We interviewed acute myeloid leukemia (AML) thought-leader Richard Stone, MD, of the Dana-Farber Cancer Institute to learn more about recent and ongoing clinical trials studying FLT3 inhibitors.
Can you please provide some background on the role of the FLT3 mutation in AML?
We have known for many years now that genetic mutations are involved in the pathogenesis of AML. FMS-like tyrosine kinase (FLT3) is one of the most commonly mutated genes in patients with AML, found in approximately 30% of patients with the disease. This occurs either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or via a point mutation in the tyrosine kinase domain (FLT3‑TKD).4‑6 FLT3-TKD mutations are less common, affecting approximately 7% of patients with AML, and do not have a characteristic clinical signature.7-9 The actual prognostic impact of the FLT3-TKD is less evident than that seen in patients with FLT3-ITD mutations. However, these mutations represent a critical mechanism of resistance to FLT3 tyrosine kinase inhibitors (TKIs), so their importance cannot be minimized.9,10 In patients ≤65 years of age with FLT3-ITD mutations, treatment with induction therapy can lead to remission, but remission durations are shorter with higher relapse rates compared to patients without FLT3 mutations. Relapsed disease is usually fatal in this patient population.
Can you review some of the key clinical trials surrounding pharmacologic agents targeting FLT3 in AML?
At this point in time, the race is on to find a small molecule inhibitor to treat patients with AML and FLT3 mutations and several are currently in clinical trials, including sorafenib and lestaurtinib. The FLT3 inhibitor midostaurin was approved in April 2017 “for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.”11
Sorafenib is an oral small molecule that has inhibitory properties against several kinases, including FLT3 and the vascular endothelial growth factor receptor that has shown promising activity against AML in clinical trials.12,13 Several studies have investigated the efficacy of sorafenib in combination with chemotherapy in the frontline setting, including Ravandi and colleagues, who demonstrated in a phase 1/2 trial that in combination with cytarabine, idarubicin, and sorafenib; sorafenib was associated with a complete response (CR) in 75% of patients ≤65 years of age with AML. Importantly, among patients with FLT3 mutated AML, 93% achieved CR.13 In another phase 2 study led by Dr. Ravandi, sorafenib in combination with azacytidine was associated with a response rate of 46% including 10 (27%) CRs. Among those treated, 64% achieved adequate FLT3 inhibition during the first therapy cycle, defined as >85% inhibition.14
The SORAML trial by Röllig and colleagues investigated the addition of sorafenib to standard induction and consolidation therapy in 267 patients who were newly diagnosed and ≤60 years of age.15 After a median of 78 months, among patients receiving the sorafenib-containing combination therapy, event-free survival (EFS) – the primary endpoint – was 26 months, compared with 9 months among patients receiving placebo. In addition, the risk reduction of relapse or death was 36% among patients receiving the sorafenib-containing combination therapy.
Conversely, in elderly patients with AML, sorafenib in combination with intensive chemotherapy (standard 7+3) and up to 2 cycles of intermediate cytarabine consolidation therapy did not lead to significant improvement in EFS or OS, including in the subgroup analyses, and including those harboring the FLT3-ITD mutation.16 In addition, sorafenib induction was associated with higher treatment-related mortality, lower rates of CR, and higher rates of toxicities.
Finally, when combined with daunorubicin- and cytarabine-based induction and consolidation chemotherapy in 54 patients ≥60 years of age with FLT3-mutated AML, sorafenib was associated with a 1-year OS of 62% for the FLT3-ITD group vs 71% for the patients with FL73-TKD-mutated AML. Median disease-free survival (DFS) and overall survival (OS) were 12.2 months and 15 months, respectively, for the FLT3-ITD group compared with 9.6 months and 16.2 months, respectively, for those with the FLT3-TKD mutation.17 At this point in time, sorafenib appears to mostly be used in medically unfit patients with AML who are not candidates for cytotoxic chemotherapy prior to hematopoietic stem cell transplant (HSCT).18
Lestaurtinib (CEP-701) is a novel receptor tyrosine kinase inhibitor (TKI) that selectively inhibits the autophosphorylation of FLT3. In an early phase 1/2 trial in 14 heavily pretreated patients with refractory, relapsed, or poor-risk AML expressing FLT3 mutations, five patients had clinical evidence of biological activity with lestaurtinib, along with measurable clinical responses that included reductions in blast in both the bone marrow and peripheral blood. These clinical responses were found to correlate with sustained FLT3 inhibition to this agent.19 In another study, lestaurtinib following chemotherapy was compared to chemotherapy alone in 224 patients with FLT3-mutant AML in first relapse from prior therapy. No difference in OS was seen between the treatment and chemotherapy control groups, and there was notable toxicity in those treated with lestaurtinib. FLT3 activity in the lestaurtinib patients was highly correlated with the remission rate. The overall conclusion was that lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival in patients with FLT3-mutant AML after first relapse.20 More recently, lestaurtinib in addition to front-line chemotherapy was studied in treatment-naïve patients (mostly <60 years old) with FLT-3 mutations. Participants received either oral lestaurtinib after 4 cycles of induction and consolidation chemotherapy or chemotherapy alone. No significant differences were observed in either 5-year OS or 5-year relapse-free survival (RFS). However, analysis of in vivo FLT3 inhibition demonstrated improved OS and significantly reduced relapse rates in patients treated with lestaurtinib who achieved a sustained FLT3 inhibition of >85%. The investigators concluded that lestaurtinib with intensive chemotherapy could be feasible for treatment of younger patients with newly-diagnosed FLT3-mutated AML, but still yielded no overall clinical benefit.21
Midostaurin (PKC412) is a multi-targeted kinase inhibitor originally developed as a protein kinase C inhibitor for treatment of patients with solid tumors.22,23 An early phase 2b trial of midostaurin (50 mg or 100 mg twice daily) by Fischer and colleagues involved 95 patients with AML or myelodysplastic syndrome (MDS) with either wild-type or mutated FLT3. Among patients with FLT3 mutations, 71% achieved a reduction by ≥50% of blasts in the bone marrow or peripheral blood (BM), as did 42% of those with wild-type FLT3. Both doses were well-tolerated with no differences found in either response rate (RR) or toxicity.24 Stone and colleagues performed a phase 1b study in newly-diagnosed patients between 18 and 60 years of age with wild-type and mutant FLT3 AML, combining midostaurin with an induction regimen of daunorubicin and cytarabine followed by high-dose cytarabine consolidation chemotherapy. A key finding was that the discontinuation rate on the 50-mg dose of midostaurin twice-daily dosing schedule was lower than for the 100-mg dose. Patients who received the lower dose achieved an 80% CR rate (74% of FLT3-wild type cases and 92% of those who were FLT3-mutant). OS probabilities at 1 and 2 years were similar for both FLT3 types.25 In the RATIFY trial, midostaurin plus standard induction/consolidation chemotherapy was compared to chemotherapy plus placebo. Among 717 patients with newly-diagnosed FLT3-mutated AML, 214 belonged to the FLT3-ITD-high subtype, 341 had low FLT3-ITD, and 162 had the FLT3-TKD mutation. Results demonstrated that both OS and EFS were significantly longer in the midostaurin cohort compared with those who received placebo. These results were consistent across all FLT3 subtypes, in both the primary analysis and a subgroup of patients who underwent HSCT.23 The results of this study led to the approval of midostaurin by the United States Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed FLT3-mutant AML in combination with chemotherapy. The drug is approved for use with a companion diagnostic mutation assay used to detect the FLT3 mutation.11
What other emerging agents and clinical trials surrounding FLT3 inhibition in AML are of particular interest?
Gilteritinib is a novel, small molecule inhibitor of two tyrosine kinases, FLT3 and AXL. This agent is currently in phase 3 development for treatment of patients with FLT3-ITD mutations. Preclinical data showed that gilteritinib in combination with azacytidine demonstrated superior antitumor activity than either drug used as monotherapy.26 Data from a phase 1/2 study showed that 75 patients among 265 enrolled had achieved a composite CR. The median duration of response to gilteritinib therapy was 17 weeks.27 The drug is currently undergoing investigation in multiple clinical trials.28 It has also been granted a fast-track designation by the FDA for treatment of FLT3-mutant relapsed/refractory AML.27
Crenolanib is a type 1, oral pan-FLT3 TKI that has shown promising single-agent activity against multiply relapsed FLT3-ITD and FLT3-TKD mutant AML. In a phase 2 safety/tolerability study of 19 patients < age 60 with newly-diagnosed FLT3-mutant AML, 93% achieved CR with this drug following 7+3 induction therapy and cytarabine consolidation chemotherapy.29 Follow-up data reported that 72% of patients achieved CR after 1 cycle of induction therapy.30 Additional data reported that CR with full count recovery was achieved in four patients who initially reported a response to crenolanib. These four patients had variant FLT2 mutations, with variant allele frequencies of up to 29%. Treatment with crenolanib was successful in eradicating these abnormalities per the lead investigator, Eunice Wang, MD, Chief of the Leukemia Service at the Roswell Park Cancer Institute.31
Finally, quizartinib (AC220) is an oral FLT3 TKI which has demonstrated good response in patients with mutant FLT3-ITD AML. A 2015 study by Hills and colleagues assessed 97 patients with FLT3-ITD disease who had received intensive chemotherapy, and had either relapsed following SCT, or who were relapsed or refractory following salvage therapy. The same criteria were applied to a database of UK Medical Research Counsel/National Cancer Research Institute patients treated intensively from 1988 to 2013 with the same mutation who only received intensive chemotherapy prior to fulfilling the eligibility criteria (n = 183; the historical cohort). Results demonstrated that OS was improved in patients who had received quizartinib. RR was 43% in the patients who received quizartinib vs 11% in the historical cohort. Median survival was 231 days for the treatment cohort compared to 60 in the comparison group for patients who relapsed post-ASCT; 128 days compared to 33 days, respectively, for relapsed patients; and 141 days compared to 61 days for refractory patients.32
In light of all of this research on FLT3 inhibition in AML, what would you consider to be the key takeaways for oncologists?
One, a new standard of care has likely emerged around mutant FLT3 AML in patients treated with 7+3 induction, where patients start midostaurin on day 8 through 14, and through day 22 during induction and consolidation. Two, there is an open question about the success of midostaurin, namely how much of that was due to inhibition of mutant FLT3 or just a general effect, because the drug also worked in patients with a rather low allele burden of FLT3 mutants. And three, the more specific inhibitors are being tested in the relapsed/refractory setting and these may soon be approved if the trials are positive for improving survival in that setting.
Finally, what do you see as the key take-home points for community oncologists around these agents?
Patients should have diagnostic material sent for assay of a broad array of potential mutations in AML, but definitely for FLT3 mutation, to see if the patient should receive these drugs; that's number one. Number two is they should be on the lookout for clinical trials of these agents which are going to become available in the next year, probably in the relapsed disease setting. And three, they should be aware that for most patients with FLT3-mutant AML, patients should be transplanted for disease remission if possible.
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- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
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- Levis M, Small D. FLT3: IT Does matter in leukemia. Leukemia. 2003;17(9):1738-1752.
- Anta A, Otrock ZK, El-Cheikh J, et al. Inhibition of FLT3 in AML: a focus on sorafenib. Bone Marrow Transplant. 2017;52(3):344-351.
- Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434-2439.
- Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113(4):983-988.
- Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013;2013:220-226.
- Smith CC, Wang Q, Chin CS, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485(7397):260-263.
- United States Food and Drug Administration. FDA approves new combination treatment for acute myeloid leukemia. (April 28, 2017). Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm555778.htm.
- Mori S, Cortes J, Kantarjian H, et al. Potential role of sorafenib in the treatment of acute myeloid leukemia. Leuk Lymphoma. 200849(12):2246-2255.
- Ravandi T, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11):1856-1862.
- Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23)4655-4662.
- Röllig C, Serve H, Huttman A, et al. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Updated results from long-term follow-up of the randomizes Soraml trial. Presented at the American Society of Hematology Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 721.
- Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110-3118.
- Uy, GL, Mandrekar SJ, Laumann K, et al. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017;1(5):331-340.
- Sammons SL, Pratz KW, Smith BD, et al. Sorafenib is tolerable and improves clinical outcomes in FLT3-ITD acute myeloid leukemia prior to stem cell transplant and after relapse post-transplant. Am J Hematol. 2014;89(9):936-938.
- Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103(10):3669-3676.
- Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117(12):3294-3301.
- Knapper S, Russell N, Gilkes A, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129(9):1143-1154.
- Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19(5):1485-1492.
- Stone RM, Manrekar BL, Sanford K, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
- Fischer T, Stone RM, DeAngelo DJ, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010;28(28):4339-4345.
- Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061-2068.
- Ueno Y, Mori M, Kamiyama Y, et al. Gilteritinib (ASP2215), a novel FLT3/AXL inhibitor: preclinical evaluation in combination with azacytidine in acute myeloid leukemia. Blood. 2016;128:2830.
- Harris J. FDA grants gilteritinib fast track designation for AML. (October 11, 1017) Available at: http://www.onclive.com/web-exclusives/fda-grants-gilteritinib-fast-track-designation-for-aml.
- ClinicalTrials.gov. (Gilteritinib Trials). Available at: https://www.clinicaltrials.gov/ct2/results?cond=Acute+Myeloid+Leukemia&term=Gilteritinib&cntry1=&state1=&recrs=.
- Wang E, Stone R, Tallman M, et al. Safety study of crenolanib, a type I FLT3 inhibitor with cytarabine/daunorubicin or cytarabine/idarubicin induction and high-dose cytarabine consolidation in newly diagnosed FLT3+ AML. (June 10, 2016). Available at: https://learningcenter.ehaweb.org/eha/2016/21st/133174/eunice.wang.safety.study.of.crenolanib.a.type.i.flt3.inhibitor.with.cytarabine.html?f=m2e968.
- Wang ES, Tallman MS, Stone RM, et al. Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Presented at: the American Society of Hematology Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 566.
- Welch A. Crenolanib shows promise in AML patients with variant FLT3 mutations. (August 21, 2017). Available at:http://www.onclive.com/web-exclusives/crenolanib-shows-promise-in-aml-patients-with-variant-flt3-mutations.
- Hills RK, Trone D, Burnett AK. Quizartinib significantly improves overall survival in FLT2-ITD positive AML patients relapsed after stem cell transplantation or after failure of salvage chemotherapy: a comparison with historical AML database (UK NCRI data). Blood. 2015;126:2557.