Post-Transplantation Cyclophosphamide Versus Low Doses ATG Fresenius As Part of Two Immunosuppression Regimens for Graft Versus Host Disease Prophylaxis: Low Severe Graft Versus Host Disease (GVHD) Incidence and y Similar Gvhd-Free and Relapse-Free Survival (GRFS)
Authors: Fernández Martínez Cristina , Bermúdez Arancha , García Ávila Sara , San Pedro Borja , Cabero Martínez Almudena , Yáñez Lucrecia , López Duarte Mónica , Colorado Mercedes , González de Villambrosia Sonia , Mora Joan Manuel , Gonzalez Romero Yolanda , Gomez David , Fenandez Luis Sara , Ormazabal Irati , Insunza Andrés , Romon Iñigo , Arroyo Jose Luis , Conde Eulogio , Richard Carlos 
Published: October 2019

Abstract
BACKGROUND AND OBJECTIVES.
Post transplantation High dose Cyclophosphamide (PTCY) used in haploidentical hematopoietic transplantations, has a high effectivity in acute Graft versus Host Disease (aGVHD), and chronic Graft versus Host Disease prophylaxis (cGVHD), however it is associated with high relapse rates. On the other hand, Anti-T-Lymphocyte Globulin (ATG-Fresenius ®) is also effective as immunosuppressive (IS) drug, but its benefit on Overall Survival (OS) and Relapse Free Survival (RFS) is unclear.
The aim of this study was to compare the effectiveness of two GVHD prophylaxis regimes used in high risk transplantation: PTCY used in Haploidentical transplantation and ATG used for peripheral blood, non-related, related and mismatched donors.
The primary endpoint was to evaluate the incidence of aGVHD and cGVHD, and its severity in both groups. As secondary endpoints we analyse the OS, RFS and GRFS (recorded adverse events include grade 3-4 aGVHD, systemic therapy-requiring cGVHD, relapse or death during median follow-up). We also consider transplantation related mortality (TRM) and post-transplantation complications.
PATIENTS AND METHODS.
We retrospectively analyse 111 allo-transplantations performed at our institution between 2012 and 2017. We analyse two cohorts: 49 haploidentical transplantation with PTCY (50 mg/kg, on day +3, +4) followed by Tacrolimus and Mycophenolate; and 62 peripheral blood related, non-related and mismatched with low dose ATG Fresenius (7mgr/Kg on days -3, -2, -1) associated with Tacrolimus/Cyclosporine starting on day -1 with a short course Methotrexate (on day +1, +3, +6) or Mycophenolate. Mycophenolate was stopped on day +28 and Cyclosporine or Tacrolimus were tapered on day +50.
RESULTS.
There were no differences in patients' age (49 vs 51), sex or pre-transplantation HCTI-score ≥ 3 (30 vs 26) between PTCY and ATG groups. We found differences between diagnosis (lymphoproliferative disorders (16 vs 4, p= 0.003), high DRI-score (18 vs 11, p = 0.04), number of previous transplantations (12 vs 5, p= 0.02), reduced intensity conditioning regimen (36 vs 20, p < 0.001) and bone marrow as stem cells source (38 vs 9, p < 0.001) between PTCY and ATG groups.
The median time to neutrophil engraftment (>500/uL) was similar: 17 days [13-34] for PTCY and 16 days [9-33] for ATG. Median time to platelet recovery was higher in PTCY cohort (33 vs 18 days, p= 0.016). There were 3 secondary graft failures in PTCY group vs 4 graft failures in ATG (3 primary, 1 secondary).
The were no differences in grade 2 - 4 aGVHD incidence between groups (PTCY:30.6% vs ATG:36.4%), but we found differences in grades 3 - 4 aGVHD (PTCY:4.1% vs ATG: 9%, p=ns).
The global incidence of any NIH grade cGVHD was 56.1% in PTCY vs 66% in ATG group. Mild, moderate and severe cGVHD incidence were 31.7%, 19.5% and 4.8% for PTCY vs 28%, 26% and 12% in ATG (p=ns).
The median duration of IS in alive patients with cGVHD was 6.5 months [3-19] in PTCY patients and 10 [3-34] in ATG group. Among moderate and severe forms, the median IS duration was 10 and 5 months in PTCY group vs 13 and 12 months in ATG respectively.
PTCY cohort developed more non-infectious complications, especially, cardiac, lung, digestive and neurologic complications, (p=0.086), however there were not differences in infectious complications (Table 1).
TRM was similar between groups, 18.4% for PTCY vs 22.5% for ATG, (p=0.250). We didn´t find differences in early toxic mortality (<100 days): 16.3% for PTCY and 14.5% for ATG (p=0,421).
With a median follow-up of 27 months in alive patients (28 months for PTCY and 22 months for ATG) we report an 67.8 % and 61% OS at 12 and 24 months for PTCY and 68.8% and 59.9% for ATG (Log Rank=0.971). Relapse free survival at 12 and 24 months was 61% and 57.9% for PTCY and 69% and 54% for ATG (Log Rank=0.839).
GRFS at 12 and 24 months was 46.5% and 42.9% for PTCY patients and 40.7% and 33% for ATG patients, (Log Rank = 0.433).
CONCLUSIONS.
Regardless the different scenarios between transplantation cohorts, the use of PTCY and low dose ATG are equally effective in the prophylaxis of severe forms of aGVHD and cGVHD, offering similar GRFS. PTCY shows higher early toxicity but a similar rate of infectious events. In order to validate these results, it would be necessary to carry out a randomized controlled trial.

Disclosures
No relevant conflicts of interest to declare.