FLT3,   NPM1

A predictive model for patients with acute myeloid leukemia without favorable karyotype

Mutation analysis of metaphase cells is essential in the evaluation of patients with acute myeloid leukemia (AML). Specific cytogenetic abnormalities permit subdivision of patients with AML into favorable, intermediate, or unfavorable-risk groups. Thus, the type of AML will define diagnostic approaches, prognostic factors, and possible therapy options for each patient.

In a Letter to the Editor of the American Journal of Hematology, Kebede H. Begna, and colleagues from the Mayo Clinic, Rochester, MN, USA, reported results of a study evaluating the prognostic value of cytogenetic and FLT3-ITD/NPM1 mutation information. The research group established a risk model to identify genetic and clinical variables as well as possible specific treatment strategies.

Three hundred and eighty AML patients (median age = 63 years, range 21–89) with intermediate risk (n = 273; 72%) and adverse risk (n = 107; 28%) karyotype and with available FLT3-ITD and NPM1 mutation information were included in this study.

Key findings:
  • Intensive chemotherapy (IC; “7+3” or equivalent) was administered in 277 (73%) patients, 52 (14%) patients received less aggressive chemotherapy with hypomethylating agents (HMAs), 51 (13%) patients received supportive care alone
  • Complete remission (CR) and CR with incomplete blood count recovery (CRi) in patients treated with IC: 42% and 39%, respectively
  • CR or CRi was not achieved in patients receiving less aggressive chemotherapy or supportive care
  • One-hundred and nine (29%) patients underwent allogeneic transplantation, of them 105 achieved CR/CRi
  • Respective CR and CRi rates:
    • 48% and 38% for primary AML vs 30% and 39% for secondary AML vs 28% and 56% for therapy-related AML, P = 0.01
    • 45% and 41% for intermediate-risk karyotype vs 33% and 35% for adverse risk karyotype, P < 0.01
    • 48% and 38% for FLT3-ITD mutated patients vs 41% and 40% for FLT3-ITD wild-type patients, P = 0.5
    • 63% and 32% for NPM1 mutated patients vs 32% and 43% for NPM1 wild-type patients, P < 0.01
    • 36% and 41% for patients aged > 60 years vs 48% and 38% for patients aged 60 years or younger, P = 0.09
  • Median follow-up = 13 months
  • During follow-up, 206 patients (54%) died
  • Median overall survival (OS): 22 months
  • 5-year OS:
    • IC-treated patients achieving CR/CRi: 69 months
    • IC-treated patients not achieving CR/CRi: 8 months
    • Patients receiving less aggressive chemotherapy: 11 months
    • Patients receiving supportive care only: 3 months
  • Significant risk factors for survival: advanced age, male sex, secondary and therapy-related AML subcategories, adverse karyotype, NPM1 wild-type, FLT3-ITD/NPM1 mutation other than FLT3-ITD-/NPM1+, treatment other than IC, not achieving CR/CRi and not receiving transplantation
  • Independent survival impact: adverse karyotype, FLT3-ITD, FLT3-ITD/NPM1 profiles other than FLT3-ITD-/NPM1+, not achieving CR or CRi and not receiving transplantation
Patients receiving IC (n = 277) had independent predictive factors of favorable outcome:
  • CR/CRi: HR = 0.2 (95% CI, 0.1–0.3); 2 risk points
  • Transplantation: HR = 0.4 (95% CI, 0.3–0.6); 1 risk point
  • Absence of adverse karyotype: HR = 0.3 (95% CI, 0.2–0.5); 1 risk point
  • Absence of FLT3-ITD mutation: HR = 0.5 (95% CI, 0.3–0.8); 1 risk point

Taken together, this study indicates that for patients with AML without favorable karyotype achieving CR or CRi is mandatory for long-term remission. CR/CRi was achieved only in patients treated with intensive chemotherapy and thus survival outcomes were not significantly different between CR and CRi rates.

References
  1. Begna K. H. et al. A novel predictive model of outcome in acute myeloid leukemia without favorable karyotype based on treatment strategy, karyotype and FLT3-ITD mutational status. Am J Hematol. 2018 Sep 19. DOI: 10.1002/ajh.25290. [Epub ahead of print].
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