Targeted Therapy Shifts AML Paradigm, But More Work Lies Ahead

Partner | Cancer Centers | <b>UT Soutwestern</b>

Prapti Patel, MD, discusses available and emerging treatment options for patients with acute myeloid leukemia.

Prapti Patel, MD

The use of next-generation sequencing in acute myeloid leukemia (AML) continues to expand as more targeted therapies emerge, giving patients the opportunity to receive treatment more suitable for their disease subtype, explained Prapti Patel, MD.

For example, FLT3 testing can determine whether patients with relapsed/refractory disease are eligible to receive gilteritinib (Xospata). Gilteritinib received FDA approval in November 2018 for the treatment of patients with relapsed/refractory FLT3-mutated AML, based on initial data from the phase III ADMIRAL trial. Updated data from the trial showed that gilteritinib significantly improved survival in patients with relapsed/refractory FLT3-mutated AML; the median overall survival was 9.3 months and 5.6 months for patients on gilteritinib versus salvage chemotherapy, resulting in a 36% reduction in the risk of death with the FLT3 inhibitor (HR, 0.64; 95% CI, 0.49-0.83; P <.001).

Other precision medicine efforts, such as the Beat AML Master Trial (NCT03013998), are evaluating investigational therapies or combination regimens to advance more targeted therapies for approval in AML.

Although the oncology community has made progress in the field of AML, curative regimens are still needed, which Patel said she is hopeful for.

“The future holds a longer remission and a better quality of life (QOL). With our current standard of care, patients are in and out of the hospital, and they're doing this for a very short period of remission,” said Patel. “The future has them out of the hospital, taking therapies, enjoying good QOL, and doing the things they would have done had they not been diagnosed with leukemia.”

In an interview during the 2020 OncLive®&#8239;State of the Science Summit on Hematologic Malignancies, Patel, an assistant professor in the Department of Internal Medicine, at Harold C. Simmons Comprehensive Cancer Center, of UT Southwestern Medical Center, discussed available and emerging treatment options for patients with AML.

OncLive®: Could you provide an overview of the Beat AML Master Trial findings?

Patel: The Beat AML Trial is important because elderly patients who get a diagnosis of AML don't have very good treatment options. The currently available treatment options tend to fail; patients cannot achieve remissions, or the therapies are too toxic. The point of this trial is to find novel therapies that are more effective and less toxic.

Generally speaking, the dogma has been that when patients are admitted for leukemia, we're starting chemotherapy within 72 hours and waiting for a remission. We now know that not all types of leukemia are the same. It's safe to get all the information to do diagnostic testing, see the molecular fingerprint, and tailor the therapy toward that “fingerprint” to make it more effective and less toxic.

The Beat AML study took about 300 patients and performed molecular testing. We proved that it's safe to wait 7 days and get all the information before making a treatment decision. The patients who were treated on this trial did very well compared with patients who were given standard-of-care chemotherapies.

Gilteritinib has been available for over 1 year now. What research led to its approval?

The initial data were presented at the 2019 AACR Annual Meeting and it compared patients with FLT3-positive disease, either the FLT3-ITD or FLT3-TKD mutations. Patients were randomized 2:1 to gilteritinib alone versus chemotherapy. Those patients were allowed to go on to transplant and, if they were randomized to the gilteritinib arm, they were also allowed to receive maintenance gilteritinib afterward. The response rates in the patients [on gilteritinib] were doubled compared with those who received chemotherapy alone, indicating that we now have an oral targeted therapy for this patient population.

[Gilteritinib] is less toxic because it's targeted. Patients who received transplant were treated with a therapy that wasn't as toxic, meaning they weren't as beat up before going into transplant. They were able to tolerate the transplant better and have an option for maintenance therapy to prevent relapse after transplant, which is a real concern for patients who have this aggressive FLT3 mutation.

Is there potential for gilteritinib to move into earlier lines of therapy?

Some groups of patients with other comutations, such as NPM1 or DNMT3A, that do better with gilteritinib compared with chemotherapy alone. The margin of improvement with gilteritinib is so great that it makes us wonder: if these patients with this co-mutation profile received gilteritinib up front, would they even need a transplant? Would they have long-term remissions?

The FDA issued a complete response letter to an application for quizartinib in 2019. Does this FLT3 inhibitor still have a future in AML?

There is a lot of space for FLT3 inhibitors because we still haven't found a long-term [fix]. When you look at the tail of the survival curves for any of these FLT3 inhibitors, it tapers off, and we don't have any long-term survivors. The space is still open for a lot of these other FLT3 inhibitors to be looked at up front in the relapsed/refractory setting. Patients with RAS mutations tend to be resistant to gilteritinib and any other FLT3 inhibitors. Novel agents have that [refractory] space to fill.

What other biomarkers are being investigated in AML besides FLT3 and IDH?

We look at other biomarkers when we do the comutation profile. The mutations WT1, DNMT3A, and NPM1 show that there is a difference in response rates when compared with chemotherapy.

The other thing that we look at is mutational burden. Patients with a higher mutational burden do better with targeted therapy than those with lower mutational burden. This shows that a targeted therapy is going to work in patients who have inherently poor prognoses.

Moving onto myelodysplastic syndromes (MDS), could you discuss the MEDALIST trial?

Some phase II data showed that patients with low-risk MDS who were refractory to erythropoiesis-stimulating agents (ESAs) had a response and became transfusion independent within 8 to 12 weeks. Patients with low-risk MDS who had ring sideroblasts did better in that phase II trial. The phase III MEDALIST trial looks at that subgroup of patients with low- to intermediate-risk MDS with ring sideroblasts who are refractory to ESAs. That population of patients did very well and became transfusion independent within about 8 weeks, which was shown to be long term.

The long-term data showed that a good percentage of patients who dropped off and started to need transfusions again, which was concerning. The next [step] for this [research] is finding new drugs that can give you a longer period of transfusion independence. At UT Southwestern Medical Center, we have a clinical trial looking at the telomerase inhibitor imetelstat in patients who are refractory to ESAs. We're trying to see whether we can maintain long-term transfusion independence for those patients.

Luspatercept is under review for this indication currently. If it receives approval, what impact do you expect this drug to have?

[This agent is] going to have a huge impact on clinical practice because once ESAs fail, there's no other option for patients except chemotherapy with decitabine or azacitidine. Those drugs, although [are “light” chemotherapy] or low-dose, have quite a bit of associated morbidity and mortality. [Luspatercept] is a great option for patients with low-risk disease [because their] survival is over 7 to 10 years, but their quality of life is poor because they're transfusion dependent.

Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the phase III ADMIRAL trial. N Engl J Med. 2019;381:1728-1740. doi: 10.1056/NEJMoa1902688.