Immune Reconstitution and Clinical Outcome After Donor Lymphocyte Infusion for Relapsed Disease After Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Diseases Other Than Chronic Myelogenous Leukemia.

Considerable evidence suggests that immune responses after allogeneic hematopoietic stem cell transplantation (HSCT) play a major role in the prevention of disease relapse, called the graft-versus-tumor (GVT) effect. In patients who relapse after reduced-intensity conditioning (RIC) HSCT, donor lymphocyte infusion (DLI) may boost donor-T cell chimerism and induce a therapeutic GVT effect. Since the advent of imatinib mesylate for chronic myeloid leukemia (CML), DLI is now mostly given to patients with hematological diseases other than CML known to be less responsive to adoptive immunotherapy.

Our intent was to study the effect of infused T cell subsets on immune reconstitution and clinical outcomes such as acute and chronic graft versus host disease (aGvHD and cGvHD, respectively), overall survival (OS), and progression free survival (PFS) in patients with relapsed hematological malignancies other than CML who underwent RIC HSCT.

The DLI products given to 22 patients with relapsed/persistent hematological diseases (8 Hodgkin lymphoma, 4 myelodysplastic syndrome, 2 acute myeloid leukemia, 2 chronic lymphocytic leukemia, 2 Non-Hodgkin lymphoma, 1 acute lymphoblastic leukemia, 1 plasma cell myeloma, 2 polycythemia vera) who received matched related or unrelated DLI after HSCT were analyzed for CD3+, CD4+, and CD8+ T cell subsets. Patients were treated with a consistent RIC with fludarabine (120mg/m2 total) and intravenous busulfan (3.2mg/kg total) at our institution from 2005 to 2008. GVHD prophylaxis in the majority of patients (77.3%) consisted of tacrolimus, sirolimus and methotrexate. Peripheral blood (PB) obtained before and after DLI was analyzed for CD3+ CD4+, CD8+, CD19+, CD20+, and CD14+ cells. The lymphocyte subset contents of DLI and changes of patients' immune reconstitution before and after DLI were correlated with clinical outcomes such as aGVHD, cGVHD, OS, and PFS.

The 2-year OS and PFS after DLI were 41% and 22%, respectively, with a median follow-up of 1.1 years for survivors. The 2-year-relapse rate was 77.8%, but treatment-related mortality (TRM) was 0%. A complete response was achieved in 18% of the patients. The cumulative incidences of grade II-IV aGVHD and cGvHD were 9.1% at 200 days and 27.8% at 2 years after DLI, respectively. A significant decrease in CD4+ (p=0.01) and a significant increase in PB CD8+ (p=0.04) cell frequency were observed after DLI infusion. Infused total and lymphocyte subset cell dose had no effect on any of the clinical outcomes. Higher pre-infusion PB CD4+ (p=0.04, HR 0.89) and lower pre-infusion CD14+ cell (p=0.03, HR 1.09) frequencies in the recipient were associated with better OS. Lower pre-infusion CD14+ cell frequency was associated with better PFS (p=0.003, HR 1.19). In addition, increased pre-to-post DLI CD19 and CD20 frequencies were associated with PFS (p=0.03, HR=1.21; p=0.04, HR=1.16, respectively). None of the changes in immune parameters after DLI were associated with cGVHD.

Clinical responses to DLI in patients with relapsed hematological malignancies other than CML remain unsatisfactory, although the associated risk of GVHD and TRM are low. The dose of CD3, CD4 and CD8 cells in the DLI product was not correlated with clinical outcome. However, pre-infusion immune status and demonstration of significant changes in immune reconstitution after DLI can affect clinical outcomes. Strategies to modulate pre- and post-immune status of the recipients warrant further investigation to improve the efficacy of DLI.

No relevant conflicts of interest to declare.