Empiric definition of eligibility criteria for clinical trials in relapsed/refractory acute myeloid leukemia: analysis of 1,892 patients from HOVON/SAKK and SWOG.

Despite incremental progress over the last several decades, adult acute myeloid leukemia (AML) remains difficult to treat, and many patients experience therapeutic resistance, i.e. never attain a complete remission (CR) despite living long enough to have done so (i.e. are “primary refractory”) or have their disease relapse after achievement of CR. It is well recognized that the likelihood of response to therapy for relapsed/refractory AML and subsequent survival varies greatly across individual patients, with CR rates of 0-70% and 5-year survival rates of 5%-45%. Considerable attention has, therefore, been paid to the assessment of covariates influencing response to salvage therapy in relapsed/refractory AML. The duration of the first CR was identified as primary predictor, but cytogenetics at diagnosis, age, receipt of allogeneic hematopoietic cell transplantation during first CR, and number of prior therapies also play a role. This variability of therapeutic success in relapsed/refractory AML offers a formidable challenge for the conduct of clinical trials for this patient population. One approach would permit inclusion regardless of prior CR duration given the possibility that a new drug might only be effective with longer CR duration, and that even in such patients standard therapies are hardly satisfactory. A second, more common approach, however, relies on CR duration to create a “homogenous” population to facilitate data interpretation; yet, various arbitrary cut-off points have been used for this purpose. Although the close association between duration of previous CR and response to subsequent therapy is widely appreciated, the relationship between primary refractory and relapsed AML is uncertain. Some have argued that these groups fall on a continuum with, for example, the difference between CR durations of 0 (primary refractory) and three months being the same as that between CR durations of three and six months. Others contend that relapsed and primary refractory AML are qualitatively distinct. Twenty-five years ago, Hiddemann et al. used a CR duration of less than six months as a criterion defining “refractory AML” based on their analyses of success rates of salvage therapies, but no recent data on this topic are available. Here, we use data from adults with newly diagnosed AML treated on cooperative group trials to examine whether a particular CR duration might be used to define AML trial eligibility based on a relationship with subsequent survival. Our analyses included data on 1892 adults with newly diagnosed AML (excluding acute promyelocytic leukemia) based on WHO 2008 classification criteria receiving curative-intent treatment on 5 trials conducted by the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology and the Swiss Group for Clinical Cancer Research (HOVON/SAKK; n=1306) or on the SWOG S0106 trial (n=586). Institutional review boards of participating institutions approved all protocols. All patients provided written informed consent for study participation and were treated according to the Declaration of Helsinki. Based on earlier work, early death was defined as death within 28 days after initiating therapy or study registration if exact date of initiation of therapy was unknown. CR was defined according to international working group recommendations. Criteria for failure of initial therapy were completion of induction therapy without CR (CR duration=0) or as relapse from CR. Survival after failure (our principal end point, henceforth referred to as “survival”) was measured from the date of completing protocol induction therapy without report of CR or from the date of relapse until the date of death from any cause with patients last known to be alive censored at the date of last contact. Survival was estimated using the Kaplan-Meier