I) received Fludarabine i.v. (25 mg/m2/day 5 days long, cycle repeat on day 28, maximum 6 cycles), whereas patients in the “watch and wait” group (cohort II) were only being observed. The third group, consisting of patients with low progression risk according to the definition above (cohort III) was also only being observed. 98 patients were randomized into cohort I (also called HR-F) and 95 patients into cohort II (also called HR-WW). The median follow-up time was for the treatment arm 44.6 months long and for the “watch and wait” arm 40.0 months. Observation points were progression free survival (PFS), overall survival (OS), response rates, adverse events and severe adverse events (SAE). Results Patients treated with Fludarabine gained an overall response rate of 85%, including 32% complete remission rate and 53% partial remission rate. Infection rate was higher in the treatment arm (23.5% vs. 9.6% of the patients) than in the “watch and wait” arm, none of the infections reached the CTC0 4, while only 3 of them reached the CTC0 3. Progression free survival after Fludarabine therapy was significant prolonged (p-value = 0.002) as the patients who received Fludarabine reached 27.9 months and those who did not receive it reached 15.3 months. Looking at the comparison concerning the overall survival between the two arms, no advantage of prolongation for the treatment arm could be noticed though. Conclusions Fludarabine prolongs progression free survival in CLL Binet stage A patients with high progression risk but not the overall survival. It cannot therefore replace the “watch and wait” strategy, which remains as the standard option for CLL Binet stage A patients with or without high progression risk.