2009

Acute myeloid leukemia is the most common indication for an allogeneic hematopoietic cell transplant. The introduction of reduced intensity conditioning has expanded the recipient pool for transplantation, which has importantly made transplant an option for the more commonly affected older age groups. Reduced intensity conditioning allogeneic transplantation is currently the standard of care for patients with intermediate or high-risk acute myeloid leukemia and is now most often employed in older patients and those with medical comorbidities. Despite being curative for a significant proportion of patients, post-transplant relapse remains a challenge in the reduced intensity conditioning setting. Herein we discuss the studies that demonstrate the feasibility of reduced intensity conditioning allogeneic transplants, compare the outcomes of reduced intensity conditioning versus chemotherapy and conventional myeloablative conditioning regimens, describe the optimal donor and stem cell source, and consider the impact of post-remission consolidation, comorbidities, center experience, and more intensive (reduced toxicity conditioning) regimens on outcomes. Additionally, we discuss the need for further prospective studies to optimize transplant outcomes. ABSTRACT as the backbone of most RIC regimens which also include either a reduced dose of an alkylating agent or a reduced dose of TBI. Fludarabine is generally well tolerated and synergizes well with alkylating agents to enhance inhibition of DNA repair mechanisms. 10 Multiple RIC regimens have been developed and described 23 McSweeney et al. described 45 patients with a median age of 56 years who had human leukocyte antigen (HLA)-identical sibling donors and relative contraindications to conventional conditioning for HCT. In these patients a conditioning regimen of TBI alone (200 cGy) produced a survival rate of >66% after a median follow-up of 417 days with a NRM rate of only 6.7%. The associated toxicities were mild, and over 50% of patients were able to have their transplant done completely in the outpatient setting. 23 This set the stage for future studies focusing on the potent immunological graft-versus-leukemia effect to induce cures as opposed to just on intensive pre-transplantation marrow ablative strategies. As the number of efficacious regimens grew, so did the number of patients for whom transplantation became a therapeutic option. Much enthusiasm has led to the widespread adoption of RIC HCT as a potentially curative option for older patients or those with comorbid disease, despite lack of supportive, prospective, randomized data. Nevertheless, studies have shown that age itself does not significantly affect outcomes, 24,25 and RIC regimens are tolerated well allowing transplants to be offered to patients up to the age of 70. McClune et al. reported a large retrospective study of the Center for International Blood and Marrow Transplant (CIBMTR) registry investigating outcomes of 1080 patients over the age of 40 and showed that neither age nor type of conditioning regimen had any impact on survival 25 Is reduced intensity conditioning better than standard chemotherapy? There are few studies that directly address the question of whether RIC HCT is better than standard chemotherapy. Mohty et al. reported a donor versus no donor comparison study that described the utility of RIC HCT in patients over the age of 50 years with high-risk AML in CR. This study included 95 patients of whom 35 (37%) with a sibling donor would go on to have a RIC HCT, while the remainder without a donor went on to receive standard chemotherapy. In their intention-to-treat analysis, the patients with donors who underwent RIC HCT with a regimen of fludarabine, busulfan, and anti-thymocyte globulin had a significantly higher 4-year leukemiafree survival (LFS) rate of 54% than the 30% in the no donor group (P=0.01). Overall survival (OS) was also improved (P=0.01), and in their multivariate analysis, the actual performance of a RIC HCT was the strongest predictor of improved LFS [relative risk (RR)=4.0; 95% confidence interval (CI): 1.7-9.6]. 26 Kurosawa et al. similarly compared a small series of patients who underwent RIC HCT between the ages of 50-70 and patients who underwent standard chemotherapy; the outcomes of the former were superior, with a reduced cumulative incidence of relapse (22% versus 62%), and improved LFS and OS. 27 Similarly, Russell et al. evaluated patients who were enrolled in the United Kingdom Medical Research Council AML15 (UK MRC AML15) trial and in their comparative analysis of patients who underwent RIC HCT versus standard chemotherapy alone, RIC transplantation significantly reduced the risk of relapse. However, there was no difference in OS at 5 years, and no evidence of benefit when stratified by risk groups. There was also significant hetero-S. Sengsayadeth et al. 860 haematologica | 2015; 100(7