More options are available than ever before for treating older patients with acute myeloid leukemia and fresh hopes are resting on combinations of venetoclax plus hypomethylating agents.
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®.1
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 and IDH1/IDH2 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 mutation—positive patients.”
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
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, is a useful candidate for older patients who are fit, Stone said, noting the formulation’s ability to preserve a 5:1 molar ratio of the drug combination over a 7-day course. A phase III randomized study evaluated CPX-351 (n = 153) versus 7-plus-3 (n = 156) in untreated patients 60 to 75 years of age as induction therapy and then as consolidation following response. Median OS was 9.56 months versus 5.95 months for CPX-351 and 7-plus-3, respectively (P = .005). The complete remission (CR)/CRi (incomplete hematological recovery) rate was 47.7% versus 33.3% in the CPX-351 and 7-plus-3 cohorts, respectively.
“There was a 31% reduction in risk of death without a concurrent increase in the early death rate,” Stone said. “The drug is much better tolerated on the whole, so there are patients who are older and who are fit who I will shift from 7-plus-3 to CPX-351.” Stone described venetoclax, a BCL-2—binding agent that triggers cell apoptosis, as “paradigm-changing. When we added venetoclax to HMAs, we got some really good results—good enough to get the drug approved [by the FDA] on an accelerated basis,” he said.
A phase Ib dose escalation trial (NCT02203773) of venetoclax at 400 mg and 800 mg in combination with azacitidine (n = 84) or decitabine (n = 31) led to an overall CR/CRi rate of 67% in older patients with AML. Median duration of response was 11.3 months and median OS was 17.5 months.
Reporting on the expansion, authors noted “rapid, deep, and durable responses.” The CR/CRi response rates with venetoclax 400 mg were 44%/27% for the azacitidine arm and 55%/19% for the decitabine arm. OS was 16.9 months versus 16.2 months, respectively. “These are patients who went on this trial who were not deemed fit for chemotherapy,” Stone remarked.
Time to CR was 1.2 months versus 1.9 months for the azacitidine and decitabine arms, respectively. The number of treatment cycles was 6 versus 6, respectively. Also, almost across the board, there were strong CR/CRi rates for cytogenic risk, de novo versus secondary AML type, and genetic mutation, including TP53 mutation, Stone noted.
He also discussed a phase II trial in which investigators evaluated the safety and efficacy of venetoclax with 10 days of decitabine. The trial included newly diagnosed elderly patients >60 years with AML or secondary AML (sAML). At the 2018 ASH Annual Meeting, investigators reported an acceptable safety profile for the combination with CR/CRi of 92% in ND AML, 71% in sAML, and 44% in relapsed/refractory AML with minimal residual disease negativity in 52% of newly diagnosed AML, 40% of sAML and 50% of relapsed/refractory AML.5
“In 27 patients who had almost never seen chemotherapy, there was an almost 100% response rate,” Stone said. Venetoclax dosage reduction was allowed during the trial for blood count recovery and to address myelosuppression, which he said helped clarify remission rates and improved response.
Stone’s talk also encompassed the use of stem cell transplants in older patients. “There was some controversy at ASH in regard to whether older patients should have transplants,” he said. “I believe in it, if they’re fit.”
Last, he cited a study in which investigators looked at transplants versus chemotherapy, which was reported at the 2018 ASH Annual Meeting. The group reported that allogeneic stem cell transplant for patients with AML over 60 years of age following first complete remission “is routinely feasible and significantly improves outcome in both intermediate and unfavorable [European LeukemiaNet] 2010 risk groups. Less than 10% of patients are long-term disease-free survival without [transplant], even in intermediate risk group, supporting that [transplant] remains the first curative option for these patients.”6