Adding the FLT3 inhibitor lestaurtinib to standard firstline chemotherapy in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) does not improve survival rates, according to an analysis of data from two large, prospective, multicenter, phase III trials published in Blood by Steven Knapper, MD, from the Department of Hematology at the Cardiff University School of Medicine in the United Kingdom, and co-authors.
The researchers analyzed data from the AML15 (which assessed different chemotherapy regimens and gemtuzumab ozogamicin in patients <60 years who had AML) and AML17 (which assessed best chemotherapy with or without molecular intervention and risk-directed chemotherapy in patients with AML, myelodysplastic syndrome [MDS], and acute promyelocytic leukemia) studies of patients with previously untreated AML or high-risk MDS. More than 130 centers in the United Kingdom, Denmark, and New Zealand participated in the two studies between May 2002 and December 2014. Between January 2007 and October 2012, patients with FLT3 mutation were randomized to receive lestaurtinib in combination with firstline chemotherapy or to chemotherapy alone. This patient cohort was younger (<60 years old), though older patients were considered for inclusion if they were deemed suitable for intensive chemotherapy.
A total of 500 patients (median age = 49 years; range = 5-68 years) were randomized and included in the analysis: 175 patients from AML15 and 325 patients from AML17. Seventy-four percent (n=370) had internal tandem duplication (ITD) mutation alone; 23 percent (n=115) had tyrosine kinase domain (TKD) mutation alone; and 2 percent (n=11) had both.
Ninety-four percent of patients had de novo AML, 5 percent had secondary AML, and 1 percent had high-risk MDS.
Induction (treatment cycles 1-2) consisted of cytarabine, daunorubicin, and etoposide (ADE); daunorubicin and cytarabine (DA); or fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida) with or without gemtuzumab ozogamicin. Consolidation therapy (treatment cycles 3-4) included 1.5 g/m2 or 3 g/m2 of high-dose cytarabine or MACE/MidAC (mitoxantrone and cytarabine).
Lestaurtinib was administered 48 hours after completion of cycle 1 of induction therapy, for a maximum of four 28-day cycles. The initial dose was 80 mg administered orally twice daily with 12 hours between doses. If that was well tolerated, a maximum dose of 100 mg administered orally twice daily was permitted after cycle 1.
As of March 1, 2015, the median follow-up was 50.5 months (range = 1.3-97 months). Patients received a median of three cycles of lestaurtinib (range = 0-4 cycles).
The five-year overall survival (OS) and five-year relapse-free survival (RFS) rates, the study’s co-primary endpoints, were similar in the lestaurtinib-treated and the chemotherapy-alone groups:
- 5-year OS: 46% vs. 45% (hazard ratio [HR] = 0.90; 95% CI 0.70-1.15; p=0.3)
- 5-year RFS: 40% vs. 36 (HR=0.88; 95% CI 0.69-1.12; p=0.3)
See TABLE for comparison of treatment outcomes.
“Only marginal differences in toxicity were seen between the lestaurtinib and control arms,” the authors reported. “There were moderate increases in nausea and diarrhea with lestaurtinib in the first two courses of treatment.” Patients treated with lestaurtinib were more likely to require antibiotics, and there was a slightly higher need for supportive care, which was associated with a two-day increase in median time to platelet recovery (p=0.01). There also was no significant difference in early (30-day or 60-day) mortality between the two treatment arms.
The researchers estimated the degree of FLT3 inhibition by measuring trough FLT3 plasma inhibitory activity (PIA), trough plasma concentration of lestaurtinib, and FLT3 ligand (FL) levels from whole blood samples in 83 patients. Sustained FLT3 inhibition (FLT3 PIA >85%) was observed in 73 percent of all evaluated time points (n=118/161).
Eighty-two percent of lestaurtinib-treated patients (n=68/83) achieved FLT3 inhibition (at least one FLT3 PIA measurement >85%), with 64 percent (n=53/83) showing >85 percent inhibition at all time points. Patients who experienced FLT3 inhibition had lower rates of relapse (43% vs. 68%; HR=0.44; 95% CI 0.23-0.86; p=0.02), leading to significantly better OS among these patients (60% vs. 33%; HR=0.50; 95% CI 0.26-0.97; p=0.04). Mean day 14 FLT3 FL concentration increased through successive courses of lestaurtinib, from 496 pg/mL during cycle 1 to 1,467 pg/mL, 2,565 pg/mL, and 2,720 pg/mL during cycles 2-4, respectively (p<0.0001).
“There was a clear relationship among patients who demonstrated sustained inhibition of FLT3 and significant improvement in OS and reduction in relapse frequency,” Dr. Knapper told ASH Clinical News. He noted that the fact that lestaurtinib failed to add any significant benefit over standard chemotherapy is a limitation of the study’s findings, but added that “these results reinforce FLT3 as a therapeutic target, because they show that if sustained inhibition is achieved, there is a significant benefit. These data provide a lot of encouragement for the FLT3 studies going forward with a better compound and more favorable pharmacokinetics.”
ASH Clinical News spoke with Mark Levis, MD, PhD, from the Division of Hematological Malignancies at Johns Hopkins Sidney Kimmel Cancer Centre in Baltimore, Maryland, and a co-author of the study, about placing the results of this study in the context of results from the RATIFY trial, which found that addition of the FLT3 inhibitor midostaurin to standard chemotherapy improved five-year OS (51% vs. 43%; p=0.007) in a similar patient population. “Lestaurtinib, like midostaurin, is a pan-kinase inhibitor, but one that is even less selective, or more pan-inhibitory,” Dr. Levis explained. “When we studied lestaurtinib in the relapsed setting, the correlative data indicated that whatever benefit the drug provided was offset by the toxicities it created. I think the field is moving in the direction of more specific, more potent FLT3 inhibitors, which will probably be better tolerated as well.”
Knapper S, Russell N, Gilkes A, et al. A randomised assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy from FLT3-mutated acute myeloid leukemia. Blood. 2016 November 21. [Epub ahead of print]
|TABLE. Comparison of Treatment Outcomes With Lestaurtinib|
|AML15 Trial||AML17 Trial||Overall HR/OR||p Value for heterogeneity by trial|
|Lestaurtinib||Control||HR/OR||p Value||Lestaurtinib||Control||HR/OR||p Value|
(95% CI 0.40-3.28)
(95% CI 0.61-4.08)
(95 %CI 0.67-2.77);
(95% CI 0.26-8.63)
(95% CI 0.43-49.9)
(95% CI 0.54-9.14); p=0.3
(95% CI 0.30-5.88)
(95% CI 0.87-25)
(95% CI 0.76-7.02); p=0.1
(95% CI 0.63-1.38)
(95% CI 0.64-1.21)
(95% CI 0.70-1.15); p=0.4
|5-year OS censored at HCT||51%||41%||0.80
(95% CI 0.48-1.33)
(95% CI 0.67-1.47)
(95% CI 0.67-1.25); p=0.6
(95% CI 0.63-1.15)
(95% CI 0.57-1.09)
(95% CI 0.66-1.10); p=0.2
(95% CI 0.28-1.71)
(95% CI 0.69-4.57)
(95% CI 0.58-2.03); p=0.8
(95% CI 0.62-1.36)
(95% CI 0.64-1.16)
(95% CI 0.69-1.12); p=0.3
|AML = acute myeloid leukemia; HR = hazard ratio; OR = odds ratio; ORR = overall response rate;
CR = complete remission; CRi = complete remission with incomplete count recovery; OS = overall survival; HCT = hematopoietic cell transplantation; CIR = cumulative incidence of relapse;
CIDCR = cumulative incidence of death in remission; RFS = relapse-free survival