Decitabine improves response rate and prolongs progression‐free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the <scp>DACO</scp>‐016 trial
Authors: Agnieszka Wierzbowska, Ewa Wawrzyniak, Agnieszka Pluta, Tadeusz Robak, Grzegorz J. Mazur, Anna Dmoszynska, Jaroslav Cermak, Albert Oriol, Daniel Lysak, Chris Arthur, Margaret Doyle, Liang Xiu, Farhad Ravandi, Hagop M. Kantarjian
Journal: American Journal of Hematology (2018)

Monosomal karyotype (MK) is associated with a particularly adverse prognosis in acute myeloid leukemia (AML).1, 2 In patients treated with chemotherapy, those who were MK+ had a 4-year overall survival (OS) of 4% compared with 26% among those without MK but with other abnormal non-core binding factor karyotypes.1 Decitabine is a hypomethylating agent indicated for the treatment of AML in patients who are not candidates for standard induction chemotherapy. In a phase 2 trial of decitabine as first-line treatment for elderly AML, the overall response rate (ORR) was higher among subjects who were MK+ than in MK– cases with abnormal cytogenetics, and OS was comparable between groups.3 This suggests a potential positive effect of decitabine in MK+ AML. We conducted a post hoc evaluation of data from the phase 3 DACO-016 study (NCT00260832) comparing decitabine versus treatment choice (TC) in patients aged ≥65 years with newly diagnosed, de novo or secondary AML (≥20% blasts), and poor/intermediate-risk cytogenetics (Southwest Oncology Group [SWOG] categorization).4 Patients were randomized 1:1 to decitabine (20 mg/m2/day for five consecutive days every 4 weeks) or TC (best supportive care or cytarabine 20 mg/m2/day for 10 days every 4 weeks). The present analysis included two subgroups from DACO-016: subjects who were MK+ (≥2 distinct autosomal monosomies; or 1 autosomal monosomy and ≥1 structural abnormality1), and subjects with poor-risk cytogenetics but without MK. The objectives were to determine the effects of decitabine versus TC on outcomes in patients with MK+ disease, and to compare versus MK– AML with other unfavorable karyotypes. The efficacy population comprised all randomly assigned patients. P-values for comparisons of baseline characteristics were based on Fisher's exact test for categorical data and t-test for continuous variables. Response rates were compared between decitabine- and TC-treated patients based on a two-sided Fisher's exact test. The Kaplan–Meier method was used to describe OS and progression-free survival (PFS), with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated using a Cox proportional hazards model; P values were based on the log-rank test. Of 485 patients in DACO-016, 64 were MK+ (decitabine, n = 33; TC, n = 31), and 99 were MK– with poor-risk cytogenetics (decitabine, n = 49; TC, n = 50). Baseline characteristics were similar between the decitabine and TC arms within the MK+ and MK– poor-risk groups (Supporting Information Table 1), and between the two groups. In the MK+ group, the combined rate of complete remission (CR) and CR with incomplete blood count recovery (CRi) was significantly higher with decitabine (n = 9 [27%]) compared with TC (n = 1 [3%]; P = .0132) (Supporting Information Table 2). Similarly, ORR was greater in the decitabine arm (n = 12 [36%]) versus TC (n = 1 [3%]; P = .0013). PFS was longer with decitabine compared with TC (median: 2.6 vs. 1.3 months, respectively; HR: 0.53 [95% CI: 0.31, 0.90]; P = .0181) (Figure 1A). There was also a trend toward longer OS with decitabine versus TC (median: 6.3 vs. 2.6 months; HR: 0.67 [95% CI: 0.39, 1.15]; P = .141) (Figure 1B). This difference became statistically significant when OS was censored at the time of subsequent therapy (median: 6.3 vs. 2.6 months, respectively; HR: 0.52 [95% CI: 0.29, 0.93]; P = .0253) (Figure 1C). The median number of treatment cycles was greater with decitabine versus TC (median: 4.5 vs. 1.0 cycles; P = .0195). MK+ subjects: progression-free survival (A), overall survival in MK+ subjects (B), and with censoring for subsequent treatment (C). MK– subjects with poor-risk cytogenetics: progression-free survival (D), overall survival (E), and with censoring for subsequent treatment (F). CI, confidence interval; DEC, decitabine; HR, hazard ratio; MK, monosomal karyotype; TC, patient choice of treatment with physician advice. [Color figure can be viewed at wileyonlinelibrary.com] In the MK– poor-risk group, there was no statistically significant difference in the rate of CR + CRi in the decitabine arm (n = 9 [18%]) compared with TC (n = 5 [10%]; P = .262) (Supporting Information Table 2), and no significant difference in ORR with decitabine (n = 10 [20%]) versus TC (n = 6 [12%]; P = .287). With regard to median PFS, there was no difference between patients receiving decitabine and those assigned to TC: 2.4 versus 2.2 months, respectively (HR: 1.13 [95% CI: 0.74, 1.72]; P = .576) (Figure 1D). There was also no difference in median OS between decitabine and TC (5.0 vs. 4.7 months; HR: 1.11 [95% CI: 0.72, 1.70]; P = .634) (Figure 1E), even with censoring at the time of subsequent therapy (median: 5.0 vs. 5.0 months; HR: 1.07 [95% CI: 0.66, 1.72]; P = .789) (Figure 1F). The median number of treatment cycles was comparable between patients receiving decitabine and TC (3.0 vs. 2.0 cycles, respectively; P = .861). Survival was also compared in the decitabine and TC arms according to cytogenetics. In the TC arm, there was a trend toward poorer survival among patients who were MK+ compared with MK– poor-risk patients, with a median OS of 2.6 versus 4.7 months, respectively (HR: 1.52 [95% CI: 0.91, 2.54]; P = .107) (Supporting Information Figure 1). In the decitabine arm, MK+ patients showed similar survival to MK– cases with poor-risk cytogenetics; median OS was 6.3 versus 5.0 months, respectively (HR: 0.98 [95% CI: 0.60, 1.58]; P = .924). Overall, decitabine improved response rates and PFS compared with other standard therapies for patients who were ineligible for intensive chemotherapy, with a benefit of almost 4 months in median OS. Although the prognosis in MK+ AML is usually particularly poor,1, 2 the median OS in decitabine-treated MK+ AML patients in the present analysis was comparable to that among MK– patients with unfavorable cytogenetics. This suggests a potential positive effect of decitabine in patients with MK+ AML, possibly by reactivating haplo-insufficient tumor suppressor gene mapping on monosomal autosomes. The data are consistent with previous results from a phase 2 study of decitabine in AML, in which the ORR was 37% in the MK+ group—higher than among MK– patients with abnormal cytogenetics.3 They also align with results from a subgroup analysis of a phase 3 study in high-risk myelodysplastic syndrome, in which decitabine improved PFS among subjects with two or more autosomal monosomies within a complex karyotype.5 The key strength of this analysis was that the data came from a phase 3, randomized, controlled trial. Important limitations include the open-label design (required for comparing intravenous decitabine with subcutaneous cytarabine), the post hoc nature of the analysis, and the relatively small numbers of patients. Hence, the findings will require confirmation in prospective studies with larger sample sizes. Overall, the data suggest that decitabine may overcome the extremely poor prognosis associated with MK, and may be a beneficial initial treatment in these patients. Under the direction of the authors, medical writing services for early versions of the manuscript were provided by Dr. Timothy Ryder of Rocket Science Medical Communications Limited. Medical writing services were funded by Janssen Pharmaceutical Companies of Johnson & Johnson in Europe. A.W. reports consultancy for Celgene, Janssen, and Novartis, and speaker bureau participation for Celgene and Janssen. T.R. reports consultancy, sponsorship and research funding from Janssen. A.O. reports consultancy and speaker bureau participation for Amgen, Janssen, and Takeda. D.L. reports consultancy for Abbvie and Roche, and speaker bureau participation for Janssen. M.D. and L.X. are full-time employees and stockholders in Janssen. F.R. reports consultancy for Amgen, Seattle Genetics, and Sunesis, and research funding from Amgen, BMS, Seattle Genetics, Sunesis, and Xencor. H.M.K. reports consultancy for Abbvie, Actinium, Amgen, Ariad, BMS, Immunogen, Orsinex, and Pfizer, and research funding from Amgen, Ariad, Astex, BMS, Novartis, and Pfizer. E.W., A.P., G.J.M., A.D., J.C., and C.A. have no relevant conflicts of interest to disclose. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Supporting Information Supporting Information Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.