FLT3 Inhibitors in Older Patients with Acute Myeloid Leukemia: More Questions Than Answers?

Chief of staff and director of the Adult Acute Leukemia Program at the Dana-Farber Cancer Institute in Boston, Massachusetts
Director of the Leukemia Program and professor of medicine at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia

Acute myeloid leukemia (AML) affects primarily older adults (with a median age of 67 years at diagnosis), and management of the disease in this population represents a therapeutic challenge – given their comorbidities and susceptibility to treatment-related toxicities. Patients who also harbor the FLT3 mutation face a particularly poor prognosis, with a high chance of relapse and a limited number of treatment options. However, several FLT3 inhibitors are under investigation and could provide alternative treatment options for these patients.

ASH Clinical News invited Richard M. Stone, MD, and Selina M. Luger, MD, to debate the question: “Should older patients with FLT3-mutated AML be treated with FLT3 inhibitors?” Dr. Stone will be arguing on the “pro” side, while Dr. Luger will be arguing on the “con” side.


Richard M. Stone, MD: Dr. Luger, I’m sure we can both agree that, in general, older adults with AML present a difficult treatment challenge. They do not tolerate the standard 7+3 regimen with cytarabine and daunorubicin as well as younger adults with the same disease. Also, older patients have a more intrinsically resistant disease than their younger counterparts. Historically, this has been a difficult area to treat.

Selina M. Luger, MD: Absolutely. In my opinion, once a physician decides a patient needs to be treated, the best therapy has always been the same therapy that you would give to a younger patient, but not all older patients can tolerate that. Full-dose 7+3 induction therapy, regardless of age, requires an in-patient hospitalization. The dosing is what we would consider full-dose therapy, and neither dose nor dosing schedule should be adjusted for age. Depending on a patients’ age, however, there is a higher chance of toxicity from the therapy, a lower chance of remission, and a higher chance of relapse.

Physicians tend to be hesitant to use the same standard treatment approaches for younger patients as they do in older patients, for fear that older patients will not tolerate the therapies as well as their younger counterparts. However, giving attenuated doses, as well as palliative chemotherapy, results in inferior outcomes – even in the short term – for AML patients who would otherwise be able to receive standard induction. In older patients we have never been able to show that there is a benefit – either early or late in treatment course – with lower-intensity treatment when compared with standard induction.

With older AML patients, the challenge lies in identifying those who can best tolerate the therapies we have available and in developing new therapies that will work as well, but with fewer safety concerns.

Dr. Stone: Another concern is that we simply do not have a cut-off age for what we consider “older” patients – is it older than 55, 60, or 65 years old? All of these different ages have been defined as older patients in clinical trials.

Along those same lines, not every 70-year-old patient with AML is the same, and one person’s AML is not the same as another person’s AML. Patients’ prognosis has more to do with their biology and disease biology than anything else.

Older adults with AML tend to have a less proliferative disease and chromosomal abnormalities that are associated with unfavorable outcomes, like monosomal or complex karyotypes. And, regardless of a patients’ age, the presence of FLT3 mutations is associated with increased white blood cell counts, a slightly higher initial response to chemotherapy, and a different disease biology.

Dr. Luger: Also, in patients with and without FLT3 mutations, we see a clear distinction in outcomes among younger patients. Patients without FLT3-ITD mutations clearly have a better outcome. In older adults, the difference in outcomes for FLT3-mutated patients is not as obvious. So yes, for all the reasons we discussed, AML in the older patients is a challenge overall – not just in the FLT3-mutated patient population.

Dr. Stone: I think, at this point, the questions physicians have to ask are, “Have we come to the point in the treatment of AML in older adults – or any-age adults, for that matter – when we can use genotype-specific therapy? Is it time to routinely add a kinase inhibitor to the standard chemotherapy given to older patients with FLT3-mutated AML?” I think the answer is a qualified “yes,” but not a very strong one.

Dr. Luger: Well, before we can commit to using a FLT3 inhibitor in any patient population, we need more data. We have seen several generations of FLT3 inhibitors, with the initial agents in this class developed for purposes other than FLT3 inhibition. Sorafenib, for example, is a multi-kinase inhibitor, with FLT3 being one of its targets. Achieving meaningful FLT3 inhibition with one of these multi-kinase inhibitors required high doses, which led to inhibition of other tyrosine kinases and a higher number of toxicities.

Newer generations of FLT3 inhibitors are more targeted. None of them, though, are free of side effects. Three of these drugs in development – quizartinib, gilteritinib, and crenolanib – have unique toxicity profiles and targeting abilities. Each has been studied in relapsed disease and has induced a leukemia-free state with tolerable toxicity.1,2,3 They are now being studied in randomized trials in patients with relapsed disease and are, or soon will be, evaluated as part of induction chemotherapy in patients with untreated AML. Hopefully, these trials will provide more information about the role of FLT3 inhibition in patients with AML.

To date, no FLT3 inhibitor has – as a single agent – resulted in a complete remission or normal hematopoiesis in patients with AML, and no FLT3 inhibitor combined with other drugs has contributed to an overall survival (OS) benefit in older patients in a randomized trial. Right now, we are at the “tolerable” stage, rather than the “superior” stage with these data.

Dr. Stone: True, we do not have much data in the setting of older AML. The only real data to suggest that we should be using a FLT3 inhibitor, along with chemotherapy, in older patients are from the RATIFY trial, which I presented at the 2015 ASH annual meeting.4 Only patients aged 18 to 60 years old, with a median age of 48 years, were included in the trial, but, in the absence of definitive data, we have to extrapolate from the data we do have.

In this phase III trial, 717 patients (341 FLT3-ITD with low mutant fraction; 214 FLT3-ITD with high mutant fraction; 162 with FLT3-TKD) were randomized to receive a standard 7+3 regimen with placebo or the investigational FLT3 inhibitor midostaurin (administered orally at a dose of 50 mg twice-daily on days 8-22). Post-remission therapy consisted of high-dose cytarabine, plus midostaurin or placebo. Patients then received one year of maintenance therapy with midostaurin or placebo.

There was a survival benefit for patients who received midostaurin compared with those who received placebo. The median OS was significantly longer (74.7 months vs. 25.6 months; p=0.007), and the median event-free survival more than doubled (8 months vs. 3 months; p=0.004).

Again, older patients were excluded, but the finding that midostaurin improved outcomes in all different subtypes of the FLT3 mutation was promising, and suggests that we could explore the safety and efficacy of midostaurin in different AML populations.

Dr. Luger: RATIFY was a remarkable study for patients with FLT3-mutated AML, who desperately need more treatment options. There are still many unanswered questions, though.
For example, we do not know exactly how midostaurin worked – whether it worked primarily as a FLT3 inhibitor or if it worked by enhancing the effect of the anthracycline. Therefore, we do not know whether these targeted drugs are really the best approach for this patient population. And, even if we had data that showed midostaurin exerted its effect through FLT3 inhibition, we do not know if it is the right FLT3 inhibitor to use.

And, since treatment toxicity is a primary concern in older patients with AML, the fact that we do not know whether midostaurin’s toxicity profile changes in older patients versus younger patients is another issue.

Dr. Stone: We will have to conduct multivariate analyses of different age groups to see if patients benefitted similarly. If we find that the older RATIFY patients (40-60 years old) benefitted equally to the younger adults (18-40 years old), then we could easily make the case that patients up to age 70 might benefit similarly when midostaurin is added to the standard 7+3 regimen.

Midostaurin is a multi-kinase inhibitor, and, as we mentioned earlier, we won’t know whether a more targeted FLT3 inhibitor would be better until we have head-to-head trials comparing these agents. Also, we don’t know if midostaurin works in patients with low ITD burden; based on the available data, it is possible that it could be effective in patients with zero mutant FLT3. That’s not to mention the older patient question, which is still wide open.

Midostaurin is not yet approved by the U.S. Food and Drug Administration, but I would expect that it will soon be approved in patients with FLT3-mutated AML who are 18 to 60 years old. Future trials will have to answer the questions, “Does it make sense to extend the drug label to include older people who are already planning to receive chemotherapy? Should the label include any patient who is going to receive 7+3, or only patients younger than 60?”

Dr. Luger: Without answers to these questions, we have to rely on the standard approaches for FLT3-mutated AML, including 7+3 chemotherapy and allogeneic hematopoietic cell transplantation (alloHCT). AlloHCT is reserved for a certain group of eligible patients, but we need to explore how old is too old for a patient to undergo transplant? The accepted limit seems to be up to 75 years, which is similar to the cut-off age for induction therapy. A retrospective analysis looking at FLT3-ITD-mutated patients actually provided data that these patients have a survival benefit when they undergo alloHCT.5

The potential benefit of transplant in these patients leads to another unanswered question about FLT3 inhibitors: Is one of their benefits that these agents can get patients to transplant? Transplant ultimately may be what these patients need, and we should use whatever agents we have to maximize their chances to get to transplant.

Dr. Stone: I agree that these patients need to be transplanted. Virtually all patients with the FLT3-ITD mutation in first remission should receive a transplant, no matter their age. There is a caveat revealed by European data that showed that patients with a low FLT3-ITD ratio and an NPM1 mutation might not need to be transplanted.6 Again, hopefully we will get more data about FLT3-TKD mutations and transplant from the RATIFY trial.

I would note that the RATIFY data showed that midostaurin benefited patients even if they had received transplant at first remission. To achieve maximum therapeutic benefit, according to the RATIFY data, it still might be a good idea to use a FLT3 inhibitor like midostaurin in these patients. But, for the time being, I would say that transplant is still part of the equation for patients with FLT3-mutated AML.

Dr. Luger: We simply need more studies. We know FLT3-ITD-mutated AML, whether in young or old patients, carries a poor prognosis, and we know we need to find new therapies. If the FLT3 inhibitors fill that need, that would be wonderful, but we need to continue the search for ways to improve on the AML therapies we have.

Dr. Stone: I agree – every clinical question surrounding FLT3 inhibitors in older patients with AML still needs to be answered. Even though we think we have proven that midostaurin should be added to chemotherapy in the younger population in the RATIFY trial, it was not powered to look at patient subsets, so we are still going to ask if this treatment benefits everyone equally when the final data are available.

Dr. Luger: The number of clinical questions remaining highlights the challenges of doing these types of studies in this patient population. These are very complicated trials that require a lot of resources. For example, we used to make decisions based on age, organ function, and cytogenetics. Now, we need to know patients’ FLT3 status to decide if they should be enrolled in an FLT3 inhibitor trial, then we need to know whether they have a high or low ITD burden and what their NPM1 mutation status is. The more we learn, the more we want to know.


References

  1. Hills RK, Gammon G, Trone D, Burnett AK. Quizartinib significantly improves overall survival in FLT3-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.
  2. Altman JK, Perl AE, Cortes J, et al. Antileukemic activity and tolerability of ASP2215 ≥80 mg in FLT3 mutation-positive subjects with relapsed or refractory acute myeloid leukemia: results from a phase 1/2, open-label, dose-escalation/dose-response. Abstract #321. Presented at the American Society of Hematology Annual Meeting, December 6, 2015; Orlando, FL.
  3. Cortes JE, Kantarjian HM, Kadia TM, et al. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. Abstract #7008. Presented at the American Society of Clinical Oncology Annual Meeting, June 4, 2016; Chicago, IL.
  4. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Abstract #6. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, FL.
  5. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735-41.
  6. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2015;106:3658-65.

Disclaimer: The following positions were assigned to the participants and do not necessarily reflect ASH’s opinion, the participants’ opinions, or what they do in daily practice.

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