Novel treatment for refractory acute myeloid leukemia

Donald Thomas and colleagues from Seattle presented the results of bone marrow transplantation in 100 patients with end stage leukemia in 1977 (1). The patients were conditioned with 10 Gy total body radiation (TBI) and 120 mg/kg of Cyclofosfamid (CY). Thirteen patients were long-term survivals. Since then, allogeneic stem cell transplantation (ASCT) has developed into a routine established treatment for hematological malignancies, mainly leukemias. Results have steadily improved, especially in patients with acute leukemia in remission (2, 3). However, for patients with refractory disease or in relapse, results have been dismal despite the use of a variety of conditioning regimens prior to transplantation (4, 5). Apart from the standard regimen of TBI and CY, CY combined with busulphan has been successfully applied in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) with similar outcome (6–9). For patients undergoing ASCT for leukemia, relapse has been the most common cause of death. Therefore, increased intensity conditioning using higher TBI doses or addition of other cytotoxic agens, for instance etoposid, melfalan etc., have been used to the decrease risk of relapse (4, 10, 11). However, more intensified conditioning regimens have resulted in an increased risk of toxicity including veno-occlusive disease of the liver, obstructive broncheolitis, severe oral mucositis, hemorrhagic cystitis, etc. To reduce toxicity, in more recent years nonmyeloablative or rather reduced intensity conditioning (RIC) have been used as an alternative to the more heavy protocols (12–14). With myeloablative conditioning, the goal is to try and kill the last leukemic cells. With RIC, the goal is to immunosuppress host immune reactivity and prevent rejection of the transplanted donor cells. Thereafter, the donor cells should take over and induce the graft vs. leukemia (GVL) effect. It is well known from several studies that the donor immune system may control recipient cancer. Graft vs. host disease (GVHD), especially chronic GVHD, has a profound anti leukemic effect (15–17). Also acute GVHD have a GVL effect and the best leukemia-free survival (LFS) is seen in patients with grade I acute GVHD (16–18). T-cell depletion of the bone marrow graft, which prevent severe GVHD, was also found to increase the risk of relapse, especially in patient with CML (19–21). Furthermore, twins undergoing ASCT run a higher risk of relapse than human leucocyte antigen (HLA)-identical siblings (5, 22). However, in identical twin bone marrow transplants for leukemia, a high nucleated cell dose may decrease the risk of relapse and improve survival (23). High nucleated cell dose transplants include more T-lymphocytes, which might induce syngeneic GVL in the absence of clinical GVHD. In ASCT for aplastic anemia and hematological malignancies, a high marrow cell dose was found in several transplant studies to be variously associated with improved survival and a decreased risk of graft rejection, relapse, death from GVHD, invasive fungal infections and cytomegalovirus (CMV) disease (24–28). A recent study from the International Bone Marrow Transplantation Registry (IBMTR) showed that using bone marrow, a CD34 cell dose above the median >3 · 10/kg improved transplant related mortality (TRM) and thereby leukemia-free survival (LFS) (29). In recipients of peripheral blood stem cells (PBSC), a dose above the median of CD34 cells (>6 · 10/kg) was associated with a decreased risk of relapse and an improved LFS. Thus, a higher donor cell dose, because it contains a higher CD34 cell dose and also more T-cells, may provide a faster engraftment, immune reconstitution and a more potent GVL effect. Furthermore, using PBSC, chronic GVHD, which has a potent GVL effect, is more common than using Pediatr Transplantation 2003: 7: 422–425