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Hematologic Malignancy
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Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population
Abstract
A dramatic improvement in the survival of patients with chronic myeloid leukemia (CML) occurred after the introduction of imatinib mesylate, the first tyrosine kinase inhibitor (TKI). We assessed how these changes affected the life expectancy of patients with CML and life-years lost as a result of CML between 1973 and 2013 in Sweden.
Patients recorded as having CML in the Swedish Cancer Registry from 1973 to 2013 were included in the study and followed until death, censorship, or end of follow-up. The life expectancy and loss in expectation of life were predicted from a flexible parametric relative survival model.
A total of 2,662 patients with CML were diagnosed between 1973 and 2013. Vast improvements in the life expectancy of these patients were seen over the study period; larger improvements were seen in the youngest ages. The great improvements in life expectancy translated into great reductions in the loss in expectation of life. Patients of all ages diagnosed in 2013 will, on average, lose < 3 life-years as a result of CML.
Imatinib mesylate and new TKIs along with allogeneic stem cell transplantation and other factors have contributed to the life expectancy in patients with CML approaching that of the general population today. This will be an important message to convey to patients to understand the impact of a CML diagnosis on their life. In addition, the increasing prevalence of patients with CML will have a great effect on future health care costs as long as continuous TKI treatment is required.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by an acquired balanced chromosomal translocation, which gives rise to a constitutively active tyrosine kinase (BCR-ABL1).1 Untreated or symptomatically treated CML is a fatal disease, with a reported median survival of approximately 2 to 3 years in seemingly unselected CML populations.2 More than 90% of Swedish patients receive a diagnosis while in the chronic phase, and the major treatment goal is to prevent the disease from progressing to more advanced phases.3 Treatment of patients with CML has changed dramatically over the years. CML therapy was restricted to busulphan and hydroxyurea before the 1980s.2 During the 1980s and 1990s, allogeneic stem cell transplantation and interferon alfa (both alfa-2a and alfa-2b) were the treatments of choice.4,5 A dramatic improvement occurred after 2000 with the introduction of imatinib mesylate (IM), the first tyrosine kinase inhibitor (TKI) that specifically targeted the BCR-ABL1 oncoprotein.1 IM treatment significantly increased the survival and quality of life for patients of all ages, particularly those in the chronic phase.6,7
The improved survival in patients with CML is increasingly prevalent, a trend that is projected to continue during the coming decades.3,8,9 For the large majority of patients, the increased survival in combination with the recommended life-long IM treatment will have a great impact on costs.9 It will be important to guide health care professionals, educators, and policy makers with regard to present and potential future achievements with a focus on population-based data. Also important for these groups as well as for patients and clinicians is the presentation of survival statistics in a way that enhances the understanding of the impact of a cancer diagnosis on a patient’s life expectancy, especially for chronic diseases such as CML.
Life expectancy is a simple, well-known concept that quantifies the expected number of life-years remaining. The loss in expectation of life (LEL) is a survival measure that presents the number of life-years lost or reduction in life expectancy as a result of a cancer diagnosis.10,11 The many advantages of these measures include their easy comprehension and, thus, communication, and the provision of a survival measure over a whole time scale.
The aim of this study was to assess how the life expectancy of patients with CML and life-years lost as a result of a CML diagnosis have changed between 1973 and 2013 in patients diagnosed in Sweden. Particular interest lies in the survival of patients after the introduction of TKIs. An additional aim was to determine whether improvements previously reported in the survival of patients with CML in Sweden have continued between 2008 and 2013.
The study included patients with CML recorded within the nationwide Swedish Cancer Registry established in 1958. By law, every incidence of cancer must be reported to this registry by each physician and pathologist/cytologist. The Swedish Cancer Registry contains information on age, sex, and date and type of diagnosis but does not contain detailed information on symptoms, routine laboratory tests, treatments, and comorbidities.12 Patients with CML were identified by using the International Classification of Diseases, Version 8 (code 2051). All residents in Sweden are given a unique national registration number for linkage with the national Cause of Death Register to obtain the date of death.
Patients who received a diagnosis between January 1, 1973, and December 31, 2013, were included in the cohort. Patients were followed until their date of death, date of emigration, or end of follow-up (December 31, 2013), whichever occurred first. Diagnoses were included from 1973 because the registry is known to have reached a high coverage for hematologic malignancies by then.13 Only the first histologically verified diagnosis of CML of patients 50 years of age or older were considered. The reason for including patients age 50 years and older at diagnosis was so that long extrapolation was not required when calculating the LEL. Incidental autopsy findings and misclassified cases were excluded. The study was approved by the Stockholm Regional Ethics Review Board. Informed consent was waived because there was no contact with study subjects.
The LEL is the difference between the life expectancy of a patient with cancer and the life expectancy of a similar individual in terms of age and sex from the general population. This measure estimates the average number of life-years lost or the reduction in the life expectancy as a result of a cancer diagnosis. The LEL can also be presented as the proportion of expected life lost (PELL), which is the proportion of remaining life-years lost as a result of a cancer diagnosis. The LEL and PELL can be estimated on the basis of the relative survival of the patients with cancer and the survival of the general population.10 Relative survival is defined as the all-cause observed survival in the cancer population under study divided by the expected survival of a comparable group in the general population.14,15
The LEL and PELL were predicted from a flexible parametric relative survival model with five degrees of freedom to model the baseline excess hazard.16,17 Age at diagnosis, year of diagnosis, and sex were all modeled (age and year that continuously used restricted cubic splines18), and interactions among these covariates were included. The model included time-dependent effects with two degrees of freedom for all covariates to allow for nonproportional excess hazards. The expected survival was obtained from population mortality files up to 2012 and predictions beyond 2012 by Statistics Sweden19 and stratified by age at diagnosis, year of diagnosis, and sex. All analyses were performed with Stata 13 software (StataCorp, College Station, TX).
A total of 2,662 patients with CML diagnosed between 1973 and 2013 at age 50 years and older (males, 1,446 [54.3%]; females, 1,216 [45.7%]) were included. The median age at diagnosis for the included cohort was 69 years (Table 1).
|
| Characteristic | Calendar Period | Total | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1973-1982 | 1983-1992 | 1993-2002 | 2003-2013 | |||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | |
| Total patients with CML | 679 | 25.5 | 690 | 25.9 | 573 | 21.5 | 720 | 27.1 | 2,662 | 100 |
| Age, years | ||||||||||
| 50-59 | 138 | 20.3 | 136 | 19.7 | 162 | 28.3 | 182 | 25.3 | 618 | 23.2 |
| 60-69 | 227 | 33.4 | 197 | 28.6 | 142 | 24.8 | 223 | 31.0 | 789 | 29.6 |
| 70-79 | 214 | 31.5 | 240 | 34.8 | 179 | 31.2 | 180 | 25.0 | 813 | 30.5 |
| > 79 | 100 | 14.7 | 119 | 17.0 | 90 | 15.7 | 135 | 18.8 | 442 | 16.6 |
| Sex | ||||||||||
| Male | 371 | 54.6 | 363 | 52.6 | 322 | 56.2 | 390 | 54.2 | 1,446 | 54.3 |
| Female | 308 | 45.4 | 327 | 47.4 | 251 | 43.8 | 330 | 45.8 | 1,216 | 45.7 |
Abbreviation: CML, chronic myeloid leukemia.
Results are presented for four selected ages at diagnosis: 55, 65, 75, and 85 years. The life expectancy of the general population for males and females increased over the follow-up period; this increase was larger for the younger populations studied. The life expectancy of the patients with CML steadily increased for all ages between 1973 and 1990. For younger patients with CML, a large increase in the life expectancy was seen after 1990, but this increase was not as great in the older patients and began later (Fig 1). The increase seen in the life expectancy in those age 55 years at diagnosis after 1990 continued until 2013; however, the largest increase was seen between 1990 and 2000, with a more steady increase after 2000. In patients with CML age 85 years at diagnosis, the greatest increase in life expectancy began from around 2000. Over the entire study period, patients with CML of all ages experienced a dramatic increase in life expectancy, which in 2013 approached that of the general population. For example, a 55-year-old male patient diagnosed with CML in 1980 would, on average, have 3.5 (95% CI, 2.9 to 4.1) life-years remaining, whereas a 55-year-old male diagnosed in 2010 would have 27.3 (95% CI, 25.7 to 28.8) life-years remaining. An 85-year-old male would have, on average, 0.8 (95% CI, 0.7 to 1.1) life-years remaining if he was diagnosed in 1980 and 4.1 (95% CI, 3.4 to 4.7) life-years remaining if he was diagnosed in 2010. The life expectancy of CML patients of all ages diagnosed in 2010 was within 3 years of the life expectancy of the general population, as shown in the LEL estimates (Table 2; Fig 2).
Fig 1. Life expectancy of the general population and of patients with chronic myeloid leukemia in Sweden, over year of diagnosis, by age at diagnosis and sex. Shaded area around the yellow line represents 95% CI. Abbreviation: CML, chronic myeloid leukemia.
|
| Measure, by year | Age 55 Years | Age 65 Years | Age 75 Years | Age 85 Years | ||||
|---|---|---|---|---|---|---|---|---|
| Males | Females | Males | Females | Males | Females | Males | Females | |
| 1980 | ||||||||
| LE | 24.3 | 29.0 | 15.3 | 19.3 | 8.7 | 11.3 | 4.5 | 5.5 |
| LE CML | 3.5 (2.9 to 4.1) | 4.1 (3.4 to 4.7) | 2.7 (2.3 to 3.0) | 3.2 (2.8 to 3.6) | 1.8 (1.5 to 2.0) | 2.2 (1.9 to 2.4) | 0.8 (0.7 to 1.1) | 1.1 (0.9 to 1.3) |
| LEL | 20.8 (20.2 to 21.4) | 24.9 (24.3 to 25.6) | 12.6 (12.2 to 12.9) | 16.1 (15.7 to 16.5) | 7.0 (6.7 to 7.2) | 9.1 (8.8 to 9.4) | 3.6 (3.4 to 3.8) | 4.4 (4.2 to 4.6) |
| PELL | 0.86 (0.83 to 0.88) | 0.86 (0.84 to 0.88) | 0.83 (0.80 to 0.85) | 0.84 (0.81 to 0.86) | 0.80 (0.77 to 0.83) | 0.81 (0.78 to 0.83) | 0.80 (0.76 to 0.85) | 0.80 (0.76 to 0.84) |
| 1990 | ||||||||
| LE | 26.3 | 30.2 | 16.8 | 20.5 | 9.4 | 12.0 | 4.8 | 6.0 |
| LE CML | 5.9 (4.9 to 7 to 0) | 6.66 (5.6 to 7.8) | 3.8 (3.3 to 4.3) | 4.5 (3.9 to 5.1) | 2.1 (1.8 to 2.4) | 2.6 (2.3 to 2.9) | 0.9 (0.7 to 1.1) | 1.1 (0.9 to 1.3) |
| LEL | 20.4 (19.3 to 21.4) | 23.6 (22.4 to 24.7) | 13.0 (12.5 to 13.5) | 16.1 (15.5 to 16.6) | 7.3 (7.0 to 7.5) | 9.4 (9.0 to 9.7) | 3.9 (3.7 to 4.0) | 4.8 (4.6 to 5.0) |
| PELL | 0.77 (0.73 to 0.81) | 0.78 (0.74 to 0.82) | 0.77 (0.74 to 0.80) | 0.78 (0.75 to 0.81) | 0.77 (0.75 to 0.80) | 0.78 (0.76 to 0.81) | 0.81 (0.78 to 0.85) | 0.81 (0.78 to 0.84) |
| 2000 | ||||||||
| LE | 28.2 | 31.4 | 18.5 | 21.7 | 10.5 | 13.0 | 5.0 | 6.2 |
| LE CML | 15.8 (13.7 to 17.9) | 17.2 (14.8 to 19.5) | 9.3 (8.2 to 10.4) | 10.6 (9.3 to 11.9) | 4.6 (4.0 to 5.2) | 5.5 (4.8 to 6.3) | 1.8 (1.4 to 2.1) | 2.2 (1.8 to 2.6) |
| LEL | 12.4 (10.3 to 14.5) | 14.3 (11.9 to 16.6) | 9.2 (8.1 to 10.3) | 11.1 (9.8 to 12.4) | 5.9 (5.3 to 6.5) | 7.4 (6.6 to 8.2) | 3.3 (3.0 to 3.6) | 4.0 (3.6 to 4.5) |
| PELL | 0.44 (0.37 to 0.51) | 0.45 (0.38 to 0.53) | 0.50 (0.44 to 0.56) | 0.51 (0.45 to 0.57) | 0.56 (0.51 to 0.62) | 0.57 (0.51 to 0.63) | 0.65 (0.59 to 0.72) | 0.65 (0.58 to 0.72) |
| 2010 | ||||||||
| LE | 29.9 | 32.6 | 20.1 | 22.8 | 11.7 | 14.0 | 5.7 | 6.9 |
| LE CML | 27.3 (25.7 to 28.8) | 29.7 (28.0 to 31.4) | 17.5 (16.2 to 18.9) | 19.8 (18.4 to 21.3) | 9.5 (8.5 to 10.5) | 11.3 (10.2 to 12.5) | 4.1 (3.4 to 4.7) | 5.0 (4.2 to 5.8) |
| LEL | 2.6 (1.0 to 4.1) | 2.9 (1.2 to 4.6) | 2.5 (1.2 to 3.8) | 2.9 (1.4 to 4.4) | 2.2 (1.2 to 3.2) | 2.6 (1.4 to 3.8) | 1.6 (0.9 to 2.3) | 2.0 (1.2 to 2.8) |
| PELL | 0.09 (0.04 to 0.14) | 0.09 (0.04 to 0.14) | 0.13 (0.06 to 0.20) | 0.13 (0.06 to 0.19) | 0.18 (0.10 to 0.27) | 0.19 (0.10 to 0.27) | 0.28 (0.16 to 0.40) | 0.28 (0.17 to 0.40) |
Abbreviations: CML, chronic myeloid leukemia; LE, life expectancy; LEL, loss in expectation of life; PELL, proportion of expected life loss.
Fig 2. Loss in expectation of life of patients with chronic myeloid leukemia in Sweden, over year of diagnosis, by age at diagnosis and sex.
The LEL decreased for all ages over the study period, but the most dramatic decrease was seen in diagnoses after 1990 in younger patients. This was because of the huge increase in the life expectancy of patients with CML at this time (Fig 2; Table 2). For example, a male diagnosed with CML in 1980 at age 55 years had, on average, a reduced life expectancy of 20.8 (95% CI, 20.2 to 21.4) years. In contrast, a 55-year-old male diagnosed in 2010 would have, on average, a reduced life expectancy of only 2.6 (95% CI, 1.0 to 4.1) years. For older patients, improvements were still seen, with a more rapid decrease after the 1990s, but not to the same scale as in the younger patients because older patients have, on average, fewer potential remaining life-years.
Estimates of PELL also suggest a vast improvement in the outcomes of patients with CML of all ages over the study period (Fig 3; Table 2). Before approximately 1990, the PELL was higher in the younger patients included in the study, whereas after this time, the PELL was higher in the older patients. For example, the PELL for a 55-year-old male and an 85-year-old male diagnosed in 1980 were 86% (95% CI, 83% to 88%) and 80% (95% CI, 76% to 85%), respectively; in 2010, these values were 9% (95% CI, 4% to 14%) and 28% (95% CI, 16% to 40%), respectively.
Fig 3. Proportion of expected life lost of patients with chronic myeloid leukemia in Sweden, over year of diagnosis, by age at diagnosis and sex.
The results show a dramatic reduction in life-years lost in patients with CML diagnosed in Sweden between 1973 and 2013. Patients age 55 years at diagnosis benefited greatly since 1990, and life expectancy improvements continued to 2013, but less dramatically from 2000. For older patients, improvements in life expectancy began a little later. The results indicate that the life expectancy of patients with CML is now close to the life expectancy of the general population for all ages.20-22 However, reports have suggested an increased incidence of other cancers20,21 and cardiovascular morbidity22 associated with the use of TKIs, which could have a negative impact on survival gains. Thus, the life expectancy of patients with CML may never reach that of the general population. In addition, approximately 10% of patients with CML in Sweden are diagnosed in an advanced phase, and life expectancy for the whole group of these patients will not likely reach the life expectancy of the whole population. Even so, the life expectancy of patients with CML was within 3 years of the life expectancy of the general population for diagnoses in 2010, which can be seen as a great success of CML treatment.
Treatment of patients with CML has changed dramatically over the years, and IM was approved as second-line CML treatment in Sweden in 2001 and first-line treatment in 2002. However, the implementation of imatinib differed among age-groups. During the period of 2002 to 2008, it was, on average, 79% in patients younger than 70 years and 47% in patients older than 70 years, which led to less conspicuous or no improvement in survival for elderly patients.2 These proportions increased to 94% for younger (< 70 years) and 79% for older (> 80 years) patients during 2007 to 2009.3 Although IM remains the gold standard for first-line treatment of CML, the appearance of IM resistance and intolerance has led to the development of several additional TKIs.23 Studies have shown that second-generation TKIs (dasatinib, nilotinib, bosutinib) improve outcome in patients with CML in whom IM therapy has failed.23,24 In addition, a third-generation TKI (ponatinib) that targets the frequently observed mutant T315I has been developed.25 Thus, CML treatment is progressing rapidly, and further advancements are anticipated. Notwithstanding that a small subgroup of patients with an excellent response to treatment has been able to stop taking TKI agents,26 most patients with CML will take the drug for life, which along with the increasing prevalence of CML, has high cost implications. Ohm et al9 evaluated the cost-effectiveness of IM in patients with CML and found that incremental cost-effectiveness ratios that compared IM with other treatments were generally acceptable by health authorities, which means that these treatments should continue to be financially feasible.
The results shown for the youngest patients with CML suggest that improvements in survival began for those diagnosed in the mid-1990s. The results also show improvements from the introduction of IM in 2001; however, great improvements were observed before its introduction. The improvements seen for older patients began slightly later than in the younger patients; however, no immediate improvement was seen after 2001 when IM was introduced. The use of interferon alfa,27 more precise diagnostics that involve centralized cytogeneic laboratories, and a more structured approach in treating and monitoring patients with CML are plausible explanations for the trend. Although the present research suggests that improvements in survival of patients with CML over the years may not have been completely a result of the introduction of IM, it is clear that the prognosis for patients with CML today is extremely positive with the current treatment.
Sasaki et al28 concluded from clinical trial data that 5-year survival of patients with chronic CML is almost the same as the general population, and the present results support this finding. Björkholm et al8 followed Swedish patients with CML on a population level and saw improvements in relative survival between 1973 and 2008 for all ages, with vast improvements in those age 79 years and younger at diagnosis from 2001. The present study shows that these improvements have continued to 2013. We chose to use LEL to present outcomes in patients with CML, whereas others quantified survival by using relative survival. These two measures are related but describe different aspects of patient survival. In particular, the relative survival is an estimate of net survival, which is interpreted in a hypothetical situation where patients with cancer can only die as a result of their cancer, whereas the LEL is a measure that represents the real-world survival patients with cancer experience.
One potential limitation of the study is that the current analysis did not capture any late lethal effects if they were to occur due to fewer years of follow-up in the later calendar years; the fewer years of follow-up also mean that the estimates presented rely more on the model assumptions. However, it is also possible that any late adverse effects may not affect patient life span.
A major strength of the current study is the use of population-based information. We include all CML diagnoses reported to the Swedish Cancer Registry between 1973 and 2013. The Swedish Cancer Registry has high completeness; in 1998, it was estimated to capture 96% of all cancers in Sweden.13 Use of population-based data is optimal because these data capture the mortality of patients with CML in Sweden on a whole, incorporate changes in treatments, and show the increasing prevalence of CML and potential adverse effects of treatments for patients with CML. Unfortunately, the Swedish Cancer Registry does not contain information on treatment and other detailed clinical information, which also means a lack of potential confounder information, such as socioeconomic status.
To present the LEL for all patients, including those diagnosed in the most recent years, extrapolation from models are required. This potential weakness of the LEL has been assessed by Andersson et al10 in various cancers, and extrapolation was shown to be accurate. However, further extrapolation is required to calculate the LEL in younger patients because of their longer potential life expectancy. Therefore, the LEL was presented for patients age 55 years and older.
In conclusion, life expectancy and number of life-years lost have vastly improved in patients with CML of all ages in Sweden since 1973, with larger improvements observed in the mid-1990s. IM, along with allogeneic stem cell transplantation and other factors, have increased life expectancy in patients with CML to almost the same as that of the general population today.
Supported by grants from the Swedish Cancer Society, the Adolf H. Lundin Charitable Foundation, and the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet. We also thank Eva Lundin for her support.
Presented at the Association of Nordic Cancer Registries Symposium 2015, Helsingbørg, Denmark, September 8-9, 2015; and the 57th American Society of Hematology Annual Meeting, Orlando, FL, December 4-8, 2015.
Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
Conception and design: Hannah Bower, Magnus Björkholm, Paul W. Dickman, Therese M.-L. Andersson
Financial support: Paul C. Lambert, Magnus Björkholm
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
No relationship to disclose
Honoraria: Celgene, Roche, Janssen Pharmaceuticals (a Johnson & Johnson co.), ARIAD Pharmaceuticals
Consulting or Advisory Role: Celgene, Janssen Pharmaceuticals (a Johnson & Johnson co.)
No relationship to disclose
Consulting or Advisory Role: Janssen-Cilag
Expert Testimony: Akinion Pharmaceuticals
No relationship to disclose
Other Relationship: Scandinavian Development Services
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