Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation.
Authors: Ciurea Stefan O. , Qureshi Suhail , Rondon Gabriela , Pesoa Susana , Cano Pedro , McMannis John , Giralt Sergio , de Lima Marcos , Fernandez-Vina Marcelo , Champlin Richard E. , Gajewski James 
Published: October 2019

BACKGROUND: Haploidentical stem cell transplantation (HaploSCT) using mega-doses of CD34 cells and a T-cell depleted allograft has generally been performed in advanced hematologic malignancies using a fractionated TBI-based conditioning regimen (CR) with very high toxicity. Here we evaluated the results of a reduced intensity chemotherapy-only conditioning regimen (RIC) with fludarabine (F), melphalan (M) and thiotepa (T) for HaploSCT.

METHODS: 24 patients (pts) with advanced hematologic malignancies (18 with AML/MDS, 3 with ALL, 2 with CML and 1 with T-cell lymphoma underwent HaploSCT from related donors at MDACC between 10/2001 and 04/2007. The median age was 36 years. At the time of transplantation 15/24 pts (63%) had relapsed or primary refractory disease and 37% were in remission. Pts received a median of 10.8x10e6 CD34 cells. The median number of CD3 cells infused was 1x10e4/kg. The number of allele mismatch was 3/10 in 4 pts, 4/10 in 10 pts, 5/10 in 9 pts and 6/10 in 1 pt. HLA antibody (AB) specificity was determined using fluorescent beads coated with single antigens and detected in a Luminex platform. The CR consisted of M 140 mg/m2 on day −8, T 10 mg/m2 on day −7, F 160 mg/m2 over 4 days on days −6, −5, −4, −3, and 1.5 mg/kg of rabbit ATG a day x 4 on days −6, −5, −4, and −3 (FMT). No GVHD prophylaxis and no growth factors were administered. The pts were evaluated for engraftment and 100-day transplant-related mortality (TRM).

RESULTS: 23 pts were evaluable for engraftment. 1 pt died on day 27 due to respiratory failure. 19/23 pts (83%) engrafted with hematopoietic recovery with donor-derived cells. 18 pts achieved a full donor chimerism while 1 had progressive leukemia. Neutrophil recovery to ANC >0.5 x 10e9/l occurred after a median of 13 days and platelet recovery to >20 x 10e9/l occurred after a median of 13.5 days. 4 pts failed to achieve primary engraftment, presumably due to rejection. No statistically significant correlation was found between graft failure (GF) and KIR-ligand mismatch (KIR-LM). In fact KIR-LM were more common in the group of pts who engrafted (7/19) than in pts with GF (1/4). After 09/2005 when anti HLA AB were started to be done, 3/14 pts had GF, 2 of which had donor directed AB. The regimen was relatively well tolerated; 4 pts experienced grade 4 nonhematologic, organ toxicities. Cumulative day 100 TRM was 25%. 19/24 pts (79%) were in CR after transplant with 6 surviving at the last follow-up (OS 25%). Only 1 pt developed aGVHD (4.1%) and 5 pts developed cGVHD (20.8%) with 3 experiencing extensive GVHD. 9 pts (37.5%) relapsed after a median of 71.5 days post transplant. The distribution of KIR-LM in the GVH direction was similar in pts with and without relapse (3/9 pts with relapse and 5/15 pts without relapse). Causes of death were disease relapse in 9 pts, infections in 3 pts, pulmonary failure/MOF in 4 pts and cGVHD in 1 pt.

CONCLUSIONS: The reduced intensity FMT regimen was sufficiently immunosuppressive to support rapid engraftment after HaploSCT in 83% of pts with advanced hematologic malignancies. In this small series, KIR-LM in the HVG or GVH direction were not associated with graft rejection or malignancy relapse. The role of anti-HLA AB need further evaluation. The rate of toxicity and 100-day TRM appears lower as compared with published studies of TBI-based CR. The FMT RIC merits further evaluation in studies of HaploSCT.