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Before the turn of the century, intensive chemotherapy was the only therapy that could produce clinically meaningful responses in older/unfit patients with acute myeloid leukemia (AML). However, concerns about toxicity and rates of treatment-related mortality meant that most of these patients were deemed unsuitable for this intensive approach.

Consequently, as demonstrated in from 2000 to 2009, 60% of AML patients ages 66 and older did not receive anti-leukemia therapies.

The development of the first-generation hypomethylating agents (HMA) azacitidine and decitabine in response to this unmet need then became a cornerstone of AML treatment.

However, "the response rate with HMA was about 20% to 25%, and with a survival of about 7 to 9 months," Naval Daver, MD, of the University of Texas MD Anderson Cancer Cancer in Houston, told 乌鸦传媒視頻. "That was one of the reasons we were not really excited about calling someone unfit, because the response rates were quite low and survival was suboptimal."

Now, older/unfit patients have more options with the recent development of safe and effective lower-intensity venetoclax (Venclexta)-based therapies.

In the of 431 elderly patients (mean age 76) with AML that evaluated the combination of azacitidine plus venetoclax versus azacitidine alone, investigators found that at a median follow-up of 20.5 months, median overall survival 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). Complete remission rates were also higher with azacitidine-venetoclax compared with the control regimen (36.7% vs 17.9%, P<0.001).

Based on this trial's results, the for newly diagnosed AML patients ages 75 and older, or those who have comorbidities precluding intensive induction chemotherapy.

"The pendulum is starting to swing," Daver said. "If we have a 70-year-old with borderline fitness, whereas 8 or so years ago I might have pushed toward intensive chemotherapy because the 20% to 25% response rate didn't excite me with HMA alone, today I am probably going to push them toward azacitidine-venetoclax, because the response rates are quite similar to what I get with intensive chemotherapy, but with a much better-tolerated regimen. It can be given predominantly outpatient, and we see much less mucositis infection, and early mortality rates are low."

"So, the pendulum is swinging toward azacitidine plus venetoclax, unless you feel the patient is really a good candidate for intensive chemotherapy," he added.

Adding Mutation-Specific Inhibitors to Backbone Regimens

In the phase III AGILE study, the addition of the IDH1 inhibitor ivosidenib (Tibsovo) to azacitidine led to a survival benefit for patients with newly diagnosed IDH1-mutant AML who were ineligible for intensive induction therapy. OS was 24 months with azacitidine plus ivosidenib compared with 7.9 months with azacitidine alone (HR 0.44, 95% CI 0.27-0.73, P=0.0005). Additionally, the complete response rate was 47.2% with the combination compared with 14.9% with azacitidine alone.

Based on these results, the FDA for newly diagnosed AML patients with a susceptible IDH1 mutation who were ages 75 and older or had comorbidities preventing the use of intensive induction chemotherapy.

"We've started to incorporate the azacitidine-venetoclax backbone with IDH inhibitors, and again , the results look very encouraging," Daver said.

In a presented at this year's American Society of Hematology (ASH) annual meeting, investigators, including Daver, reported that the triplet of azacitidine, venetoclax, and the FLT3 inhibitor gilteritinib was effective for patients unsuitable for chemotherapy with FLT3-mutated AML.

"It's a single-arm study, but the data look very encouraging," Daver noted. "Close to a 100% remission rate, with 2-year survival looking at 60%. It's very encouraging for this older, unfit population."

Among 21 patients with newly diagnosed disease, all had responded to the therapy, and with a median follow-up of 10 months, the estimated OS rate was 80%. Among 19 patients with relapsed/refractory disease, there was a 74% response rate, and with a median follow-up of 24.1 months, the 1-year OS rate was was 27%.

TP53-mutated disease is a particularly difficult challenge, with patients facing poor outcomes.

About 10% of all newly diagnosed patients have the mutation, and it is even more common in older patients. TP53-mutated AML is associated with poor response to chemotherapy, with a . Thus, more optimal treatment strategies are needed for these patients.

Daver and colleagues conducted a who were not suitable for intensive chemotherapy and were treated with a combination of azacitidine and the anti-CD47 antibody magrolimab, observing an objective response rate of 48.6%, a complete response rate of 33%, and a median OS of 10.8 months at a median follow-up of 8.3 months.

A phase III trial of this combination versus standard of care for patients with TP53-mutated AML () is ongoing.

Daver and colleagues are also investigating magrolimab as part of a triplet combination with azacitidine and venetoclax in older/unfit or high-risk patients with AML and relapsed/refractory AML. In presented at this year's ASH annual meeting, they found that this combination resulted in promising response rates, and was well tolerated in patients with or without TP53 mutations.

Who Is Suitable for Intensive Therapy?

Considering that the average age of patients when first diagnosed with AML is almost 70, determining who is suitable for a particular therapy is important.

According to Daver, most leukemia experts would probably agree that patients over the age of 75 are unlikely to tolerate intensive chemotherapy and will have a high risk of early mortality.

However, as Tapan Kadia, MD, also of the University of Texas MD Anderson Cancer Center, put it, "there are many older patients that are not unfit, and many that are unfit are not necessarily older."

In 2006, investigators at MD Anderson developed a risk classification model by identifying risk factors for after starting chemotherapy, which included tumor burden, leukemia karyotype, existing infections, and age. They determined that 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very-high-risk groups, respectively, while mortality rates with low-intensity therapies were 3%, 9%, and 20%, respectively.

"Age certainly plays a strong role," Kadia told 乌鸦传媒視頻. "Someone who is 70 to 75 years of age, we are hesitant to give them intensive chemotherapy. Now, there are some people who are fit over the age of 70 and we may still consider for them intensive chemotherapy, but with the new agents that are currently available, it may not be necessary to give them intensive chemotherapy because we are getting great outcomes with lower-intensity therapy."

"It turns out that it's not only that the patient can be fit or unfit, but it's also important to look at the underlying disease characteristics," he added. "If it is a disease that is sensitive to chemotherapy, like core-binding factor AML or a diploid karyotype which has NPM1 mutations, those patients' leukemia will be sensitive to intensive chemotherapy, so there may be a risk-benefit in taking advantage of that and giving them intensive chemotherapy. Whereas you might have a 50-year-old who is not in great shape, but has a very complex karyotype P53-mutated AML, which we know will not respond well to intensive chemotherapy, so there is really no point to intensify the chemotherapy there because you may not get a benefit."

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