Prophylaxis with ATLG Significantly Improves Chronic Graft-Versus-Host Disease / Relapse-Free Survival and Quality of Life after a Myeloablative HLA Identical Sibling Transplant for Acute Leukemia Patients in Complete Remission. Long-Term Follow-up of the Randomized ATG Familystudy

Introduction

Chronic GVHD is a major complication after allogeneic stem cell transplantation (HSCT) affecting both survival and quality of life (QoL). Several strategies are currently used to limit the incidence and severity of GVHD. All but one prospective randomized studies demonstrated in the unrelated and related settings a significant reduction of cGVHD when anti-T cell lymphocyte globulin (ATLG) or anti-thymocyte globulin (ATG) is added to the standard GVHD prophylaxis (cyclosporine and methotrexate) with significant improvement of survival free from relapse and cGVHD (cGRFS), similar overall survival and no increase of relapse risk. In the setting of sibling transplants, the ATGfamilystudy demonstrated that in acute leukemia patients in complete remission the addition of ATLG (Grafalon, NEOVII) at the dose of 10 mg/kg per day from day -3 to day -1 to the standard GVHD prophylaxis within a myeloablative conditioning regimen resulted in a significant reduction of cGVHD (68.7% vs 32.2% at two years), especially of the extensive form (52.4% vs 7.6%) without a significant increase of relapse, infection and non relapse mortality (NRM). Overall survival resulted similar in the two arms while cGRFS was significantly improved (37% vs 16.7%). The risk of relapse is claimed as the major concern for a broader adoption of ATLG in the GVHD prophylaxis and a longer follow-up is strongly claimed by the scientific community to definitely unravel the issue of disease recurrence after in vivo T cell depletion with ATLG.

Methods

We updated the follow-up of the trial NCT 00612875 (Kröger et al. NEJM 2016) and analyzed data of QoL. The primary endpoint was the CI of cGVHD. CI of cGVHD, NRM, relapse, overall survival, disease-free survival and chronic GVHD and relapse-free survival (cGRFS) were analysed. The trial included also quality of life (QoL) questionnaires (EORTC QLQ-30 and HDC29 ) before and after SCT. The QLQ-C30 includes a global QoL scale, 5 functional scales (physical, role, emotional, cognitive and social function) and 9 symptom scales (fatigue, nausea-vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial problems).

Results

Out of 155 patients analyzed for safety and efficacy in the randomized study 119 were still alive at study end after 2 years and 114 provided any follow-up data. The median observation time was 5.2 and 6.0 years, in the experimental and control arm, respectively, with a maximum follow-up time >10 years in both groups.

The CI of cGVHD overall was 31.3% (95% CI: 22.6% - 43.3%) in the ATLG arm vs 69.1% (95% CI: 59.1% - 80.7%) in the control arm (p <0.001); the CI of relapse was 36.6% (95% CI: 27.5% - 48.7%) and 23.9% (95% CI: 15.8% - 36.2%, p = 0.09). 5-ys overall survival, disease-free survival and cGRFS in the experimental and control arm were 61.8% and 67.1% (p=0.564), 53.6% and 61.7% (p=0.364), 40.4% and 18.1% (p = 0.001), respectively.

Patients who received ATLG showed significantly greater improvement of global health status / QoL over time compared to non-ATLG (p=0.02), with a difference between the two arms of 2.8 ± 3.9 points (marginal mean ± SEM) at day 100 and increasing to 10.5 ± 5.3 points at month 24 in favour of ATG. Patients in the ATG arm showed also a significant superiority in 4 of the 5 functional scales as well as for several symptom scales scores such as appetite loss, insomnia, nausea-vomiting and dyspnea. For the QLQ-HDC29, significant treatment effects favoring ATG were observed for side-effects on gastrointestinal effects and impact on family, impact of family, urinary frequency, helping to distinguish what is important in life.

Conclusions

This long-term follow-up of the ATGfamilystudy confirmed a significant benefit of ATLG in reducing chronic GVHD without significant increase of relapse in patients with acute leukemia undergoing HLA-identical sibling allogeneic peripheral stem cell transplantation resulting in a significant benefit in chronic GVHD/relapse-free survival with a significant improved quality of life.