ADMIRAL: Gilteritinib as treatment for patients with relapsed or refractory acute myeloid leukaemia

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Published: 15 Apr 2019
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Prof Alexander Perl - University of Pennsylvania, Philadelphia, USA

Prof Alexander Perl speaks to ecancer at the 2019 American Association for Cancer Research (AACR) meeting about results from the ADMIRAL trial which looked at the use of gilteritinib as treatment for patients with elapsed or refractory acute myeloid leukaemia (AML) in comparison with standard chemotherapy regimens.

He explains that patients with relapsed or refractory FLT3-mutated AML have historically had a very poor prognosis, with chemotherapy treatment generally yielding low remission rates.

Prof Perl reports that the FLT3-targeted drug gilteritinib was compared with the best available current chemotherapy treatment, with response doubled in almost every metric looked at (in favour of gilteritinib).

Read more about this research here.

The presentation related to the final results of the ADMIRAL study which is a phase III registration trial for the FLT3 tyrosine kinase inhibitor gilteritinib. FLT3 is a gene that’s commonly mutated in AML, about a third of patients with AML have a mutation in this gene and the gene encodes tyrosine kinase that contributes to the oncogenic potential for these cells – it drives their growth, it is associated with very proliferative disease, very aggressive disease and unfortunately disease that often relapses after frontline chemotherapy and relapses quickly. So patients who go into remission don’t stay in remission and if they relapse they’re generally not cured. So it’s been very hard to treat patients with FLT3 mutations, particularly a type of FLT3 mutation called an internal tandem duplication or ITD mutation because that’s the one that’s actually the most sinister type of mutation of FLT3 and the one associated with the worst prognosis. So typically in patients who are candidates for very aggressive approaches, newly diagnosed patients with FLT3, ITD positive AML, get intensive chemotherapy, now they actually get a FLT3 inhibitor with their frontline therapy and then go on to bone marrow transplant.

This study enrolled patients generally that had that kind of an approach but then it was not successful. They either were patients that went into remission but it was briefly lived and fell out of remission or they never entered remission with frontline therapy. The question of what to do with these patients is really hard because for many, many years there have been a number of studies looking at what would be the best therapy for patients with relapsed or refractory AML and there has really been no agreement on what is the best way forward. Since we know that FLT3, being a tyrosine kinase, is something we can target with drugs there’s been a lot of interest in developing drugs that can target FLT3 and that could potentially improve outcome. One of the challenges is that every drug really to date that has tried to do that has always had limitations – either the drug is not potent enough, it doesn’t work as a single agent or it’s potent enough but it adds side effects or it works and it inhibits the kinase but you quickly see resistance. The resistance is something we can actually track and we know the mutations that confer resistance so we wanted a drug that would work both against FLT3 ITD and those mutations and that’s what gilteritinib is. So it basically ticked all the boxes of it works as a single agent, it is tolerable, it’s a pill, you take it in the outpatient setting and it has relatively few side effects. Patients generally feel well while on it, they do need supportive care while on it, it can cause cytopenias but it’s not a hard drug to take by any measure. So this study looked at the relative benefits of single agent gilteritinib versus best available therapy. Investigators on the study could choose from one of four different chemotherapy regimens – either highly intensive, really toxic chemotherapy that has to be administered in the hospital both for side effect monitoring and also supportive care, typically that requires a month of hospitalisation minimum, either MEC, which is mitoxantrone, etoposide, cytarabine, or FLAG-Ida, fludarabine, Ara-C, GCSF, idarubicin. Or they could receive low intensity cytarabine at low doses or azacitidine, all of which have been looked at in the relapsed and refractory setting. But the choice of salvage chemotherapy was locked in at the time prior to randomisation. Patients were randomised 2:1 to gilteritinib single agent versus the preselected investigator choice of chemotherapy. They were then followed for overall survival as the primary endpoint. Patients who responded and went on to transplant on the gilteritinib arm could stay on study and then basically go back onto gilteritinib after transplant as a maintenance therapy to prevent relapse. There was no crossover from the control arm to gilteritinib for patients who got standard therapy and it didn’t work or they responded and lost response.

So, if we look at the outcome from this study response was doubled for virtually every metric that we looked at. We saw twice as many complete remissions, more than twice as many complete remissions with either partial hematologic recovery or incomplete hematologic recovery. The duration of these remissions achieved on the gilteritinib arm were substantially longer, as was the therapy on that side. Patients on the gilteritinib arm stayed on the drug until intolerance or progression; patients on the chemotherapy arm were generally on for a cycle or two and then went on either to other therapy if it had been ineffective or they could go on to transplant if it had worked. When we look at how well the therapies worked the best marker of that was overall survival which was statistically significantly better in the gilteritinib arm with a 36% reduction in the hazard risk for death associated with gilteritinib therapy. The median overall survival in the gilteritinib arm was 9.3 months versus 5.6 months for the standard chemotherapy arm. It was also associated with a more than doubling of overall survival at one year after randomisation with 31% one year survival in the gilteritinib arm and 17% in the standard arm. Excuse me, I think 37% in the gilteritinib arm and 17% in the standard chemotherapy arm. So for all measures – response, survival and also toxicity – gilteritinib was better than the standard chemotherapy. It’s not to say there weren’t side effects in the gilteritinib arm, we did see cytopenias which were actually relatively common but they’re also expected for patients with leukaemia and it’s hard to sometimes know how much is drug related versus how much is treatment related. We did see asymptomatic elevation of liver function test with some frequency and we rarely, if ever, saw grade three toxicities that were drug related beyond that. We did see infections and that again is also expected in AML patients.

So, in general, what we’ve learned from this study is potentially less is more. We can use a less toxic therapy to get more in the way of better outcomes for a hard to treat population with a short expected survival. This is targeted therapy, we now have a target that is better than available alternatives and is currently approved. So we can change the standard of care right now based on these results and actually write our patients for what has been proven to be better therapy. That’s a very exciting result for me and the field and really something exciting to offer my patients.