Dynamics and Predictive Value of T-Cell Chimerism after Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Background: T-cell chimerism after allogeneic hematopoietic cell transplantation (alloHCT) is an important tool to investigate T-cell reconstitution. Haploidentical HCT (haplo-HCT) using post-transplantation cyclophosphamide (PTCy) has been increasingly applied due to readily available donors and favorable outcomes. PTCy induces immune tolerance by depleting expansion of alloreactive T-cells. However, limited clinical data exist regarding the impact of PTCy on the dynamics of T-cell chimerism.

Methods: Adult patients receiving haplo-HCT with PTCy and reduced-intensity conditioning regimens were retrospectively reviewed. Patients with primary graft failure or receiving donor-lymphocyte infusion prior to +90 days were excluded. T-cell chimerism was measured from sorted CD3+ cells collected from peripheral blood or bone marrow at 1, 2, 3, 6, and 12 months. Complete chimerism was defined as < 5% donor T-cells. Patients were divided into full and partial T-cell chimerism groups based on their T-cell chimerism status at Month 1 and 3.

Results: From 1/2017 to 6/2021, 34 patients underwent haplo-HCT and met inclusion criteria (Table 1). One month post HCT, 29 (85.3%) patients achieved complete T-cell chimerism; 3 months post HCT, 31 (93.9%) patients achieved complete T-cell chimerism (Figure A). In univariate logistic regression analysis, peripheral blood rather than bone marrow as the donor source, and the occurrence of cytokine-release syndrome (CRS), were significantly associated with higher incidences of full T-cell chimerism at Month 1 (Table 2). In multivariable analysis, only the occurrence of CRS was significantly associated with full T-cell chimerism at Month 1 (odds ratio 18.7, 95% confidence interval [CI] 1.30 to 641, p=0.04, Table 2). Next, we investigated whether early achievement of full T-cell chimerism would affect clinical outcomes. After a median follow up of 363 and 530 days for patients with full and partial T-cell chimerism at Month 1, respectively, there was no significant difference of progression-free survival (PFS) (median PFS not reached v.s. 367 days, hazard ratio [HR] 0.54, 95%CI 0.14 to 2.07, Figure B) or overall survival (OS) (median OS not reached vs 530 days, HR 0.41, 95%CI 0.10 to 1.69, Figure C). In contrast, patients who achieved full T-cell chimerism at Month 3 had significantly longer OS than those with partial T-cell chimerism (median OS not reached v.s. 492 days, HR 0.18, 95%CI 0.03 to 0.90; p=0.04, log-rank test; Figure E). Of note, for the two deaths in the partial T-chimerism group, 1 died from relapse and the other from sepsis in the setting of Grade 4 acute graft-versus-host disease. Moreover, patients who achieved full T-chimerism at Month 3 had a trend of improved PFS over those with partial T-chimerism, although the difference was not statistically significant (HR 0.23, 95%CI 0.05 to 1.11; p=0.07; Figure D). Lastly, achieving partial T-cell chimerism at Month 1 or Month 3 was not associated with an increased risk of bacteremia (p=0.83 for Month 1; p=0.99 for Month 3; Chi-square test) or pneumonia (p=0.31 for Month 1; p=0.38 for Month 3), compared with those with full T-cell chimerism.

Conclusion: For patients receiving haplo-HCT with PTCy, the majority achieved full T-cell chimerism within the first month. The occurrence of CRS was associated with a significantly higher chance of achieving full T-cell chimerism at Month 1. Achieving a full T-cell chimerism at Month 3 was associated with significantly improved OS compared with those with partial T-cell chimerism. These data should be confirmed in a larger patient cohort.

Malek:Amgen: Speakers Bureau; AdaptiveBio: Consultancy, Honoraria; BMS: Speakers Bureau; Sanofi: Consultancy; Takeda: Consultancy, Speakers Bureau; GSK: Speakers Bureau; janssen: Consultancy; Karyopharm: Consultancy, Speakers Bureau. Metheny:Gamida: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. de Lima:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.