Decision Analysis of Postremission Therapy in Cytogenetically Intermediate-Risk Acute Myeloid Leukemia: The Impact of FLT3 Internal Tandem Duplication, Nucleophosmin, and CCAAT/Enhancer Binding Protein Alpha  Saiko Kurosawa, Hiroki Yamaguchi, Takuhiro Yamaguchi, Keiko Fukunaga, Shunsuke Yui, Satoshi Wakita, Heiwa Kanamori, Kensuke Usuki, Nobuhiko Uoshima, Masamitsu Yanada, Katsuhiro Shono, Toshimitsu Ueki, Ishikazu Mizuno, Shingo Yano, Jin Takeuchi, Junya Kanda, Hiroshi Okamura, Yoshihiro Inamoto, Koiti Inokuchi, Takahiro Fukuda  Biology of Blood and Marrow Transplantation  Volume 22, Issue 6, Pages 1125-1132 (June 2016) DOI: 10.1016/j.bbmt.2016.03.015 Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 A Markov decision model generated by TreeAge is shown. The first (leftmost) line shows the targeted patients, cytogenetically intermediate risk AML in CR1. The second line shows 2 compared postremission strategies, plan allo-HCT and plan chemotherapy. The third line right after the Markov node (indicated as a circled M) shows the Markov health states, “alive after plan of HCT,” “alive after relapse (before receiving allo-HCT in CR1)”, and “dead” after “plan allo-HCT”, and “alive after chemotherapy” and “dead” after “plan chemotherapy.” The health state of “alive after relapse” after “plan allo-HCT” was allocated the same QOL estimate as “alive after chemotherapy”. The numbers under the branches, 1 and 0, mean that all members of the cohort were either “alive after plan of HCT” or “alive after chemotherapy” at the beginning of the analysis. After the third line, possible health states are indicated with estimated transition probabilities shown under each branch as tProb, tMort, or # (the value of the transition probability on the opposite branch subtracted from 100%). tProb_relapse defines transition probabilities for relapse (without receiving allo-HCT), tMort_HCT defines transition probabilities for mortality after receiving allo-HCT, and tMort_chemo for mortality after receiving chemotherapy. For the health state of “relapse before HCT in CR1” after “alive after plan of HCT”, estimated probabilities of relapse were assigned for 2 cycles, 6 months. Biology of Blood and Marrow Transplantation 2016 22, 1125-1132DOI: (10.1016/j.bbmt.2016.03.015) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Survival curves of plan allo-HCT (blue line) and plan chemotherapy (red line) as generated by TreeAge are shown for (A) FLT3-ITD–positive, (B) FLT3-ITD–negative/NPM1–negative, or (C) FLT3-ITD–negative/NPM1–positive patients, and patients with (D) CEBPA biallelic mutations or (E) CEBPA monoallelic mutation/wild-type. This figure is available in color online at www.bbmt.org. Biology of Blood and Marrow Transplantation 2016 22, 1125-1132DOI: (10.1016/j.bbmt.2016.03.015) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 In the 2-way sensitivity analyses, we assessed whether a result changes (the favored treatment strategy switch to the other) if QOL values fluctuate in the range of possible values (plausible range). We adopted 95% confidence intervals of the patient-reported EQ-5D index as the plausible range, which the orange rectangles indicate (chemotherapy, .68 to .75; HCT, .63 to .83). Y-axis and X-axis respectively show QOL after chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT). Higher values represent better QOL. Blue areas indicate where QOL-adjusted life expectancy (QALE) is superior in the allo-HCT group, whereas red areas indicates where QALE is superior in the chemotherapy group. Results are shown in each genetic group of (A) FLT3-ITD–positive, (B) FLT3-ITD–negative/NPM1–negative, or (C) FLT3-ITD–negative/NPM1–positive patients, and patients with (D) CEBPA biallelic mutations or (E) CEBPA monoallelic mutation/wild-type. In (A), (D), and (E) in which the plausible ranges of QOL estimates did not cross the threshold lines, results regarding the favored strategy did not change in these sensitivity analyses, which showed the robustness of the conclusions. On the other hand, in (B) and (C), the orange rectangles showing the plausible ranges of QOL estimates crossed the threshold lines. These results indicated that the benefit of allo-HCT in these genetic groups were not robust enough. With the upper limit of 95% confidence intervals of QOL estimate for chemotherapy (.75), the preferred strategy for FLT3-/NPM1- patients (B) may turn to chemotherapy if QOL estimate after allo-HCT falls below .68, which was equivalent to the overall QOL estimate in patients with GVHD. In FLT3−/NPM1+ patients (C), the preferred strategy was shown to turn to chemotherapy even with a higher QOL estimate after allo-HCT. The asterisks in (B) and (C) show the threshold where favored treatment strategy switches to the other, with the upper limit of QOL after chemotherapy. This figure is available in color online at www.bbmt.org. Biology of Blood and Marrow Transplantation 2016 22, 1125-1132DOI: (10.1016/j.bbmt.2016.03.015) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions