Donor Lymphocyte Infusion for Relapsed Hematological Malignancies After Allogeneic Hematopoietic Cell Transplantation: Prognostic Relevance of the Initial CD3+ T Cell Dose
Authors: Bar Merav , Storer Barry , Bruno Benedetto , Hari Parameswaran , Chauncey Thomas , Inamoto Yoshihiro , Martin Paul J. , Storb Rainer , Maloney David G. , Sandmaier Brenda M. , Flowers Mary E.D. 
Published: October 2019

Abstract
Abstract 354
Relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies. Relapse after HCT can be treated with donor lymphocyte infusion (DLI). Initial low dose DLI followed by escalating DLI doses has been used to minimize the risk of GVHD in patients with relapsed chronic myeloid leukemia. The impact of initial CD3+ cell dose on outcome after DLI in patients treated for other hematological malignancies is limited. We conducted a retrospective analysis of 225 patients with relapsed hematological malignancies after HCT treated with DLI over the last 20 years. The primary objective of this study was to determine the effect of the initial DLI CD3+ cell dose on graft-versus-host disease (GVHD) and overall survival (OS). Other potential risk factors for the development of GVHD (i.e. patient/donor gender, patient age, HLA-match, diagnosis, conditioning type, prior acute or chronic GVHD, donor chimerism, lymphocyte count, interval between transplant to DLI, and initial DLI TNC dose) and for survival after DLI (i.e. diagnosis, disease status at DLI, transplant conditioning type, time from transplant to relapse and to DLI, prior history of GVHD) were included in the analysis. For assessment of survival, patients were classified into a high risk group (AML, MDS, ALL, CML (BC, AP), high grade lymphomas (Hodgkin lymphoma, DLBCL, transformed NHL)) (n=145) or low risk group (CML-CP, CLL, MM, other lymphomas) (n=80). The median age of the cohort was 46 (range, 3–74) and 59% (n=132) were male. DLI was given for treatment of chronic myeloid leukemia (n=56), acute myeloid leukemia (n=71), myelodysplastic syndrome (n=25), acute lymphoblastic leukemia (n=21), multiple myeloma (n=23), lymphoma (n=21) and chronic lymphocytic leukemia/lymphoma (n=11). Patients received transplants from HLA-matched related (n=171) or unrelated (n=41) donors. Thirteen patients had HLA-mismatched donors. 58 patients (26%) received non-myeloablative conditioning regimens. The median time intervals were 11.3 months (range, 0–180) from HCT to relapse and 15.5 months (range, 21.1–215) from HCT to DLI. 144 patients (64%) received cytoreductive therapy before DLI, and 55 patients (24%) had complete remission at time of DLI. Initial DLI CD3+ cell dose/kg was ≤1×107 (n=84; Group A), >1.0 to <10 x107 (n=58; Group B), and ≥ 10×107 (n=66; Group C). Of the 225 patients, 86 (39%) developed GVHD after DLI. The median time to onset of GVHD after DLI was 39 days (range, 6–1029). The cumulative incidence (CI) of GVHD at 12 months after DLI was 39%. In the multivariate analysis, risk factors that were statistically significant for the development of GVHD after DLI included higher initial DLI CD3+ cell dose/kg with a hazard ratio (HR), 3.16; 95% CI, 1.7 to 5.9 (P=0.0003) for Group C and HR, 2.24; 95% CI, 1.2 to 4.2 (P=0.01) for Group B compared to Group A, and shorter interval between transplant and DLI with a HR, 3.38; 95% CI, 2.0 to 5.6; P <0.0001 for DLI less than one year after transplant. The CI of GVHD at 12 months after DLI were 21%, 45% and 55% for Groups A, B, and C respectively (Figure 1, Panel A). Acute or chronic GVHD before DLI and donor type were not statistically significantly associated with increased risk of DLI-associated GVHD. Initial DLI CD3+ cell/kg ≥ 10×107 was statistically significantly associated with an increased risk of overall mortality after DLI (HR, 1.84; 95% CI, 1.2 to 2.9; P=0.01) compared to lower doses. OS rates at 3 years were 47%, 45%, and 32% for Groups A, B, and C respectively (Figure 1, Panel B). Additional factors that had a statistically significant association with an increased risk of mortality after DLI included high risk disease (HR, 3.53; 95% CI, 2.2 to 5.7; P <0.0001), absence of complete remission state at time of DLI (HR, 2.17; 95% CI, 1.4 to 3.4; P =0.0008), and relapse within one year after HCT (HR, 2.42; 95% CI, 1.6 to 3.6; P <0.0001). A low initial CD3+ cell dose was not associated with an increased risk of relapse after DLI.
Our results show that an initial DLI CD3+ cells dose/kg ≥ 10×107 is associated with increased risks of GVHD and mortality after DLI, without reducing the risk of relapse. These findings are clinically relevant, since they support a recommendation to infuse less than 10×107 CD3 cell/kg as the initial cell dose of DLI for treatment of recurrent hematological malignancy after allogeneic HCT.
Figure 1. Cumulative incidence of GVHD and overall survival after DLI Figure 1. Cumulative incidence of GVHD and overall survival after DLI

Disclosures:
No relevant conflicts of interest to declare.