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.”
In an interview during the 2018 OncLive®
State of the Science SummitTM
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.
OncLive: Please discuss the 2017 FDA approvals in the field of acute leukemia?
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
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.
These 7 new drug approvals are what made 2017 a blockbuster year for [acute leukemia].
What combination approaches are being explored with these drugs?
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
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.