Dose Escalation Prophylactic Donor Lymphocyte Infusion (pDLI) after T-Cell Depleted (TCD) Matched Related Donor (MRD) Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Is Feasible and Results in Higher Donor Chimerism, Faster Immune Re-Constitution and Prolonged PFS

Abstract Background: Alemtuzumab based TCD allografts allow low rates of acute and chronic GVHD. However, delayed immune reconstitution and mixed donor chimerism (MDC) may increase infection rates, if not relapse. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) followed by dose-escalation pDLI after alemtuzumab-based TCD conditioning for patients (pts) with high-risk hematologic diseases. Methods: High-risk hematologic malignancies were eligible if planned for matched related or matched unrelated donor TCD allografts and tacrolimus for GVHD prophylaxis. Patients began WOI as early as day 60 if no GVHD or relapse, followed by escalated doses of pDLI every 4-8 weeks for up to 5 treatments starting at 2x105 CD3/kg for MRD and 1x105 for MUD with half-log dose escalation. The primary aim was for over 50% of patients to receive at least one DLI. Results: 75 patients (pts) thus far have been enrolled. A planned interim analysis of 59 pts demonstrated that very few MUD allografts were evaluable since it was not possible to achieve WOI and at least one DLI; thus, MRD grafts were primarily enrolled thereafter. In total, 46 pts (61%) received MRD. 37 pts (49.3%) had AML, including 16 (42%) not in remission. Pts received fludarabine/melphalan (n=47), flu/busulfan (n=26), or TBI/etoposide (n=2) with alemtuzumab 30-100mg. 40 pts (53%) did not undergo WOI due to acute GVHD (n=16), relapse (n=9), death (n=8), too early for WOI (n=2), poor graft function (n=2) or were enrolled to another study (n=3), and 5 (6.6%) underwent WOI but did not receive pDLI due to acute GVHD (n=4), death (n=1). Successful WOI and receipt of at least one pDLI was achieved in 30 (39.5%) pts, with 4, 9, 5, 5, and 7 pts receiving 1, 2, 3, 4 and 5 total pDLI, respectively. 61.9% (26/42) of MRD patients could undergo WOI and at least one pDLI versus only 14.2% (4/28) of MUD patients. Median time from transplant to first pDLI was 97 days (range 84 to 164). After pDLI, 11 pts developed grade I-IV aGVHD. Rates of aGVHD, grades II-V at 1 year post-HCT were 47% for all pts versus 27.5% for those receiving at least one pDLI. One year NRM rate was 16.7% in all pts and 3.5% in pDLI pts. Median PFS and OS for all pts were 322 days and 644 days, respectively. The median PFS and OS for those receiving at least one pDLI were not reached. 2 year PFS and OS for all the patients were 36.8% and 45.3% compared to 52.5% and 60.7% for patients who received at least one pDLI. At one year, among pts receiving at least one pDLI , 95% of evaluable pts (20/21) had full donor chimerism compared to 59% (10/17) of those not receiving any pDLI. There was also a clear increment in chimerism with each pDLI. Pts receiving pDLI had faster lymphocyte count recovery and higher IgG levels at one year post allo-SCT. Minimal residual disease was monitored by WT1 qRT-PCR in 16 AML/MDS pts who received pDLI; 11/16 (69%) pts had WT1 transcript decrease, which suggests a better outcome for those treated with pDLI. TCR sequencing was done in 8 pts who received between 2-5 pDLI to assess if pDLI could change T cell clonality, resulting in enrichment of possible leukemia-antigen associated T cell proliferation, TCR sequencing using peripheral blood revealed reduction in the TCR diversity and clonal enrichment of T cells. Direct comparison of the outcomes between our historical control pts and the pts treated with pDLI having the same disease risk index (DRI) is ongoing with the hope to provide more definitive PFS benefit using early WOI and pDLI. Conclusions: This prospective trial demonstrates that early WOI followed by dose-escalation pDLI is feasible after alemtuzumab based regimens for matched related donors and may suggest favorable results mediated by improved donor chimerism. For matched unrelated donors, WOI should occur later and/or pDLI given prior to tapering immune suppression. Disclosures Park: OncoTherapy Science, Inc.: Consultancy. Stock: Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larson: Amgen Inc.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Odenike: Jazz: Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Riedell: Kite Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Liu: BMS: Research Funding; Karyopharm: Research Funding.