Splenomegaly May Increase Rejection Rates in Matched-Related Transplants for Thalassemia, This Effect Is Mitigated by Additional Immunosuppression.

Abstract

Background Severe thalassemia syndromes (ST) are highly curable by BMT but rejection may occur in 5 to 30% of cases. Splenomegaly was shown to increase the risk of rejection even in low risk transplant setting in our earlier review (https://ash.confex.com/ash/2017/webprogram/Paper104001.html). Objective To assess the impact of splenomegaly on rejection and study the effectiveness of increased immunosuppression in the preparative regimen. Methods We compared transplant outcomes in patients with splenomegaly between two conditioning regimens: Our earlier protocol (Regimen A) and a more recent modified one (Regimen B) (Fig 1). Our BMT network used Regimen A between August 2013 and Dec 2016 which comprised of 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). Regimen B consisted of 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 Jun 2108). G-CSF-primed bone marrow (5 μg/kg/dose twice daily for 3 to 5 days prior to harvest) was the source of hematopoietic stem cells in all cases. All patients were considered low risk based on liver size 3 by ultrasound measurement adjusted for height. All sibling couples were HLA-compatible. Results In total of 168 patients analyzed, 87 for Regimen A and 81 with Regimen B. Regimen A had 11 patients and Regimen B had 20 patients with significant splenomegaly. There was noticeable overall improvement in rejection rates between Regimen A and Regimen B patient groups (Fig 2) (p = 0.028) while improvement in rejection rates within the splenomegaly group between Regimen A and Regimen B was far more significant (Fig 3) (p = 0.0045). We could not detect any difference in variables potentially associated with rejection risk such as donor-recipient sex mismatch (p = 0.4), serum ferritin at BMT (p = 0.17), pre-BMT blood transfusions (p = 0.37), age at BMT (p = 0.59), ABO mismatch (p = 0.53) and spleen Z scores measured by ultrasound at BMT(p = 0.54) by univariate analysis. The median total nucleated cell dose was higher on Regimen B (9.45, IQR 7.065 – 11.815) compared to Regimen A (6.47, IQR 5.725 – 8.102) (p = 0.023) and the median follow up was shorter (median 15.8 vs 9.35 months) factors which may have contributed to improved results in Regimen B. Conclusion The increased risk of rejection related to splenomegaly can be decreased by adding fludarabine to the standard ATG- Bu-Cy protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.