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Background:Allogeneic stem cell transplant (SCT) recipients suffer from a defective T cell mediated immunity causing potentially fatal reactivation of latent viruses. After T cell depleted SCT we have observed over 80% CMV reactivation and significant additional costs ($58-74k/patient). Despite aggressive monitoring and pre-emptive therapy, reactivation and/or positive CMV serology brings a significantly higher risk for non-relapse mortality (NRM). Adoptive transfer of ex vivogenerated virus specific donor T cells is effective as a treatment of infection post-SCT but it has not been tested as a prophylaxis of early reactivation. Here in a Phase I study we transferred multi-virus specific T cells (MVSTs) immediately post SCT, targeting CMV, Ebstein-Barr virus (EBV), BK and adenovirus (Ad) as a novel strategy to prevent viral reactivation in the recipients of T cell depleted sibling HLA-matched SCT.

Ex vivoT cell depletion (TCD) of the graft by CD34+ selection improves the tolerability of allogeneic hematopoietic stem cell transplantation (HCT). Clinical comorbidity measures enhance the estimates of HCT tolerance and outcomes. However, clinical prediction tools such as the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) have not been validated in TCD transplants. To improve outcome prediction we therefore evaluated published comorbidity measures and other standard clinical biomarkers of outcome in a series of patients with hematological malignancies receiving myeloablative TCD transplants. Pre-transplant factors compared were: HCT-CI, European Group for Blood and Marrow Transplantation (EBMT) risk score, Eastern Cooperative Oncology Group (ECOG) Performance Status, serum C-reactive protein (CRP), albumin (ALB), pre-albumin (PAB), ferritin, absolute lymphocyte counts (ALC), and absolute lymphocyte / monocyte ratio (LMR). All patients received a myeloablative preparative regimen (Flu 125 mg/m2, Cytoxan 120mg/kg, TBI 400 cGy if older than 55 or 1200 cGy if younger than 55) followed by the infusion of a CD34+ selected graft from a HLA-identical sibling containing 1 to 5x10e4 CD3+/kg. Of the 79 recipients, 34 (43%) had standard risk disease, and 45 (57%) recipients had high-risk disease. At a median follow up of ~ 5 years, overall survival (OS) was 42.9% and nonrelapse mortality (NRM) was 32.9%. In the initial analyses we eliminated pre-transplant ECOG, ferritin, ALB, PAB, ALC and EBMT. The independent pre-transplant comorbidity variables identified for further testing were HCT-CI, CRP and LMR. We demonstrated that LMR and HCT-CI score are important independent clinical predictors of OS and NRM in TCD HCT. In univariate analysis of OS, significant factors were HCT-CI scores ≥ 5 (Hazard ratio (HR) 2.125, p= 0.018), CRP (HR=1.016, p=0.058, a trend) and LMR ≤ 1.3 (HR=2.054, p= 0.036). In multivariate models of OS, CRP (HR 1.02, p= 0.029), HCT-CI≥5 (HR 1.966, p= 0.04) and LMR ≤1.3 (HR 2.206, p= 0.029) retained significance. Further refinement of the multivariable model was made by classifying the LMR into a low-risk group (LMR 3-25) versus high-risk groups (LMR< 3 or > 25), then the significant factors were HCT-CI ≥5 (HR 3.008, p= 0.002), LMR < 3 (HR=3.292, p= 0.0014) and LMR > 25 (HR=5.648, p= 0.0008) compared to the LMR 3-25 group. In multivariable analysis of NRM, significant factors were HCT-CI ≥5 (HR 3.283, p= 0.015), LMR < 3 (HR=5.891, p= 0.0008), and LMR > 25 (HR=9.008, p= 0.0011) compared to the LMR 3-25 group. To evaluate the relevance of these factors in predicting the 5-year mortality and NRM beyond traditional risk indicators, we used the continuous net reclassification improvement (NRI) and the C-statistic (area under the receiver operating characteristic (ROC) curve). LMR was found to be the most important risk predictor for both OS and NRM (NRI was 84% and the C-statistic was improved from 0.59 to 0.68 with the addition of LMR to the multivariate model for OS; NRI was 108% and the C-statistic was improved from 0.57 to 0.72 with the addition of LMR to the multivariate model for NRM). Based on our results, we propose a simple novel predictive score for CD34+ selected myeloablative transplantation calculated by summation of scores derived from the HCT-CI [≤4 =Score 0, ≥5=Score 1] and LMR [3-25= Score 0, <3=Score 1, >25=Score 2]. The scores [range, 0 to 3] differentiate three risk groups for hematopoietic cell transplantation OS (p=0.001) and NRM (p=0.004). In conclusion, this is the first study to explore pre-transplant comorbidity measures after TCD HCT, identifying HCT-CI and LMR as critical predictors of OS and NRM.

Clinical comorbidity measures enhance the estimates of HCT tolerance and outcomes, thereby aiding therapeutic decisions. Ex vivo T cell depletion (TCD) of the graft reduces the risk of graft-versus-host disease and improves the tolerability of allogeneic transplantation in patients with impaired pretransplant performance. However, prediction tools such as the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), have only been validated in conventional T-replete HCT. To improve outcome prediction in TCD transplants we therefore evaluated published comorbidity measures and other potential biomarkers of outcome in a series of myeloablative TCD transplant recipients. Pre transplant (week -2) factors measured were: HCT-CI, ECOG performance status, serum C-reactive protein (CRP), albumin (ALB), pre-albumin (PAB), ferritin, absolute lymphocyte counts (ALC), and absolute lymphocyte / monocyte ratio (LMR). CRP was also studied serially post transplant. CRP increased after conditioning, peaked (p =0.0001) in the first week of HCT, with recovery to baseline at 5 weeks post-HCT. We evaluated outcomes in a cohort of 79 patients in our institute with hematological malignancies receiving myeloablative total-body irradiation, and an HLA-identical sibling peripheral blood HCT, T cell depleted using Miltenyi CD34+ selection. The median age of recipients was 43 years (range 13-68 years). Of the 79, 34 (43%) had standard risk disease, and 45 (57%) recipients had high-risk disease. At a median follow up of ∼ 5 years, overall survival (OS) was 42.9% and nonrelapse mortality (NRM) was 33.9%. Comorbidity measures were first screened to eliminate highly-correlated covariates. Univariate Cox regression models were used to identify significant factors (p<0.05) associated with OS and NRM (with relapse as a competing risk), which were then further evaluated by multivariable Cox regression models. In the initial analysis we eliminated pre-HCT ECOG (94% were ECOG 0) and ferritin (median 1408 mcg/L, range 11-1444), which were highly correlated (p =0.003) to the HCT-CI score (median 3, range 0-9). Similarly, ALB (median 3.9 g/L, range 2.1-5.1, p = 0.002), PAB (median 25.6 mg/dL, range 6.9-56, p =0.001) and ferritin levels (p =0.005) were excluded as highly correlated to the pre-HCT CRP (preCRP) (median 5.8 mg/L, range 0.92-96.8). CRP levels measured at 2 weeks post transplant (postCRP) (median 10.4 mg/L, range 1.9-180) and ALC (median 0.96 K/uL, range 0.02-104.6) were not correlated to the pretransplant CRP. The independent pretransplant comorbidity variables identified for further testing were HCT-CI, preCRP, post CRP, ALC and LMR. In univariable analysis of OS, significant co-variates were HCT-CI scores ≥ 5 (HR 2.09 p= 0.02), preCRP (HR=1.016, p=0.07, a trend), postCRP (HR=1.014, p<0.001) and LMR ≤ 1.3 (HR=2.04, p= 0.04). In multivariable models of OS, postCRP ≥ 15 (HR 2.39, p =0.009) and LMR ≤ 1.3 (HR 2.25, p =0.04) retained significance. Confining the model to pretransplant data, then significant factors were pre CRP (HR 1.024 p= 0.02), HCT-CI≥5 (HR 2.08 p= 0.03) and LMR ≤1.3 (HR 2.43 p= 0.02). In univariable analysis of NRM, only continuous postCRP and postCRP ≥10 were significantly associated with NRM (HR=2.5, p =0.03) and in multivariable modeling of NRM, only postCRP ≥10 (HR=2.57, p=0.04) or continuous postCRP (HR=1.018, p=0.004) was found to be significant. LMR ≤ 1.3 and ECOG > 0 were found to be significantly associated with the cumulative incidence of relapse (both p=0.01). In conclusion, this is the first study to explore comorbidity scores and biomarkers to predict outcome after ex vivo TCD HCT. Our results suggest that HCT-CI score, preCRP, postCRP and the LMR are important independent clinical predictors of OS and NRM in TCD HCT.