Splenomegaly may increase the risk of rejection in low risk matched related donor transplant for thalassemia and this risk can be partially overcome by additional immunosuppression during conditioning.

Severe thalassemia syndromes (ST) are highly curable by BMT but rejection may still occur. We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol. In this study we compared rejection rates between patients with and without splenomegaly in 189 consecutive low risk ST transplants across two sequential conditioning regimens: Regimen A (Aug 2013 and Dec 2016) - busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg) and anti-thymocyte globulin (ATG) (Genzyme 4 mg/kg or Fresenius 16 mg/kg on days -12 to -10) and Regimen B - same backbone as Regimen A except Fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and/or sex mismatched transplants (Jan 2017 to Sep 2018). Compared to Regimen A in Regimen B both overall rejection rates (RR) (16 % vs 6.5 %, p=0.023) and treatment-related mortality (TRM) (9.9 % vs 2.8%, p=0.038) improved significantly. By Cox regression analysis the improvement in RR between the two protocols was particularly significant in patients with splenomegaly (RR 54.5% vs 6.5 %, p=0.00015, TRM 18.2 % vs 6.5 %, p=0.25) (HR 4.13, CI 1.61-10.6 p=0.003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG- Bu-Cy protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.