New ASH Guidelines Highlight a Call to Action for Treatment of Older AML Patients

Mikkael A. Sekeres, MD, MS

New guidelines from he American Society of Hematology (ASH) for treating newly diagnosed acute myeloid leukemia (AML) in older patients recommend intensive antileukemic therapies over more conservative approaches, such as less-intensive therapies or supportive care, when treatment is considered tolerable.¹

The guideline panel included physicians based in the United States and Canada who represented a variety of subspecialties including frailty, geriatric oncology, and patient-reported outcomes. In an interview with Targeted Therapies in Oncology, primary guidelines author Mikkael A. Sekeres, MD, MS, said the panel selection process was sensitive to gender and geographic distribution and included 3 leaders of cooperative groups in the United States for leukemia, as well as one from the National Cancer Institute of Canada’s leukemia group.

“These are the first guidelines published by ASH for any hematological malignancy. They are unique in how rigorously developed they were, [as they were] based on stringent standards for guideline development,” said Sekeres, a professor in the Department of Medicine at Case Western Reserve University School of Medicine as well as medical director of the Clinical Trials Unit at Taussig Cancer Institute of Cleveland Clinic, both in Ohio.

In weighing multifactorial risks and benefits of initiating potential antileukemic therapy in patients with AML older than aged 65 years, decisions to pursue treatment may be influenced by the physician’s or patient’s reluctance to assume an aggressive treatment strategy. The health care system also may contribute to poor prognoses in this patient subset due to treatment reluctance, as more than half of patients in this AML subgroup received no therapy and were not provided equal access to allogenic transplant once achieving remission.1 Because survival rates for this vulnerable population remain historically low, data regarding best practices are limited.

Methods for Determining Recommendations The recommendations were developed through a systemic review of evidence using the McMaster University Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, allowing the panel to provide recommendations that vary in strength based on certainty of evidence available. “Strong” to “conditional” recommendations were based on investigator-assessed certainty of evidence available.¹

Patient data included in the review were from patients with newly diagnosed de novo, treatment-related, and secondary AML aged 55 years or older with receipt of less-intensive or intensive antileukemic therapy and treated as part of a clinical trial with 20 or more patients. Patient data from those with acute promyelocytic leukemia, myeloid neoplasms associated with Down syndrome, and studies in which more than 75% of the population did not meet criteria for inclusion were excluded from the review.¹

The data reviewed by the panel showed a limited number of randomized studies available for this population. Although a number of retrospective data studies were examined, Sekeres pointed out the potential for “high selection bias in [such] studies” due to factors like existing serious comorbidities, such as end-stage lung cancer. “We made recommendations at different levels based on the quality of supporting data, couching our recommendations in the quality of data that we had,” he said, adding that critical outcome factors such as caregiver burden, quality-of-life (QOL) impairment, functional status impairment, and severe toxicity also factored in to the panel’s decisions. The weight of these factors varied slightly with each clinical question. Sekeres said the panel tailored factors they considered relevant in managing an older adult with AML to each specific clinical question. Unfortunately, often due to poor health or functional status within this population, patients did not participate directly in providing this data.

Panel Recommendations

Although the panel began with approximately 20 clinical questions, Sekeres said they narrowed down the guidelines to 6 key areas of consideration. Clinical questions were determined and prioritized by the panel and are shown below with corresponding recommendations.

With strong evidence based on moderate certainty provided by the clinical data, the panel recommends offering antileukemic therapy to patients over best supportive care whenever possible. The comparison of intensive therapy versus best supportive care suggests a hazard ratio for death of 0.36 (95% CI, 0.26-0.50) based on low quality of evidence.

“This recommendation may seem incredibly obvious, but when you examine the data in the United States, you realize that a lot of older adults with AML are told to ‘get their affairs in order’ and seek no treatment,” said Sekeres. “Let’s be clear at the very beginning. If someone wants treatment, you should treat them,” and this should be done in alignment with their overall QOL goals.

Level of evidence is of a lower certainty based on the data available, but the panel favors intensive therapy—but placed a conditional recommendation on this determination. A review suggested that intensive therapy may produce a lower risk of death versus the alternative (HR, 0.78; 95% CI, 0.69-0.89) and that the risk of death may be lower at 1 year with this strategy (risk ratio [RR], 0.93; 95% CI, 0.85-1.01).¹ “The [limited available] studies support more intensive antileukemic therapy if it is consistent with the patient’s individual goals,” Sekeres said. “That involves the careful balance of potential benefit in terms of getting into remission and survival versus risks of dying.” The risks to QOL and of being hospitalized for the first 4 to 6 weeks of diagnosis also weigh heavily on the decision-making process.

Sekeres said certain patients who receive one therapy and achieve remission still need additional intervention. “[Remission] is not enough. You need to give more [treatment] or else the chances of long-term survival diminish,” he said. Moderate quality evidence supports consolidation therapy for lower mortality (RR, 0.96; 95% CI, 0.89-1.03), longer survival times by a median of 3 months, and longer time to recurrence by a median of 1 month versus no consolidation.

“We only know this through indirect evidence. Long-term survivors who are older always receive more than one course of chemotherapy, but there are no randomized trials stating that more...is better than just one course [of treatment] or that a certain number of courses is the ideal amount,” Sekeres said. As such, the panel suggests treating patients who are not candidates for allogeneic hematopoietic stem cell transplantation with at least 2 cycles of intensive antileukemic therapy based on low certainty of evidence.

Considering potential treatment planning factors such as age, comorbidities, and patient goals can sometimes lead to a third branch of decision-making for older patients, Sekeres said. For example, some patients with AML are under the initial impression that they likely have 2 options for treatment: intense chemotherapy or no treatment with supportive care only. Sekeres explained that less-intensive therapy is a third option to strongly consider when trying to align care with the patient’s goals and life experiences. “In the United States, this commonly includes hypomethylating agents azacitidine and decitabine.”

As such, recommendation 4 is divided into 2 subgroups focusing on less-intensive therapy options using hypomethylating agents. “There doesn’t seem to be one preference for one hypomethylating agent over another or over other low-dose approaches,” said Sekeres. “As our guidelines were breaking, we knew of some trials that were going to be published that looked at combination therapy versus monotherapy.”

In a phase 1/2 study (NCT02203773) reviewed by the ASH panel, azacitidine plus venetoclax (Venclexta) demonstrated a promising efficacy rate with a tolerable safety profile versus administrations of azacitidine alone. However, the patients in this positive study were subjected to required hospitalization to receive the combination therapy.² “In this case, if you think back to where we started regarding patient goals, you are now mixing goals,” Sekeres said. “If a patient wants a less-intensive approach, they typically want out of the hospital and to be at home.”

As such, the official recommendation from the panel suggests the use of either a hypomethylating agent or low-dose cytarabine as monotherapy based on moderate certainty of evidence in patients who are not eligible for intensive regimens. The second part of the recommendation suggests favoring monotherapy over combination therapy. However, if the patient chooses to move forward with combination treatment, low-dose cytarabine plus glasdegib (Daurismo) or a hypomethylating agent plus venetoclax can be used based on randomized trial data.

A conditional recommendation based on a low level of certainty led to the panel suggesting continuous therapy versus a time-limited approach.

Sekeres said that although this recommendation had limited supporting evidence, the specific amount of time is somewhat irrelevant. “[Patients] should continue to receive [the treatment] as long as they are responding,” he said. “There is currently no study that stops this therapy at a certain point.”

The last recommendation is a favorite of Sekeres’ because “this is where we make the very clear statement that if a patient wants blood transfusions while on hospice, that person should be allowed to do so. We consider it to be supportive care and not heroic,” he said.

Sekeres also explained the importance of finding a less-intensive approach for patients who have concerns about the effects of intensive therapy but still desire treatment, perhaps because of an expressed wish to live long enough for an upcoming family celebration or other personal reasons. Concerns such as hospitalization time, tolerability, potential adverse effects, overall QOL, and functional status are all incredibly important factors to consider when deciding the best course of action. In some instances, it may be more important to focus on tolerability than overall survival in this fragile population.

Applying Recommendations to Practice

The ASH guidelines “are not intended to serve or be construed as a standard of care,” said Sekeres, but they are intended to assist physicians and educate patients in making decisions about potential diagnostic and treatment alternatives.1 The data herein highlight an unmet need for continued advocacy and research.

Sekeres said his interest in this patient population and corresponding research focus began during his fellowship, where he felt that a set of guidelines were important to address this clinical question with evidence-based treatment support for newly diagnosed AML.

“This is an extremely vulnerable population for whom the treatment decision at the very beginning of diagnosis is far from straightforward,” Sekeres said. “My job is somewhat easy because my decision trees don’t have a lot of branches to them. However, it’s hard because the therapy we are giving has an appreciable mortality itself.”

To provide fellow treating physicians with a key takeaway, Sekeres advised, “Your most important job as a health care provider working with a patient who has leukemia is making sure you are helping that person identify what his or her goals are and then meeting those goals with the treatments that you are offering.”

_References:

_{1. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020;4(15):3528-3549. doi:10.1182/bloodadvances.2020001920}

_{2. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. doi:10.1016/S1470-2045(18)30010-X}