Splenomegaly May Increase the Risk of Rejection in Low-Risk Matched Related Donor Transplant for Thalassemia, This Risk Can Be Partially Overcome by Additional Immunosuppression during Conditioning

Abstract

Severe thalassemia syndromes (ST) are highly curable by bone marrow transplant (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 2 sequential conditioning regimens: regimen A (August 2013 to December 2016): busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg), and anti-thymocyte globulin (ATG) (Genzyme (Sanofi, Paris, France) 4 mg/kg or Fresenius (Grafalon, Neovii Biotech GmbH, Gr€ afelfing Germany) 16 mg/kg on days À12 to À10), 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 (January 2017 to September 2018). Compared with regimen A, in regimen B, both overall rejection rates (RRs) (16% versus 6.5%, P = .023) and treatment-related mortality (TRM) (9.9% versus 2.8%, P = .038) improved significantly. By Cox regression analysis, the improvement in RR between the 2 protocols was particularly significant in patients with splenomegaly (RR 54.5% versus 6.5%, P = .00015; TRM 18.2% versus 6.5%, P = .25) (hazard ratio, 4.13; confidence interval, 1.61 to 10.6; P = .003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG-Busulfan-Cyclophosphamide (ATG-Bu-Cy) protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion‐dependent hemoglobin (Hb) Hammersmith and massive splenomegaly

“…Hypertransfusion maintaining pretransfusion hemoglobin level between 11 and 15 g/dL and preconditioning with hydroxyurea/azathioprine 3 months before transplant may help to shrink splenic size. However, in older children as in our case or adults, splenomegaly is more difficult to ameliorate due to multiple factors such as portal hypertension, proliferation of reticuloendothelial cells, alloimmunization, increased consumption of transfused cells leading to hypersplenism, and an overactive immune system 20 . Splenectomy is associated with faster neutrophil engraftment and reduced need of transfusion support, 20,22–24 but increased risk of infection‐related mortality and thus decreased overall and event‐free survival without any reduction in rejection rates 20,23,24 .…”

“…However, in older children as in our case or adults, splenomegaly is more difficult to ameliorate due to multiple factors such as portal hypertension, proliferation of reticuloendothelial cells, alloimmunization, increased consumption of transfused cells leading to hypersplenism, and an overactive immune system 20 . Splenectomy is associated with faster neutrophil engraftment and reduced need of transfusion support, 20,22–24 but increased risk of infection‐related mortality and thus decreased overall and event‐free survival without any reduction in rejection rates 20,23,24 . Splenic irradiation was thus performed for this patient based on the experience from patients with myeloid proliferative disorders 25–27 .…”

“…18 Splenomegaly is also increasingly being recognized as an independent risk factor for transplant rejection in patients with transfusion-dependent thalassemias or hemoglobinopathies. 19,20 Even without splenomegaly, a rejection rate of 5%-10% has to be anticipated due to resistant autologous T cells. Splenomegaly could attribute to extramedullary hematopoiesis as part of chronic anemia compensation, splenic pooling, and chronic passive splenic congestion due to portal hypertension and/or heart failure.…”

“…20 Splenectomy is associated with faster neutrophil engraftment and reduced need of transfusion support, 20,[22][23][24] but increased risk of infection-related mortality and thus decreased overall and event-free survival without any reduction in rejection rates. 20,23,24 Splenic irradiation was thus performed for this patient based on the experience from patients with myeloid proliferative disorders. [25][26][27] Even though our patient still developed acute cellular rejection after the initial haploidentical transplantation, adopting a rescue transplant regimen, 28 repeated serotherapy with antithymocyte globulin and alemtuzumab, together with stem cell boost, enabled sustained engraftment.…”

“…immune system. 20 Splenectomy is associated with faster neutrophil engraftment and reduced need of transfusion support, 20,[22][23][24] but increased risk of infection-related mortality and thus decreased overall and event-free survival without any reduction in rejection rates. 20,23,24 Splenic irradiation was thus performed for this patient based on the experience from patients with myeloid proliferative disorders.…”