Ciclosporine and Metotrexate Reduce the Risk of High Grade Acute Gvhd after Busulfan, Fludarabine and Anti-Thymocyte Globulin conditioning Regimen in Comparison with Cyclosporine Alone
Authors: Tabrizi Reza , Vigouroux Stephane , Pigneux Arnaud , Leguay Thibaut , Bouabdallah Krimo , Dilhuydy Marie-Sarah , Foucaud Carine , Dumas Pierre-Yves , Lascaux Axelle , Zarrouk Mohamed , Boiron Jean-Michel , Bijou Fontanet , Turlure Pascal , Melot Cyril , Marit Gerald , Milpied Noel 
Published: April 2020

Abstract
We have performed a study in 137 adult pts who were transplanted with BFA (busulfan 8 mg/kg, fludarabine 150 mg/m^2 and ATG (Thymoglobuline Genzyme)) conditioning regimen in our centre between 11/1998 and 12/2007. The aim of the study was to evaluate the prognostic factors in this cohort of pts. The group consisted of 87 men and 50 women, median age was 54.5 yo (17–66). The diagnosis was AML (43), Myelodysplasia/Myeloproliferative disease (20), CML (2) (Myeloid group, MG: 65), ALL (14), Multiple Myeloma (MM: 30), Lymphoma (LYM: 28). Pts had received a median of 2 lines of treatment before transplantation (0–6). Sixty-four pts (47%) had previous autologous transplants (50 pts one and 14 pts 2 autologous transplants). At time of transplant, 80 pts were in CR, 38 in PR and 19 refractory or in relapse. The donor was a sibling for 85 and a MUD in 52 pts with HLA compatibility 10/10 in 37pts and 9/10 in 15 pts (2 one A mm, 2 one B mm, 10 one C mm and 1 one DQ mm). Graft consisted of PBSC in 128 pts, the median number of CD34 cells infused was 6.3 × 10^6/kg (0.92–25.47). The median of nucleated cells infused in 9 pts grafted with bone marrow cells was 1.5 × 10^8/Kg (0.71–3.42). The ATG dose was 2.5 mg/kg in 49, 5 mg/kg in 54 and more than 5 mg/kg in 34 pts. GVHD prophylaxis was with CSA in 67 pts, CSA-MTX in 70 pts. With a median FU of surviving pts of19 m (1.5–103 m) the 3y OS and PFS were 50 and 40% respectively. Four pts with refractory disease at transplantation had no engraftement. The remaining 133 pts experienced neutrophil recovery at a median time of 18 days (0–30), and platelet recovery at a median time of 11 days (0–130). Sixty-one pts died. The 2 main causal factors being: relapse in 37 of the cases (59%), GVHD and infection in 16 cases (26%). The probability of TRM at 100 days and 1 y were 6% and 15% respectively. The 3 y probability of relapse was 45%. 58 pts (42%) developed aGVHD (grade I–II, n=37, 27%; grade III–IV, n=21, 15%). One hundred and ten pts were evaluable for cGVHD. The incidence of cGHVD was 42% (46 pts) and the incidence of its extensive form was 18% (20 pts). Fourteen pts received DLI for progressive disease (6 MM, 3 AML, 2 follicular Lymphoma, CLL, HD, ALL 1 each). The complete remission was obtained in patients with follicular lymphoma and CLL. Only one pt with MM reached the CR post Mel 100 and DLI. Two pts received the DLI for mixed chimerism with successes. The OS and PFS at 3y were significantly higher in patient who had a cGVHD, disease in CR, received higher than median of CD34, and without grade III–IV aGVHD (p&lt;0.05). The study revealed that the dose of ATG has little influence on PFS (2.5mg/kg: 44%, 5 mg/kg: 48%, &gt;5mg/kg: 26%) (p=0.1). The multivariate analysis showed a significant association between OS and cGVHD (76 vs 43%), and grade III–IV aGVHD (56 vs 0%). PFS was significantly associated with the cGHVD (53 vs 37%), grade III–IV aGVHD (45 vs 0%), CD34 numbers (50 vs 30%) and dose of ATG. GVHD prophylaxis regiment with CsA alone (23 vs 10%) is the only factor increasing the incidence of grade III–IV aGVHD. In univariate analysis two factors associated with high risk of cGVHD were presence of all grade aGVHD and use of CsA alone in GVHD prophylaxis but in multivariate analysis only presence of aGVHD increase the cGVHD incidence significantly. In univariate analysis, the TRM was higher in pts with advanced disease, receiving lower doses of CD34 and with grade III–IV aGVHD. In multivariate analysis, high grade aGVHD (55 vs 11%) and low dose of CD34 (30 vs 10%) significantly increase the TRM. The relapse rate was high in patients receiving a high dose of ATG, low dose of CD34 (58 vs 36%) and without cGVHD (53 vs 38%) and in multivariate analysis, it depends on presence of cGVHD and number of CD34 infused. In this retrospective study, presence of cGVHD and number of infused CD34 cells were the most important factors influencing the outcome. This was borne out by their positive effect on both the OS ans PFS data. The primary cause increasing mortality in the study group was identified as relapse. The cGHVD reduced the relapse risk and increase the OS probably due to the Graft versus Disease reaction. These results show that prophylaxis of GVHD by CsA and MTX reduced the incidence of grade III–IV aGVHD, without affecting the incidence of cGVHD, and more than 5 mg/kg of ATG decrease the PFS.