Novel Therapies in AML

Gail Roboz, MD, Weill Cornell Medicine & NewYork-Presbyterian Hospital, summarizes her presentation on novel therapies in acute myeloid leukemia (AML) at the 2019 Lymphoma & Myeloma Congress.

Transcript

My name is Dr. Gail Roboz. I'm a professor of medicine and director of the Leukemia Program at Weill Cornell Medicine and the NewYork-Presbyterian Hospital.

In today's meeting, I had a pretty big job of going over novel therapies in AML. I wanted to summarize a little bit of what was discussed. On the intensive front, for younger and more fit patients, we discussed a variety of things that have actually beaten standard 7+3.

7+3 has been the backbone intensive regimen for AML for decades, and there are a couple of additions to that that have actually optimized outcomes for selected patients. For example, for those patients with FLT3 mutations, the addition of midostaurin to 7+3, resulted in an overall survival benefit with acceptable toxicity. This has become the standard of care for FLT3 mutated younger patients.

That said, the RATIFY trial which actually resulted in approval was treating patients up to age 60. In a recently published trial by the German AML Study Group, patients were treated in a similar manner to RATIFY, using midostaurin in combination with 7+3, up to age 70.

Actually, this is a feasible regimen for selected older patients who are in good shape. That trial also continued to use midostaurin in a maintenance setting.

The drug is not approved for that in the United States, but we still have that as an unanswered question of whether FLT3 mutated patients, either with or without stem cell transplant, should be treated with FLT3 inhibitors. If so, which one?

The other standard therapy backbones that I discussed, were actually in two randomized trials, so 7+3 versus 7+3 plus gemtuzumab ozogamicin, and 7+3 versus CPX-351. In the first one that I mentioned, the alpha trial was a comparison of 7+3 versus 7+3 plus Gemtuzumab.

This is in a fractionated and lower dose schedule than what was previously approved in 2000 when gemtuzumab initially became available. In this lower dose unfractionated schedule, the combination with 7+3 resulted in an event-free survival benefit, in patients ages 50 to 70.

While many centers have adopted the addition of gemtuzumab to 7+3 as standard of care, it's a bit controversial who exactly should be included in the patients who get gemtuzumab, in addition to standard therapy.

What's less controversial though, is the application of gemtuzumab in patients with core-binding factor AML. For them, adding gemtuzumab to 7+3 in core-binding factor patients is the standard of care, with improved overall survival for a substantial percentage of those patients.

In the third trial, the standard backbone therapy 7+3 was compared to CPX-351, which is a liposomal formulation of 7+3. Here, the goal was to optimize drug delivery. It worked, because in this randomized trial, there was a survival benefit of CPX-351, most specifically seen in patients with myelodysplasia related changes and those with secondary AML.

This agent represents a new standard for those subtypes of AML, which are particularly difficult to treat and traditionally associated with poor outcomes.

Another thing that I mentioned in the context of standard intensive chemotherapy, was the recent press release announcing the final results from the QUASAR trial, which was a phase 3 randomized international placebo-controlled trial using oral azacitidine or CC-486, as maintenance therapy for patients who are treated with conventional 7+3 induction plus or minus consolidation.

There, what the press release has shown so far, was a survival benefit, an overall survival benefit, and a relapse-free survival benefit, for maintenance treatment with oral azacitidine. We're hopeful that more data from this exciting study will be presented at the ASH meeting coming up in December 2019.

Moving on to less intensive induction strategies, I discussed the approval of glasdegib in combination with low-dose cytarabine, which yielded improvements over low-dose Cytarabine alone for older patients with AML, who weren't fit to receive intensive chemo.

We then launched into a discussion of low-dose cytarabine, azacitidine, decitabine, in combination with venetoclax. Venetoclax has been FDA approved for the treatment of patients older than 70, who are unfit to receive standard chemotherapy. The partner can be either decitabine, or azacitidine, or low-dose cytarabine.

Actually, the response rates and overall survival with these regimens, appear to be higher than anything that we have seen so far for older patients with AML, with the caveat that the phase 3 randomized trial of venetoclax plus azacitidine versus azacitidine alone, have not been announced yet.

While we don't have phase 3 data, there are very compelling phase two data that resulted in the approval of the combination, suggesting CR rates or total response rates of over 60%, some patients achieving MRD negativity, and actually responses being seen across subgroups: older patients, abnormal cytogenetics, complex cytogenetics, and abnormal mutational profiles.

In particular, patients with IDH mutations seem to have particularly high response rates to venetoclax and azacitidine. That brings up an interesting question because we know that IDH inhibitors, direct IDH inhibitors, are also available for the therapy of AML.

There was a little bit of discussion, whether, for a newly diagnosed IDH1 mutated patient, one would have the option of ivosidenib, an IDH1 inhibitor as a single agent, or the combination of azacitidine and venetoclax.

Both of these are resulting in high response rates, and in pretty prolonged survival out beyond a year for patients who respond, but there have to be selected clinical circumstances that would dictate which of these choices to pick for which patient.

The IDH inhibitors ivosidenib and enasidenib were also discussed in the context of relapsed AML. Relapsed AML patients with IDH mutation should be strongly considered for these therapies, which are now the standard of care.

We discussed a little bit, the specific toxicity of differentiation syndrome, which is well known with these agents, but which can be managed with aggressive attention, supportive care, and knowledge.

We talked about it, that for patients who might end up in an emergency room where physicians may not have experienced treatment differentiation syndrome, that this should be something that the patients even have some awareness of. Presentations with, for example, hypoxia, pleural effusions, fever, these can be frequently mistaken for sepsis, which is also common in leukemia patients.

A little bit of diagnostic help for physicians who don't have a lot of experience with these drugs is warranted, and hopefully, there are some guiding publications to help patients and physicians manage these particular side effects.

We also discussed FLT3 inhibitors, other than midostaurin. There are second-generation more potent FLT3 inhibitors under development, one of which is currently approved already in the United States, which is gilteritinib, which is a highly selective next-generation FLT3 inhibitor, that can be offered to patients with relapsed FLT3-mutated AML.

The data combining gilteritinib with intensive chemotherapy or with hypomethylating agents are not yet available, but there are highly awaited results. We look forward to figuring out whether or not, the second-generation inhibitors should be moved into the front-line setting.