High Incidence of Mixed T Cell Chimerism with Reduced Toxicity Conditioning Regimens in Non-Malignant Diseases Are Not Associated with Adverse Outcomes

Abstract

<h3>Introduction</h3> Following hematopoietic stem cell transplant (HSCT) for non-malignant diseases (NMD), mixed donor chimerism is a common occurrence in reduced toxicity myeloablative (RTM) and reduced intensity conditioning (RIC) conditioning regimens. Several strategies such as donor lymphocyte infusions (DLI), stem cell boost, or decreasing immune suppression are implemented with limited evidence to guide clinicians. We systematically assessed the effect of low mixed donor T chimerism on different HSCT morbidities and overall survival. <h3>Methods</h3> At a single institution from 2012-2018 there were 112 HSCT for NMD. 88 patients were identified with 100% donor myeloid (CD33) chimerism at one month post-HSCT. Of the patients without 100% CD33 engraftment, 7 achieved and 9 failed to achieve 100% myeloid (CD33) chimerism one year post-HSCT. For the entire cohort 6 developed primary graft failure. CD3 and CD33 chimerisms were longitudinally assessed at 1, 3, 6, and 12 months post-HSCT. The analyzed cohort was further divided into subgroups (SG) of conditioning regimens: myeloablative busulfan (Bu) and cyclophosphamide (Cy) (SG1; n = 2), reduced toxicity myeloablative Bu-Cy-Fludarabine (Flu) (SG2; n = 35), Bu-Flu (SG3; n = 24), reduced intensity conditioning based on melphalan and Flu (SG4; n = 10), and Cy based immune-ablative regimens (SG5; n = 17). Acute and chronic graft versus host disease (GVHD), viral reactivation, need for DLI, and survival data were collected. The average age at HSCT was 8.8 years. The majority of patients received bone marrow grafts (4 cord and 7 peripheral stem cell infusions) and from a matched related donor (n = 51, 58%), MUD (n = 27, 31%), MMUD (n = 6, 7%), MMRD (n = 4, 5%). <h3>Results</h3> For the analyzed cohort overall survival was 95%. At 1 month post-HSCT, average T cell chimerism was lowest in SG3 (58.6%); other groups had similar higher T cell chimerism (SG1 84%, SG2 80.3%, SG4 86.8%, SG5 78.6%). When followed longitudinally, average T cell chimerism improved with time without need for additional intervention (Fig 1). Despite the disparity between T cell chimerism overall survival was not affected for SG3 (96%) and the rates of acute GVHD (37.5% v. 30.1%), chronic GVHD (8% v. 19%), and viral reactivation (8% v. 25%) was not significantly higher than rest of the analyzed cohort. Only 4 patients in the cohort were treated with DLI when the myeloid chimerism showed a decreasing trend (2 from SG3, 2 from SG4). <h3>Conclusion</h3> Decreasing T cell chimerism can raise concern for impending graft failure in patients with NMD treated with RTM and RIC conditioning. In our cohort we have shown that in the majority of patients without pursuing DLI or a CD34 cell boost or changes in immune suppression, T cell chimerism continues to improve provided a robust myeloid graft. Patients with mixed T cell chimerism have an excellent survival rate, without increased second graft loss, GVHD, or viral reactivation.