NEW YORK—Inhibitors of fms-related tyrosine kinase 3 (FLT3) show great promise in improving outcomes among acute myeloid leukemia (AML) patients, but are the drugs ready yet to be included into routine clinical care?
Speaking here at the Great Debates and Updates in Hematologic Malignancies meeting, two leukemia experts debated the value of FLT3 inhibitors for FLT3-mutated AML patients. And while the speakers took opposite sides, they both said they hoped that FLT3 inhibitors would eventually prove themselves to be effective and provide better medications to treat AML patients.
A pre-debate poll found three-quarters of the audience was also optimistic about the use of FLT3 inhibitors in the near future. However, after hearing the evidence presented by the two debaters, the audience became more circumspective about using these medications right now for AML patients.
Yes, FLT3 Inhibitors Improve Outcomes
Gail Roboz, MD, Director of the Leukemia Program and Associate Professor of Medicine at Weill Medical College of Cornell University, presented evidence supporting that FLT3 inhibitors will improve outcomes in FLT3-mutated AML in the near future.
She began by noting that FLT3 is a transmembrane tyrosine kinase receptor that stimulates cell proliferation. The FLT3-ITD mutation results in constitutive activation of FLT3. There is a high incidence of this mutation among normal karyotype AML (about one-third of patients), which is associated clinically with higher blast counts, increased relapse rates, more rapid relapse, and lower overall survival (about 15 percent at five years).
“There was an assumption from retrospective data that patients have to have a transplant if they have a FLT3 mutation,” she said. “This actually made it difficult to design clinical trials and know what to do with the FLT3 inhibitors.”
FLT3 signaling has been unraveled in a variety of pathways, and several FLT3 inhibitors are under development, including lestaurtinib, midostaurin, sorafenib, and quizartinib. “It's unlikely that there will be any one drug to treat AML,” Roboz said. “Brian Druker has said about CML that if you have a good target and a good drug, you will have a good outcome. We have a good target, but do we have a good drug yet? We need to find synergistic, complementary therapies.”
Quite a few of the drugs have already been tested in early trials, Roboz noted. The results show a need for sustained, effective inhibition of FLT3. A crucial disease property is dependence on the FLT3 pathway.
“We see blast reductions and evidence of biologic activity, but that activity is not sustained. Drug properties are critical to these compounds. It is also relevant to figure out if another drug reduces the FLT3 inhibitor from working properly. We don't know how to define response with FLT3 inhibitors. The usual way does not work, so we need to come up with a new world of clinical trial design.”
Survival after relapse for patients with FLT3- ITD+ AML is poor, she said. Overall survival is slightly higher for FLT3- patients than FLT3+ patients, but the difference is not significant. Marrow responses appear to be different among patients.
“The marrows look different in FLT3+ patients,” Roboz said. “Molecular negativity is not happening. Patients don't get their counts back.”
Turning to FLT3 inhibitors in development, she said that sorafenib is clearly active in this disease and in subsets of patients, but it does not lead to an improvement in overall survival. Perhaps the drug will be more successful when combined with other chemotherapies, she said, adding that clinicians do not yet know exactly how to use sorafenib in AML patients.
Treatments with lestaurtinib show no difference in complete response or overall survival. “To learn why [lestaurtinib] did not work we need to combine it with other agents,” she said. Midostaurin shows response rates, but “it has been difficult to accrue patients because they want to move to transplant.”
Quizartinib, or AC220, is a second-generation FLT3 inhibitor that is highly selective and potent, she continued. Quizartinib has a high response rate in relapsed/refractory FLT3-ITD+ AML and is very well-tolerated, with manageable toxicity, which includes reversible QT prolongation and myelosuppression, possibly related to KIT inhibition. Responses are clinically meaningful with durable disease control of five months or more.
“If FLT3+ patients get to transplant, quizartinib appears to help them live longer,” Roboz said. “More than one-third of patients can be bridged to transplant with quizartinib. This drug may not be the last therapy, but it will help get them to transplant.”
Future directions include a randomized two-dose study of quizatinib in relapsed/refractory FLT3-ITD+ AML that is currently accruing patients, and a Phase III randomized study is planned to start at the end of this year.
“Looking forward, the feeling is that we are helping people with FLT3 inhibitors,” said Roboz, who noted that salvage therapy using FLT3 inhibitors at MD Anderson Cancer Center has led to longer overall survival (about seven months), in particular for patients with a short first complete response and primary refractory disease.
Responses to sorafenib are longer and better after allotransplant, with about one-third of patients achieving a hematologic response, about one-quarter a complete response, and 10 percent a molecular response at a median of about 200 days.
In conclusion, Roboz said, “FLT3-ITD is a driver mutation, not a passenger mutation. We must be on the right track.”
No, FLT3 Inhibitors Not Ready for Prime Time ‘Any Time Soon’
The other debater, Richard Stone, MD, Director of the Adult Leukemia Program at Dana-Farber Cancer Institute and Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School, took the opposing side of the debate, saying that he would interpret the same data more conservatively.
“I believe that FLT3 inhibitors in AML are not ready for prime time any time soon,” he said.
Is FLT3 a viable target in AML? “A function of the target is that it should be required to maintain leukemogenesis. Inhibition of the target should kill the leukemia stem cell and allow normal physiology. On or off target side effects should be minimal.”
The central hypothesis for FLT3 inhibition in AML is that activated FLT3 contributes to a proliferative/survival signal, Stone explained. “There are two flavors of FLT3 mutations. One is an ITD mutation, which has poor prognosis, and the other is a point mutation, which occurs in five to 10 percent of cases of AML, and has neutral or a good impact on the disease. Relapse is more common with an ITD mutation. FLT3 is not a founder mutation.”
He added that not all ITD mutations are the same. Those patients who have a higher ratio of mutant to wild-type mutations seem to have a worse prognosis.
Some researchers believe inhibition of FLT3 may lead to therapeutic activity in AML that is similar to that seen with imatinib in CML blast crisis. “We hope that with more follow-up we will see the same activation as with TKIs in CML,” he said.
At the moment, “single-agent FLT3 inhibitors show biological activity, but insufficient clinical activity. The inhibitors are not potent enough, and enzyme inhibition is not prolonged. Other leukemogenic pathways are active, and the leukemic stem cell is in a protected niche.”
Potential solutions to these issues are new drugs, new schedules of existing drugs, combination therapy, and mobilization of the stem cell by altering the microenvironment.
Stone looked at study results for two FLT3 inhibitors, quizartinib and midostaurin. Quizartinib is a potent, selective FLT3 inhibitor that shows small improvements in complete response rates. Patients develop resistance to quizartinib, he noted, and a high percentage of AML patients who are not transplanted develop disease progression at about four months. Also, there have been adverse events problems, including QT prolongations, and patients may develop new FLT3 point mutations at a mean treatment time of 14 weeks.
“The question is will a safer, lower dose of quizatinib be as effective?” Stone asked. Combined with chemotherapy, quizartinib shows no added benefit, he said, adding that there is no role for quizartinib in combinations in relapsed AML.
The second FLT3 inhibitor, midostaurin, is a potent inhibitor of a spectrum of FLT3 mutants, showing impressive blast reductions, but few, if any, complete responses.
Additional quizartinib data will not be available until next year, he said, and midostaurin plus chemotherapy is under investigation in a randomized, Phase III trial, with final analysis still two years away. “We live in an era of limited resources. Before we use drugs that are expensive, we better be sure they are better than what is currently available,” Stone said, adding that it is important to use survival as the endpoint of these trials.
In conclusion, he said, “FLT3 is not as good a target as originally hoped. The major reason is there is a late hit in the leukemic progression cycle, not in the founder clone. Single-agent use is disappointing, with low response rates that are not durable. Even with higher response rates with quizartinib, there are issues with myelosuppression, QT prolongation, liver function tests, and emergence of tyrosine kinase resistance mutations.
“Analyzes of randomized trials of FLT3 inhibitors with and without chemotherapy have been negative—one trial with sorafenib in older adults, and the other with lestaurtinib in relapsed mutant FLT3. Others are not yet analyzed. I don't think FLT 3 inhibitors will be ready sometime soon. I hope something works. We have patients dying with AML and we need something better.”
The post-debate survey showed Stone to be the clear winner. Only about one-third of the audience favored using FLT3 inhibitors in AML patients, while half now said they would be cautious in using them for these patients.