Tacrolimus (FK) Compared to Cyclosporine a (CyA) after Haploidentical T Cell Replete Stem Cell Transplantation (Haplo-SCT) with Post-Infusion Cyclophosphamide: A Retrospective Analysis
Authors: Castagna Luca , Bramanti Stefania , Furst Sabine , Sarina Barbara , Crocchiolo Roberto , Giordano Laura , El Cheikh Jean , Granata Angela , Morabito Lucio , Mauro Elisa , Faucher Catherine , Mothy Bilal , Harbi Samia , Chabannon Christian , Carlo-Stella Carmelo , Santoro Armando , Blaise Didier 
Published: October 2019

Abstract

Introduction. Investigators from Johns Hopkins University pioneered the use of post-transplantation cyclophosphamide (PT-Cy) after T cell-replete haploidentical bone marrow (BM) infusion. A significant component of this scheme is tacrolimus (FK), associated to mycophenolate mofetil (MMF), to prevent immunological complications. FK is a calcineurin inhibitor, almost 100-fold more potent than cyclosporine A (CyA) in its inhibitory activity.
In this retrospective study, we analyzed 100 patients grafted with Haplo-SCT with PT-Cy, and receiving FK or CyA.
Patients and Methods. From April 2009 until April 2013, we analyzed 100 consecutive patients at two institutions (Institut Paoli Calmettes Marseille, France and Humanitas Cancer Center, Rozzano, Italy). Conditioning regimen was identical consisting of Fludarabine, Cyclophosphamide, and low dose TBI. GVHD prophylaxis consisted of Cy 50 mg/kg on days +3 and +4, FK or CyA and MMF. FK (at a total dose of 1 mg) was administered as a continuous infusion and then converted to oral formulation. CyA was dosed at 3 mg/kg as a continuous infusion and was then converted to oral formulation. MMF was administered at 45 mg/kg/day until day +35. FK, CyA and MMF were started on day +5. FK and CyA were tapered by day +100-180. Stem cell source was BM or peripheral blood stem cells (PBSC).
Results. Patient and transplant characteristics are shown in Table 1. The cumulative incidence of engraftment was similar between FK and CyA groups: 30-days absolute neutrophil count > 500 was 79% vs 91% (p 0.3), and unsupported platelet count more than 20 000 at 60 days was 77% vs 84% (p 0.7), respectively.
The incidence of grade 2-4 acute GVHD was 26% vs 30% (p 0.5) and the incidence of chronic GVHD was 13% vs 8% (p 0.9), respectively. The 2-year progression free survival (PFS) and overall survival (OS) were 53% vs 64% (p 0.2) and 65% vs 65%, respectively (p 0.7). The 2-year relapse incidence (RI) was 28% vs 12% (p 0.08) and the 2-year non relapse mortality was 16% vs 14% (p 0.7), respectively. In univariate analysis, only disease status (CR vs not CR) impacted the PFS, OS, and RI.
Patients were regrouped in 3 cohorts (1 patient excluded because received FK + PBSC): FK + BM (n 42), CyA + BM (n 14), and CyA + PBSC (n 43). 1-year NRM was not different (17% vs 14% vs 15%, p 0.8). Compared to FK +BM and CyA + PBSC, a trend in favor of CyA + BM was observed in terms of aGVHD (7% vs 24% vs 38%, p 0.05) and cGVHD (0 vs 13% vs 10%, p 0.9).
Conclusions. Although this is a retrospective study with potential selection bias, using CyA instead of standard FK did not seem to affect any major clinical outcome, with special interest for aGVHD and cGVHD. The NRM is acceptable in line with that published. GVHD incidence was lower in the group CyA + BM compared to other 2 groups. Disease status before haplo SCT was the only prognostic factor for survival and relapse.
Table 1. Patient and transplant characteristics. All pts FK CSA p N % N % 100 43 57 Male Female 58/42 22/21 51/49 36/21 63/37 0.229 Age (mean) 46 44 48 0.135 Disease status at haplo 0.466 CR 56 23 53 33 58 PR 29 14 33 15 26 SD 6 1 2 5 9 PD 9 5 12 4 7 Armand Risk 0.646 Low 9 3 7 6 11 Int 72 33 77 39 68 High/Very high 19 7 16 12 21 Previous transplant <0.001 Relapse after ALLO 8 0 0 8 14 Relapse after HDC 40 21 49 19 33 Sex D/R 0.533 F/F 16 9 21 7 12 F/M 21 8 19 13 23 M/M 38 14 33 24 42 M/F 25 12 28 13 23 CMV D/R 0.009 POS/POS 70 35 81 35 61 NEG/NEG 18 2 5 16 28 POS/NEG 11 6 14 5 9 Donor 0.578 children 26 12 28 14 25 Mother 15 7 16 8 14 Father 11 6 14 5 9 Sibling 47 17 40 30 53 Cousin 1 Stem cell source <0.001 BM 56 42 98 14 25 PBSC 44 1 2 43 75 HCT-CI 0.007 0 31 18 42 13 23 1-2 23 13 30 10 18 >3 46 12 28 34 60 CD34 (mean) 4,4 3,5 5,2 <0.001

Disclosures
No relevant conflicts of interest to declare.