Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome

Discussion

These population-level findings reveal that AYAs diagnosed with ALL at <30 years or with AML at <22 years have poor outcomes when not treated at CCC/COG sites when compared with CCC/COG sites, and treatment at CCC/COG sites can mitigate the outcome difference between AYAs and children in these patients. We identify age, lack of private insurance, and nonwhite race/ethnicity as potential barriers to receiving treatment at a CCC/COG in ALL and AML, while living further from the nearest CCC/COG did not serve as a potential barrier.

In the setting of AYA disparities and the IOM call to action (5, 10), both the potential effect of quality of care on survival and barriers to access to quality care, deserve examination. System-level effects on outcomes in cancer have been evaluated in terms of payor, surgical volume, safety net status, technology, and academic status and size (bed number); the influence of decision-making and care delivery has been examined with respect to guideline adherence, clinical trial enrollment, and cooperative group affiliation (2, 11–13). However, previous studies explored these factors in older patients, or in patients with specific nonhematologic malignancies and/or in specific surgical settings (14). Facility factors have been explored in common adult-onset malignancies (12, 15, 16). Many aspects of health care delivery remain unmeasured, with neither AYAs nor patients with hematologic malignancies examined in detail. Relevant unmeasured items include supportive care, multidisciplinary decision-making, and therapy delivery mechanisms, all components of the NCI comprehensiveness designation (17); the absence of a granular, validated measure delving into cancer care delivery (10) necessitates evaluation of surrogate measures such as care at an NCI designated comprehensive cancer center or a COG member site.

Multiple domains potentially contribute to the AYA Gap: host and cancer biology, therapeutic exposures, health behaviors, and health care delivery [sociocultural factors, access, clinical trial enrollment, and unmeasurable aspects of treatment site (supportive care, therapy decisions)]. We find that care at CCC/COG sites mitigates poor survival in 15- to 21- and 22- to -29-year-olds when compared with 10- to 14-year-old children in ALL, with no apparent impact in 30- to 39-year-olds. Similarly in AML, care at CCC/COG sites mitigates poor survival in 15- to 21-year-olds while in 22- to 39-year-olds there is no apparent impact on survival. In older patients (30- to 39-year-olds with ALL, 22- to 39-year-olds with AML), other aspects of disease or care are likely too dominant to be overcome by treatment site alone. These findings are comparable across both overall and leukemia-specific survival.

In ALL, groundbreaking genome-wide work in the last decade has revealed unique AYA susceptibility profiles (18), and the predominance of the novel Philadelphia-like phenotype, which likely requires an additional component to therapy (19). Comparable AML studies have been less conclusive; however, age-based biologic differences exist (20) and hypotheses regarding novel risk stratification are being tested (1). ALL and AML have traditionally been treated with different approaches dependent upon the service/clinic to which the AYA presents (adult vs. pediatric; ref. 21, 22). Although the field now recognizes that multiagent, pediatric-inspired chemotherapy regimens have superior outcome to other regimens in AYA patients with ALL (21, 23–25), these regimens have not been uniformly adopted, and their adoption could possibly differ by site of treatment. Guidelines for treatment of AYA patients with ALL were instituted in 2012 by the National Comprehensive Cancer Network; ALL is the only diagnosis to have distinct AYA therapeutic recommendations which have included treatment either with pediatric-inspired multiagent chemotherapy or enrollment on clinical trial (26, 27). During the time period covered by our study (1998–2008), there is evidence for support for these ALL regimens in younger AYAs and minimally in older AYAs, with the approach still evolving both within and outside of NCICCCs (28). Previous studies indicate that the key difference in the AML therapeutic approach is dose intensity which is higher in pediatric protocols. In these AML trials, patients on pediatric protocols had superior outcome to those on adult protocols; however, interpretation of the specific predictors of outcome is challenging as age played a significant role in the outcome (22). On pediatric AML protocols, AYAs saw higher risk of treatment-related mortality (29). Our study finds that treatment at CCC/COG facilities mitigates the difference in outcome between younger AYAs and children. We speculate that aspects of the NCI designation of comprehensiveness or designation as a COG member site, which impact outcome in AYAs likely include: supportive care, multidisciplinary care coordination, therapy choice, and delivery.

Understanding access to specialized care becomes crucial with the demonstrated impact of CCC/COG care on AYA outcomes. Adolescents (15- to 21-year-olds) with ALL and AML were less likely to receive treatment at CCC/COG when compared with those <15 years of age, despite adjustment for sociodemographic factors. In fact, sociodemographic factors did not impact access to care at CCC/COG facilities in this age group. However, among 22- to 39-year-old leukemia patients, lacking private insurance was associated with lower odds of utilizing CCC/COG; this is consistent with Californians “aging out” of federally mandated coverage at 21 years of age.

Distance did not impact CCC/COG utilization in ALL or AML. Distance has been associated with care at CCC/COG sites in older AYAs in Los Angeles County with central nervous system tumors (30) and adult-onset tumors (31); thus these findings in ALL and AML could reflect a lower level of comfort among non-CCC/COG facilities to treat acute leukemia, including a need for higher intensity supportive care; these aspects were examined using NCI designation as a surrogate. It is conceivable that distance is less of a factor in this study due to examination of a single county, which would limit the generalizability of these findings across the United States; however, Los Angeles County spans 4,751 square miles and was home to 9.8 million people in 2008. The strong presence of health maintenance organizations in California could possibly confound a distance effect, as distance may behave differently in an alternate health care landscape. Nevertheless, potential limitations to the generalizability of these findings are minimized by the size and population of the county, which alone would rank as the eighth most populous state with robust multiracial, multiethnic representation.

Payor predicts CCC/COG utilization for older AYA patients with ALL and AML, whereas SES does not; race/ethnicity remains an independent predictor of treatment site in older AYAs with ALL. This pattern is consistent with the notion that payor serves as a significant driver of the location of care after adjusting for race/ethnicity and neighborhood-level SES. An association between payor contracts and referral patterns is implicated by the different behavior among age groups of publicly insured patients; whereas publicly insured older AYAs are less likely to be treated at CCC/COG sites, there is a trend toward younger publicly insured AML patients being more likely to receive such care. This conflicting pattern between patients ≤21 years and those >21 years is in line with the concept that the patients <21 years may be receiving pediatric services at the specialized site; this also echoes studies (32) that have reported that pediatric centers accept 15- to 21-year-olds regardless of insurance status.

In addition, race/ethnicity and age emerge as independent predictors of treatment site among older AYAs with ALL, with patients from African American and Hispanic backgrounds and 22- to 29-year-olds less likely to receive treatment at CCC/COG than their NHW and 30- to 39-year-old counterparts. AYAs are a unique population, and may be at one of many different phases of young adulthood, whether at school or work full- or part-time, with a living situation that ranges from living alone or with friends to living with spouses, partners or parents; these aspects likely impact the source of insurance for an AYA as well (employer-based, parent-based, public, none). Each of these findings warrants investigation to understand these barriers at a granular level.

Registries provide unique population-level data, but with inherent limitations; these include a lack of detailed clinical, health behavior and care delivery data including adherence to prescribed therapy. For example, these data lack white blood cell count at diagnosis, chromosome copy number, or cytogenetic details, thus limiting our inclusion of these in analyses. The neighborhood-level sociodemographic factors (income and education) used to create the SES variable may vary from individual-level measurements; in addition, race/ethnicity is abstracted from the medical record and may differ from the gold standard of self-report. Nevertheless, these variables serve as the best available measures in population-level analyses which are able to uncover novel findings outside of the idealistic clinical trial setting. Decisions regarding physician assignment (pediatric or adult service) by age at diagnosis vary by treatment facility, and the registry does not document which specialty/service treated a patient at any particular site, nor the therapy given. We have previously published our observations for other cancer diagnoses, and found that health coverage predicts treatment site (30). Thus, in this study, we have grouped patients with comparable access to public coverage; 15- to 21-year-olds at a site designated as COG for pediatrics (but not as CCC) were assigned to COG. Repeating analyses without inclusion of the 3 COG sites that were not affiliated with an NCI-designated CCC yielded comparable findings (Supplementary Table S4). Our a priori assignment conservatively assigns 15- to 21-year-olds to pediatric services. Any misclassification bias would mute our results rather than changing their direction or enhancing them; in fact, our treatment site effect would be more pronounced if we considered this age cutoff to be younger.

These population-level findings indicate that poor survival among the younger AYA with ALL (<30 years) and AML (<22 years) as compared to children can be mitigated by treatment at CCC/COG facilities. We present a novel, systems-level approach to a pervasive challenge. This study highlights the need for ongoing investigations into health care delivery in cancer, specifically in AYAs and patients facing barriers to access (lacking private insurance; underrepresented minorities). No individual element of healthcare delivery is mutually exclusive, and generalizing outcomes from one component overlooks the quintessential integrative model (33) in which each element contributes to the overall end point of high-quality care. Our recognition of barriers to care at specialized centers highlights a gap in provision of high-quality cancer care in vulnerable populations. It becomes imperative to respond to IOM recommendations to both develop quality measurement and simultaneously improve access, as it is crucial that attention to these items moves beyond typical adult-onset cancers and older populations and includes AYAs who remain stranded between the pediatric and adult healthcare systems.