Mutations of KIT tyrosine kinase (TK) gene predict relapse in adult patients (pts) with core binding factor acute myeloid leukemia (CBF AML): A Cancer and Leukemia Group B (CALGB) study.

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 4 de junio del 2006

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Presenter: P. Paschka
Presenter's Affiliation: Ohio State University, Columbus, OH
Type of Session: Plenary

Background

  • Core binding factor acute myeloid leukemia (CBF AML) is a specific subtype of leukemia.
  • CBF AML has 2 of the most prevalent cytogenetic subtypes of primary AML, t(8;21) and inv(16)
  • These genomic aberrations disrupt genes encoding subunits of a protein called core binding factor (CBF), which is a regulator of hematopoiesis.
  • CBF AML is generally associated with a favorable prognosis, and makes up 15-20% of AML cases.
  • CBF AML patients have a particularly high complete response (CR) rate following induction therapy, and t(8;21) patients have an extremely high disease free survival (DFS) with high dose ara-c.
  • KIT is a cell surface protein tyrosine kinase (TK).
  • When KIT ligand binds to activate KIT, a cascade of signals tell the cell to grow and divide.
  • KIT can have a number of different mutations that can cause constitutive activation.
  • Small molecule KIT inhibitors have proven successful in the treatment of certain cancers with KIT mutations (like GIST).
  • In patients with CBF AML, mutations in KIT at exons 17 and 8 have been associated with a worse prognosis and higher relapse rate.

Materials and Methods

  • 110 patients treated on one of four CALGB protocols were identified with CBF AML.
  • All patients achieved a CR and were assigned to consolidation therapy.
  • None of these patients underwent a bone marrow transplant.
  • A cell bank was utilized, and specimens from each of these patients were analyzed.
  • 61 patients with inv(16) and 49 patients with t(8;21) were analyzed for KIT mutations using denaturing high performance liquid chromatography and direct sequencing.
  • Median follow-up was 5.3 years.
  • All patients except 1 were under the age of 60.
  • Inv(16) patients had a median age of 40 and were 57% male; t(8;21) patients had a median age of 37 and were 49% male.

Results

  • 29.5% of the inv(16) patients had KIT mutations; 16.4% at exon 17 and 13% at exon 8.
  • Amongst the inv(16) patients, the CR rate, relapse rate, and 5 year overall survival were, respectively: 92%, 36%, and 62%.
  • 22.4% of the t(8;21) patients had KIT mutations; 18.4% at exon 17 and 4% at exon 8.
  • Amongst the t(8;21) patients, the CR rate, relapse rate and 5 year overall survival were, respectively: 88%, 44%, and 62%.
  • In both inv(16) and t(8;21) patients, the CR rates were similar for patients with KIT mutations and patients with wild-type KIT.
  • In both groups, the 5 year cumulative incidence of relapse (CIR) was significantly higher in patients with mutated KIT [(inv(16) 56% vs 29%, p=0.05), (t(8;21) 75% vs 36%, p=0.017)].
  • In inv(16) patients, the CIR was 89% in patients with mutated KIT at exon 17 (mutKIT17), 17% in patients with mutated KIT at exon 8 (mutKIT8), and 29% in patients with wildtype KIT (wtKIT).
  • There was a trend for mutKIT17 patients with inv(16) to have worse overall survival (HR 3.9, p=0.09).
  • On multivariate analysis of patients with inv(16), mutKIT17 was a significant prognosticator for increased risk of relapse (HR 6.4, p<0.001).
  • In t(8;21) patients, there were not enough mutKIT8 patients (n=2) to analyze the mutant KIT patients separately by exon mutation.
  • On multivariate analysis of patients with t(8;21), mutKIT was a significant prognosticator for increased risk of relapse (HR 5.2, p=0.005).
  • There was no significant difference in overall survival seen in mutKIT patients with t(8;21) (HR 1.8, p=0.23).

Author's Conclusions

  • Mutations in exon 17 of KIT independently predict for a higher risk of relapse in patients with inv(16) and t(8;21) CBF AML.
  • KIT mutations in t(8;21) patients do not predict worse survival.
  • More aggressive therapy such as bone marrow transplant may be indicated for patients with KIT mutations.
  • Utilizing a KIT tyrosine kinase inhibitor may improve outcomes in these high risk patients.
  • Effectively using a KIT tyrosine kinase inhibitor in CBF AML patients depends on knowing the specific position of the particular KIT mutation.

Clinical/Scientific Implications

The authors present a thought provoking piece of retrospective research on patients with CBF AML.  Their results are in keeping with 4 previous studies of KIT mutations in CBF AML patients, and there is now enough evidence to consider the presence of a KIT mutation (particularly at exon 17) a new prognostic factor.  This will allow future investigators to produce elegant studies for this subgroup of patients, and open the door for new therapeutic modalities like tyrosine kinase inhibitors.  It would have been nice if the investigators of this study performed the same analysis on specimens gathered from all relapsed patients.  This would have allowed them to see if the KIT mutations persisted, and help prove that the mutation itself was responsible for the more aggressive behavior of the leukemia.  It is only a matter of time before the small molecule KIT tyrosine kinase inhibitor, imatinib, is studied in these patients.  This research is certainly a major breakthrough in hematologic oncology, and the authors should be commended for their efforts.

English
News
Average of 13 Mutations ID'd in Adult AML Genomes

May 2, 2013 - Adult acute myeloid leukemia genomes have an average of 13 mutations, and almost all cases have at least one nonsynonymous mutation in a category of genes relevant for pathogenesis, according to a study published online May 1 in the New England Journal of Medicine.



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