Adoptive Immunotherapy of Acute Leukemia and Acute Phase Chronic Myeloid Leukemia after Allogeneic Bone Marrow Transplantation

Abstract

Recurrence of leukemia after allogeneic hematopoietic transplantation presents a serious therapeutic problem. Chemotherapy and second transplants have been of limited value. In contrast, transfusion of lymphocytes from the original donor has induced remissions in more than 70% of patients with recurrent chronic myelogenous leukemia (CML) in chronic phase or cytogenetic relapse, in about 30% of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), and in about 10-15% of patients with acute lymphoid leukemia (ALL). In most CML patients remissions were lasting without further therapy, but in most patients with AML/MDS or ALL remissions were of limited duration. The differences in the response of CML, AML/MDS and ALL could best be explained by differences in antigen presentation. Indeed in CML dendritic cells are of leukemic origin as shown by FISH analysis. AML blasts may differentiate to dendritic cells in culture, but ALL blasts do not produce dendritic cells. More than 80% of fresh AML blasts do not express the co-stimulatory molecules B7.1 and B 7.2 and fail to stimulate allogeneic cells. However after culture in the presence of granulocyte-monocyte-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) cells of AML patients express co-stimulatory molecules and stimulate allogeneic cells. Another possibility to improve antigen presentation is the substitution of deficient antigen presenting by donor stem cells along with T-cells. Therefore we studied the transfusion of donor blood stem cells including T-cells and the treatment with GM-CSF after transfusion of donor cells in patients with recurrent AML, ALL and acute phase CML. Complete remissions could be induced in the majority of AML and some acute phase CML patients without intensive chemotherapy. Several patients remained in remission for a prolonged period of time. In ALL intensive chemotherapy was required for remission induction. Patients treated with intensive chemotherapy had a high risk of acute and chronic GVHD. These results confirm an allogeneic graft versus leukemia effect in acute leukemia and acute phase CML. They indicate an improvement of the response rate by the combination of PBSC and GM-CSF.