Heidi Klepin, MD, MS
In a recently published set of recommendations, the International Society of Geriatric Oncology Task Force outlined the latest information on the treatment of APL in older patients. Medscape spoke with the lead author of the article, Heidi Klepin, MD, MS, professor in the section on hematology and oncology at Wake Forest School of Medicine in Winston Salem, North Carolina, who highlighted the key points that clinicians need to know about this often highly treatable subtype of acute myeloid leukemia (AML). This interview has been edited for length and clarity.
Medscape: How do the potential benefits of therapy for APL compare with other AML subtypes in older persons?
Dr Klepin: Potential benefits of therapy are dramatically better for APL compared with other AML subtypes. The use of non–chemotherapy-based regimens with ATRA and ATO has substantially changed options for APL management. ATRA+ATO are associated with high remission and cure rates. The chance of cure with less toxicity extends the clinical benefit to adults of advanced age and, to some extent, with comorbidities.
How has the management strategy for this subgroup of patients with APL changed in recent years?
Management options have changed dramatically with the advent of non–chemotherapy-based regimens. The majority of treated older adults could be expected to achieve remissions that are durable, with less risk of major side effects during treatment. Adults with comorbid conditions, at advanced age, and with some functional limitations could also still benefit from treatment.
Does that management strategy change based on whether patients are considered low-risk or high-risk?
Clinical trials are lacking to provide best evidence for the optimal treatment for adults over age 70 years. However, based on available data and experience, the expert consensus provided in this report recommends that older adults regardless of age with low-risk disease should be offered ATRA+ATO-based therapy if available.
The optimal approach for patients with high-risk disease is less clear based on available studies. For fit older adults without cardiac disease, the use of single-drug anthracycline chemotherapy with ATRA plus/minus ATO is appropriate. However, treatment with ATRA+ATO may also provide a good response with less side effect risk. For older patients with high-risk disease and comorbidity or poor functional status, the use of non-chemotherapy regimen ATRA+ATO is preferred.
What role does frailty have in making treatment decisions in this population?
Although frail older adults have not been specifically studied in clinical trials, it is reasonable to offer treatment with a non–chemotherapy-based regimen for many of these patients, particularly if frailty may in part be related to disease burden. Frailty is a dynamic state. Rapid initiation of therapy can improve function and symptoms, potentially reversing the phenotype of frailty if driven largely by disease burden.
What is the role of consolidation and maintenance therapy in older patients with APL?
Consolidation therapy is recommended with ATRA+ATO as a standard consideration for most patients when available, although protocol-based treatments may vary. For those older adults treated with chemotherapy+ATRA for high-risk disease, decreased anthracycline (chemotherapy) exposure during consolidation results in less mortality risk. Maintenance therapy is not needed when ATRA+ATO are used for induction and consolidation, and after achieving a molecular remission.
What other patient factors should influence treatment decisions?
In practice, older age, concurrent comorbid conditions (particularly cardiac disease), and physical function may all influence treatment decisions. Regarding the disease itself, a high white blood cell count at diagnosis, which is classified as higher-risk disease, directs choice of therapy, particularly for fit older adults. Cardiac disease can limit certain treatment options due to risk of side effects. In particular, the use of anthracycline chemotherapy is contraindicated for people with heart failure, and the use of ATO can increase risk of arrhythmia and is not used with certain EKG findings.
Special Considerations in Older Patients With APL
How would you characterize older individuals’ involvement in clinical trials?
Older adults are underrepresented on clinical trials, with very limited inclusion of those over age 75 years. Some APL trials have had upper age exclusions, which is something we have advocated to remove.
Are there unique challenges in diagnosing older adults with APL?
The presentation of APL with low blood counts can look similar to other types of AML or myelodysplastic syndrome when reviewing routine lab results. If additional testing is not done quickly, the diagnosis will be missed as well as the opportunity for effective treatment. Rapid diagnosis is essential in this disease.
Are there age-related differences in the presentation of APL?
There are no available data to support more-aggressive APL biology in older adults.
How does age impact the outcomes of patients with APL?
Although the outcomes in APL have improved, the survival difference between age groups has not decreased in recent years and the magnitude of improvement in survival in older patients still lags behind younger patients. Older age is also associated with worse outcomes driven largely by increased early death, with greater rates of infection and multi-organ failure leading to a decreased overall survival.
How important is a geriatric assessment for older patients with APL? What role does it play in management?
There are no data on the use of a geriatric assessment specifically in APL, although a geriatric assessment is recommended for older adults starting new chemotherapy in general. A geriatric assessment may help determine who is fit enough to be treated like a younger patient, which has the greatest implications for those with high-risk disease where chemotherapy would be added.
A geriatric assessment can also play an important role in management by identifying vulnerabilities that could be addressed to minimize complications during treatment regardless of the type of treatment given. An example would be identifying and addressing polypharmacy (commonly defined as ≥ 5 medications). One challenge faced when treating older patients is the use of multiple concomitant medications. Polypharmacy is common among older patients with cancer. Among older adults, each new drug increases the risk of adverse drug events by 10%. Drugs commonly used for the treatment of APL, such as ATRA and ATO, have many potential drug interactions, which must be carefully assessed by a pharmacist prior to and during treatment. Active deprescribing of medications that are not critical during treatment for APL should be done to minimize risks.
What is differentiation syndrome? What role does age appear to play in the risk of developing it and in strategies for managing it?
Differentiation syndrome is a serious side effect that may occur in patients with APL who have been treated with certain anti-cancer drugs. Differentiation syndrome usually occurs within a week or two of starting treatment. It is caused by a large, rapid release of cytokines (immune substances) from leukemia cells. The most common symptoms include fever; cough; shortness of breath; weight gain; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; low blood pressure; and kidney failure. Differentiation syndrome can be life-threatening if not recognized and treated early.
Some evidence suggests older adults may be at a higher risk for developing differentiation syndrome and may be less likely to tolerate it. A risk factor is kidney dysfunction, which is more common in older adults.
It is not clear that management should differ by age, but vigilance is critical. The use of prophylactic steroids is considered for high-risk patients (high white cell count or kidney disease). The treatment for differentiation syndrome involves rapid use of steroids.
Does the management of infections differ in older people with APL?
There is no clear data to support a different management of infection prevention for older adults, although preventive antibiotics can be considered as older adults are at a higher risk for infectious complications. However, drug interactions need to be carefully considered in this context.
Guiding Clinicians Toward Better Treatment of APL
Why did you decide to formulate these recommendations now?
It is particularly important to draw attention to the management of older adults with APL given the availability of effective non–chemotherapy-based therapies and the large distinction between expected outcomes with APL vs other types of acute leukemia in this population. This diagnosis should not be missed. Further, we highlight the importance of ensuring that older adults are included in trials to provide best evidence for both treatment choice and supportive care management.
How do you see these recommendations impacting clinical practice?
We want to emphasize that advanced age should not preclude treatment, which can have meaningful benefit with expectation of remission and quality time gained.
We hope that these recommendations provide a useful blueprint for guiding the management of older adults, particularly consolidating information to help inform treatment for those patients over age 75 years that can provide best estimates of side effects and benefits when making a decision with patients. We also hope that these recommendations will be used to educate providers on the importance of looking for this diagnosis in our older patients.
From a practical standpoint, it will be important that this information gets to those providers who are making the referrals to oncologists, which can include primary care physicians and emergency room providers, to ensure prompt diagnostic workup. Treatment decisions can only be made once a diagnosis has been recognized, and time is critical with this disease.
Dr. Klepin disclosed a consultancy for Genentech and Pfizer, and is a contributor to UpToDate.
Kate O’Rourke is a freelance writer in Portland, Maine. She has covered the field of oncology for over 10 years.
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