General AML

ISAL 2019 | Precision medicine in acute myeloid leukemia – fact or fiction?

On 25 February 2019, at the Acute Leukemias XVII Biology and Treatment Strategies biennial symposium in Munich, Germany, Professor Lars Bullinger, Charite University, Berlin, Germany, presented data evaluating the role of precision medicine in acute myeloid leukemia (AML).

Recent advances in high throughput technologies which have led to the generation of vast amounts of clinical data and the development of personalized medicine approaches in AML. The ability to treat cancer patients based upon their individual molecular characteristics or drug sensitivity profiles is expected to significantly advance cancer treatment and improve the long-term survival of patients with refractory AML, for whom current treatment options are restricted to palliative approaches.

Prof. Bullinger expanded on the clinical developments of omics-based and phenotypic screens, however, acknowledged that this development is limited by a number of bottlenecks including the generation of cost-effective high-throughput data, data interpretation, and integration of multiple approaches, sample availability and clinically relevant timelines.

Recently, a number of small clinical trials have shown survival benefits in patients treated based on personalized medicine approaches. While these preliminary studies are encouraging, larger trials are needed to evaluate the utility of these technologies in routine clinical settings.

Prof. Bullinger explored the findings of the randomized, double-blind RATIFY study (Alliance 10603) which focused on patients with leukemia cells with the abnormal FLT3 gene. The research evaluated the prognostic impact of FLT3-TKD and NPM1mutations in a post hoc analysis. Additionally investigating the relationship between ITD insertion sites and patient outcomes, using next-generation sequencing (NGS).

Patients and methods
  • Median age: 49 years (range, 45.5–51.1 years)
  • Patients were randomly assigned to receive midostaurin or a placebo together with standard induction and consolidation therapy followed by 12, 28-day cycles of maintenance therapy with midostaurin or placebo
  • FLT3-TKD mutation was detected by PCR and capillary electrophoresis at reference laboratories
  • Follow up: 1 year
  • Patients were categorized as NPM1mutated (mut) or NPM1 wild-type (WT) using PCR
  • Efficacy outcomes included complete remission (CR), overall survival (OS), event-free survival (EFS) and disease-free survival (DFS). EFS and DFS analyses were performed considering CR within a 60-day window

Key findings

  • Of the total randomized 162 FLT3-TKD patients, 134 with available NPM1data had consented for exploratory analysis and were included in the subgroup distribution
  • The median white blood cell (WBC) count was higher in patients with NPM1-mut than in patients with NPM1-WT (34.1 vs5 × 109/L, = 0.0011)
  • CR rates (during the first 60 days) were higher in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT (66% vs 53%)
  • This was driven by the higher rate of CR in the midostaurin arm (76% NPM1-mut vs 44% NPM1-WT) rather than the placebo arm (53% NPM1-mut vs 60% NPM1-WT)
  • NGS identified 908 ITDs with up to 9 ITDs per case

Prof. Lars Bullinger concluded that this post hoc analysis showed the high prognostic value of NPM1 mutational status. Whereas midostaurin showed an overall benefit in the FLT3-TKD patients for OS, EFS, CR and DFS, the impact of treatment on outcome varied between the individual NPM1 subgroups within these FLT3-TKD patients. Further analyses to investigate potential predictive effects of midostaurin treatment are ongoing.


Bullinger L.Precision medicine in AML – fiction or reality? 2019 Feb 25. Acute Leukemias XVII Biology and Treatment Strategies biennial symposium, Munich, Germany.

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