T-Cell Replete Peripheral Blood Haploidentical Transplant Using Immunogenic Dose of Cyclophosphamide with Fludarabine/Melphalan Results in Enhanced Cytokine Release Syndrome (CRS) with Robust Immune Recovery and Low Relapse Rate

Abstract

In contrast to Chimeric-Antigen Receptor (CAR) T-Cell therapy, there is limited literature if any that has addressed the impact of intensity of lymphodepletion rather than myeloablation on relapse after HID HCT. We hypothesize d that enhanced lympho-depletion would create a host immunogenic microenvironment that would enhance donor T cell expansion and alloreactivity after HID HCT. We utilized an intensified lympho-depleting conditioning regimen with Fludarabine (Flu) 150 mg/m2, Melphalan (Mel) 140 mg/m2 and Cyclophosphamide (CY) 29 mg/m2 prior to HID HCT to treat 15 consecutive patients with HM between July 2015 and June 2017. The intensity of lymphodepletion was confirmed in 12 evaluable patients at day (0) by complete absence of lymphocytes in peripheral smear. In contrast, myeloid elements were detected in 7/12 patients suggesting more intense lympho-depletion than myeloablation. All Patients received GVHD prophylaxis with Tacrolimus/Mycophenolate with post-transplant Cyclophosphamide according to Hopkins regimen. Patient characteristics are shown in Table 1. Eight patients had relapsed/refractory disease at time of transplant. The median duration of follow up is 29 months (range 13-37). All patients engrafted and achieved 100% Chimerism in BM and PB by day 100 except for 1 patient who died at day +25 prior to engraftment. Median time to neutrophil engraftment was 21 days (range 12-57). All evaluable patients with relapsed/refractory disease (7/8) achieved complete remission post-transplant. The day 100, 1-year & 2 year overall survival was 93%, 73% & 66% respectively. We observed very low cumulative incidence of relapse of 7% at 2 years post-HCT (only 1/15 patients). Treatment related mortality (TRM) was 6%, 20% and 27% at day 100, 1 and 2 years respectively (4/15 patients). Severe Cytokine Release Syndrome (CRS), grade 4 by Lee Criteria occurred in 4 patients, all of them have died at day 25, 258, 288 and 540. Grade II-IV acute GVHD developed in 4/15 patients (27%), 2 of whom had grade III-IV by day +180. Chronic extensive GVHD developed in 7 patients (46%). At 2 years, post HCT, only 1/7patients remain with extensive chronic GVHD requiring active treatment. Post -transplant immune reconstitution panels were obtained at day 60, 120, 180 and 360 as shown in Fig 1. We observed early recovery in all T-cell subsets at day 60 with activated T cells (CD3+, HLA-Dr+) being most pronounced. While there was a steady decline of activated T cell, the NK cells and CD4 maintained their early recovery through the first year. There was initial decline in the number of B cells at day 120 which gradually recovered by 1 year. Conclusion: Enhanced lymphodepletion prior to peripheral blood HID HCT may enhance early T cell proliferation, alloreactivity and immune reconstitution. Future strategies directed at improving management of severe CRS are needed to harness the benefits of the observed low relapse rate.