High Doses of Moternal Lymphocyte Infusions to Treat EBV-Associated Lymphoma in Pediatric Patients.

The ability of allogeneic T cells to effect anti tumor responses had greatly improved the outcome of malignant EBV-associated lymphoproliferations. But high doses of DLI (donor lymphocyte infusion) could arise severe GVHD (graft versus host disease), and affect clinical outcomes. Recently, we successfully treated four EBV-associated lymphoma children with high doses of DLI from their IPA (inherited paternal antigens)-positive mothers, with no obvious GVHD occurred, which indicated that high doses of maternal leukocytes infusions could be an effective and safe therapy for EBV-associated lymphoma.

Epstein-Barr virus (EBV) associated lymphoproliferative disorders(LPD) or hemophagocyticlymphohistiocytosis(EBV-HLH) in pediatric patients is classified into malignant lymphoma due to 2008 WHO International Working Formulation for lymphoma classification. In pediatric patients, cure is rarely get through conventional therapy such as chemotherapy. Approaches using adoptive immunotherapies offer very attractive alternative options for this subgroup of patients. The rationale for this strategy was that most EBV seropositive individuals have a high frequency of EBV specific precursors so that transfer of unmanipulated donor lymphocyte populations should be able to restore the immune response to EBV. However, these products may also contain a high frequency of alloreactive T cells so there is a significant risk of GVHD. Reciprocal cell traffic between mother and fetus during pregnancy gives rise to long-term postpartum fetal–maternal lympho-hematopoietic microchimerism (MC). Recent experimental evidence have suggested the association of MC with acquired immunologic hyporesponsiveness, which would benefit solid organ and hematopoietic stem cell transplantation. Some research have showed that mother-to-child transplantations involved significantly less GVHD and better outcome than father-to-child transplantations. Based on this fetal-maternal tolerance theory, we treated four EBV-associated lymphoma children with high doses of DLI from their mothers.

Our four patients were all developed with fever over than 6 months, accompanied with lymphadenopathy, hepatosplenomegaly, two of them with skin lesion. The diagnosis were confirmed by skin or lymphnode biopsies. EBV-DNA is positive in all of the patients' plasma at the quantitation of >1×10⁴ copies /ml. One of the patient had accepted chemotherapy in the past but got no remission. Using sex determining region Y chromosome (SRY) gene and insertion-deletion (InDel) polymorphism as fetal markers, child's DNA (IPAs) were detected through nested PCR and QT-PCR technology in all of the four mothers' blood at the level of 1: 10⁴-10⁵. With the approval of Ethics Committee, we treated these patients with infusions of unmanipulated leukocytes from their HLA-haploidentical, EBV-seropositive mothers. First at the doses below 10⁷ PBNC cells/kg, while no side effects occurred, we began infusing high doses of mother's PBMC at above 10⁸ PBNC cells /kg per time.

Clinical remissions were achieved in all of the patients within 3 to 10 days after the infusions, with remarkable reduction of the lymphnode and spleen, the EBV-DNA were undetectable in the patients' plasma. The remissions were sustained without further therapy for 5-10 months except one patient who got recurrance of lymphadenopathy and fever about two months after each infusion. We had monitored the quantitation of his mother's lymphocyte in the child's blood and found no detectable maternal MC a week after the infusion. During the process, none of our patients developed obvious GVHD.

High doses of maternal lymphocyte infusions could be an effective and safe treatment for EBV-associated lymphoma. Further research is needed to improve the sustained effect.

No relevant conflicts of interest to declare.