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Objectives Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T‐cell reconstitution, potentially influencing long‐term outcomes. Methods Based on donor‐derived T‐cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30‐day post‐transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T‐cell depletion with 5.1 mg kg−1 antithymocyte globulin (administered over 3 days, Day −9 through to Day −7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day −1 and Day 0). Patients underwent HLA‐matched related and unrelated donor haematopoietic cell transplantation (HCT). Results Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T‐cell, as well as T‐cell subset recovery and a trend towards superior T‐cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T‐cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. Conclusion The long‐term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the ‘immune‐milieu’ following allogeneic HCT is feasible and may influence long‐term T‐cell recovery.

Reduced intensity conditioning (RIC) is fraught with risk for disease relapse. This may be overcome by donor T cell alloreactivity. Reducing the duration of intense immune suppression in the early term following transplantation may create an immunologic environment favoring rapid T cell reconstitution to influence longer term transplant outcomes. Twenty-six patients were adaptively randomized based on donor-derived T cell recovery, between 2 different dosing schedules of mycophenolate mofetil (MMF): MMF for 30 days post-transplant, with filgrastim for cytokine support (MMF30 arm, 11 patients), or MMF for 15 days post-transplant, with sargramostim (MMF15 arm, 15 patients). All patients were treated with anti-thymocyte globulin at a dose of 1.7 mg/kg/day from day - 9 through day -7 and total body irradiation, 450 cGy given in 3 fractions. Patients were well matched between the study arms and underwent HLA matched related and unrelated donor hematopoietic cell transplantation (HCT). The MMF15 arm demonstrated superior T cell recovery in the first month. This difference persisted through the first year for total T cells, T cell subsets and NK cells. T cell repertoire tended to be more diverse in the MMF15 arm. The long term superior immune recovery in the MMF15 arm is consistent with a disproportionate impact of early interventions in HCT. Clinically, shorter course MMF post-transplant was not associated with increased risk of acute or chronic graft vs. host disease (GVHD), and relapse and there was a trend toward improved overall survival in the MMF15 arm. Reducing the duration of intense immunosuppression in the early term and the use of sargramostim following allogeneic HCT is feasible and leads to superior long-term T cell recovery. This regimen should be studied to improve immune recovery in large cohorts of patients undergoing HCT with RIC.

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Anti-thymocyte globulin (ATG) mitigates graft vs host disease (GVHD) risk in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Due to T cell depletion there remains a concern that ATG administration may be associated with an increased risk of malignancy, relapse, and infection in recipients of reduced intensity conditioning (RIC). It was hypothesized that ATG infusion early in the course of conditioning will promote rapid immune reconstitution because of lower levels at the time of graft infusion and will thus help to improve clinical outcomes in RIC. Rabbit ATG (Thymoglobulin, Sanofi Aventis) was administered from day (d) -9 to -7 to HLA matched-unrelated (MUD; 5 mg/kg in divided doses) and -related (MRD; 3.5 mg/kg) donor transplant recipients conditioned with Fludarabine and Melphalan (ATG -9 cohort; N=36). Immune reconstitution and clinical outcomes were compared with a historical control group of patients who received the same doses of ATG from d-3 to -1 (ATG -3 cohort; N=28). Standard GVHD prophylaxis with calcineurin inhibitor and antimetabolite was administered, with CMV and EBV monitoring. ATG -9 cohort had more, MUD recipients 80% vs. 64%; myeloid malignancy (AML, MDS, MPD) 83% vs. 35%. Age (56 vs. 57), graft type (97 vs. 92% PBSC) and CD34+cell dose infused (4.8 vs 4.7 E6/KG) were similar. Immune reconstitution was uniformly superior in ATG -9 cohort, with significantly higher absolute monocyte counts (AMC) at d30, 60 and 90 (P<0.001), as well as higher donor derived CD3+ (ddCD3+) and CD3+/8+ cell counts at d60 and 90 (P<0.01), and CD3+/4+ cells at d90 (P=<0.05). T cell - monocyte interactions were modelled as 2 dimensional vectors in the immune phase space, (Figure 1) with a consistently higher vector magnitude observed in ATG-9 cohort (P<0.01). Rate of T cell reconstitution was determined by calculating the derivative of ddCD3+ cell count as a function of time (dT/dt) post-transplant (Figure 2) and was generally higher in the ATG-9 cohort, particularly at d60. With a median follow up of 14.9 months in the ATG-9 cohort, and 47.2 months in the ATG -3 cohort, there is a non-significant trend for improved survival (72.2% vs. 46.4% at 2 years) and relapse (19.4% vs. 35.7% at 2 years) in the ATG -9 cohort. TRM and acute GVHD were similar, with a trend towards greater risk for chronic GVHD in the ATG -9 cohort, albeit of a lower severity. Given the relatively low number of patients in each cohort, the effect of immune reconstitution on clinical outcomes was evaluated in the pooled population. Survival was improved in those with AMC and ddCD3+ cell counts >200/µL at d60 (P=0.004 & 0.016 respectively), and in patients with T cell - monocyte vector magnitude > median (577.48/µL) at that time (P= 0.008), as well as in those with a calculated dT/dt > median (1.96 cells/µL/day) at d45 (P=0.047). The latter was also associated with a reduction in relapse rate (P=0.04), as was ddCD8+ cell count >145/µL at d60 (P=0.04). Acute GVHD risk was increased when dT/dt was >median (7.60 cells/µL/day) at d15 (P=0.0095), and correspondingly with T cell - monocyte vector magnitude > median (1033.3/µL) at d30 (P=0.017). In conclusion, this retrospective study demonstrates that equal doses of ATG administered earlier (d -9 to -7 as opposed to d-1 to -3) during conditioning yield more rapid and robust immune reconstitution. Monocyte and ddCD3+ cell recovery kinetics have a favorable impact on survival and relapse risk following HLA matched HCT. Patients at risk for acute GVHD may be identified as early as d15 post HCT by analyzing ddCD3+ cell reconstitution kinetics. Different ATG administration schedules should be studied prospectively with a focus on immune reconstitution kinetics as a determinant of clinical outcomes. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Rabbit anti-thymocyte globulin for GVHD prophylaxis.