Efficacy and Safety of Deferasirox in Patients with Transfusional Iron Overload After Allogeneic Hematopoietic Cell Transplantation: The CICL670ADE02 Trial

The study was conducted in 6 German centers. The primary objective was to evaluate if DEX could provide clinically acceptable chelation in a target pool of 76 adult patients (pts) with TIO 3–12 months after related/unrelated HCT irrespective of conditioning regimens. TIO was defined as a serum ferritin (SF) ≥1000ng/ml without active inflammation (CRP <10mg/l), and a history of >20 units of red blood cell transfusions (RBC) or 100mL/kg of prepacked red blood cells. Main exclusion criteria were ANC <1000/mm³, transaminases (TA) >5xULN, and serum creatinine (Cr) >1.5xULN. DEX 30 minutes prior to lunch was started with 10 mg/kg/d over 52 weeks or until SF <500ng/ml was reached. Subsequent dose adjustments were performed in steps of 5–10 mg/kg/d based on SF and safety assessments. DEX was reduced by 10mg/kg if Cr increased by >33% of baseline (BL) or was >1.5xULN. DEX had to be interrupted if any toxicity > grade 2 according to the NCI common toxicity criteria (CTC) occurred. An independent Data Safety Monitoring Board reviewed safety data on an ongoing basis. Surrogate markers monitored were SF, serum transferrin and transferrin saturation (TS).

After a median of 168 days after HCT, 47 (62%) males and 29 (38%) females [median age 56 y] were included. Cyclosporine was taken by 54 (71%) pts. Median number of RBC prior to study entry was 37 units. Post-HCT, 14 (18.4%) pts received transfusions. Post-HCT HFE genotype was mutated in 27/67(40%) pts (heterozygote-H63D,n=13; heterozygote-C282Y,n=7; heterozygote for other mutations, n=6; homozygote-H63D,n=1). At BL, median SF and TS were 2045ng/ml and 56% respectively at a median CRP of 2.7 mg/l. SF correlated with TS (r=0.5, p<.0001), and the number of RBC (p=0.01). DEX was started with a median daily dose of 625mg. From BL to the end of study (EOS), mean daily dose was 629 (9 mg/kg/day) with a median of 503.7mg. SF declined steadily with a median of 957ng/ml at EOS representing a 53% reduction from BL (p<.0001). An initial rise in TS with a median of 92% at a median of 7 weeks was followed by a steady decrease reaching a median of 44.4% at EOS. Over time, stable trough serum cyclosporine levels per patient were measured irrespective of DEX dose. Hb improved under treatment with a median Hb of 12.7g/dl at EOS representing a 12.4% increase from BL. Chronic GvHD was documented in 34 (44.7%) pts (limited 79%; extensive 21%). DEX was discontinued in 8 (9.3%) pts due to relapse/progression of hematologic disease and in one patient (1.3%) due to anemia. Overall, in 1008 safety assessments performed, leucopenia, neutropenia, thrombocytopenia, and TA elevations >grade 2 were 1.6%, 2.3%, 5.5%, and 2.8% respectively. Main non-hematologic adverse events (AEs) were gastrointestinal (GIT) (nausea, vomiting, diarrhea) (16.9%); infections (15.1%); skin (rash, erythema) (4.4%). Cr values above BL were observed in 41 (54%) pts. At EOS, median Cr was above BL by a median of 10 μmol/l. AEs were mostly mild to moderate, transient, and dose-related. On study, a median of 2 drug dosage adjustments/interruptions were made mainly for Cr elevation (27%), GIT-AEs (15%), TA elevation (10.4%), and skin AEs (3.8%). Study drug was permanently discontinued because of GIT-AEs in 3 (4%), skin AEs in 3 (4%), TA in 2 (2.6%), and Cr in 2 (2.6%) pts.

A highly significant reduction in serum ferritin could be induced with deferasirox after allogeneic HCT with an acceptable safety profile. Stable trough serum cyclosporine levels could be maintained over time irrespective of the daily dose of deferasirox. Our results indicate that a daily dose of 7.5–10mg/kg is effective, and well tolerated in a complex cohort with TIO after allogeneic HCT.

Al-Ali:Novartis: Honoraria. Lieder:Novartis Germany: Employment. Albrecht:Novartis Germany: Employment. Leismann:Novartis Germany: Employment. Bug:Novartis Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other. Kroeger:Novartis Germany: Honoraria, Research Funding. Platzbecker:Novartis Germany: Advisory Board Other, Honoraria.