Page 179 - 2022_03-Haematologica-web

Letters to the Editor
treated at National Cancer Institute-Designated Cancer Centers (NCI-CC). Overall, 7- and 30-day mortality were 9.2% and 11.1%, respectively. From the pre-ACA to full ACA era, 7-day mortality decreased from 13.0% to 5.5% (P-value for trend=0.011) and 30-day mortality decreased from 14.4% to 7.3% (P-value for trend=0.029) (Table 1). With a median follow-up of 4.7 years (range, 0-14.1), 80 patients died during the study period: 48 (60%) died within 7 days and 58 (72.5%) died within 30 days of the diagnosis of APL. The 3-year survival increased from 79.8% before the ACA to 92.7% in the full ACA era (P- value for trend=0.0004).
Across treatment eras, there was a decrease in adoles- cents and young adults who were uninsured or obtained Medicaid insurance at APL diagnosis, from 28.2% (pre- ACA) to 18.3% (full ACA). Among those, a few adoles- cents and young adults (n=9, 1.7%) remained uninsured in the pre- and early-ACA eras, but none was uninsured in the full ACA era. In addition, there was a substantial increase in continuous Medicaid enrollment prior to diag- nosis, from 13.9% (pre-ACA) to 40.2% (full ACA) (P-value<0.0001). Furthermore, we observed a trend towards increased initial care at NCI-CC, from 35.7% before the ACA to 41.5% in the full ACA era, although this difference was not statistically significant.
In multivariable models, compared with the pre-ACA era, the odds of both 7- and 30-day mortality were about 50-60% lower in the full ACA era (OR=0.42, 95% CI: 0.18-0.98 and OR=0.51, 95% CI: 0.24-1.08, respectively) (Table 2). Remarkably, the odds of 7- and 30-day mortal- ity were approximately 5-fold higher among adolescents and young adults who did not receive initial care at a NCI-CC (OR=4.85, 95% CI: 1.96-12.0 and OR=5.28, 95% CI: 2.26–12.2, respectively). Likewise, the hazard of death decreased in the full ACA era compared to that in the pre-ACA era (HR=0.39, 95% CI: 0.20–0.76), and was nearly 4 times higher for patients who did not receive ini- tial care at a NCI-CC (HR=3.71, 95% CI: 1.97-6.99). Age at diagnosis, sex, race/ethnicity, socioeconomic status and health insurance were not associated with early mor- tality or overall survival.
Our findings of reduced early mortality and improved overall survival during the study period are relevant. Most early deaths after APL result from severe hemor- rhage (intracranial and, less often, pulmonary) and are the major cause of treatment failure.6 Another potential- ly fatal manifestation of APL is thrombosis (e.g., stroke, acute myocardial infarction, and pulmonary embolism). These manifestations can occur within a few hours or days of diagnosis or even prior to the recognition of APL, supporting the concept that APL should be considered as a medical emergency.7 Thus, timely access to optimal treatment is lifesaving. Several factors may have con- tributed to the better outcomes we observed among ado- lescents and young adults with APL in the more recent treatment eras. These include increased awareness of APL-related coagulopathy, improved physicians’ adher- ence to treatment guidelines, and early referral to hema- tology/oncology centers.6,8
In our previous study, Hispanic patients and those without health insurance experienced worse outcomes. In this update, we did not observe differences in early mortality or survival by race/ethnicity. This observation is encouraging and is likely the result of the increased insurance coverage we observed among Hispanics over time (uninsurance decreased from 46.3% before the ACA to 21.1% in the full ACA era). Historically, in the USA, adolescents and young adults have been the most highly uninsured or underinsured population.9 It is likely that
adolescents and young adults without health insurance delay seeking medical care until the APL symptoms become severe, whereas those with insurance may be encouraged to seek medical attention earlier, when the first manifestations of APL appear. In this current study, we found increases in continuous Medicaid and reduc- tion in Medicaid enrollments at diagnosis or uninsurance among adolescents and young adults with APL. Before implementation of the ACA, a restricted number of adults with a cancer diagnosis would qualify for Medicaid coverage.10 In California, a Medicaid expansion state, the ACA increased health insurance coverage to low-income young adults through the Dependent Coverage Expansion and Low-Income Health Plan as early as 2010. At the beginning of 2014, the Low-Income Health Plan ended, and patients obtained coverage under the California regular Medicaid program (Medi-Cal) or acquired private health insurance through the establish- ment of marketplace coverage. Marketplace insurance plans are prohibited to deny coverage to insurers or set higher premiums for pre-existing conditions such as can- cer.10 Although we did not find an association between insurance and APL outcomes in our cohort, when we separately analyzed patients who remained uninsured (n=9), we found that their 7-day and 30-day mortality were significantly higher. This suggests that uninsured patients are at risk of not having prompt access to opti- mal care during the initial diagnosis of APL.
Importantly, we found that higher early mortality and worse survival were strongly associated with location of initial care, consistent with prior reports.2 This may be related, in part, to greater awareness and provider expert- ise gained by treating a larger volume of patients with acute leukemias at NCI-CC.11 In addition, these facilities generally have better access to blood products and broad- er specialist support to care for severely ill patients. Changes in therapy during the study period are risk-strat- ified approaches that include the combination of ATRA and ATO, cytotoxic chemotherapy for high-risk patients, pre-emptive therapy for differentiation syndrome, and more aggressive blood product support for coagulopathy.8,12,13 Adherence to more modern approach- es is more likely at NCI-CC and may have contributed to the improvement in outcomes we observed. In California, there are eight NCI-CC in seven cities, so timely access to NCI-CC may not be possible for many adolescents and young adults with APL, reinforcing the need to improve care at non-NCI-CC.
Our study limitations include a lack of treatment details, which prevented us from assessing adherence to treatment guidelines. In addition, we did not have clinical information for APL risk stratification. These data could contribute to our understanding of different factors that can influence early mortality in young patients with APL. Regardless of these limitations, we used population- based data from the most populous and diverse U.S. state where cancer registration is mandatory, providing infor- mation on virtually all adolescents and young adults diag- nosed with APL during the study period. We showed a considerable reduction in early mortality and increased survival over time. The higher 7-day and 30-day mortal- ity and lower survival observed in adolescents and young adults cared for outside of NCI-CC underscore the need for earlier recognition and better implementation of treat- ment guidelines, particularly at non-NCI-CC.
Renata Abrahão,1,2 Raul C. Ribeiro,3 Marcio H. Malogolowkin,4 Ted Wun1 and Theresa H.M. Keegan1
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