Deferasirox (Exjade®) Given During Conditioning Regimen (FLAMSA/Busulfan/ATG) Reduces the Appearance of Labile Plasma Iron in Patients Undergoing Allogeneic Stem Cell Transplantation

Abstract 3023

In patients undergoing allogeneic stem cell transplantation (SCT) non-transferrin-bound iron (NTBI) has been shown to appear quickly after onset of chemotherapy, while not being detectable at baseline. This indicates that cytotoxic therapy is associated with release of catalytically active iron. Pre-transplant iron overload has been associated with a higher risk of complications like infections, liver dysfunction, veno-occlusive disease and acute graft-versus-host disease (GvHD). This could be due to released NTBI catalyzing the generation of reactive oxygen species and being an essential cofactor for pathogen growth.

Labile plasma iron (LPI) represents the chelatable, redox-active and toxic fraction of NTBI. It has not yet been assessed in patients undergoing SCT. Treatment with deferasirox (DFR) has been shown to produce sustained reduction in LPI at doses > 20mg/kg/d in patients with β-thalassemia and myelodysplastic syndromes. The aim of this study was to investigate, whether DFR given off-label during conditioning regimen can prevent the formation of NTBI/LPI.

A total of 9 patients - all receiving a conditioning regimen with fludarabine, amsacrine, cytosine-arabinoside, busulfan and anti-thymocyte globulin - were enrolled so far. Five consecutive patients received DFR in a mean dose of 16.8mg/kg/d (range 14.5 – 19.7) for the first 5 days of chemotherapy, while 4 patients served as control without DFR. Blood samples were taken daily during chemotherapy and following SCT on day +1, +4, +7 and +14 for assessing selected parameters of iron status (serum iron, transferrin, transferrin saturation (Tfs), serum ferritin) as well as renal and liver function (serum creatinine, ALT, AST, AP, bilirubin). Blood samples for assessment of NTBI and LPI were taken on second (d2) and fifth day (d5) of chemotherapy regimen and d+1 after SCT. NTBI was measured by graphite furnace atomic absorption spectrometry after mobilization of free iron by nitrilotriacetic acid (NTA) and centrifugal filtration of the iron-NTA complex. LPI levels were analyzed according to a previously reported method using an assay kit (Aferrix, Tel Aviv, Israel) that measures iron-specific redox activity in serum in the presence of ascorbate. LPI units > 0.4 were counted as weakly positive and > 0.6 as positive (according to Aferrix).

Median baseline Tfs was below the threshold of 80% in both groups (DFR = 38% (range 28–88), control = 59% (range 18–91)). Therefore the presence of NTBI/LPI is very unlikely. During treatment with DFR no LPI was detectable on d2 and d5 whereas in control group 3/4 patients had positive LPI values. On day +1 LPI-values were higher in DFR-group with 3/5 LPI-positive samples (median 0.4 LPI units (range 0–2)) in contrast to 1 positive control sample (1.3 LPI units). Median NTBI-levels in DFR-group on d2 were 3.8 μM (range 3.3–4.8) and decreased notably in 3/5 patients until d5: median 2.1 μM (range 2.0–3.6). In the control group median NTBI values were higher on both days with a median of 5.0 μM (range 2.6–6.3) at d2 and of 4.1μM (range 2.9–6.0) at d5. On day +1 median NTBI-values were similar in both groups: 3.0 μM (range 2.3–4.0) in the DFR and 3.2 μM (range 2.0–3.5) in the control group.

Regarding clinical effects the DFR-group had a lower incidence of bacterial bloodstream infections with 2/5 vs. 4/4 control patients.

In total DFR was well tolerated and all patients completed chelator therapy. There were no differences between the groups in renal or liver function, except a higher (reversible) increase of bilirubin during ATG treatment in the DFR-group (4/5 patients with grade 3, 1 patient with grade 1 (CTC); median c_max 5.5mg/dl (range 1.4–10.4)) as compared to control (2/4 patients with grade 3, 2 with grade 2; median c_max 3.3mg/dl (range 1.9–4.9)). The DFR-group had a higher incidence of diarrhea during ATG (4/5 patients) and mucositis (5/ 5 patients) than control patients (2/4 and 1/4 patients, respectively). Moreover there were no differences in engraftment or development of acute GvHD.

These findings suggest that DFR given during SCT conditioning regimen may prevent the appearance of LPI and reduce the level of NTBI. Therefore it may decrease the risk of infections and organ toxicity by iron-induced radical formation. These preliminary results should be verified in further studies.