Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Author:

Levis Mark1,Ravandi Farhad2,Wang Eunice S.3,Baer Maria R.4,Perl Alexander5,Coutre Steven6,Erba Harry7,Stuart Robert K.8,Baccarani Michele9,Cripe Larry D.10,Tallman Martin S.11,Meloni Giovanna12,Godley Lucy A.13,Langston Amelia A.14,Amadori Sergio15,Lewis Ian D.16,Nagler Arnon17,Stone Richard18,Yee Karen19,Advani Anjali20,Douer Dan21,Wiktor-Jedrzejczak W.22,Juliusson Gunnar23,Litzow Mark R.24,Petersdorf Stephen25,Sanz Miguel26,Kantarjian Hagop M.2,Sato Takashi1,Tremmel Lothar27,Bensen-Kennedy Debra M.27,Small Donald28,Smith B. Douglas1

Affiliation:

1. Department of Oncology, Johns Hopkins University, Baltimore, MD;

2. Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX;

3. Roswell Park Cancer Institute, Buffalo, NY;

4. University of Maryland, Baltimore, MD;

5. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

6. Stanford University School of Medicine, Stanford, CA;

7. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI;

8. Medical University of South Carolina, Charleston, SC;

9. Bologna University, Seragnoli Institute of Hematology and Medical Oncology, Bologna, Italy;

10. Indiana University Simon Cancer Center, Indianapolis, IN;

11. Northwestern University Feinberg School of Medicine, Chicago, IL;

12. Universita La Sapienza, Rome, Italy;

13. University of Chicago Medical Center, Chicago, IL;

14. School of Medicine, Emory University, Atlanta, GA;

15. Department of Hematology, University Tor Vergata, Rome, Italy;

16. Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia;

17. Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel;

18. Dana-Farber Cancer Institute, Boston, MA;

19. Princess Margaret Hospital, Toronto, ON;

20. Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH;

21. University of Southern California Keck School of Medicine–Norris Cancer Center, Los Angeles, CA;

22. Departments of Hematology/Oncology & Internal Diseases, Medical University of Warsaw, Warsaw, Poland;

23. Department of Hematology, Lund Stem Cell Center, Lund, Sweden;

24. Hematology, Mayo Clinic, Rochester, MN;

25. Seattle Cancer Care Alliance, Seattle, WA;

26. Hospital Universitario La Fe, Valencia, Spain;

27. Cephalon, Inc, Frazer, PA; and

28. Oncology and Pediatrics, Johns Hopkins University, Baltimore, MD

Abstract

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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