Pursuing Pairings of Targeted Agents and HMAs in AML

Alison R. Sehgal, MD

Combinations of targeted agents and hypomethylating agents (HMAs) have become the focus of research in newly diagnosed acute myeloid leukemia (AML), providing elderly patients with an opportunity for tolerable treatments that elicit enhanced and durable responses, explained Alison R. Sehgal, MD.

“The median age of diagnosis of AML is 65. Trials in older patients are harder, because patients have increased comorbidities, perhaps decreased mobility, or interest in trials. Those are all physical challenges in patients with AML. Moving toward increasingly tolerable therapies and oral therapies is one way to overcome that particular challenge,” said Sehgal, an assistant professor of medicine, hematologist/medical oncologist, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center.

Such combinations include that of venetoclax [Venclexta] and azacitidine, as well as ivosidenib [Tibsovo] and azacitidine. In the phase 3 VIALE-A trial, the combination of venetoclax/azacitidine led to a median overall survival (OS) of 14.7 months (95% CI, 11.9-18.7) versus 9.6 months (95% CI, 7.4-12.7) with placebo/azacitidine in patients with newly diagnosed disease (HR 0.66; 95% CI, 0.52-0.85; P < .001).¹

In October 2020, the FDA granted a regular approval to venetoclax/azacitidine, decitabine, or low-dose cytarabine for patients with newly diagnosed AML who are 75 years or older or who have comorbidities precluding intensive induction chemotherapy.

The latter combination of ivosidenib and azacitidine led to a 78% overall response rate (ORR) in a phase 1/2 trial in newly diagnosed patients with IDH1-mutant AML aged 75 years or older or those ineligible for intensive induction chemotherapy.² In March 2019, the FDA has granted a breakthrough therapy designation to the combination in this patient population.

Notably, advances in AML have not been restricted to patients who are not eligible for induction therapy, added Sehgal, who stated that findings from the phase 3 QUAZAR AML-001 trial demonstrated improved survival with oral azacitidine (Onureg, CC-486) in transplant-ineligible patients who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and in doing so, carved out a role for maintenance therapy in the field.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on hematologic malignancies, Sehgal discussed some of the novel approaches that have been adopted into practice and ongoing research building on the advances that have been made with targeted therapy.

OncLive^®: What novel approaches are being adopted into clinical practice in AML? 

Sehgal: The combination of venetoclax and azacitidine showed an improved survival compared with azacitidine alone in newly diagnosed patients with AML. Ivosidenib is another option for up-front therapy in patients with newly diagnosed AML with IDH1 mutations, and some emerging data with [ivosidenib in combination with] azacitidine showed improved response rates and hopefully durability of response. [With regard to] postinduction and consolidation therapy with oral azacitidine in patients that had achieved a CR or CRi, there was an advantage in OS compared with patients that stopped treatment after consolidation therapy.

Has the combination of venetoclax and azacitidine become a standard up-front treatment approach?

Venetoclax has been a real practice-changing drug in leukemia as well as in some lymphomas. The most promising data on venetoclax in AML has been in combination with HMAs. The publication in the New England Journal of Medicine of azacitidine and venetoclax was really useful and promising. That data showed that patients who were randomized to azacitidine with venetoclax had a survival advantage of about 5 months compared with azacitidine plus placebo. The CR rate was higher with azacitidine and venetoclax compared with azacitidine alone. There was a slightly increased risk of febrile neutropenia [with venetoclax], but in general, the tolerability was very good.

I’m sure that venetoclax will be combined with other agents. We know that as a single agent, it is not the most effective, although there is still some response rate by itself, but combining it with some of the other targeted agents with HMAs or subcutaneous cytarabine will all be stuff to watch for.

How has the mutational landscape of AML evolved?

AML has really changed in the past few years as more mutations are better characterized, and we know the frequency of those mutations better. The more common mutations include NPM1 and FLT3, particularly the ITD variation, which we’ve known about for a while. There’s also IDH1 and IDH2, which have been key targetable mutations in AML. There’s a host of others that we use to prognosticate and then also hopefully target as time goes on. 

The mutations that have been useful for targeted therapy in AML has been IDH1 and IDH2, both of which have specific drugs to target those mutations that are FDA approved. Trying to better understand where in therapy those agents fall and if they should be combined with any other agents [is ongoing]. Gilteritinib [Xospata] is now approved [for patients with] FLT3 [mutations]. Work with that agent is ongoing to better understand when to use it and how to combine it in the pre- and posttransplant setting. I’m sure there will be additional molecules that are targeted. One of the key areas where we need improvement is in TP53-mutated AML. There are some agents out there that are showing promising data, although not yet FDA approved [in that area].

What do we know about the durability of response to some of these targeted agents, like ivosidenib?

Ivosidenib is approved up front for older patients or those who are not able to tolerate induction therapy. Right now, it’s approved as a single agent in those with appropriate mutations. Many patients are achieving long-lasting responses with this oral agent. This is especially useful in those who can’t tolerate frequent visits to the clinic or have significant comorbidities that don’t allow them to get in get an agent like azacitidine or azacitidine plus venetoclax that are going to cause significant cytopenias. An area of promise is combining ivosidenib with other therapies to see if we can enhance response rates and durability of responses.

One such combination that’s being investigated is ivosidenib and azacitidine. What data have we seen so far with it?

This study was presented by Courtney DiNardo, MD, of The University of Texas MD Anderson Cancer Center. The study enrolled 23 patients, all of whom had 500 mg of ivosidenib and subcutaneous azacitidine. The ORR was about 80% and CR rates were around 60%. The median response duration [of response] wasn’t reached. Therefore, the high response rate is pretty durable in these patients.

What should be watched for in patients who start ivosidenib?

There’s a risk for differentiation syndrome. This is an important thing to know, especially as people take this orally and as an outpatient approach that providers need to be aware of. The syndrome is seen in up to 10% of patients who receive the drug, and it’s similar to the differentiation syndrome we see in acute promyelocytic leukemia; it can cause a rise in the white blood cell count, fevers, dyspnea, edema, and it’s typically managed with steroids, usually dexamethasone. Symptomatic treatment of the edema [is treated] with furosemide, sometimes hydroxyurea can be used to bring down the white blood cell count. If those interventions don’t help, we can the drug temporarily.

Maintenance is not traditionally used in AML. Have the results of the QUAZAR AML-001 trial changed that?

That trial evaluated maintenance therapy after consolidation with oral azacitidine. This was a phase 3 randomized trial that enrolled about 500 patients. Patients underwent standard induction therapy and then consolidation if their treating physician felt that was appropriate for them. After achieving a CR/CRi, they were randomized to oral azacitidine versus placebo. If they received the oral azacitidine, they took it for 2 weeks on and 2 weeks off, and then continued that indefinitely until progression or toxicity, or if they became transplant candidates. This was intended for patients with intermediate- or high-risk disease but who were not transplant candidates.

The results showed an improvement in OS as well as progression-free survival [with oral azacitidine]. The OS advantage was approximately 10 months. It did seem like the curves eventually coalesced, which suggests to me that perhaps there’s not a distinct cure advantage, but indeed an OS advantage, which is really important. 

What are some of the key challenges faced regarding research now?

AML is a fairly rare disease and not all patients can come to a tertiary care center for their treatment. Therefore, that’s one challenge. There are many different driving mutations in AML. Being able to personalize therapy is a challenge all of oncology is facing. Coming up with really collaborative efforts is very important to be able to [conduct] trials. 

For anyone treating a patient with newly diagnosed AML, what would you like to convey about the state of treatment today? 

There are very real options for older patients or patients with multiple comorbidities that have newly diagnosed AML. The decision tree used to be simpler, where patients were candidates for induction therapy or not. If not, they were often treated with supportive care alone. The approval of HMAs changed that a little bit, but it was still sort of a 2-pronged decision.

Now, more agents are approved. It is important to look at the [patient’s] next-generation sequencing to understand what their molecular subtype of AML is because we can use that to understand response to therapy. Even if we’re unable to get [that information], there are very real options with venetoclax and HMAs. We need to really consider adding venetoclax up front in those who are appropriate candidates. 

Finally, if someone is an induction candidate, if they have intermediate- or high-risk disease, there should be a conversation with the oncologist and the patient about whether or not they would be interested in oral azacitidine as a maintenance option.

References

1. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. News release. FDA. October 16, 2020. Accessed January 6, 2020. https://bit.ly/2Hgqoos
2. Agios receives FDA breakthrough therapy designation for Tibsovo (ivosidenib) in combination with azacitidine for the treatment of newly diagnosed acute myeloid leukemia (AML) with an IDH1 mutation in adult patients ineligible for intensive chemotherapy. News release. Agios Pharmaceuticals. Published March 27, 2019. Accessed January 6, 2020. https://bit.ly/2FB4Uyt