Acute Myeloid Leukemia.

Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord-blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry. Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose. Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor--that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit--that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background. Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. (Funded by the Office of Naval Research, Department of the Navy, and the Health Resources and Services Administration, Department of Health and Human Services.).