Global Perspectives: FLT3 Inhibitors for AML - Episode 15
Naval G. Daver, MD: The RATIFY and QuANTUM-R trials are the first 2 large phase III studies that have shown positive outcomes in patients with FLT3 mutations. What is good about these 2 studies is they may actually target different patient populations since they don’t compete with each other. The RATIFY study basically shows that in a newly -diagnosed acute myeloid leukemia patient, where you would use standard induction with 3+7 or FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], the addition of an FLT3 inhibitor can improve both your overall response rate as well as your overall survival. We recommend most community doctors check for FLT3 mutation in their new AML patients and try to add a FLT3 inhibitor during induction, consolidation, and maintenance.
Another important finding from the RATIFY study is that transplants were allowed. Patients with FLT3­ mutations who received induction with midostaurin and transplants were the ones who had the best outcomes, so we think it’s really a 3-pronged attack. You want to check for FLT3 in all your patients recently diagnosed with AML and call that lab to expedite the process so you receive results in 7 or 8 days, after which midostaurin can be added. Additionally, you want to schedule a stem-cell transplant consultation early on, within the first few days of these people presenting, so that once you give them the induction and perhaps 1 consolidation and once they’re in remission—which about 70% to 80% will be—you can prescribe, very quickly, an allogeneic stem-cell transplant, whether it’s a sibling, matched, unrelated or haploidentical donor.
The third emerging finding, which is not yet clearly defined, is the recommencing of FLT3 inhibitor utilization post stem cell transplant. There are 3 phase II studies exhibiting a long-term survival of 75% to 85% in patients who are newly diagnosed with FLT3 mutations if all 3 interventions are administered. This is quite dramatic because 10 years ago, when we first looked at FLT3 and the outcomes, the overall 5-year survival rate was 25%.
The QuANTUM-R study now looks at a different group of patients—people receiving standard induction, whether it was 3+7, FLAG-IDA, decitabine, or 3+7 midostaurin—who for some reason never responded, this is called primary refractory, or who relapsed. If the patients were concurrently refractory and relapsed, one would say, “Well, what would I treat them with?” Historically, we didn’t have many choices, so we would just give them another cocktail of chemotherapy or perhaps use higher doses or different drugs like purine analogues or etoposide, hoping that somehow they’d work: which, experts have found, most often did not. The response rates were 10% to 20%. You would get much more toxicity because you were giving chemotherapy after chemotherapy.
According to the QuANTUM-R study, we can look at a single-agent FLT3 inhibitor in this situation. And, of course, there were already 2 phase II studies that were nonrandomized and showed that you could get 45% to 50% remission rates. If that were true, then this was clearly going to be better than using more chemotherapy in these people who had already failed chemotherapy. Indeed, that’s what was shown: When you randomize these patients and give them single-agent quizartinib versus more chemotherapy or more hypomethylating therapy, you are getting response rates of 50% versus 20% to 25% and improved tolerability and overall survival.
The goal of any patient with an FLT3 mutation is to receive a stem-cell transplant because whether you use an FLT3 inhibitor or chemotherapy—even if you get a response rate—most of these are short-lived, even with the FLT3 inhibitors. The secondary endpoint of the QuANTUM-R study was the increased rate at which patients received stem-cell transplants. As compared to only 12% of patients who received the “standard of care” chemotherapy or hypomethylating therapy, 30% of patients who received quizartinib were able to make it to stem-cell transplant. Thus, 3 times more people can receive stem-cell transplants, which is the only realistic chance of a long-term cure for these patients. All patients with relapsed AML should be tested for FLT3 mutations and administered the FLT3 inhibitor if positive. Quizartinib is the only one that was conclusively tested in QuANTUM-R. Gilteritinib is the other one that is being tested, and I think either of these could be very good options in the future.
Harry Erba, MD: The goal of our therapy in acute myeloid leukemia is cure for the majority of patients who are able to tolerate intensive chemotherapy, in addition to improvements in supportive care and allogeneic stem cell transplantation, donor availability, conditioning regimens, and the increased eligibility of patients for stem cell transplantation and intensive curative therapy. In other words, our goal really needs to be getting patients with these high-risk mutations into a durable remission, such that they may be a bridge to transplant or survive longer. I believe it’s going to happen by the movement of second-generation, more potent inhibitors such as quizartinib, gilteritinib, and crenolanib, which are the frontrunners in clinical development now into initial therapy. I think midostaurin has led the way with a type 1 first-generation drug showing some improvement in survival. I personally believe that it may be mostly due to the presence of the FLT3 mutation, but the improvement in survival was statistically significant but not as robust as we’d had hoped for our patients. We’re hoping to see better improvement in survival by moving these drugs up front.
I think there has been some very interesting phase I studies looking at the combinations of second-generation drugs like crenolanib with chemotherapy, showing not only very high response rates, but compared to historical controls with all the caveats there, the survival of patients appears to be superior when these patients are exposed to a second-generation drug.
Richard F. Schlenk, MD: The field has moved forward enormously by the specific FLT3 inhibitors. We have the multi-tyrosine kinase inhibitor [multi-TKI] midostaurin, now approved in Europe and the United States. It will be used in patients with newly diagnosed acute myeloid leukemia and this activating FLT3 mutation, comprising both internal tandem duplication [ITD] and a tyrosine kinase mutation. We already see that we will have a head-to-head comparison of midostaurin with a second-generation inhibitor such as gilteritinib and crenolanib in the first-line setting.
The field will move forward insofar as we know whether a patient will benefit more in the frontline setting from a specific inhibitor or a multi-agent or multi—tyrosine kinase inhibitor, and which is better: comparing midostaurin, for example, with gilteritinib and crenolanib. Secondly, we are progressing towards answering the question regarding the best consolidation therapy. Once a patient achieves a complete remission with a specific FLT3 inhibitor, what is the best consolidation therapy? Should we go to an allogeneic transplantation for everybody, or should we aim to have patients with a low mutant allelic ratio, for example, focusing on consolidation chemotherapy? Lastly, there is an important part in the RATIFY study covering the maintenance therapy, including crizotinib, which will also be done in the QuANTUM-First study; we do not know if it is necessary to keep the patients in complete remission and to prevent relapse.
There is also a new development that may be measurable residual disease, which will impact the post-remission treatment. Should maintenance therapy succeed it? We do not know for sure, which is why the results of new trials will change the landscape of treatment with patients with acute myeloid leukemia and activating FLT3 mutations.
Naval G. Daver, MD: The hardest-to-treat forms of AML include, in my opinion, about 3 or 4 different groups. One is the FLT3 ITD group. As I said, in the new FLT3 ITD patients about 10 years ago, the 5-year survival was 25%. Today, in some of our most recent updates from MD Anderson, MRC [Medical Research Council] Germany, and other United States groups, we’re getting 75% to 80% survival. So I think, in a way, the addition of FLT3 inhibitors, the appropriate use of stem-cell transplant, and potentially the use of post-stem cell transplant maintenance has converted what used to be a high-risk group to a neutral one. Perhaps in the future, with the use of more potent FLT3 inhibitors, it may actually become a favorable group. This is really quite amazing. This is where we can convert a negative prognostic factor to a neutral, and eventually positive, one. This is the hope of the personalized targeted therapy that we are seeing in the FLT3-mutated groups.
Now, there are other high-risk forms of AML where we don’t have the similar success story: these include TP53 [tumor protein 53]-mutated AML; AML with adverse or complex cytogenetics; or AML with other high-risk mutations such as ASXL1 and DNMT3A inversion 3. For many of these settings, there’s a lot of preclinical as well as early clinical research looking at new targeted agents or cytogenetically selected agents. But there’s nothing that is really changing the landscape and the survival outcomes for those patients like we’ve seen with the FLT3 ITD. This is a unique success story, that the addition of FLT3 inhibitors in frontline setting—now in relapsed setting—can dramatically improve your survival. These patients are no longer truly high-risk if we do everything appropriately for them.
Transcript Edited for Clarity