Survival after T-Cell Replete Haploidentical Related Donor Transplant Using Post-Transplant Cyclophosphamide Compared with Matched Unrelated Donor (MUD) Transplant for Lymphoid Malignancies
Authors: Mussetti Alberto , Kanate Abraham Sebastian , Kharfan-Dabaja Mohamed A , Woo Ahn Kwang , DiGilio Alyssa , Ciurea Stefan O , Armand Philippe , Salit Rachel B. , Fenske Timothy S. , Smith Sonali M. , Sureda Anna , Bolanos-Meade Javier , Hamadani Mehdi 
Published: October 2019

Abstract

Background: The use of haploidentical hematopoietic cell transplantation (HCT) using post- transplant cyclophosphamide (PT-Cy), calcineurin inhibitors (CNI) and mycophenolate as graft-versus-host disease (GVHD) prophylaxis is rapidly increasing in patients (pts) lacking suitable HLA-matched donors. Herein we compare outcomes of haploidentical HCT using this GVHD prophylaxis with 8/8 allele-level MUD HCT.
Methods: Included are 917 adult (>18) lymphoma pts who underwent allogeneic HCT between 2008 and 2013. All pts received non-myeloablative or reduced-intensity conditioning regimens. The study cohort was divided into 3 groups; haploidentical (n=185), MUD without (w/o) antithymocyte globulin (ATG; n=491) and MUD with (w/) ATG (n=291). The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence (Cum-Inc) of acute GVHD, chronic GVHD, non-relapse mortality (NRM), relapse/progression (rel/prog) and progression-free survival (PFS). The study had an 83% power to detect an 11% difference in OS.
Results: The baseline characteristics are shown in Table 1. Pts in the haploidentical group received conditioning with Flu/CY/2Gy TBI and PT-Cy + CNI and mycophenolate as GVHD prophylaxis, while the two MUD cohorts received fludarabine-based (+ an alkylator or 2GyTBI) conditioning and CNI-based GVHD prophylaxis. Graft source was bone marrow in 93% of the haploidentical pts and peripheral blood in 94% and 91% of MUD w/o ATG and MUD w/ ATG pts, respectively.
The 28-day neutrophil recovery and platelet recovery were 94%, 97%, 97% (p=0.32) and 63%, 89%, 84% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups respectively. Cum-Inc of grade II-IV acute GVHD at day100 and chronic GVHD at 1 year was 27%, 40% and 49% (p=0.07) and 13%, 51% and 33% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups, respectively. On multivariate analysis (MVA) higher risk of chronic GVHD was seen in MUD w/o ATG (RR=5.85, 95%CI 3.96-8.64; p<0.0001) and MUD w/ ATG (RR=3.64, 95%CI 2.37-5.59; p<0.0001) groups relative to the haploidentical cohort. The 3 year NRM was 17%, 22% and 26% in the haploidentical, MUD w/o ATG and MUD w/ ATG groups (p=0.08), respectively. On MVA a trend towards higher NRM was noted in MUD w/ ATG cohort, RR 1.54 (95%CI 0.98 - 2.41, p=0.06), relative to the haploidentical group. Among the haploidentical, MUD w/o ATG and MUD w/ ATG cohorts the 3 year Cum-Inc of rel/prog was 36% vs. 28% vs. 36%, PFS was 47% vs. 49% vs. 38% and OS was 60%, 62% and 50% (Figure), respectively. MVA demonstrated no significant difference between the three groups in terms of rel/prog (p=0.27) and PFS (p=0.07). Compared to the haploidentical group, the two MUD groups did not have a significantly different mortality risk (inverse of OS; p>0.05), but compared to MUD w/ ATG, the MUD w/o ATG pts had a reduced mortality risk (RR=0.67; p=0.001). We tested for a transplant center effect on survival and found none.
Conclusion: With lower-intensity conditioning regimens the early (up to 3 years) survival outcomes are comparable between conventional MUD transplants (w/ or w/o ATG) and haploidentical HCT with PT-Cy approach. Chronic GVHD was significantly lower with haploidentical HCT. Prospective, randomized confirmation of these findings is necessary before wide spread adoption of haploidentical HCT over MUD transplants in lymphomas.Table 1.Haploidentical N=185 (%)MUD w/o ATG N=491 (%)MUD w/ ATG N=241 (%)p-valueAge @ HCT, median (range)55 (18-75)55 (19-74)55 (20-73)0.13Male sex118 (64)301 (61)163 (68)0.25White race149 (81)469 (96)227 (94)<0.001KPS ≥ 90145 (78)311 (63)153 (63)<0.001HCT-CI≥355 (30)175 (36)88 (37)<0.001Histology NHL Hodgkin139 (75) 46 (25)386 (79) 105 (21)193 (80) 48 (20)<0.001Months from diagnosis to HCT, median (range)31 (<1-255)34 (<1-342)32 (4-460)0.19High LDH @ HCT16 (31)31 (33)11 (27)<0.001BM +ve @ HCT6 (12)5 (5)2 (5)0.35Extranodal disease @ HCT18 (35)20 (21)6 (15)0.11Prior lines of therapy, median (range)3 (1-7)3 (1-12)3 (1-8)0.41Remission @ HCT CR PR Refractory Untreated / missing72 (39) 99 (54) 10 (5) 4 (2)215 (44) 215 (44) 55 (11) 6 (1)100 (41) 96 (40) 40 (17) 5 (2)0.02Disease Risk Index Low Intermediate High45 (24) 126 (68) 13 (7)199 (41) 263 (49) 48 (10)75 (31) 129 (54) 37 (15)<0.001Median follow-up, months (range)36 (5-73)35 (4-74)35 (<1-75)
Figure 1. Figure 1.

Disclosures
Armand: Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Sequenta, Inc.: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.