Clinical implications of <em>FLT3</em> mutations in pediatric AML

Soheil Meshinchi

Todd Alonzo

Derek Stirewalt

Michel Zwaan

Robert Gerbing+2 authors

From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Pediatrics, University of Washington Medical Center, Seattle; the University of Southern California Keck School of Medicine, Los Angeles; the Department of Pediatric Hematology/Oncology, Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands; the Dutch Childhood Oncology Group, Rotterdam, The Netherlands; the AML-BFM Study Group, Münster, Germany; the Department of Pediatric Hematology/Oncology, Vrije Universiteit (VU) University Medical Center, Amsterdam, The Netherlands; the Dutch Childhood Oncology Group, Amsterdam, The Netherlands; The Ohio State University, Columbus; the Children's Hospital of Philadelphia, PA; and the Children's Oncology Group, Arcadia, CA.

Correspondence: Soheil Meshinchi, Fred Hutchinson Cancer Research Center, Clinical Research Division, D5-380, 1100 Fairview Ave N, Seattle, WA 98103; e-mail: gro.crchf@cnihsems.

Received 2006 Mar 31; Accepted 2006 Jul 24.

Abstract

Activating mutations of the FLT3 gene occur because of an internal tandem duplication of the juxta-membrane domain (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM). The presence of FLT3 mutations as well as the allelic ratio of FLT3/ITD (ITD-AR, mutant–wild type ratio) may have prognostic significance. FLT3 mutation status of 630 children with de novo acute myeloid leukemia (AML) treated on CCG-2941 and -2961 was determined, and ITD-AR was calculated for patients with FLT3/ITD. Clinical characteristics and outcomes for patients with FLT3/ALM and FLT3/ITD at varying ITD-ARs was determined and compared with those without FLT3 mutations (FLT3/WT). FLT3/ITD and FLT3/ALM were detected in 77 (12%) and 42 (6.7%) of the patients. Progression-free survival (PFS) was similar in patients with FLT3/ALM and FLT3/WT (51% versus 55%, P = .862). In contrast, PFS at 4 years from study entry for patients with FLT3/ITD was inferior to that of patients with FLT3/WT (31% versus 55%, P < .001). PFS decreased with increasing FLT3/ITD-AR (P < .001), and those with ITD-AR greater than 0.4 had a significantly worse PFS than those with lower ITD-AR (16% versus 72%, P = .001) or with FLT3/WT (55%, P < .001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML, and ITD-AR greater than 0.4 is a significant and independent prognostic factor for relapse in pediatric AML.

Abstract

For the univariate analysis, n = 630; for the multivariate analysis, n = 375.

Acknowledgments

We thank Ms Cristina Galer and Ms Kristen Miller for excellent technical contribution to this work. We also thank Ms Mariko Kawabori in the COG reference laboratory for assistance in specimen identification. We are grateful to the patients and families of patients who consented to the use of biologic specimens in this trial.

This work was supported by the National Institutes of Health (grants R21 CA10262-01, K23 CA092405, and R01 CA114563-01).

Acknowledgments

Notes

Prepublished online as Blood First Edition Paper, August 15, 2006; DOI 10.1182/blood-2006-03-009233.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Notes

Prepublished online as Blood First Edition Paper, August 15, 2006; DOI 10.1182/blood-2006-03-009233.

References

1. Tse KF, Novelli E, Civin CI, Bohmer FD, Small DInhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia. 2001;15: 1001-1010. [[PubMed][Google Scholar]
2. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JTIdentification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113: 983-988. [[PubMed][Google Scholar]
3. Abu-Duhier FM, Goodeve AC, Wilson GA, et alFLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol. 2000;111: 190-195. [[PubMed][Google Scholar]
4. Kiyoi H, Naoe T, Yokota S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11: 1447-1452. [[PubMed]
5. Stirewalt DL, Kopecky KJ, Meshinchi S, et alFLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001; 97: 3589-3595. [[PubMed][Google Scholar]
6. Kiyoi H, Naoe T, Nakano Y, et alPrognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93: 3074-3080. [[PubMed][Google Scholar]
7. Kottaridis PD, Gale RE, Frew ME, et alThe 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][Google Scholar]
8. Yamamoto Y, Kiyoi H, Nakano Y, et alActivating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97: 2434-2439. [[PubMed][Google Scholar]
9. Fenski R, Flesch K, Serve S, et alConstitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells. Br J Haematol. 2000;108: 322-330. [[PubMed][Google Scholar]
10. Meshinchi S, Woods WG, Stirewalt DL, et alPrevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97: 89-94. [[PubMed][Google Scholar]
11. Kondo M, Horibe K, Takahashi Y, et alPrognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol. 1999;33: 525-529. [[PubMed][Google Scholar]
12. Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia. 1999;13: 38-43. [[PubMed]
13. Meshinchi S, Stirewalt DL, Alonzo TA, et alActivating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood. 2003;102: 1474-1479. [[PubMed][Google Scholar]
14. Thiede C, Steudel C, Mohr B, et alAnalysis 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][Google Scholar]
15. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe TPrognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19: 1345-1349. [[PubMed][Google Scholar]
16. Sievers EL, Lange BJ, Alonzo TA, et alImmunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood. 2003; 101: 3398-3406. [[PubMed][Google Scholar]
17. Lange BJ, Dinndorf P, Smith FO, et alPilot study of idarubicin-based intensive-timing induction therapy for children with previously untreated acute myeloid leukemia: Children's Cancer Group Study 2941. J Clin Oncol. 2004;22: 150-156. [[PubMed][Google Scholar]
18. Lange BJ, Gerbing RB, Feusner J, et alMortality in overweight and underweight children with acute myeloid leukemia. JAMA. 2005;293: 203-211. [[PubMed][Google Scholar]
19. Zwaan CM, Meshinchi S, Radich JP, et alFLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood. 2003;102: 2387-2394. [[PubMed][Google Scholar]
20. Murphy KM, Levis M, Hafez MJ, et alDetection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5: 96-102. [Google Scholar]
21. Kaplan EL, Meier PNonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: 457-481. [PubMed][Google Scholar]
22. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY: John Wiley and Sons; 1980.
23. Cox DRRegression models and life-tables (with discussion). J R Stat Soc Ser B. 1972;34: 187-220. [PubMed][Google Scholar]
24. Lacayo N, Meshinchi S, Kinnunen P, et alFLT3 mutations with good clinical outcome are identified by gene expression profiles at diagnosis in de novo childhood AML. Blood. 2004;104: 2646-2654. [[PubMed][Google Scholar]
25. Choudhary C, Schwable J, Brandts C, et alAML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood. 2005;106: 265-273. [[PubMed][Google Scholar]
26. Grundler R, Miething C, Thiede C, Peschel C, Duyster JFLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005; 105: 4792-4799. [[PubMed][Google Scholar]
27. Schlenk R, Krauter J, Fröhling S, et alPostremission therapy with an allogeneic transplantation from an HLA-matched family donor seems to overcome the negative prognostic impact of FLT3-ITD in younger patients with acute myeloid leukemia exhibiting a normal karyotype [abstract]. Blood. 2005;106: 662a. Abstract 2353. [PubMed][Google Scholar]
28. Gale RE, Hills R, Kottaridis PD, et alNo evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005;106: 3658-3665. [[PubMed][Google Scholar]
29. Meshinchi S, Arceci R, Sanders J, et alRole of allogeneic stem cell transplantation in FLT3/ITD-positive AML [letter]. Blood. 2006;108: 400. [[PubMed][Google Scholar]
30. Levis M, Smith BD, Beran M, et alA randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition [abstract]. Blood. 2005;106: 121a. Abstract 403. [PubMed][Google Scholar]
31. De Angelo DJ, Stone RM, Heaney ML, et alPhase II evaluation of the tyrosine kinase inhibitor MLN518 in patients with acute myeloid leukemia (AML) bearing a FLT3 internal tandem duplication (ITD) mutation [abstract]. Blood. 2004;104: 496a-497a. Abstract 1792. [PubMed][Google Scholar]
32. Giles F, Schiffer C, Kantarjian H, et alPhase 1 study of PKC412, an oral FLT3 kinase inhibitor, in sequential and concomitant combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine (HDAra-C) consolidation in newly diagnosed patients with AML [abstract]. Blood. 2004;104: 78a. Abstract 262. [PubMed][Google Scholar]