Risk-stratified therapy for childhood acute lymphoblastic leukemia (ALL) has been around for decades and has previously been shown to greatly improve 5-year survival rates. But a look at longer-term outcomes associated with risk-stratified treatment had not previously been done.
Now researchers have reported the results of an analysis that tracked long-term health outcomes of childhood ALL survivors treated in the 1970s, 1980s, and 1990s to measure how changes in treatments have affected those outcomes. The data were published online ahead of print in the Journal of Clinical Oncology (2020; doi: 10.1200/JCO.20.00493).
"This was the first analysis to really attempt to compare long-term outcomes by risk-stratified therapy groups. Before this analysis, we could talk about an ALL survivor of the 1980s or 1990s compared to the 1970s, but we hadn't attempted to differentiate them by their risk-stratification in a large cohort study," explained study author Stephanie Dixon, MD, an instructor at St. Jude Children's Research Hospital. "This is important because risk-stratification largely determines the intensity of their treatment."
Here's what else Dixon told Oncology Times about the new data.
1 What were the key findings of your report and what do they reveal about mortality and morbidity rates in children with ALL?
"To me, the most impactful findings from this work are that, not only has risk-stratified therapy for childhood ALL improved survival-which had been demonstrated in multiple prior studies-it has also decreased late mortality, second cancers, and occurrence of chronic health conditions for survivors treated similar to contemporary standard-risk therapy compared with survivors treated in an earlier era.
"One of the findings is that survivors treated with therapy that is consistent with standard-risk treatment of the 1990s and early 2000s are at similar risk for health-related late mortality and subsequent cancers as the general U.S. population. However, we have to be careful not to gloss over that even among this contemporary, standard-risk group many chronic health conditions were still more prevalent than we would expect in similar aged peers. Also, survivors of more recent high-risk therapy and those who had intensive treatment including bone marrow transplant or for relapsed disease were at high risk for chronic health conditions, including some conditions (diabetes, major joint replacement) experienced with a much higher frequency than both similar aged peers (siblings) and survivors treated with earlier era therapy."
2 What does your work tell us about risk-stratified therapy for these patients?
"Risk-stratification of patients to try to improve treatment outcomes began for most groups treating childhood ALL in the 1980s. This approach attempted to identify demographic, biologic, and genetic features of childhood ALL that would signify a high-risk (or low-risk) for treatment failure or future relapse and therefore poor outcomes. What determines high-risk and low- or standard-risk patients has been refined over decades and has been used to tailor the intensity of treatment to try to improve cure rates, but also minimize long-term complications related to treatment-especially for standard-risk patients, who make up more than 50 percent of patients with ALL).
"Treatment for high-risk or standard-risk ALL has varied over time and is different between different cooperative groups or treating institutions, but there has been major trends with a dose-reduction in anthracycline chemotherapy over time (which is lower dose for standard-risk than high-risk); decreased use/dose of prophylactic cranial irradiation with eventual elimination of cranial radiation from most protocols for standard-risk patients beginning in the 1990s; and increases in use of asparaginase, dexamethasone (a steroid used in addition to or in place of prednisone), and high-dose methotrexate. Again, higher intensity of therapy [is recommended] for high-risk protocols.
"Risk-stratification has allowed oncologists to more accurately identify which patients need high-intensity treatment and who may have a leukemia that could be cured with a little bit less therapy.
"I think the next steps from this research are to try to identify how we may be able to further improve outcomes for survivors of childhood ALL. Of course, we are always trying to improve survival and long-term survival, which is still needed in the highest-risk patient groups, particularly those who experienced relapse or required a transplant. However, because most patients are surviving long-term, we also need to focus on chronic conditions that may significantly impact their quality of life.
"For example, [we need] to identify why survivors of more recent high-risk disease and of relapse/transplant experience have such a high incidence of diabetes and major joint replacement, and then attempt to target interventions that can reduce this risk. In high-risk patients, therapy reductions or substitutions may or may not be possible. If not, we need to identify which conditions should be screened for aggressively, when this screening is most effective, and then how we can prevent or delay these conditions."
3 What would you say is the most important takeaway message from this work?
"The goal of risk-stratified therapy for children with standard-risk ALL-to reduce late morbidity and mortality while maintaining excellent outcomes-has been realized, but [that] doesn't mean our work is done or these patients don't need continued medical care.
"There remains an urgent need to decrease the burden of chronic health conditions experienced in this aging population. Even contemporary standard-risk patients experience some chronic conditions at a higher-rate than we would expect in similar aged peers who did not have a childhood cancer. And for patients treated for high-risk ALL or who experienced a relapse or required a transplant, they need comprehensive care to monitor for chronic conditions, and in some cases second cancers, that may occur as a result of prior cancer treatment."