Low-dose alemtuzumab for GvHD prevention followed by prophylactic donor lymphocyte infusions in high-risk leukemia

Abstract

We analyzed the use of low-dose alemtuzumab in a cohort of 158 consecutive patients who underwent allogeneic PBSC transplantation. Patients with high-risk acute leukemia were prospectively screened for prophylactic donor lymphocyte infusion (pDLI). Lymphocytes were administered repeatedly at low and non-escalating doses (0.5-1 × 10/kg). Low-dose alemtuzumab was effective in prevention of acute GvHD after sibling or well-matched unrelated transplantation, whereas a more intensified approach was needed after mismatched transplantation. The cumulative incidence of chronic moderate/severe chronic-GvHD (cGvHD) was 15.6%. In total, 63 high-risk leukemia patients were eligible for pDLI. Only 1 out of the 39 pDLI recipients relapsed as compared with 7 out of the 24 recipients, who did not receive pDLI due to logistical hurdles. In multivariate analysis, the use of adjuvant lymphocyte therapy was significantly associated with reduced incidence of relapse and improved disease-free survival. In summary, low-dose alemtuzumab confers to a low cGvHD incidence and the administration of pDLIs in this context is very likely to reduce relapse risk in high risk leukemia patients. This is translated in an estimated 5-year probability of GvHD-free and relapse-free survival of 43.3% for the 136 leukemia patients.

How much immunosuppression do we need?

“…However, because this is the first comprehensive study proposing CD10 as a stratification marker for maturation state and suppressive potential of neutrophils, further investigations in independent patient cohorts are required to validate and extend these findings-especially in cancer, where a pathophysiologic role for suppressive neutrophils has been proposed. 8,9 The findings of Marini and coworkers are also of particular importance because they may help to explain previous findings on T-cell-suppressive effects in neutrophils defined by surface markers and segmentation status instead of by density. 5 Several aspects arising from this study require further investigation: (1) beyond G-CSF-treated patients, it remains to be defined how useful CD10 positivity is to characterize immunosuppressive neutrophils in different malignant and nonmalignant pathologies; (2) Marini and coworkers studied peripheral blood-derived neutrophils only and, accordingly, it remains to be defined whether CD10 also distinguishes neutrophil subtypes within tissue; (3) in contrast to the study by Marini et al, where mature neutrophils were T-cell-suppressive and immature counterparts T-cell-stimulatory, Solito et al reported previously that an immature promyelocyticlike population was responsible for the immune suppression mediated by MDSCs.…”

“…The immunosuppressionfree survival rates reported here cannot be compared with the ones reported in the ATG/alemtuzumab studies, which contain mainly recipients of peripheral-blood stem cells. [5][6][7][8] However, it is fair to say that the data presented here do suggest that control of GVHD, and especially of chronic GVHD, can be achieved in bone marrow-transplanted patients with PTCy given either alone or with the addition of modest amounts of pharmacological immunosuppression. These results compare favorably with the 41% to 53% expected incidence of chronic GVHD after sibling or unrelated T cell-replete BMT with the use of a standard methotrexate/cyclosporine combination.…”

Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia

“…Patients with persistent MC and AML or ALL not fulfilling the criteria for a high-risk definition were not included in this analysis. A percentage of the patients reported in our study have been previously presented in a manuscript, including patients from two academic centers [ 17 ]. However, the present study includes a much larger number of patients treated in a single institution, with the same protocol of DLI administration and with longer follow-up.…”