Posted: Thursday, January 7, 2021
Targeting an Activating Mutation
Acute myeloid leukemia (AML) harboring an FMS-like tyrosine kinase 3 (FLT3) activating mutation is characterized by an aggressive clinical course and relative refractoriness to conventional chemotherapy.1,2 Until fairly recently, patients with this disease had few treatment options and a comparatively poor prognosis.3-5
Gilteritinib is an oral tyrosine kinase inhibitor that predominantly targets the FLT3 receptor tyrosine kinase, inducing both apoptosis and differentiation of leukemic cells.6 The pivotal ADMIRAL phase III randomized controlled trial found the drug to be efficacious and safe among adults with relapsed or refractory AML having a FLT3 mutation of the internal tandem duplication (ITD) type or of the tyrosine kinase domain (TKD) D835 or I836 type.7
Compared with subjects assigned to chemotherapy, patients assigned to gilteritinib had longer median overall survival (9.3 vs. 5.6 months; hazard ratio for death = 0.64; P < .001) as well as higher rates of complete remission with full or partial hematologic recovery (34.0% vs. 15.3%) and complete remission (21.1% vs. 10.5%). After the duration of therapy was taken into account following adjustment, those in the gilteritinib group had lower rates of adverse events of grade 3 or higher and of serious adverse events.
Gilteritinib is approved by the U.S. Food and Drug Administration (FDA) for use in patients with relapsed or refractory AML having a FLT3 mutation, as detected by an FDA-approved assay.6,8,9 Notably, it is the only tyrosine kinase inhibitor for AML that is approved as a single agent. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia (NCCN Guidelines®) list this agent for use in this patient population.10
Treatment of Aggressive Subtype of AML
“FLT3-mutated AML is the most aggressive subtype of AML. These patients have the most proliferative disease and the ones whom we worry the most about going from well to sick quickly,” commented Alexander E. Perl, MD, Associate Professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia, and a principal investigator on gilteritinib trials. “That aggressiveness just disappears within a couple of days of starting gilteritinib. It’s remarkable how quickly things turn off; the response is like a light switch. There have been many prior FLT3 inhibitors developed, but this is the most successful drug targeting FLT3 to come down the pike in terms of its ability to hit the target and avoid many of the resistance and tolerability problems that we’ve had with other drugs.”
This is the most successful drug targeting FLT3 to come down the pike in terms of its ability to hit the target and avoid many of the resistance and tolerability problems that we’ve had with other drugs.
“Patients take gilteritinib as a once-a-day pill. It’s compatible with most of their other medications, and the monitoring that we do is done in the office,” he told JNCCN 360. “People are surprised it can be this ‘easy’ to treat aggressive leukemia. This drug has been revolutionary in that regard; it has really changed our practice.”
“It has been great being a part of this drug’s development,” agreed Lisa McNey, NP, MSN, a nurse practitioner with the University of California, San Francisco (UCSF), Hematology and Blood and Marrow Transplant Program, which also participates in gilteritinib trials. “We were in on the ground floor and had a chance to see this evolution happen. We have come a long way, and it’s really exciting because these patients had such poor outcomes before we had the ability to hit the target.”
The drug has improved prognosis for this subset of patients, according to Ms. McNey. “I just saw a patient who was on the initial phase I trial, and nothing had worked for him; he had completely refractory leukemia. Gilteritinib therapy enabled him to receive his transplant. He is now many, many years out,” she reported. “Early on, I realized how potent this drug could be.”
About one-third of patients with newly diagnosed AML and with relapsed AML have a FLT3 mutation.11 “Look for the mutation, you’ll find it,” Dr. Perl told JNCCN 360. “The phenotype is rapid growth, meaning a white blood cell count that doubles quickly, and relapse. So, if you see that combination, think FLT3 mutation,” Dr. Perl observed. “Also, look for the mutation in patients who haven’t had it. People who have had a FLT3 mutation at initial diagnosis usually have it again at relapse. However, those who did not have it initially can acquire it after relapse as well.”
On the other hand, several factors are noteworthy for their lack of association with benefit from gilteritinib. “Allele burden is not a good predictor of response. You might think that if you have a lot of FLT3 mutation, you are more likely to have a response than if you did not have much. But we have not found that to be the case,” he elaborated. “Gilteritinib is still better than chemotherapy in both cases, so you really shouldn’t use allele burden to determine who should be treated.”
Similarly, FLT3 mutation type (ITD vs. TKD) should not influence its use. “The ITD mutations are more common and more sinister, but both types of mutations activate the kinase that gilteritinib targets, and both mutations respond to the drug,” Dr. Perl noted. Because TKD mutations are less common, the ADMIRAL trial lacked statistical power to show a superior response rate with gilteritinib in this subset, but the remission rates and survival were similar across mutation types. “I’m reasonably confident that these patients [ie, those with TKD mutations] can see a clinical benefit, and they should get the drug as a first approach,” Dr. Perl told JNCCN 360.
Findings from the ADMIRAL trial suggest that primary resistance to gilteritinib is rare, although few enrolled patients had previously received any FLT3 inhibitor therapy. “Today, that’s less commonly encountered because midostaurin is approved,” Dr. Perl reported. “I have treated people with gilteritinib who have previously received midostaurin, and they responded fine,” he continued. “Some people do develop resistance to FLT3 inhibitors that can extend past one drug to another, so they will be primarily refractory to gilteritinib, but that’s pretty uncommon.”
The recommended starting dose for gilteritinib is 120 mg once daily.6 “We start with this full dose, 120 mg,” Ms. McNey commented, “and observe how they do on that. We only dose-reduce if the patient is unable to tolerate that dose.”
Dose escalation up to 300 mg daily was tolerated in early-phase trials but is not discussed on the drug’s label. Dose escalation sometimes may be needed to overcome secondary resistance, according to Dr. Perl.
“Patients can develop F691L, a resistance mutation in FLT3 itself, which is structurally and functionally similar to the T315I mutation in BCR-ABL1 that causes drug resistance in chronic myeloid leukemia. When we see F691L emerge on gilteritinib or other FLT3 inhibitors, we know higher doses of gilteritinib are needed to inhibit the kinase,” he explained. “It’s not pan-resistance—you don’t necessarily have to change to a different drug—but 120 mg is not enough, and even 200 mg may not be enough. I try higher doses in patients who have blast growth on the drug to see if that will recapture response. Within a week or so of the higher dose, we’ll know if it is helping, or alternative therapy should be pursued.”
Clinical and Laboratory Monitoring
Patients receiving gilteritinib need ongoing clinical and laboratory monitoring. “We follow these patients very closely, especially initially—we typically see them at least once a week,” Ms. McNey said. “They need frequent monitoring for their blood cell counts and for side effects, as well as response to therapy.”
We follow these patients very closely, especially initially—we typically see them at least once a week.
“Blood cell counts will quickly reveal whether the patient is responding or not,” Dr. Perl stated. “The extremely rapid proliferation often stops within a few days. The blasts should clear within a week of starting this drug; if they do not, then you should think about possible resistance.” Leukemia-associated symptoms should also largely resolve within this time frame.
Blood cell counts will quickly reveal whether the patient is responding or not.
“In contrast, determining whether there is a response in the marrow could take months, so you shouldn’t give up too quickly,” he advised. The full 6 months recommended on the drug label6 is seldom needed, he pointed out, but the marrow response may deepen, and the peripheral response may continue to improve over time. “It’s not uncommon for patients to need a lot of transfusion support for a 1 or 2 months, but it tends to get better thereafter,” he told JNCCN 360.
Laboratory monitoring should include assessment of mutational status at disease progression. “I check for BCR-ABL mutations if someone has disease progression on gilteritinib, because we’ve seen that in occasional patients, and that’s something you can treat,” Dr. Perl explained. “I also follow the FLT3 mutations because if disease becomes resistant, I want to know if the mutation is still present or has disappeared. Also, I look for something else that might be targeted. I may then use the drug in combination, but more typically, I move on to other agents because some of those patients—particularly those in whom clones lacking FLT3 mutation are selected—will have a response to salvage chemotherapy, either with standard cytotoxic agents or with venetoclax and azacitidine.”
Preventing and Managing Adverse Effects
“Gilteritinib seems to be pretty well tolerated in the eligible patient population,” Ms. McNey reported. She noted that in her experience, dose reductions and treatment discontinuations have seldom been needed for adverse effects. “Most patients feel well on this medicine. They don’t have a lot of side effects, and most of the side effects are things we notice on lab results rather than symptoms patients might complain about,” Dr. Perl concurred.
Of note, gilteritinib does carry a boxed warning about differentiation syndrome, a potentially fatal condition that occurs in roughly 3% of patients and results from rapid proliferation and differentiation of myeloid cells.6 Treatment consists of corticosteroid therapy and hemodynamic monitoring until symptom resolution, but for at least 3 days.
In the ADMIRAL trial, the leading adverse events of grade 3 or higher with gilteritinib were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).7 “Patients need close monitoring for cytopenias. We should absolutely expect them,” Dr. Perl commented. “I usually do not dose-reduce for them, certainly not in the first couple of months of treatment, because it takes several months to see the best response, and you need to treat people long enough to see that happen.”
The course varies, with three main patterns, according to Dr. Perl. “In about one-third of patients, the cytopenias completely resolve and patients become transfusion-independent. In another third, the cytopenias stabilize and improve, but people may still need transfusions,” he said. “And in the last third of patients, transfusion needs can develop or worsen on gilteritinib, and they can require a lot of supportive care, or the blood cell count recovery can be suboptimal, even if they have relatively few leukemic blasts in the bone marrow.”
Patients receiving gilteritinib require monitoring for QT prolongation.6 In the ADMIRAL trial, 1 of 250 treated with gilteritinib had a QT interval exceeding 500 msec on the drug, and none had to stop the drug for this side effect.7 “However, that study enrolled people with normal cardiac function. If you start the drug in patients with a history of cardiac ischemia or arrhythmia, in those who take amiodarone, or in individuals with other factors that would put them at higher risk for QT prolongation, you have to be careful,” Dr. Perl cautioned.
More commonly, patients’ risk for QT prolongation increases because they are given other QT-prolonging drugs—often a quinolone antibiotic and/or an azole antifungal—along with gilteritinib. “That’s when you are going to see this, especially if there is an electrolyte abnormality,” he explained. “I have only rarely run into clinically significant QT prolongation, and when I see it, it’s usually from another drug and not from gilteritinib. I am more inclined to change those other drugs because of what we know about resistance to gilteritinib, which is that if you drop the dose too low, you are more likely to get on-target resistance, meaning the FLT3 mutation reactivates and the cells start growing again.”
Elevation of Liver Function Tests
A common adverse effect is minor elevation of liver function tests, particularly transaminase levels. On the ADMIRAL trial, 41.9% and 42.0% of patients experienced any-grade elevations of alanine aminotransferase and aspartate aminotransferase, respectively; however, 13.8% and 14.6% of patients experienced grade 3 or worse elevations of alanine aminotransferase and aspartate aminotransferase, respectively.7 “If the elevations are minor, I don’t do very much,” Dr. Perl said. “If they are grade 3, I will often reduce the dose from the standard dose of 120 mg down to 80 mg.”
GI Adverse Effects
Mild nausea is fairly common with gilteritinib therapy, and some patients will require antiemetics, according to Dr. Perl. More often, nausea is related to the hydroxyurea, which is used as a bridge to gilteritinib therapy.
“Mornings are hard for some patients receiving gilteritinib, from a GI perspective, but evenings may be better. Finding the time of day that works best is important. We work with patients to individualize the timing of drug administration—once daily, either in the morning or in the evening,” Ms. McNey noted.
In Dr. Perl’s experience, taste abnormalities are a more common adverse effect of gilteritinib. “It’s kind of a dysgeusia, but the food doesn’t taste bad—patients usually still have an appetite and still eat, but they say, the food doesn’t taste the way they expect,” he elaborated. “However, they like the fact that gilteritinib doesn’t give them nausea, the way chemotherapy does.”
“One side effect of gilteritinib that I’ve had to dose-reduce for is peripheral neuropathy, especially in patients who have had a prior allogeneic transplant,” Ms. McNey acknowledged. Many of these patients have preexisting peripheral neuropathy from exposure to calcineurin inhibitors such as tacrolimus, which may increase susceptibility.
“We have dose-reduced these patients from 120 mg to 80 mg, and they are usually able to tolerate that lower dose,” she said. “That’s helpful, now that we are using gilteritinib more after transplant.”
“We are really fortunate to have a strong clinical pharmacy team working with us at UCSF. They do a great job, especially with all the oral chemotherapy agents, and are usually part of the education process,” Ms. McNey explained. As a result, most of her patients come to their visit already having had some education about gilteritinib.
“We are also lucky to have social workers who assist patients and practice nurses who help obtain insurance approval and financial resources for patients,” she further noted. “In my mind, it usually takes a village to take care of patients with leukemia, so a multidisciplinary team is really the key to management.”
Notably, gilteritinib has also reduced the need for other professionals, according to Dr. Perl. “This is a much easier therapy requiring much less supportive care,” he pointed out. “We used to treat patients with relapsed and refractory AML in a hospital with toxic therapies that required a lot of supportive care. Today, my patients are treated with gilteritinib primarily in the outpatient setting. I don’t admit them to the hospital unless they are having complications, and those are usually complications of leukemia and not of treatment.”
Transplant and Maintenance Therapy
A few patients can achieve durable responses on gilteritinib, according to Dr. Perl. “But don’t expect this drug to cure AML as a single agent. Patients who respond still need a transplant,” he cautioned.
“If patients with relapsed or refractory FLT3-mutated AML are taken to transplant, in my opinion, they should have maintenance therapy after transplant,” Dr. Perl told JNCCN 360. Patients who go to transplant after FLT3 inhibitor salvage therapy and don’t receive maintenance have a high likelihood of relapse, even within a 1 or 2 months of engraftment, and sometimes within a few weeks,” he added. “So, as soon as they achieve engraftment, you have to get them back on gilteritinib,” he recommended.
Gilteritinib is also increasingly used in the maintenance setting at Ms. McNey’s center. “We are using it a lot now in the early posttransplant period because these patients with FLT3 mutations tend to relapse quickly post–allogeneic transplant—before day 100. So, we are moving toward introducing gilteritinib earlier after transplant, as soon as blood cell counts and symptoms indicate they will tolerate it,” she explained.
“Gilteritinib is going to continue to play an important role in the management of FLT3-mutated AML,” she predicted. “Going forward, I think it will be used in combinations based on different targets with other AML-targeted drugs.”
Alexander E. Perl, MD, has served as a consultant to AbbVie, Daiichi Sankyo, and Astellas and his institution have received research funding from AbbVie, Daiichi Sankyo, Astellas, Fujifilm, and Novartis.
Lisa McNey, NP, MSN, reported no conflicts of interest.
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- U.S. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). Available at https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools. Accessed December 13, 2020.
- Invivoscribe Technologies, Inc. LeukoStrat® CDx FLT3 Mutation Assay. Available at https://catalog.invivoscribe.com/product/leukostrat-cdx-flt3-mutation-assay-2/. Accessed December 13, 2020.
- Tallman MS, Pollyea DA, Altman JK, et al. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 2.2021. Accessed December 8, 2020. To view the most recent version of these guidelines, visit NCCN.org.
- Ravandi F, Kantarjian H, Faderl S, et al. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34:752–756.