Expert Highlights Game-Changing Therapies for Acute Leukemia

William Donnellan, MD

While 2017 was a milestone year for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), where a combined 7 agents were approved by the FDA, the research is far from complete, as trials are exploring combinations and novel therapies.

“It's what we've been hoping for,” said William Donnellan, MD. “Now we have these 7 new drugs on the market, how do you combine them? Going forward, there will be a lot studies evaluating these drugs in combination.”

OncLive: Please discuss the 2017 FDA approvals in the field of acute leukemia?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Donnellan, investigator of hematologic malignancies at Sarah Cannon Research Institute and Tennessee Oncology, discussed recent FDA approvals for the treatment of patients with AML and ALL, and highlighted emerging agents in the pipeline.Donnellan: There were many approvals that started in April with the approval of the FLT3 inhibitor midostaurin (Rydapt). It was approved based on the RATIFY study that showed a significant improvement in overall survival (OS) in patients with FLT3-ITD— and FLT3-TKD—mutated AML in combination with high-dose induction chemotherapy. Now, it’s really the standard of care around the country for patients with newly diagnosed AML who are receiving induction chemotherapy with anthracycline and cytarabine to add midostaurin and in combination with consolidation.

Liposomal cytarabine with daunorubicin, or CPX-351 (Vyxeos), was approved in August 2017 for secondary AML, or AML with antecedent hematologic disorder. The IDH2 inhibitor enasidenib (Idhifa) was approved for patients with relapsed/refractory AML harboring an IDH2 mutation.

Finally, gemtuzumab ozogamicin (Mylotarg) made a reappearance. It was reapproved after being pulled from the market several years ago because of toxicity concerns. Based on emerging data and a reanalysis of previous studies, it was reapproved for newly diagnosed CD33-positive AML in combination with high-dose induction chemotherapy. It was also approved for relapsed patients with CD33-positive AML.

In ALL, inotuzumab ozogamicin (Besponsa), the anti-CD22 antibody-drug conjugate, was approved in August 2017 for relapsed/refractory B-cell precursor ALL. There was also the approval of the first chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) for relapsed ALL in patients up to 25 years of age. Blinatumomab (Blincyto) was originally approved in 2014 for Philadelphia chromosome (Ph)-negative ALL. It recently received an expanded approval in July for Ph-positive ALL.

What combination approaches are being explored with these drugs?

These 7 new drug approvals are what made 2017 a blockbuster year for [acute leukemia].That’s the next big question. We’ll have to determine whether there is an added benefit of combining CPX-351 with a FLT3 inhibitor, such as midostaurin, or some of the second-generation FLT3 inhibitors. [Or, whether we can combine] enasidenib, the IDH2 inhibitor, with other small molecules in patients with secondary AML who also have a FLT3 mutation.

Combinations with developing drugs are also something to look forward to. The big story at the 2017 ASH Annual Meeting was venetoclax, which showed very high response rates when used in combination with a hypomethylating agent in newly diagnosed AML. We're seeing response rates almost 3 times what you would expect with a hypomethylating agent alone. There's a big phase III study that’s launching, which will compare azacitidine either in combination with venetoclax or placebo. That could potentially change the treatment paradigm for elderly patients who are not fit for induction.

We're also evaluating a study combining the hedgehog inhibitor, glasdegib (PF-04449913), with low-dose chemotherapy in older patients and high-dose induction therapy in younger, fit patients. As far as the relapse setting, the IDH2 inhibitor was approved this past August. We're hoping for an approval for the IDH1 inhibitor ivosidenib (AG-120) based on data that were presented at the 2017 ASH Annual Meeting by Dr Courtney DiNardo. There's also second-generation IDH inhibitors like FT-2102, which is an IDH1 inhibitor that is being combined with hypomethylating agents.

We have second-generation FLT3 inhibitors that are also coming along like quizartinib, crenolanib, and gilteritinib—just to name a few. We're also evaluating splicing modulators because spliceosome mutations.

Going back to gemtuzumab ozogamicin, how comfortable are physicians using this agent now? Is there still skepticism in its administration?

You mentioned the hedgehog inhibitor. What’s the rationale behind using that drug?

Are there any other trials being done at Sarah Cannon Research Institute that you would like to speak to?

Of course, the big theme across oncology is immune therapy. Admittedly, in the myeloid neoplasms, we are slightly behind the B-cell lymphomas with regard to CAR T cells and immunotherapies, but there are cellular immunotherapies that go along with antibodies. There are now antibody-drug conjugates to CD123 and CD33; these bispecific antibodies are redirecting T cells towards the myeloid leukemia cells. CAR T cells and T-cell receptor products are beginning to be developed for myeloid malignancies, as well.There will always be hesitation based on past experiences, but the drug is given differently now. It's given in a fractionated lower dose, which is felt to be safer. In the cohort of favorable-risk patients and, to some degree, intermediate-risk patients there is a proven benefit. Therefore, it could be considered a standard of care at this point for those patients. Going back to the toxicity, this was often seen in the stem cell transplant setting. For the favorable-risk patients who are less likely to need a transplant, they are at lower risk for complications. It’s definitely a drug that has its challenges and toxicities, but it’s very manageable given the percentage of patients who will significantly benefit from the drugs.Hedgehog inhibitors have been evaluated in myeloid neoplasms for years now, and they are known to be effective. They have been quite toxic in the past. Some of the unusual side effects we've seen are dysgeusia, where patients get very altered taste sensations and have a hard time eating. Because of their efficacy, we want to evaluate those in combination with standard therapies. The study we're evaluating has 2 large cohorts—patients who are fit for high-dose induction in combination with 7+3, and then with a hypomethylating agent. I mentioned the trial with venetoclax. Everybody is excited to see the outcome of that trial because it could potentially change how we treat older patients with AML. In other diseases, we have several studies in myelofibrosis; we have the PAC203 study, which is evaluating pacritinib, a JAK/FLT inhibitor, that has been shown to be effective in myelofibrosis and in patients who are resistant or refractory to ruxolitinib (Jakafi).

Is there anything else that you'd like to emphasize?

There was a large phase III study which showed that the drug was effective compared with best available therapy. There was some concern about toxicities, specifically cardiac and hematologic toxicities. The study is now evaluating a different dosing scheme that will hopefully be shown to be as effective and safer. It's a very critical population of patients because, once they progress on standard of care ruxolitinib, there aren't a lot of other approved therapies that are beneficial. I’d like to talk a little bit about minimal residual disease (MRD) monitoring. We’ve known for a long time from pediatric literature that [having] MRD in ALL is a very bad prognostic indicator. Now, we're trying to develop that in the myeloid neoplasms, such as AML, and determine how best to measure MRD. Is it by flow cytometry? If so, by what techniques in molecular testing? Then, how do we use that information? For favorable-risk who have MRD, we are determining whether or not we should change our treatment algorithm. There are still a lot of unanswered questions that will hopefully be addressed in the next 1 or 2 years.