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Randomized Controlled Trial
. 2021 Sep;35(9):2539-2551.
doi: 10.1038/s41375-021-01179-4. Epub 2021 Mar 2.

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Richard A Larson  1 , Sumithra J Mandrekar  2   3 , Lucas J Huebner  3 , Ben L Sanford  4 , Kristina Laumann  3 , Susan Geyer  3 , Clara D Bloomfield  5 , Christian Thiede  6 , Thomas W Prior  5 , Konstanze Döhner  7 , Guido Marcucci  8 , Maria Teresa Voso  9 , Rebecca B Klisovic  10 , Ilene Galinsky  11 , Andrew H Wei  12 , Jorge Sierra  13 , Miguel A Sanz  14 , Joseph M Brandwein  15 , Theo de Witte  16 , Dietger Niederwieser  17 , Frederick R Appelbaum  18 , Bruno C Medeiros  19 , Martin S Tallman  20 , Jürgen Krauter  21 , Richard F Schlenk  7   22 , Arnold Ganser  21 , Hubert Serve  23 , Gerhard Ehninger  6 , Sergio Amadori  9 , Insa Gathmann  24 , Hartmut Döhner  7 , Richard M Stone  11
Affiliations
Randomized Controlled Trial

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Richard A Larson et al. Leukemia. 2021 Sep.

Abstract

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

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Figures

Figure 1.
Figure 1.
CONSORT diagram
Figure 2.
Figure 2.
Cumulative incidence of relapse (CIR) for 441 CRind patients with either non-AML death or non-AML death and transplantation as competing risks, (a,b) overall and (c-h) for the 282 CRind patients with available cytogenetic and molecular data by ELN 2017 risk classification.
Figure 2.
Figure 2.
Cumulative incidence of relapse (CIR) for 441 CRind patients with either non-AML death or non-AML death and transplantation as competing risks, (a,b) overall and (c-h) for the 282 CRind patients with available cytogenetic and molecular data by ELN 2017 risk classification.
Figure 2.
Figure 2.
Cumulative incidence of relapse (CIR) for 441 CRind patients with either non-AML death or non-AML death and transplantation as competing risks, (a,b) overall and (c-h) for the 282 CRind patients with available cytogenetic and molecular data by ELN 2017 risk classification.
Figure 3.
Figure 3.
Cumulative incidence of relapse (CIR) for the 182 patients who underwent allogeneic transplantation in first CR according to randomized treatment arm.
Figure 4.
Figure 4.
Landmark analysis of overall survival (a) and disease-free survival (b) for the 205 patients who began maintenance therapy by treatment arm.
See this image and copyright information in PMC

References

    1. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10(12): 1911–1918. - PubMed
    1. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752–1759. - PubMed
    1. Nagel G, Weber D, Fromm E, Erhardt S, Lübbert M, Fiedler W, et al. Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol 2017; 96: 1993–2003. - PMC - PubMed
    1. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335. - PubMed
    1. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res 2001; 61: 7233–7239. - PubMed

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