Improved Survival Outcomes By Iron Chelating Therapy with Deferasirox after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Background

The negative prognostic impact of hyperferritinemia before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established in hematologic malignancies, and recent two small prospective studies of post-transplantation iron-chelating therapy (ICT) with deferasirox reported the safety and efficacy in lowering serum ferritin (SF), but the impact of ICT on survival is not yet known.

Material and methods

We retrospectively evaluated 326 consecutive patients with acute myeloid leukemia in remission who underwent allo-HSCT at a single institution between 2007 and 2012. The SF levels and immune subsets in peripheral blood (PB) were regularly monitored before and after transplantation. With an exclusion of 50 patients with SF levels less than 1000 ng/ml at a month after transplantation, 276 patients with hyperferritinemia (≥1000 ng/ml) after transplantation were recommended to receive deferosirox, and finally 128 patients (46%) agreed (ICT group), whereas 148 patients (52%) did not (non-ICT group). Deferosirox (10 or 20 mg/kg) was started mostly at a month after transplantation with a median of 30 days (range, 18~50), and continued to the ferritin level lower than 500 ng/ml unless serious adverse effects and/or relapse.

Results

The ICT group consisted of higher aged and more haploidentical-related donors than non-ICT group, which were associated with more reduced-intensity conditioning and HLA-mismatched donors in the ICT group, and otherwise similar in both groups. The median duration of ICT was 5.4 months (range, 1.0~13.1). The starting dose of deferosirox was mainly 20 mg/kg (91%) with an exception of 11 patients (10 mg/kg, 9%) due to remained mild gastrointestinal symptoms after transplantation. The ICT group showed a significantly faster decline in SF than non-ICT group. Adverse events were frequent (65%), but mild to moderate and transient. Dose reduction and temporary interruption of deferosirox were required in 64% and 4% of patients, respectively, mainly because of creatinine elevation and gastrointestintal symptoms.

With a median follow-up of 41 months (range, 1~100 months) for survivors, the 4-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 55%, 53%, 24%, and 23%, respectively. The ICT group had significantly better OS (68% vs. 43%, P<0.001) and DFS (66% vs. 40%, P<0.001) with lower CIR (13% vs. 33%, P<0.001) than non-ICT group, but no significant difference of NRM (20% vs. 26%, P=0.285). Multivariate analysis with significant factors in univariate analysis and an adjustment with different factors between the two groups revealed that the ICT with deferosirox independently improved OS, DFS, and CIR. Of note, chronic graft-versus-host disease (GVHD) developed more in the ICT group (66% vs. 39%, P<0.001), which was significant on multivariate analysis, but no difference in acute GVHD. Immune subsets analysis with PB within a year after transplantation showed no significant difference between the two groups in immune recovery of CD3, CD4, CD8, CD19, and CD56 positive cells. However, we found that regulatory T cells were significantly suppressed at 3 months after transplantation in the ICT group compared to non ICT group (0.01% vs. 3.6%, P<0.001).

Conclusions

The present study demonstrates that the ICT by deferosirox was well tolerated and beneficial when initiated after allo-HSCT. The increased occurrence of chronic GVHD in the ICT group might be related with less frequency of regulatory T cells induced by iron chelation with deferosirox, which could promote graft-versus-leukemia effects resulting in the reduced incidence of relapse and better survival outcomes, even though the ICT group had more high risk features. Further controlled studies would be worth to confirm the benefit of ICT after allo-HSCT.