Improving Survival in Acute Myeloid Leukemia: Pick the Best Subjects?
Authors: Hillard M. Lazarus, Mark R. Litzow, Robert Peter Gale
Journal: Journal of Clinical Oncology (2013)

Every year in the United States more than 14,000 people are diagnosed with acute myeloid leukemia (AML); more than 10,000 will die. This number accounts for approximately 2% of cancer deaths, not exactly a public health hazard but important, especially if you are one of the fatalities. In the article accompanying this editorial, Mawad et al from Seattle report encouraging results of using allogeneic hematopoietic cell transplantations (HCTs) to treat persons with AML in first complete remission (CR1). They employ novel approaches including: alternative donors (some of whom are HLA-mismatched); diverse graft types (such as umbilical cord blood units); relaxed selection criteria; and less intensive pretransplantation conditioning regimens (as opposed to more conventional intensity). Some of their strategies are interesting and innovative, such as using radio-labeled monoclonal antibodies for pretransplantation conditioning. In sum, they report that an increasing proportion of persons with AML are able to get to a transplantation. Two hundred eighty-seven subjects were evaluated during a 4-year period, but the authors indicate that seven were lost to follow-up, 15 expired within 30 days of initiating therapy, and 53 were not treated at their center. One hundred sixteen of their 212 starting subjects achieved CR1 or CRi (ie, CR but incomplete blood count recovery); they were considered transplantation eligible. Others (n 96) were considered transplantation ineligible based on age older than 75 years (n 19) or because they had favorable risk AML (n 33); also excluded were 44 subjects not achieving CR1. The bottom line is they were able to get 78 of 212 subjects or approximately 40% of persons with newly-diagnosed AML to a transplantation in CR1. This appears to be remarkable, but what is the importance of this finding? Experts have long debated the role of transplantations in persons with AML. Nearly all studies comparing transplantation to chemotherapy show a marked decrease in leukemia relapse. Most of this effect is attributed to immune competent donor cells attacking residual recipient leukemia cells. Whether this effect, often referred to as graft-versus-leukemia, is really leukemia-specific or a reflection of graft-versus-host disease is controversial. The Seattle data are interesting but raise several important questions including: (1) Can single-center studies of this type, no matter how well done, apply to most persons with AML; (2) Can results from a center of excellence inform us of how to treat persons with AML in a conventional setting; and (3) What is a reasonable estimate of the impact on the US AML population were the strategies executed by Mawad et al used nationwide? Answers to these questions hinge, importantly, on how representative the Seattle data are. Namely, did selection biases operate? First, to critically evaluate the results we need to know how typical the Seattle subjects are of the US AML population. Patient demographics, however, are provided only for the 116 patients considered transplantation eligible. An important issue is selecting the correct denominator for the Seattle subjects. Were they randomly chosen from the entire US AML population (obviously not), the Pacific Northwest population (unlikely), the Seattle metropolitan area population or something else? These data also were not provided and the true denominator is likely unknowable. Most physicians use a complex, poorly-defined calculus to decide which persons with AML should be referred to a distant center for consideration of HCT, typically accompanied by their family. Important selection biases also must operate in this internet age when people self-refer to physicians that they do not know, located at a distant center. Race, ethnicity, socioeconomic status, insurance coverage and other factors also are known to play important roles in selection biases. Part of this process is conscious and rational, but much of it is not. Next we have to deal with the issue of when a person arrives at Seattle, does he or she always get a transplantation? In their report, Mawad et al indicate 53 of 287 persons evaluated at their center were treated elsewhere. However, they do not indicate the disposition of these persons. Our Seattle colleagues have considerable expertise and surely are skilled in identifying, not always consciously, who is likely to do well with a transplantation and who will not. For example, the intensity with which one searches for an unrelated HLA-matched donor may depend on the physician’s enthusiasm for doing a transplantation which may, in turn, correlate with his/her estimation of a successful outcome. Numerous studies, including one from Seattle in AML, show persons randomized to receive a therapy on a clinical trial do considerably better than persons at the same center assigned to receive similar therapy off study. Why? A likely explanation is that when a new therapy is being compared to a standard therapy in a randomized study, physicians typically (and illogically) may believe the randomly assigned subject is more likely to receive the new therapy. Consequently, when there is a fit subject they likely are willing to spend considerable time to convince him/her to participate in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 31 NOVEMBER 1 2013