Non myeloablative conditioning in preparation for allogeneic stem cell transplantation: the future treatment of choice of hematologic malignancies and genetic diseases

Allogeneic bone marrow or blood stem cell transplantation (altoBMT) is commonly indicated for a large number of high risk hématologie malignancies and genetic diseases. The conditioning prior to alloBMT is based on myeloablative therapy aiming to eliminate tumor cells. Unfortunately, myeloablative chemoradiotherapy is associated with morbidity and mortality yet, relapse represents the major cause of failure. Considering the fact that the major therapeutic component of alloBMT is alloreactivity of donor derived T lymphocytes against hematopoietic cells of host origin and the fact that relapse following myeloablative chemoradiotherapy can still be frequently rescued by donor lymphocyte infusion (DLI). It appears rational to establish new protocols for alloBMT bated primarily on the use of the transplant procedure as a means to induce host vs graft tolerance to enable immunotherapy by donor derived T lymphocytes rather thin to as a means to accomplish physical elimination of tumor cells and of normal item cells during the short period of the conditioning. Non myeloablative regimen avoiding radiation therapy at our center consists of Fludarablne 30mg/m /6 days, busulfan 4mg/kg 12 days and ATG (fresenius) lOmg/kg 14 days. Patients received G-CSF mobilized blood stem cells from matched siblings using cyclosporine A (CSA) as anti-GVHD prophylaxis. Our protocol was extremely well tolerated among all patients with no mucosltii, some patients retained neutrophils throughout the post-BMT period and some never required platelet transfusions. Out of the first 25 patients (acute leukemla=9; CML-7: [1 juvenile and 1 In accelerated phase]; MDS-1; NHL-2; multiple myeloma=1; thalassemia msjor-2; Fanconi's anemia= 1; Blackfan's diamond tyndrome-1) observed over the last year, none rejected the graft. Only 2 patients were lost to GVHD; 1 was denied treatment due to technical reasons and 1 discontinued CSA due to late engraflment following ralnfuslon of blood stem cells with no CSA therapy. Of the patients maintained on CSA, only 1 had grade IV disease. As of to date, relapse was observed only In 1 patient wtth advanced resistant NHL but remission was relnduced with DLI. Based on our initial experience we concluded that conventional myeloablative therapy may not be required for eradication of disease, since Immunocompetent donor-derived lymphocytes can eradicate malignant and non malignant host-type clonogenelc cells much better and safer. We predict that allogeneic non-myeloablatlve stem cell transplantation (alloNST) will replace conventional myeloablative regimen with significant reduction of short and long-term procedure related toxlcity and mortality towards shifting the balance from myeloablative chemotherapy towards safer application of allogeneic cell therapy at an early stage of the disease.