T-Cell Depletion Improves the Composite End Point Graft-Versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:             Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies. Unfortunately it is associated with significant morbidity and mortality related to cancer relapse and transplant complications, including graft versus host disease (GvHD). GvHD-free, relapse-free survival (GRFS) is a recently reported composite end point which allows estimating risk of death, relapse and GvHD simultaneously [Holtan et al., Blood 2015]. T-cell depletion (TCD) is a well established strategy for GvHD prevention, but is probably associated with increased risk of relapse. In the present work we investigated the effect of partial TCD (pTCD) on GRFS in order to evaluate its impact on patientsÕ morbidity-free survival.

Patients and methods: We performed a retrospective study on 333 patients who underwent allogeneic HSCT for hematologic malignancies at our center from 2004 to 2014 with grafts from HLA identical siblings or HLA 10/10 matched unrelated donors. 171 patients received pTCD grafts, obtained through incubation with alemtuzumab in vitro washed before infusion followed on day +1 by an add-back of donor T cells. 162 patients received T cell repleted (non-TCD) grafts. Donor lymphocyte infusions were given at three months to all patients without GvHD who had received pTCD grafts with reduced intensity conditioning and when needed to patients, transplanted with either pTCD or non-TCD grafts with mixed chimerism. Kaplan-Meier estimates were employed to determine the probability of 1-year and 5-year overall survival (OS), progression free survival (PFS) and GRFS. Events determining GRFS included grade 3-4 acute GvHD, systemic therapy-requiring chronic GvHD, relapse, or death. Differences between survival curves were determined using Log-rank Mantel-Cox test. Cox regression was used to examine the independent effect on OS, PFS and GRFS of clinical factors including age, underling disease, disease status at transplant, disease risk index, conditioning, donor type, stem cell source, year of transplantation and T-cell depletion. Cumulative incidence estimates of relapse and non-relapse mortality (NRM) were calculated with relapse or death from other causes defined as competitive events with the Fine and Gray method.

Results: According to institutional practices, the group receiving pTCD grafts comprised more patients transplanted in complete remission (67%) than the group receiving non-TCD grafts (41%, p <0.0001). Similarly, the pTCD group comprised fewer patients with a high/very high disease risk index (17%) than the non-TCD group (51%, p <0.0001). pTCD was associated with improved 1-year and 5-year OS and PFS in univariate analysis, but this association failed to reach significance in multivariate analysis taking into account clinical factors differing among patients groups. pTCD was associated with significantly improved GRFS (1y 53.2%, 95%CI 45.4%-60.4%; 5y 40.3%, 95%CI 32.5%-47.9%) compared to non-TCD transplantations (1y 36.6%, 95%CI 29.1%-44.0%, p<0.0001; 5y 24.1%, 95%CI 17.1%-31.9%, p<0.0001) [Figure 1]. The effect of pTCD on GRFS remained highly significant in multivariate analysis performed taking into account clinical factors including disease status at transplant and disease risk index (1y HR 0.624, 95%CI 0.440-0.884, p=0.0079; 5y HR 0.625, 95%CI 0.454-0.861, p=0.0040). No effect of pTCD was observed on relapse cumulative incidence (1y pTCD 37.4%, 95%CI 29.9%-45%, non-TCD 33.3%, 95%CI 26.3%-40.5%, p=0.317; 5y pTCD 49.4%, 95%CI 40.4%-57-9%, non-TCD 47.2% 95%CI 39%-54.9%, p=0.396), although this result may be the consequence of aforementioned differences in patient groups studied. Conversely, 1-year and 5-year NRM cumulative incidence was significantly decreased in patients receiving pTCD (1y 4.8% 95%CI 2.2%-8.7%; 5y 9.7%, 95%CI 5.6%-15%) compared to patients receiving non-TCD allogeneic HSCT (1y 12.5%, 95%CI 7.9%-18.2%, p=0.0098; 5y 15.9% 95%CI 10.5%-22.2%, p=0.0449).

Conclusion: pTCD appears to improve GRFS in allogeneic HCST recipients without significantly affecting OS and PFS. These results extend our knowledge about the effects of TCD on transplant-related morbidity and mortality, suggesting that pTCD could improve patientsÕ quality of life by reducing acute GvHD and NRM without impairing the curative potential of allogeneic HSCT.

Figure 1. Impact of pTCD on GRFS.