Survival of chronic myeloid leukemia patients in comparison to the general population in the tyrosine kinase inhibitors era: A <scp>US</scp> population‐based study
Authors: Omer Jamy, Richard Godby, Rehan Sarmad, Luciano J. Costa
Journal: American Journal of Hematology (2021)

Treatment of chronic myeloid leukemia (CML) was revolutionized by the introduction of ABL tyrosine kinase inhibitors (TKIs) in 2001, leading many patients to achieve deep and even durable responses. Recent studies have suggested that a substantial subset of patients with CML, responding to TKIs, have a life expectancy approaching the general population.1, 2 However, those studies are somewhat limited by small sample size, possible selection bias, and/or a less diverse population. Moreover, recent analyses using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database found that many older adults diagnosed with CML had difficulty initiating TKI therapy, but those who received appropriate TKI therapy achieved near normal survival, underscoring the impact of real-world variables, including access to care.3 In this context, we sought to compare the relative survival (RS) of patients with CML in the United States (US) during the TKI era, analyzing several sociodemographic factors. We utilized the SEER 18 registries to select patients diagnosed with BCR-ABL positive CML (ICD-O-3 code 9875/3) between 2001 (introduction of TKIs) and 2014 (most recent year with follow up available). The SEER-18 registry includes cancer populations from Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, Rural Georgia, Alaska Native, Greater California, Kentucky, Louisiana, New Jersey, and Greater Georgia registries, representing 27.8% of the US population. For different subsets we described RS, the ratio between actual survival of CML patients and the survival expected in a population with same age, sex and race/ethnicity characteristics. We subsequently performed sensitivity analysis to identify a time landmark beyond which CML patients are expected to have survival more closely resembling the survival of the general population. These analyses were performed for different sex, age (<50 years, 50–64 years, ≥65 years), era of diagnosis (2001–2007, 2008–2014), race/ethnicity and insurance-status subsets. Analysis per insurance-status was partially limited by unavailability of this information for cases diagnosed before 2007. A 6-month landmark analysis was performed to exclude patients expiring either due to advanced phase CML or early transformation to acute leukemia. The analysis was performed using the survival function in SEER*Stat v 8.3.4. There were 3946 patients included in the analysis with a median follow up of 72 months. Of these, 2253 (57.1%) were males and 1693 (42.9%) were females; 1738 patients (44.0%) were < 50 years, 1204 (30.5%) were between 50–64 years, and 1004 (25.4%) were ≥ 65 years. There were 2514 (63.7%) Non-Hispanic Whites (NHW), 602 (15.2%) Hispanics and 426 (10.8%) Non-Hispanic Blacks (NHB). There were 1764 (73.1%) insured, 491 (20.4%) Medicaid and 156 (6.5%) uninsured patients. The five-year and ten-year RS for the entire population was 83.4% (95% C.I. 81.6%–85.0%) and 72.8% (95% C.I. 69.7%–75.6%), respectively. For 6-month survivors, the 5-year and 10-year RS was 85.6% (95% C.I. 84.2%–89.9%) and 75.1% (95% C.I. 74.6%–80.4%), respectively. Ten-year RS for male patients was 71.1% (95% C.I. 66.8%–74.9%) vs 74.7% (95% C.I. 70.2%–78.7%) for female patients (p = .118). Ten-year RS for patients ≥65 years was 46.9% (95% C.I. 37.3%–55.9%), inferior to 10-year RS of patients <65 years (78.9%, 95% C.I. 77.8%–82.6%, p < .001), <50 years (80.5%, 95% C.I. 77.1%–83.4%, p < .001) and 50–64 years (77.0%, 95% C.I. 71.2%–81.8%, p < .001). There was no significant difference in 10-year RS between patients <50 years and those 50–64 years. The 5-year RS for patients diagnosed between 2008–2014 and 2001–2007 was 87.0% (95% C.I. 85.2%–88.6%) and 81.0% (95% C.I. 78.2%–83.5%), respectively (p < .001). There was no significant difference in 10-year RS according to race/ethnic, reaching 73.7% (95% C.I. 69.8%–77.2%) for NWH, 68.0% (95% C.I. 60.0%–74.7%, p = .09 for comparison with NHW) for Hispanics and 64.8% (95% C.I. 53.8%–73.8%, p = .05 for comparison with NHW) for NHB. Six-year RS was 88.4% (95% C.I. 85.4%–90.8%) for insured patients vs 85.7% (95% C.I. 77.0%–91.3%, p = .237 for comparison with insured) for uninsured patients and 70.6% (95%. C.I. 61.3%–78.2%, p < .001 for comparison with insured) for Medicaid beneficiaries (Figure 1, Panel A). A sensitivity analysis identified 7 years from CML diagnosis as the time landmark that best identified patients with subsequent survival resembling that of the general population. With a drop-off rate of 9% for years 1 and 2 and 15%–20% for years 3 to 7, there were 1113 patients remaining for the sensitivity analysis. The 12-year RS for seven-year survivors of CML was 91.2% (95% C.I. 85.7%–98.3%). Seven-year survivors of CML had a 12-year RS that approached the general population, particularly for females (95.0% 95% C.I. 87.9%–100.0%), patients <50 years (94.0%, 95% C.I. 89.2%–98.1%), patients 50–64 years (93.3%, 95% C.I. 82.7%–100.0%) and NHW (92.5%, 95% C.I. 85.9%-97.4). The 12-year RS was somewhat lower for male survivors (88.1%, 95% C.I. 81.1%–94.3%) as well as Hispanics (86.5%, 95% C.I. 73.9%–97.2%) and NHB (86.8%, 95% C.I. 68.8%–100.0%). The 12-year RS for patients ≥65y was very low (69.3%, 95% C.I. 50.0%–84.0%) (Figure 1, Panel B). Based on this analysis, the RS of patients with CML, in the US, is not similar to the general population. It is worse for patients ≥65y compared to patients <65 years and for Medicaid beneficiaries when compared to insured patients. Relative survival improved from 2001–2007 to 2008–2014, perhaps due to broader use of novel TKIs and a better understanding of both disease and TKI management. Contingent upon surviving the first 7 years after CML diagnosis, the 12-year RS of females, NHW and patients <65 years does appear to approach the general population. Unfortunately, males, Hispanics/NHB and older patients still demonstrate worse survival despite receiving treatment in the TKI era and having survived the diagnosis of CML for 7 years. The reasons for these outcomes are not exactly clear and are possibly influenced by outcomes disparities by age, race/ethnicity and insurance status, highlighting challenges such as access to care, medication adherence and tolerance as well as timely response assessments.3, 4 Whereas clinical trial populations have been shown to have RS comparable to the general population, it is challenging to extrapolate the same outcomes to real-world CML patients, given the stringent inclusion/exclusion criterion for enrollment as well as financial assistance available to patients through trial participation.1 Population-based studies, on the other hand, have shown conflicting results. Chen et al. utilized the SEER 9 registries (covering 10% of the US population) to report a 5-year RS of only 56% for CML patients diagnosed between 2001–2009. They also observed a significant improvement in RS for 2005–2009, compared to 2001–2004.5 A Swedish study found the life expectancy of patients with CML approaching that of the general population. Despite being developed countries, both the US and Sweden differ in terms of healthcare metrics as well as policy which may partly explain the discordant outcomes.6 Medicaid is a government insurance program for persons of all ages whose income and resources are insufficient to pay for health care. Our findings should not be interpreted as an assessment of the value of Medicaid service, as other confounding factors such as burden of comorbidities may explain the difference when compared to insured or uninsured patients. In fact, studies have found uninsured patients to have less comorbidity burden when compared to Medicaid beneficiaries. However, whereas Medicaid has expanded access to care for its recipients, there is data showing that variation in health care plans such as copays can result in adverse outcomes.7 Perry et al. reported inferior survival outcomes for Medicaid beneficiaries and uninsured patients with CML, when compared to insured patients.8 The RS for 7-year CML survivors was encouraging for females, NHW and younger patients. Older patients still did poorly. Although this landmark analysis may have addressed barriers such as initial access to care as well as filter out patients with accelerated or blast-phase CML, issues pertaining to compliance, access to novel TKIs, and drug-related toxicity remain. Novel TKIs may have to be taken twice a day with dietary restrictions and have rare but severe cardiovascular, pulmonary and renal side effects, making them difficult to tolerate for many elderly patients with comorbidities. Lack of access to novel TKIs, due to socioeconomic reasons, and lack of proper response monitoring as well as timely interventions for early signs of treatment failure are issues that exist at the population-level as well.4 A poor response to TKIs has been reported in unmarried individuals as well as those residing in rural areas and having a low education level again highlighting that optimal management may not be available to all patients with CML.6 Our analysis needs to be interpreted within the limitations of the SEER database. Lack of treatment data, comorbidity assessment and treatment facility limit our ability to adjust for potential confounders. Furthermore, the insurance models captured by SEER may not be uniform across the country and may limit the generalizability of our findings. Nonetheless, the SEER database has extensively been used to assess the impact of sociodemographic factors on survival in various hematological malignancies at the population-level. Our findings highlight that the care of CML patients remains complex despite recent therapeutic advances. Proper management should encompass disease, comorbidity, and sociodemographic related variables which, unfortunately, may not be available to all patients. In addition to understanding the underlying biology of disease to come up with effective treatment options, analyzing sociodemographic variables also provides an opportunity to improve outcomes in the general population. The authors declare no conflict of interest. . Omer Jamy, Richard Godby and Luciano J. Costa contributed towards the conception of the presented study, data collection and analysis. Omer Jamy, Richard Godby, Rehan Sarmad and Luciano J. Costa contributed towards drafting, revising, and approving the manuscript. The data that support the findings of this study are available on request from the corresponding author.