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About 20% of acute myeloid leukemia (AML) harbors a mutation in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2.

Within the last decade, treatment for these patients "has changed significantly" with the development of first-in-class IDH1 and IDH2 inhibitors, said Tapan Kadia, MD, of the MD Anderson Cancer Center in Houston. Moreover, "treatment paradigms are going to be different in different institutions. If you look outside of most academic institutions, younger patients who are fit for intensive chemotherapy for newly diagnosed disease will still receive some anthracycline and cytarabine-based chemotherapy like 7+3 [a course of cytarabine continuously for 7 days, along with infusions of an anthracycline in the first 3 days]."

"As you go more and more into academic centers, we are starting to incorporate some of the new targeted agents in our young patients in the front line," he told 番茄社区app.

He pointed out that at MD Anderson, individuals with IDH1- or IDH2-mutated AML would get intensive chemotherapy plus venetoclax (Venclexta), or intensive chemotherapy plus one of the IDH inhibitors. Ivosidenib (Tibsovo) and enasidenib (Idhifa) are targeted, oral, small-molecule inhibitors of the mIDH1 and mIDH2 enzymes, respectively, and have been approved by the FDA as monotherapies for adults with relapsed or refractory AML.

"There have been studies for each of these, with very nice response rates and excellent long-term survival when you combine chemotherapy with the targeted agent," he said.

Supporting Studies

For example, a combined ivosidenib or enasidenib with intensive chemotherapy in patients with newly diagnosed AML. Among 60 patients treated with ivosidenib, the complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematological recovery (CRi) rate was 77%. Among the 91 patients treated with enasidenib, the CR/CRp/CRi rate was 74%.

"I think the more interesting standard approach is using targeted agents in those patients who are unfit for intensive chemotherapy," Kadia said. "I think HMA [hypomethylating agents] plus venetoclax in these older, unfit patients is still the standard of care. It showed response rates over 75%-80% and excellent long-term survival in the IDH2 subgroups -- similar in IDH1, albeit the response rates were lower, in the range of 60%."

The effectiveness of the HMA azacitidine plus venetoclax was demonstrated in the phase III randomized of 431 elderly patients (mean age 76) with AML. The trial evaluated the combination versus azacitidine alone, and investigators found that at a median follow-up of 20.5 months, median overall survival (OS) was 14.7 months in the combination group versus 9.6 months in the azacitidine-alone group (HR 0.66 95% CI 0.52-0.85, P<0.001).

Based on the trial results, the FDA granted approval to venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML patients ages 75 and older, or those who have comorbidities precluding intensive induction chemotherapy.

Based on preclinical results suggesting that the addition of azacitidine to ivosidenib enhances IDH1 inhibition-related differentiation and apoptosis, Courtney DiNardo, MD, also of MD Anderson, and co-authors conducted a of ivosidenib in combination with azacitidine in newly diagnosed AML patients ineligible for intensive induction chemotherapy. They reported a response rate of 78.3% that was durable, and a CR rate of 60.9% (95% CI 38.5%-80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached.

AGILE

Results from that study led to the phase III AGILE trial, which was presented a 2021 American Society of Hematology (ASH) meeting press briefing.

In AGILE, investigators randomly assigned patients with newly diagnosed IDH1-mutated AML, who were ineligible for intensive induction chemotherapy, to receive oral ivosidenib (500 mg once daily) and subcutaneous or IV azacitidine (75 mg/m² of body-surface area for 7 days in 28-day cycles) or to receive matched placebo and azacitidine.

Hartmut Döhner, MD, of Ulm University Hospital in Germany, reported that at a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio 0.33 for treatment failure, relapse from remission, or death, 95% CI 0.16-0.69, P=0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib-and-azacitidine group and 12% in the placebo-and-azacitidine group. The median OS was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (HR 0.44 for death, 95% CI 0.27-0.73, P=0.001).

Based on those results, the FDA approved ivosidenib in combination with azacitidine () for newly diagnosed AML with a susceptible IDH1 mutation, as detected by an FDA-approved test in adults, ages 75 or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

ASH press briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami, said that AGILE's results raised the question of whether the AGILE regimen is the preferred choice for patients unsuitable for intensive therapy, or if the preferred choice is the current standard of care of azacitidine plus venetoclax (regardless of their IDH1 mutational status).

One consideration is whether physicians should wait for IDH1 mutation testing before starting treatment in patients who are elderly or unsuitable for induction chemotherapy, advised Naval Daver, MD, also of MD Anderson.

"And that's important because the timing of testing can be quite varied," he told 番茄社区app, adding that at a large center like MD Anderson, mutation testing can be conducted in 3-5 days, whereas it could take 2-3 weeks at some community hospitals and smaller academic centers. "So waiting could be a big issue when you are talking about 8%-10% of patients who have this mutation," he noted.

Daver also noted that while AGILE looked at azacitidine plus ivosidenib versus azacitidine alone, "it did not look at azacitidine plus ivosidenib versus what is now considered the standard of care -- azacitidine plus venetoclax."

"So there is a lot of debate," he said. "[AGILE] took place before azacitidine plus venetoclax became the standard of care, so we really can't say azacitidine plus ivosidenib is better than azacitidine plus venetoclax. Yes, 24 months [survival] looks better than 15 or 17 months, but this isn't a randomized comparison."

Single Agents

"There are new single-agent IDH1 and IDH2 inhibitors that are out there, as well," Kadia said. "So far the early data seem promising."

One is the IDH1 inhibitor olutasidenib (Rezlidhia). In a study involving 153 adults with relapsed/refractory IDH1-mutant AML, those treated with olutasidenib achieved a CR plus CR with partial hematologic recovery (CRh) rate of 35% (with a 32% CR rate).The median time to CR/CRh was 1.9 months. The duration of response was CR+CRh was 25.9 months (95% CI 13.5 months-not reached).

This study included some patients who had received prior IDH1 inhibitors, "so this is an area of interest, because there is nothing else after that, save venetoclax," Kadia observed.

Olutasidenib received FDA approval in December 2022 for relapsed/refractory AML associated with an IDH1 mutation.

Kadia noted that other approaches to treating IDH-mutant AML include an investigational , as well with intensive chemotherapy with in IDH1-mutated AML.

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