Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study.

This is an update of a randomized study comparing low-dose intravenous Cyclsporin A (CyA) (1 mg/kg/day) with high dose CyA (5 mg/kg/day).1 The results in 1991 suggested that diseasefree survival was superior in patients receiving low-dose CyA, and this was mainly due to protection against leukemia relapse (Table 1). In that study 81 patients with acute leukemia (acute myeloid leukemia 5 44; acute lymphocytic leukemia 5 37; first complete remission [CR] 5 53; .first CR 5 28) were randomized to receive cyclosporin (CyA) 1 mg/kg intravenously (IV) or 5 mg/kg from day 21 to day 120. It is important to note that the average CyA serum levels were significantly different in the 2 arms only from day 21 to day 110 (295 ng/mL vs 686 ng/mL; P 5 .004), but not between day 111 and 120 (465 ng/mL vs 650 ng/mL, P 5 .1): this was due to the fact that patients in the CyA–1-mg arm had their dose increased beyond day 110 because of acute graft-versus-host diesase (GvHD) and patients in the CyA–5-mg arm had their dose decreased due to toxicity. Updated follow-up. The median follow-up for surviving patients is now 11.7 years with a minimum follow-up of 10 years (range 10.2-13 years). There have been 8 additional deaths, 4 in both arms: in the CyA–1-mg arm they were all caused by transplantation-related complications (Table 1). This brings the crude transplantation-related mortality (TRM) in the CyA–1-mg arm from 27% to 38%. In the CyA–5-mg arm, the 4 additional deaths were caused by leukemia relapse in 2 patients and by transplantation complications in 2 patients. This brings the crude TRM in the CyA–5-mg arm from 25% to 30% and the relapse from 38% to 43%. Figure 1 outlines the actuarial 10-year TRM (Figure 1A), relapse (Figure 1B), and disease-free survival (Figure 1C) in the CyA–1-mg/kg vs CyA–5-mg/kg, respectively: TRM 39% vs 32% (P 5 .8), relapse risk 20% vs 59% (P 5 .002), and diseasefree survival 49% vs 27% (P 5 .05). For patients in first CR the figures are as follows: TRM 28% vs 21% (P 5 .3), relapse risk 10% vs 45% (P 5 .01), and disease-free survival 56% vs 44% (P 5 .3). For patients with advanced disease (beyond first CR) the figures are TRM 46% vs 60% (P 5 .6), relapse risk 43% vs 100% (P 5 .03), and disease-free survival 36% vs 0% (P 5 .05). The effect of patient age. TRM is significantly affected by patients age: 22% for patients aged 1 to 20 years, 21% for patients aged 21 to 30 years, and 71% for patients older than 31 (P 5 .02). There is no difference in TRM for patients receiving CyA 1 mg or CyA 5 mg in the 1 to 20 age group (27% vs 28%) or in the 21 to 30