Timing of Bone Marrow Transplantation in Leukemia Allogeneic transplantation in first remission, in general, is recommended as the standard approach for patients at high risk for relapse with conventional therapy. Without doubt, allogeneic transplantation provides the most efficacious anti-leukemic therapy due to the potent graft-versus-leukemia (GVL) effect, and data have confirmed that allogeneic transplantation

confers the lowest relapse rate for every subtype of AML. The high transplant-related Inhibitors,research,lifescience,medical morbidity and mortality is the only reason for not offering this to every patient with ALL or AML. In essence, this is a delicate balance between JAK phosphorylation efficacy and toxicity.16 One of the most important issues relates to the timing of transplant. The foremost question among practitioners and patients is, given the high procedural mortality, should such a procedure be preferably reserved for patients in second complete remission or at relapse? Such considerations are Inhibitors,research,lifescience,medical bolstered by data demonstrating reasonable survival if transplant is performed in second remission (Figure 12). Given the high non-relapse mortality in allogeneic transplantation, such transplantation may sway patients Inhibitors,research,lifescience,medical away from transplant in first remission. While there is no doubt that allogeneic transplantation can be performed successfully in second

complete remission, such reports are highly selective and confined to a small group of patients who have survived the relapse, achieved a second complete remission and were fit enough to undergo a trasnsplant, and for whom a donor was available. This represents a small minority of patients. If one considers the overall survival for all relapsed patients, this is no more than about 10%.17,18 Inhibitors,research,lifescience,medical Thus, presenting the optimistic data of second complete remission (CR2) to patients at diagnosis is thoroughly misleading and clearly needs to be avoided. Inhibitors,research,lifescience,medical Figure 12 Acute leukemia overall survival following second remission transplant. INTENTION-TO-TREAT ANALYSES Phase

III studies, representing prospective randomized trials, are the gold standard, especially when analyzed by intention to treat. However, it is crucial to understand the limitations of such analyses. For example, phase III studies of transplantation usually underestimate the toxicity of the procedure because the donor arm is diluted by the number of patients who do Phosphatidylinositol diacylglycerol-lyase not receive the transplant. They may also underestimate or overestimate efficacy depending on whether transplant is better than the comparator group. Furthermore, intention-to-treat analyses from diagnosis do not provide information for individual patients, as specified time points. Importantly, a generic issue of transplant studies relates to the large number of patients who do not undergo the assigned or randomized procedure. Any intention-to-treat analysis can only be reliably assessed if patients actually receive the treatment specified in their assignment or randomization.