Seven Years of Haplo-Cord Transplantation: Immune Reconstitution and Outcomes Using Anti-Thymocyte Globulin

Abstract

Introduction Haplo-cord transplantation – the co-infusion of a single cord unit with CD34-selected cells from a haplo-identical donor, provides an alternate stem cell source for patients lacking HLA-matched donors. Anti-thymocyte globulin (ATG) is routinely used in haplo-cord preparative regimens to reduce graft failure, graft vs. host disease (GVHD) and graft vs. graft reactions. However, excessive depletion of cord lymphocytes may compromise immune reconstitution and graft vs. tumor (GVT) effects. Methods We reviewed lymphocyte recovery and outcome data for consecutive patients with hematologic malignancy who underwent haplo-cord transplantation at Weill Cornell Medicine between June 2012 and June 2019. All were conditioned using fludarabine and melphalan with or without total body irradiation (200-600cGy). All received rabbit ATG (Thymoglobulin), initially at a total dose of 6mg/kg (2012-2013) and later at a total dose of 4.5mg/kg (2013 onward). Data was collected as part of study 01810588 registered at clinicaltrials.gov. Probabilities of relapse and non-relapse mortality (NRM) were generated using cumulative incidence estimates to accommodate competing risks. Probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates. Results Our study included 220 haplo-cord transplant recipients with a median age of 58 yrs (Range: 18 – 76 yrs). The majority had myeloid disease (AML – 54%, MDS/MPN – 19.5%, CML – 2%). Conditioning incorporated TBI for 120 patients (55%). ATG was dosed at 6mg/kg for 41 patients (19%). The median absolute lymphocyte count (ALC) at first ATG exposure was 0.4 × 10^9/L (IQR25-75: 0.2-0.7 × 10^9/L). The median patient weight was 75.5kg (IQR25-75: 65.4-89.9kg). Neutrophil and platelet engraftment occurred at a median of 12 days (IQR25-75: 10-16 days) and 22 days (IQR25-75: 17-35 days) respectively. Graft failure was observed in 16 patients (7%). Rapid early recovery of CD19+ lymphocytes, CD56+ natural killer cells and IgG levels was observed. T-cell recovery was delayed, with a gradual increase observed from Day 100 (Figure). Overall PFS and OS at 2 yrs were 30% (CI 24-37%) and 39% (CI 32-46%) respectively. The 2 yr cumulative incidence of NRM was 33% (+/- 3% SEM). The overall 2 yr incidence of relapse was 37% (+/- 3% SEM), however there was a significant difference in relapse incidence between patients treated with 6mg/kg ATG (54%) versus 4.5mg/kg (31.5%) (p=0.009). Conclusion Haplo-cord transplant facilitates early neutrophil engraftment with early normalization of B- and NK-lymphocytes. An observed delay in T-cell recovery may be due to the use of ATG in this platform and higher ATG doses result in a greater incidence of relapse. Our data supports the minimization or replacement of ATG in haplo-cord transplant. An analysis of GVHD incidence and viral reactivation events is ongoing and will be presented.