Expert Highlights Recent Advancements and Current Challenges in Acute Leukemias

Michael R. Grunwald, MD

Michael R. Grunwald, MD

While consistent progress is being made in the fields of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), new drug approvals in both paradigms have brought along challenges, including optimal sequencing and managing toxicity profiles, explained Michael R. Grunwald, MD.

“Things are getting better both for patients with AML and those with ALL,” Grunwald said. “We're seeing progress from decade to decade, and a lot of it has been advances in supportive care and decreased toxicity of transplant. Now, we have some new agents in the mix, and I'm very hopeful that we're going to be able to offer patients therapies that are both gentler and more efficacious in the near future.”

Among the therapies available for patients with ALL, inotuzumab ozogamicin (Besponsa) is associated with hepatotoxicity, especially in patients with liver disease. Moreover, blinatumomab (Blincyto) may be linked with neurotoxicity and cytokine release syndrome.

For AML, several new therapies have been added to the treatment armamentarium that have been shown to improve survival in both the frontline and relapsed/refractory setting. As the sequence of these agents is further refined, physicians are hopeful that they will be able to deliver more effective, less toxic treatments than stem cell transplantation, said Grunwald.

In an interview withTargeted Oncology, Grunwald, a physician at Levine Cancer Institute, discussed new and emerging agents in AML and ALL, as well as sequencing and toxicity challenges with these treatments.

TARGETED ONCOLOGY:Can you give an overview of new therapies in acute leukemia, specifically AML and ALL?

Grunwald:Over the past few years, especially this past year, we've gotten some exciting new drug approvals in both AML and ALL.

There are a lot of challenges in various groups of AML. One challenge is the relapsed/refractory population; these are the patients who either don't respond to therapy or who were in remission and later come out of remission. We have a group of patients whom we consider elderly. These are generally patients over 60 and carry a poor prognosis.

Then, we have challenges related to certain groups of patients with specific mutations or abnormalities, includingFLT3mutations, which carries a poor prognosis. There areIDH1/2mutations, which have been recently discovered to be targetable, andp53mutations, which carry poor prognosis in AML and in other diseases.

For AML, therapies that are new to our armamentarium include the FLT3 inhibitor midostaurin (Rydapt). Midostaurin has been shown to improve overall survival in combination with induction therapy if patients have aFLT3mutation. We also discussed frontline therapies for secondary AML, including therapy-related and myelodysplastic syndrome-derived AML. CPX-351 (Vyxeos) is the liposomal 7+3 [daunorubicin and cytarabine] that has been shown to improve survival in secondary AML in patients aged 60 to 75.

Gemtuzumab ozogamicin (Mylotarg) is a therapy that has recently been reapproved for AML, both as upfront therapy and in the relapsed/refractory setting. ForIDH2-mutated patients, I discussed enasidenib (Idhifa), which is a targeted therapy that's approved for patients with relapsed/refractory AML harboring theIDH2mutation.

There are also therapies that are currently in development. Ivosidenib is an exciting therapy for patients withIDH1-mutated AML. We have venetoclax (Venclexta), which is a therapy currently approved for [patients with] chronic lymphocytic leukemia. It's used off-label to treat patients with AML and might be an option in the future for patients with AML as further trials investigate this agent both alone and in combination with hypomethylating agents.

Additionally, there is decitabine, which is an approved therapy used commonly for AML. It has shown efficacy specifically in the patient population withp53mutations.

In ALL, the challenges consist of older, relapsed/refractory patients and those with a Philadelphia chromosome (Ph). Some therapies that have been approved in recent years include ponatinib (Iclusig), which is efficacious in the Ph-positive population. Blinatumomab is a CD19/CD3 bispecific antibody approved in the relapsed/refractory setting and the minimal residual disease setting. Inotuzumab ozogamicin is also an agent approved for relapsed/refractory ALL that targets CD22.

Finally, tisagenlecleucel (Kymriah) is the chimeric antigen receptor T-cell therapy that is approved for patients 25 and under with relapsed/refractory B-cell ALL. With all of these new approvals in the ALL arena over the past few years, patients have a lot more options in the relapsed/refractory setting than they used to have. It will be interesting to see these therapies as they're moved [into earlier settings] and eventually into frontline care for patients with ALL.

TARGETED ONCOLOGY:How have clinicians addressed sequencing?

Grunwald:The order of therapy has been a real challenge. For ALL, for example, the toxicities can determine choice of therapy a lot of the time. One concern with inotuzumab ozogamicin is hepatotoxicity. This is especially an issue in patients who already have liver disease or are worried about veno-occlusive disease of the liver. Patients who have a plan for transplant or have some adverse events on their liver from a previous transplant are at a higher risk with this agent, so it may not be the best drug for some of those patients.

Blinatumomab (Blincyto), on the other hand, has some challenges with neurotoxicity and cytokine release syndrome. The risk of neurotoxicity is higher in an older patient population. A patient with some liver disease might prompt the choice of blinatumomab over inotuzumab ozogamicin. However, inotuzumab ozogamicin might be a better option for an older patient who has an intact liver. If the patient progresses through that first therapy, then the other one might be a good consideration as the next line of treatment if we think the patient might tolerate it well.

TARGETED ONCOLOGY:Are any combination therapies showing lower toxicity profiles?

Grunwald:There have been some encouraging data with combinations of inotuzumab ozogamicin with mini—hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone] in elderly patients with ALL. Thus far, this seems to be reasonably well tolerated in early studies. Ponatinib plus hyper-CVAD as upfront therapy for Ph+ ALL seems to be tolerated with an acceptable level of toxicity. Most of the new combinations, though not without risk, have been reasonably well tolerated in the ALL population.  Are there any antibody-drug conjugates in development?

For AML, there have been a couple of agents under development. I'm not aware of any for ALL, but for AML we've seen a CD33-targeted [antibody-drug conjugate]. There have been a number of companies involved in that space that are trying to develop the next generation of gemtuzumab ozogamicin. For CD123, which is another target on myeloblast, we are seeing some agents in development in that arena, as well.

TARGETED ONCOLOGY:Looking to the future, what is an area of research you would like to see addressed?

Grunwald: