How do we define complete remission for acute myeloid leukemia in the current era? Results of an international survey
Authors: Michael J. Burke, Linda Burns, Michael A. Linden, Bruce Lindgren, Michael R. Verneris, Daniel Weisdorf, Celalettin Ustun
Journal: American Journal of Hematology (2013)

Interpretation of complete remission (CR) in acute myeloid leukemia (AML) remains a topic of debate. In 2003, the International Working Group (IWG) published recommendations for standardization of response criteria in AML 1. The combination of morphologic remission (<5% marrow blasts) and absence of a unique phenotype by flow cytometry was used. Whether practioners still use these or have begun to incorporate cytogenetic/molecular markers into their definition of CR is not known. With increasing knowledge of cytogenetic/molecular changes for AML that could define CR, 2, 3 this information may already be in use to classify remission for treatment decisions. To address this question, we created an electronic survey comprised of questions to identify criteria physicians use to classify CR in AML and how these influence treatment recommendations. The survey was sent to members of the Children's Oncology Group, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Pediatric Blood and Marrow Transplant Consortium. Responses were compared between pediatric and adult, oncologists and bone marrow transplant (BMT), and North American and non-North American physicians. Survey responses for each question were summarized by frequency and percentage. Comparisons between physician characteristics were carried out by either Chi-square or Fisher's exact tests. P-values less than 0.05 were considered statistically significant. We received 553 responses (Table 1), of which 38 did not treat AML and were excluded. The remaining 515 surveys were completed by 207 (40.2%) adult and 308 (59.8%) pediatric physicians; 175 (34.0%) who identified as hematology–oncology and 340 (66.0%) BMT (or BMT/Hem-Onc) physicians. Pediatric physicians were significantly more likely to use cytogenetic/molecular markers to define CR than adults. Pediatric physicians were also more likely to recommend further chemotherapy over hematopoietic cell transplantation (HCT) compared to adult physicians in cases of flow cytometric, cytogenetic or molecular evidence of residual disease after two courses of induction therapy. Other differences included recommending additional chemotherapy over HCT by Hem–Onc physicians in patients with flow cytometric evidence of disease, as well for patients in cytogenetic remission (by G-banding). It is interesting to note that in three of five scenarios, BMT physicians were more in favor of HCT then Hem–Onc physicians but similar in the other two scenarios which suggest management of patients is influenced not only by objective criteria but subjective considerations as well. The response did not vary if the physician was in North America or elsewhere (not shown). It is interesting that many participants considered flow cytometry an important tool to asses CR, as recommended by the IWG 1. However in general, flow cytometric evidence of leukemia after induction therapy was more often managed as CR (recommending additional consolidation) rather than persistent leukemia (proceeding with a clinical trial or salvage chemotherapy). On the other hand, for patients with no morphologic or flow cytometric evidence of leukemia, but molecular evidence (e.g., FLT3-ITD mutation positivity), consolidation chemotherapy was recommended more often than HCT by pediatric physicians. This survey highlights the somewhat surprising differences between pediatric, adult, Hem–Onc, and BMT physicians for defining CR and making decisions. How to integrate newly evolving diagnostic methods with more traditional approaches is difficult. As recently outlined 2, 3, it may now be time for further redefinition of CR in AML by combining flow cytometric and molecular techniques, but whether this will translate to improved outcomes is yet to be shown. MJB: conceived the study, developed the survey, reviewed data, and writing of the manuscript; LB: developed the survey, reviewed data, and writing of the manuscript; MAL: reviewed data and writing of the manuscript; BL: statistical analysis; MRV: developed the survey, reviewed data, and writing of the manuscript; DW: developed the survey, reviewed data, and writing of the manuscript; CU: conceived the study, developed the survey, reviewed data, and writing of the manuscript. Special thanks to members of COG, ASBMT, ASH and PBMTC who completed the survey for this analysis as well as to ASBMT/ PBMTC leadership who helped make this study possible. The NCI CA96028 (M.J.B.), Children's Cancer Research Fund (M.J.B., M.R.V.), American Cancer Society RSG-08–181 (M.R.V.), and the University of Minnesota Pediatric Leukemia Program supported this work. Michael J. Burke1* Linda Burns2 Michael A. Linden3 Bruce Lindgren4 Michael R. Verneris5 Daniel Weisdorf2 Celalettin Ustun2 1Division of Pediatric Hematology-Oncology, University of Minnesota Amplatz Children's Hospital, Minneapolis, Minnesota 2Division of Hematology-Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 3Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 4Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 5Division of Pediatric Blood and Marrow Transplantation, University of Minnesota Amplatz Children's Hospital, Minneapolis, Minnesota