Pre-Graft Immune Status Predicts Survivals and Relapse in Adults Receiving Matched Peripheral Blood Stem Cell Allotransplants for Myeloid Malignancies

Abstract

Background The impact on outcomes of pre-graft immune status has not been explored so far in recipients of allogeneic stem cell transplant (allo-SCT). Patients and Methods This was a retrospective and monocentric study including all consecutive adults who underwent a peripheral blood stem cell (PB) allo-SCT for a hematological malignancy between May 2017 and December 2021 in our Hematology Department. Immune status was routinely evaluated before transplant in each patient. Absolute lymphocyte (ALC) and monocyte counts were obtained from complete blood counts, while absolute counts of lymphocyte subsets (CD3+, CD4+ and CD8+ T cells, B and NK cells) were assessed by multiparameter flow cytometry, and gamma globulin levels by standard serum electrophoresis. We evaluated the impact of these parameters, considered as continuous variables, on overall survival (OS), progression-free survival (PFS), graft-versus-host disease (GVHD)-free, progression-free survival (GRFS), non-relapse mortality (NRM), and relapse incidence (RI), according to the type of the disease (myeloid vs. lymphoid) and the type of the donor (matched vs. haploidentical). Results This study included 264 patients with a median age of 59 years old (range 20-73, Table). A majority had a myeloid malignancy (75%, n=196) and received a graft from a matched donor (64%, n=170, sibling n=46; matched unrelated n=124) and a reduced-intensity conditioning regimen (80%, n= 211). Almost all (96%) patients with a matched donor received anti-thymoglobulin as GVHD prophylaxis while it was the case for 79% of those receiving a graft from a haploidentical donor. With a median follow-up of 32 months estimated by reversed Kaplan Meier analysis, 3-year (y) OS, PFS, and GRFS were respectively 53%, 46% and 31%, while 3-y NRM and RI were 28% and 25%, for the whole cohort. Pre-graft immune status was evaluated at a median of 20 days before transplant, showing significant higher median T and B cell counts and gamma globulin level in patients with myeloid malignancy, reflecting probably the less immunosuppressive intensity of chemotherapies received before transplant ( Table). Considering myeloid malignancies, OS and NRM were not impacted by the pre-graft immune status. In multivariate analysis, adjusting for disease type, status, donor type (sibling versus [vs] unrelated), and conditioning (RIC vs MAC vs sequential), a higher ALC was associated with significant lower PFS (hazard ratio [HR] 1.39, 95%CI: 1.11-1.74, p=0.004) and GRFS (HR: 1.30, 1.07-1.59, p=0.009), and a significant higher risk of relapse (HR 1.85, 1.32-2.59, p=<0.001), but this was true only in case of a matched transplant. Interestingly, T-cell subsets were associated with relapse (CD3: HR 1.94, p<0.001; CD4: HR 2.34, p=0.004; CD8: HR 2.34, p<0.001), but not B-cells (HR 2.23, p=0.56), gamma-globulin levels (HR 0.98, p=0.68), nor NK-cells (HR 2.72, p=0.17). T cell subsets, B cells, NK cells, gamma-globulin and monocytes were not associated with PFS and GRFS. Also, to highlight the adverse effect of an elevated ALC, and using a ROC curve, a threshold of 1.23 Giga/L was retained as the best cut-off to predict relapse. This was then applied to create a visual comparison of PFS, GRFS and RI ( Figure), revealing an early increased RI in patients with ALC > 1.23 Giga/L (3-month relapse rate: 13% vs 2.3%, p=0.03). Finally, the pre-graft immune status did not impact the outcomes of patients receiving a PB haplotransplant for a myeloid malignancy. This was true also for those who received a PB matched or again a haploidentical transplant for a lymphoid disease. Conclusions This retrospective analysis suggests that higher ALC at transplant predicts lower PFS and GRFS due to higher RI in adults receiving a PB matched transplant for a myeloid malignancy. Patients with a myeloid malignancy had also a better immune status at transplant which may reflect less immunosuppressive treatments received before transplant. Paradoxically, this better immune status may interfere with allogeneic T lymphocytes by reducing the graft-versus-leukemia effect. Thus, increasing immunosuppression (via the conditioning or drugs used for GVHD prophylaxis) may improve outcome in some specific sub-groups of patients with higher autologous T lymphocytes at transplant.