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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.

Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery, improved survival, and less chronic GVHD. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modelling ‘early-term immune reconstitution’ following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.HighlightsATG given early (day -9 to -7) prior to HCT leads to improved survival and non-relapse mortality. Improved monocyte counts as well as donor-derived T cell counts are seen in recipients of early ATG. Improved clinical outcomes are observed in patients with enhanced monocyte and T cell recovery after HCT.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. Mathematically accounting for KIR-KIRL interactions may identify donors with optimal NK cell mediated alloreactivity and GVL. In this retrospective study of 2359 donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML, KIR-KIRL interaction scores were determined. Relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. The inhibitory KIR-KIRL (iKIR) interaction score components were summed to give an inhibitory-missing ligand (IM-KIR) score, which if it was 5 as opposed to HighlightsInhibitory and missing KIR-KIRL interactions, both individually and collectively are predictive of relapse following URD HCT for AML.Amongst 8/8 HLA matched donor recipient pair relapse reduction was observed in those undergoing in vivo T cell depletion with ATG.TRM is increased in patients with greater magnitude of inhibitory and missing KIR-KIRL interactions.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer (NK) cell mediated graft versus leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Herein a novel mathematical model designed to quantify these interactions is presented to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA matched unrelated donor (URD) HCT recipients were retrospectively studied. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction and directionality of interactions was denoted by, either a positive (activating) or negative symbol (inhibition); these interactions were then summed. The absolute values of both the missing KIRL as well as inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted (w-KIR Score) and subsequently a simplified, non-weighted KIR-KIRL interaction scores (IM-KIR Score). Increased w-KIR Score and IM-KIR Score were both predictive of all-cause mortality and relapse; w-KIR score HR of 0.37 (P=0.001) and 0.44 (P=0.044) respectively; IM-KIR score HR of 0.5 (P=0.049) and 0.44 (P=0.002) respectively. IM-KIR score was also associated with NK cell reconstitution post HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA matched URD HCT with hematological malignancies.HighlightsKiller immunoglobulin-like receptor (KIR) – KIR-ligand (KIRL) interactions display a high degree of variability in HLA matched stem cell transplant (SCT) recipients.Individually, the magnitude of inhibitory and missing KIR-KIRL interactions predicts overall survival and relapse risk following SCT.Taken together the known KIR-KIRL interactions also predict clinical outcomes after HLA matched unrelated donor stem cell transplantation.