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Phase II trial designs that ignore between-patient heterogeneity and do not allow for treatment-subgroup interactions may produce very large false positive and false negative error rates if efficacy varies by subgroup. Recent discussions of this problem were illustrated with scenarios and computer simulations. In this short communication, we reanalyzed a published phase II trial to highlight the need to consider between-patient heterogeneity and the possibility of treatment-subgroup interaction when designing and analyzing phase II studies. The single-arm trial evaluated amsacrine plus cytosine arabinoside, vincristine, and prednisone (a combination abbreviated as OAP) for adult acute leukemia, when standard treatment was adriamycin plus OAP. We carried out an analysis of covariance (ANCOVA) incorporating data from historical control patients who met eligibility criteria for the trial and received standard treatment at the study center in the years immediately preceding the trial. Patients administered experimental treatment and control patients were classified as having favorable or unfavorable prognosis according to their predicted probability of response to standard treatment. When the prognostic subgroup of patients was ignored, the response rates for experimental and standard treatment appeared similar. However, fitting an ANCOVA model determined that the effects of subgroup, treatment, and their interaction were statistically significant: experimental treatment was superior to standard treatment in patients with unfavorable prognosis and inferior to standard treatment in patients with favorable prognosis. This real-world example of treatment-subgroup interaction highlights the need to employ phase II designs that consider between-patient heterogeneity and the possibility that efficacy differs by subgroup.

In the era of cytomegalovirus (CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients aged 0-18 who underwent primary HSCT for acute leukemia in 1997-2007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and nonrelapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D-/R-). On univariate analysis, D-/R- grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, P < .05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D-/R- graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46-6.76) and treatment failure (2.45, 1.46-4.12) but not significantly with NRM (2.00, 0.44-9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors.