Phase II Clinical Trial Evaluating the Standardization of CD3+ T-Cell Dose for Patients Receiving Allogeneic Peripheral Blood Stem Cell Transplants (PBSCT) from Matched Related Donors

Introduction Seminal studies of peripheral blood versus bone marrow grafts have elucidated the crucial role of CD3+ T-cells in mediating engraftment, immune reconstitution, disease control, and graft versus host disease (GVHD). An optimal dose-response relationship between the T-cell dose in the graft and outcomes is yet to be defined. Therefore, we performed a phase II clinical trial to evaluate whether T-cell dose standardization would adequately support engraftment and immune reconstitution while mitigating the risk of GVHD. Methods We conducted a clinical trial of dose standardization of T-cells between December 2014 and May 2018. Eligible adult patients (pts) with hematologic malignancies undergoing peripheral blood matched sibling allogeneic stem cell transplant were enrolled. Standardized T-cell dose was targeted 15-20 × 10e7. Tacrolimus and methotrexate were utilized for GVHD prophylaxis. The primary endpoint was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and time to engraftment. Chronic GVHD was captured using conventional criteria. Results 17 pts were included in the study. Peripheral blood stem cell (PBSCT) graft from matched sibling donors was used in all pts. The mean age was 52 years (20-68 years). 53% pts were female and 82% were Caucasian. The median T-cell dose was 19.1 × 10e7 (range 9.1-21.8 × 10e7). Indications for PBSCT included AML/MDS (70.6%), ALL (17.6%), NHL and MPN (11.8 %). 35% pts received myeloablative and 65% received reduced-intensity conditioning. 59% had age-adjusted HCT-CI scores ≥3. 16 pts received tacrolimus and methotrexate for GVHD prophylaxis, with 1 patient receiving tacrolimus and mycophenolate. All pts successfully engrafted. The median time to engraftment was 15 days for neutrophils (range 10-20), and 12 days for platelets (range 9-22). The cumulative incidence of grade II-IV and grade III-IV acute GVHD at 1 year was 27% (95%-CI: 7-52) and 22.5 (95%-CI: 4.7-48.4) (no grade IV) and that of chronic GVHD was 47% (22-69) (N=8, all extensive by conventional criteria). 18% pts reactivated CMV (median - 40 days, range 33-50). 47% pts were alive in remission after a median follow-up of 18.1 months (3.3-52.2). The cumulative incidence of relapse at 1 year was 23.5% (95% CI: 7-46) (Figure 1). The 1 year PFS was 53% (95% CI: 28-73), and the OS was 65% (95% CI: 37-82). Conclusion Administration of a lower standardized T-cell dose is feasible, and when used in combination with standard immune suppression did not negatively affect outcomes. This study paves the way for a larger trial to evaluate the optimal T-cell dose and immune suppressive therapy to strike a favorable GVHD/GVL balance. Such a strategy could be used as a platform for additional interventions aimed towards improving the outcome of PBSCT for hematologic malignancies.