Differences Between Gvhd and GVL May be Rather Quantitative and Not Dependent on a Malignant Transformation of the Target Cell

The therapeutic potential of allogeneic stem cell transplantation (allo-SCT) in patients with malignant diseases of the hemato-lymphatic system is thought to depend apart from conditioning with high dose therapy on the anti-tumor effect provided by the immune system of the donor. However, the immune system of the donor may exert severe and difficult to control graft-versus-host-disease (GvHD). Efforts to dissect GvHD and graft versus-leukemia/lymphoma reactions (GvL) have remained dissatisfying. Here, we report immune reactions observed after allo-SCT suggesting that GvHD and GvL are related rather quantitatively and correspond with achieving 100% donor chimerism allowing the extinction of remaining host immune cells regardless whether malignant or not. Clinical findings: A patient wit relapsed T-PLL was treated with allo-SCT and received stem cells from a matched unrelated donor (MUD). After being in complete cytological and molecular remission she relapsed molecularly on day +351. The molecular analysis revealed malignant cells at the level of 0.16% in the blood. While alemtuzumab was used for bridging, on day +383 a first donor lymphocyte infusion (DLI) was applied. Despite a second and third DLI application later, a steady increase in the MRD level above 2x10-2 was noted. However, the fourth DLI application on could not be given because the patient had developed acute GvHD of the skin. At the same time MRD no longer was detectable by RQ-PCR with a detection limit below 1x10-5. GvHD resolved upon treatment and the patient is in continuous complete remission for more than 5 years. Likewise, a quantitative effect in the balance between donor and host immune cells was observed when a patient received an ABO blood group major incompatible graft from a MUD. Frequently, in those situations a delayed recovery of the major incompatible erythropoiesis is observed due to persisting isohemagglutinin producing donor cells. Here, even after complete tapering of the immunosuppression and therapeutic approaches including rituximab anemia persisted. After DLI application, the patient developed acute GvHD of the skin but consecutively the anemia resolved. Conclusion: In these informative situations DLI documented their efficacy in correcting a misbalanced immune system after allo-SCT. While in the MRD situation remaining tumor cells vanished with increasing doses of DLI exactly when first signs of GvHD occurred, in the ABO incompatible scenario few remaining host immune cells producing isohemagglutinins were eradicated with a small dose of DLI. This leads to the conclusion that donor immunosurveillance may be independent of whether the phenotype of the donor immune cells is malignant and that GvHD and GvL may be more a quantitative than qualitative effect.