Efficacy and Safety of Donor Lymphocyte Infusion after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for pediatric patients with high-risk malignancies and genetic diseases. However, relapse and graft rejection remain major reasons for treatment failure. Donor lymphocyte infusion (DLI) is a promising strategy to enhance graft-versus-leukemia (GVL) effect and increase donor chimerism. However, DLI can cause graft-versus-host disease (GVHD). This study describes the successful long-term use of DLI with a gradual dose increase to balance efficacy and safety.

Methods: We included 34 pediatric patients (20 male, 14 female) who underwent allogeneic HSCT at a median age of 6.5 years in a single center. The underlying diseases were genetic diseases (n=11), acute lymphoblastic leukemia (ALL) (n=10), acute myeloid leukemia (AML) (n=6), juvenile myelomonocytic leukemia (JMML) (n=2), chronic myeloid leukemia (CML) (n=1), myelodysplastic syndrome (n=1) and solid tumors (n=3). Based on the reason for DLI administration we defined a preemptive cohort (n=23), a prophylactic cohort (n=6), and a therapeutic cohort (n=5). Patients of the preemptive cohort were divided into those receiving DLI because of reappearance of minimal residual disease (MRD) in patients with hematological malignancies (n=12) and those with mixed chimerism in patients with genetic disease (n=11). The prophylactic cohort included six patients with a very high risk of relapse. The therapeutic cohort consisted of four patients who suffered from hematological relapse and one patient who was affected by recurrent autoimmune hemolytic crises. All patients received at least two doses of DLI from the donor who provided the hematopoietic stem cells. We started the administration of DLI at a median of four months after HSCT with a median DLI dose of 1.0 x 10⁵ CD3 cells/kg and increased in half log dose increments to a maximum of 3.2 x 10⁷ CD3 cells/kg. All patients were closely monitored for symptoms of GVHD according to the classification by the Mount Sinai Acute GVHD International Consortium. We increased the DLI dose only in the patients who tolerated the previous dose without any symptoms of GVHD and administered DLI monthly with a median number of eight infusions (range: 2-48).

Results: In the preemptive cohort, we were able to prevent hematological relapse in ten of the twelve MRD-positive patients (83%) by using DLI. Because of high MRD load in patients with ALL, DLI was combined with either blinatumomab, inotuzumab ozogamicin or zoledronic acid, which promotes γδ T-cell cytotoxicity. We successfully added ponatinib to DLI in one patient with CML who became BCR-ABL fusion transcript positive after HSCT. Two patients suffered from hematological relapse despite DLI administration. We treated eleven patients with genetic disease and mixed chimerism who were at risk for graft rejection with preemptive DLI. In total, nine patients (82%) responded with either increasing donor chimerism above 95% (n=6) or stable mixed chimerism (n=3) at a median of 70%. The remaining two patients had to be retransplanted. All six patients (100%) of the prophylactic cohort had a successful outcome without relapse or GVHD. One of them who suffered from relapsed JMML before HSCT received azacytidine in addition and another patient with pulmonary relapse of Ewing sarcoma before HSCT received zoledronic acid additionally. Three of the five patients (60%) of the therapeutic cohort were successfully treated with DLI. We administered sorafenib in addition to DLI in two patients with relapsed AML and achieved molecular remission in both cases. The remaining two patients with relapsed AML did not respond. The fifth patient of the therapeutic cohort, affected by recurrent autoimmune hemolytic crises, was successfully treated with DLI. We observed acute GVHD (grade I and II) in only two patients (6%) who could be cured with immunosuppressive therapy.

Conclusions: In conclusion, the results of our study indicate that DLI is a promising strategy if administered in a preemptive, prophylactic and therapeutic cohort. DLI can effectively prevent relapse, graft rejection, and even cure relapse. The observed high response rates in our three cohorts may be attributed to the long-term use of DLI. We increased the DLI doses gradually and observed a very low rate of GVHD. Therefore, we consider DLI as a safe and highly effective therapeutic option to enhance GVL effect and increase donor chimerism.