Unmanipulated Haploidentical Marrow Transplantation with a Modified Post-Transplant Cyclophosphamide (PT-CY) Regimen: An Update on 444 Patients
Authors: Bacigalupo Andrea , Raiola Anna Maria , Dominietto Alida , Di Grazia Carmen , Bregante Stefania , Gualandi Francesca , Van Lint Maria Teresa , Chiusolo Patrizia , Laurenti Luca , Sora Federica , Giammarco Sabrina , Sica Simona , Angelucci Emanuele 
Published: October 2019

Abstract

Background. We have reported the use of two myeloablative regimens, for unmanipulated related haploidentical transplants (HAPLO) with post transplant cyclophosphamide (PT-CY) on 50 patients (BBMT 2013; 19: 117).
Aim of the study. The aim of the present study is to update the outcome of our HAPLO program on 444 patients grafted between 2011 and 2017, in two transplant Units (Genova and Rome Gemelli).
Patients. Patients were selected for HAPLO grafts in the absence of a suitable HLA matched related or unrelated donor. The median age of the patients was 52 years (14-74), and 106 patients were over 60 years of age. Remission status was as follows: CR1 (n=171), CR2 (n=112) and advanced disease (n=161). The median donor age was 34 years (18-67). The diagnosis was AML (n=154), ALL (n=87), MDS (n=83) , myelofibrosis (n=47), non Hodgkin lymphoma (n=31) other (n=44).
Conditioning regimens: we used 2 myeloablative conditioning regimens , one chemotherapy based (n=346) including Thiotepa, Busulfan, Fudarabine (TBF) as described (BBMT 2013), and one radiation based (n=99) with full dose radiation (999-1200 rads) (TBI) and fludarabine (BBMT 2013). The TBF regimen was used with full dose Busulfan 3.2 mg/kgx3, or 3.2 mg/kg x2 , for patients over 60 years of age. The median age for the TBF regimen was 55 years (18-74), whereas for the TBI it was 35 years (14-64) .
GvHD prophylaxis for all patients, was Cyclosporin (CsA) 2 mg/kg i.,v. starting day 0, mycophenolate 2 gr/day p.o, starting day+1 to day+30, PT-CY 50 mg/kg day +3 and day+5. When possible CsA was tapered starting day +100 and discontinued day +180. All patients received unmanipulated marrow as a stem cell source.
Failure to engraft: the proportion of patients rejecting the graft was 0% for patients receiving TBI, 2.7% for TBF (BU3 days) and 6.7% for TBF (BU2 days ). Fourteen patients received a second HAPLO graft with the Baltimore regimen, and 11 achieved trilineage recovery . Death due to rejection was overall 0.75%.
GvHD : The cumulative incidence of acute GvHD II-IV was 28% and of aGvHD grade III-IV 3%. The CI of moderate severe chronic GvHD was 18%.
Cross section study 1 year post HAPLO. At one year post transplant 88% of patients were off CsA and 83% were off steroids .The average Karnofsky score was 97%. Chronic GvHD was scored as absent (68,7%) minimal (24.8%), moderate (4.8%) and severe (1.4%). Chimerism was scored as full chimera, in 96% of patients.
Outcome. Non reapse mortality (NRM) at 4 years , was 16% for remission patients and 22% for patients with advanced disease (p=0.1). Relapse was 20%, 27%, 43% for patients in CR1, CR2, advanced disease (p<0.0001). Actuarial 4 year survival was 72%, 54, 35% for patients in CR1, CR2, advanced disease. Survival was comparable for remission patients receiving either TBF (BU3)(n=111, 72%) or TBF (BU2) (n=54, 64%) , despite a significant age difference (44 vs 61 years).
Conclusions. We confirm very encouraging outcome of a HAPLO program using myeloablative conditioning , a modified PT-CY day+3+5, and CsA starting on day0. Engraftment, GvHD and disease control have been have been consistent across different age groups and diagnoses. Post-transplant interventions for patients with advanced acute leukemia are being designed.

Disclosures
Angelucci: Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Celgene: Honoraria, Other: Chair DMC.