Novel Reduced Toxicity Conditioning Regimen for Older Severe Thalassemia Patients: Sequential Immunoablative Concept

CIBMTR reported that severe thalassemia patients older than 7 years with hepatomegaly (> 2 cm below costal margin) achieved poor outcome after transplant; DFS = 55% since they had high rejection and mortality rates (Blood, 2011). We therefore developed the novel reduced toxicity conditioning (RTC) regimen to overcome these problems. Fifteen severe thalassemia patients, median age 17 years; range 10 – 22, were enrolled (Feb 2007 – July 2012). All had hepatomegaly. Median ferritin level was 3,500 ng/mL. All of them received hydroxyurea (20 mg/kg/day) for at least 6 months. They also received sequential immunoablative regimen consisted with 2 monthly cycles of fludarabine 40 mg/m2 and dexamethasone 25 mg/m2 x 5 days prior to conditioning regimen. The conditioning regimen consisted with busulfan 130 mg/m2 x 4 days, fludarabine 35 mg/m2 x 6 days and ATG 6 mg/kg. GVHD prophylaxis consisted with FK 506 or cyclosporine and MMF. All of them received peripheral blood stem cells with a target dose of CD34+10 x 106 cells/kg. Eleven patients received matched related and 4 received matched unrelated donor stem cells. Median time of neutrophil and platelet engraftment was day +10 and + 15 respectively. Three patients had mild VOD. Four patients had grade II-IV and none had grade III-IV GVHD. Five patients had mild chronic GVHD which subsequently was resolved. All 15 patients achieved full (100%) donor chimerism at day +30 and these chimerisms were sustainable. Overall and disease free survival rates were 91.2 % (95%CI:50-96). No rejection was observed. One patient died from cerebellar hemorrhage. We suggest that our sequential immunoblative regimen prior to conditioning regimen is a key factor for this favorable outcome in these difficult patients. We also proved that T cell proliferation assay (stimulation with PHA) was suppressed in all patients after 2 cycles of sequential immunoablative regimen. This could explain the immunoablative concept in our study. Our novel approach may be suitable for transplant in other non malignant diseases.