Management of older adults with acute lymphoblastic leukemia: challenges & current approaches
Abstract
The management of acute lymphoblastic leukemia (ALL) in older patients is challenging. Older patients often have multiple comorbidities and poor performance status, and disease factors associated with poor prognosis are more common in this age group. Patient and disease-related factors should be taken into account to determine whether intensive therapy is appropriate. The use of comorbidity indices and comprehensive geriatric assessment tools can be valuable in this setting. Fit patients should be considered for aggressive therapies including allogeneic hematopoietic stem cell transplantation, whereas low intensity options may be more suitable for the frail. The Philadelphia (Ph) chromosome is present in up to half of the cases of ALL in older patients. The incorporation of TK inhibitors into the treatment plans of older patients with Ph-positive ALL has improved the outcomes significantly. For less fit patients with Ph-positive ALL, the use of TK inhibitors with reduced-intensity chemotherapy or steroids alone results in high rates of remission, but, without further consolidation, relapses are inevitable. Many novel targeted and immunotherapeutic agents are being developed, offering more effective and tolerable treatment options.
Approximately 20–30% of all acute lymphoblastic leukemia (ALL) cases occur in patients older than 55–60 years. While the long term outcomes of ALL have improved significantly in the pediatric population and to a lesser extent in young adults, elderly patients still have a very poor prognosis . Half of the deaths from ALL occur in patients older than 55 years and their 5-year overall survival (OS) rate is at or below 10–20%. The age cutoff to define elderly may vary, but as adopted in most clinical trials, 55–60 years will be used here in this review. The relatively low-age cutoff reflects the substantial challenges in treating this patient population. This review article focuses mainly on studies related to older patients with ALL. If not available, studies that included both younger and older patients were included, with points/outcomes related to older patients highlighted. Randomized clinical trials and studies published in the last 5 years, whenever available, were emphasized.
Older patients with ALL commonly have multiple comorbidities and poor performance status and less often participate in clinical trials or receive intensive therapy. As discussed later in this review, the inability to deliver optimal therapy to older patients and the higher induction death rate are important factors that contribute to the poor outcomes seen in older patients with ALL. However, even in studies looking at ‘fit’ patients treated with intensive chemotherapy, older age was associated with worse outcomes highlighting different disease biology in this group. Factors associated with poor outcomes are more common in elderly patients, and include poor-risk cytogenetics such as the Philadelphia (Ph) chromosome, B-cell immunophenotype and secondary ALL.
Approach to treatment of elderly patients with ALL
The first step in treating older patients with ALL is to assess their ability to undergo aggressive therapy. Chronological age alone does not necessarily provide enough information regarding an individual's fitness or frailty, and other important determinants have to be considered. These include the presence of medical comorbidities, cognitive decline, polypharmacy, poor functional status, malnutrition, depression, and lack of social support. Comorbidity burden can be measured by standardized indices such as the Charlson comorbidity index and the hematopoietic cell transplantation comorbidity index. In addition, there are various geriatric assessment tools that incorporate assessment of multiple other domains including cognitive and social function. These have shown to provide valuable information in predicting treatment-related toxicities when applied in older patients with acute myeloid leukemia treated with intensive chemotherapy regimens. Patients deemed unfit for intensive chemotherapy can be considered for less intensive approaches or supportive care only. Enrollment on appropriate clinical trials should always be encouraged, especially for this age group, given the paucity of data and the very poor outcomes achieved with current therapies.
Induction
Most ALL induction regimens include vincristine, a corticosteroid, and an anthracycline as a backbone, with other agents such as methotrexate, cytarabine, and cyclophosphamide often added. Asparaginase is also used in many regimens after it demonstrated efficacy in the pediatric population. Pegylated-asparaginase has replaced native Escherichia coli asparaginase as it offers a longer half-life and a lower risk of antiasparaginase antibody formation . Asparaginase is typically given at lower doses in older patients, given its considerable toxicity, especially hepatotoxicity, pancreatitis and thrombosis.
Data have demonstrated that elderly patients may derive a benefit from intensive chemotherapy, although less than half of them are able to receive it. In an analysis of 100 patients with ALL between the ages of 55 and 65 years treated with intensive chemotherapy, drug-dose reductions, omissions or delays occurred in approximately 50% of patients. Intensive multiagent chemotherapy regimens in older populations achieve complete response (CR) rates of around 50–70%, with treatment-related mortality rates approaching 20–40%.