Richard M. Stone, MD
More options are available than ever before for treating older patients with acute myeloid leukemia (AML) and fresh hopes are resting on combinations of venetoclax (Venclexta) plus hypomethylating agents, said Richard M. Stone, MD, at the 23rd Annual
International Congress on Hematologic Malignancies®
In a talk on managing older patients with AML, Stone, chief of staff and director of Translational Research and the Adult Leukemia Program at Harvard Medical School, discussed emerging agents and combinations along with his preferences for treatment. “We know it’s a tough disease,” he said. “When patients are older, they can’t clear the chemotherapy. The stem cells get a little more tired. Equally important, the disease is more intrinsically resistant, there’s more likelihood of an antecedent hematological disorder, more likelihood of having chromosomal problems, and now, bad genetics.”
In a study reported in 2015, investigators sought to improve what they called inexact classification of patients with AML by defining a set of mutations highly specific to AML and ranking outcomes by secondary-type, TP53, and de novo/pan-AML-type mutations.2
“You could see a subgroup of older adults who did fairly well—the chemo-responsive ones,” said Stone. “There were subgroups, unfortunately, who don’t do well with chemotherapy, and we need other approaches for them.”
Additionally, older patients do poorly with high-dose cytarabine and, historically, choices were largely 7-plus-3 cytarabine and anthracyclines for fit patients and hypomethylating agents (HMA) for the unfit, he added.
Improved management now calls for the assessment of patient comorbidities, goals, family support, performance status and prior treatment for cancer, as well as other factors. A disease assessment for core binding factor (CBF) and TP53
mutations, among others, is also needed.
Geriatric assessments, such as simply observing patients walk short distances also contribute greatly to understanding their fitness for intensive therapy, Stone noted.
He also stressed the importance of improved doctor-patient communication, noting evidence that patients “massively overestimate” cure potential despite what physicians tell them, leading to choices of less-intensive therapy.3
“Almost all thought they had a 50% chance to be cured,” he said. “I think people cannot deal with the terrible news that we give them, and by human nature, they inflate that, so that’s important to know.”
Stone said that if older patients appear fit, he’ll align their treatment with what younger adults would receive. Fit patients with core binding factor would receive standard chemotherapy with gemtuzumab ozogamicin (GO; Mylotarg).
“If they have bad chromosomes or a history of [myelodysplastic syndromes] or prior therapy for cancer, maybe we should give them CPX-351, rather than 7-plus-3,” said Stone. “And if they’re unfit, azacitidine plus venetoclax, or maybe we should give them an IDH1/2 inhibitor, although it’s not approved [by the FDA for use] in the upfront setting. I really like 10-day decitabine plus venetoclax for TP53
Midostaurin (Rydapt) is an option for older patients with FLT3
mutation, although in the study leading to its FDA approval “there wasn’t 1 patient over the age of 59.9 years,” Stone said, remarking that the FDA was under pressure at the time to address charges of ageism in its approvals process.
GO initially lost its approval for use in patients with refractory AML, then had it restored, aided partly by results from the ALFA 0701 study of patients aged 50 to 70 with untreated AML, which demonstrated that fractionated, lower-dose GO had efficacy. Two-year overall survival was 53.1% (n = 139) for the GO group versus 43.5% for the control group (n = 139), hazard ratio 0.70. Median survival in the GO and control arms was 34 months versus 19 months, respectively, and there were 59 deaths versus 71. The data were determined to be statistically significant.
“There was a clear benefit in event-free survival (EFS),” Stone added. EFS was estimated as 40.8% in the GO cohort versus 17.1% in the control group.4