Transplant Outcomes in High-Risk (Class 3) Patients with Thalassemia Treated with a Modified Protocol Are Equivalent to Low/Intermediate-Risk (Class 1/Class 2) Patients

Introduction. Bone marrow transplantation (BMT) for class 3 patients with thalassemia is challenging due to high rates of graft rejection and transplant-related mortality. Since the first studies of BMT in the late 1980s, a number of conditioning regimens have been designed to improve outcomes, but with suboptimal results. Here we report the outcome of transplantation in class 3 patients using a modified protocol.

Methods. Between July 2004 and May 2015, 68 consecutive patients of 5-16.6 years of age with class 3 thalassemia received their first BMT from HLA-identical sibling donors. Of these patients, 26 were prepared for transplantation with the original protocol (Protocol 26) and 42 patients (since February 2007) with the modified protocol. The original protocol started with a preconditioning phase during which patients received hydroxyurea (30 mg/kg/day) and azathioprine (3 mg/kg/day) from day −45 pre-transplant, and fludarabine (20 mg/m²/day) from day −16 through day −12. Conditioning regimen included oral or intravenous (i.v.) busulfan and cyclophosphamide 160 mg/kg total dose. The modified protocol started with the same preconditioning phase except with 30 mg/m²/day of fludarabine. The conditioning regimen comprised i.v. Bu, thiotepa 10 mg/kg/day, and cyclophosphamide 160 mg/kg total dose. We compared the outcomes between these two groups. The two groups showed similar patient demographics. Patients in both groups had moderately severe iron overload, as evidenced by high median serum ferritin and liver iron concentrations. The median liver fibrosis score in the original and modified protocol-treated patients was 2 (range, 1-4) and 1 (range 1-5) (p=0.22), respectively.

Results. At day 0, the degree of cytoreduction (lymphopenia, neuthropenia and thrombocytopenia) achieved by the modified protocol was significantly higher than the original protocol. Overall, 22 (84.6%) original protocol-treated patients and all 42 modified protocol -treated patients showed sustained engraftment. Platelet and neutrophil engraftment kinetics were similar between groups. All patients with sustained engraftment achieved RBC transfusion independence, with a median time to transfusion independence of 19 days (range, 0–88) with original protocol  and 20 days (range, 0–85) with modified protocol. Among original protocol-treated patients, two experienced primary graft failure and two experienced secondary graft failure. No modified protocol-treated patients exhibited graft failure. Competing-risk analysis showed a significantly higher cumulative incidence of graft failure with original protocol (15%) compared to modified protocol (0%) (p=0.010). At the time of survival analysis, 22 original protocol -treated patients (85%) and 39 modified protocol-treated patients (93%) were alive, with median follow-up durations of 8.8 years (range, 8.2–10.8 years) and 3.5 years (range, 0.4–8 years), respectively. The 5-year probabilities of thalassemia-free survival were 93% with modified protocol and 73% with original protocol (p=0.032). The respective probabilities of overall survival were 93% and 85% (p=0.37). The incidence of grade 2-4 acute GVHD was 46% in the original and 24% in the modified group (p=0.066). Respective incidences of chronic GVHD were 12% and 5%. At present all patients are off immunosuppressive medication. There were 4 deaths in the original group and 3 deaths in the modified group. The most frequently observed toxicities were grade 2 elevations in AST and ALT, followed by grade 2 oral mucositis and diarrhea with similar rates in both groups. Few patients experienced grade 3 liver and gut toxicities in either groups with similar rates. There was no difference in the rate of infectious complications between the two groups. One patient in each group developed moderate hepatic VOD, both of which resolved with supportive care

Conclusions. Modified treatment protocol effectively and safely prevented graft failure/rejection and significantly improved thalassemia-free survival of class 3 patients. Importantly, the treatment intensification was not associated with increased nonhematological toxicity, even though these patients suffer from pre-existing organ damage due to iron overload and/or hepatitis. Modified protocol makes allogeneic BMT accessible to all class 3 younger patients with results equal to class 1 or class 2 patients with thalassemia.