Long-term Patterns of Oral Anti-cancer Agent Adoption, Duration and Switching in Patients with CML

Abstract

BACKGROUND:

Oral tyrosine kinase inhibitors (TKIs) have been the standard of care for chronic myeloid leukemia (CML) since 2001. However, few studies have evaluated changes in the treatment landscape for CML over time. This study assessed the long-term treatment patterns of oral anti-cancer therapies among CML patients.

METHODS:

This retrospective cohort study included patients newly-diagnosed with CML between 01/01/2000–12/31/2016 from ten integrated health care systems. The proportions of patients treated with five Food and Drug Administration-approved oral TKI agents—bosutinib, dasatinib, imatinib, nilotinib, ponatinib—in the 12 months after diagnosis were measured, overall and by year, between 2000–2017. We assessed use of each oral agent through the fourth-line setting. Multivariable logistic regression estimated the odds of receiving any oral agent, adjusting for sociodemographic and clinical characteristics.

RESULTS:

Among 853 CML patients, 81% received an oral agent between 2000–2017. Use of non-oral therapies decreased from 100% in 2000 to 5% in 2005, coinciding with imatinib uptake from 65% in 2001 to 98% in 2005. About 28% of patients switched to a second-line agent, 9% to a third-line agent, and 2% to a fourth-line agent. Age at diagnosis, year of diagnosis, and comorbidity burden were statistically significantly associated with odds of receiving an oral agent in adjusted analysis.

CONCLUSION:

We found a dramatic shift in CML treatments away from traditional, non-oral chemotherapy toward use of novel oral TKIs between 2000–2017. As costs of oral anti-cancer agents reach new highs, studies assessing the long-term health and financial outcomes among CML patients are warranted.

Introduction

Approximately 8,430 patients will be newly diagnosed with Chronic Myeloid Leukemia (CML) and 1,090 patients will die from CML in 2018 in the United States (U.S.).¹ Treatment advances in CML using targeted oral therapies have led to dramatic improvements in prognosis, with a 50% decrease in the mortality rate from 2000 to 2015.² CML patients’ life expectancy is now approaching that of the general population.³ Imatinib, an orally-administered tyrosine kinase inhibitor (TKI), was approved by the U.S. Food and Drug Administration (FDA) in 2001 as a first-line therapy for CML in adults. However, resistance to imatinib is well-documented, with nearly 20% of patients displaying primary resistance (initial refractoriness to imatinib) and another 20% of patients presenting with secondary, or acquired, resistance (developing during imatinib treatment).⁴ To overcome mutational resistance, three second-generation oral TKIs—dasatinib, nilotinib and bosutinib—and one third-generation oral TKI, ponatinib, have received approval for use as first-line treatments or salvage therapy options, following the use of prior agents.⁵ These five oral agents have become the standard of care and compose a complex treatment landscape for patients with CML.

While prior studies have assessed the use and adherence of oral TKIs to treat CML,^6–12 few have evaluated the entire scope of treatment patterns among CML patients, including the use non-TKI oral therapies, non-oral therapies, and those who never receive therapy.^13,14 Current guidelines recommend treatment with TKIs indefinitely for some patients with CML,¹⁵ while evidence suggests that imatinib, dasatinib or nilotinib can safely be discontinued in patients with sustained molecular response.^16,17 Nevertheless, the optimal sequential use of specific TKIs is unclear due to the similarities in their mechanisms of action; particularly, in the third-line setting and beyond.¹⁸ Further, there is limited research describing the use of sequential treatment regimens for CML in community practice.

To address this knowledge gap, we used tumor registry data linked to comprehensive electronic health record (EHR), insurance claims, and pharmacy data from ten large U.S. health care systems to conduct an assessment of treatment use patterns, switching, duration, and adherence among adult patients diagnosed with CML. To our knowledge, this is the first study to assess multi-modality treatment utilization, as well as to provide detailed information on treatment switching patterns across all FDA-approved oral anti-cancer agents, among patients with CML.

Methods

Study Setting and Data Sources

This retrospective analysis of oral and non-oral cancer therapy use was conducted using data on patients diagnosed with CML who received care at one of ten integrated health systems (Kaiser Permanente Colorado, Kaiser Permanente Northern California, Kaiser Permanente Northwest, Kaiser Permanente Hawaii, Kaiser Permanente Washington, Reliant Medical Group/Meyers Primary Care Institute, Marshfield Clinic, Geisinger, Henry Ford Health System, and HealthPartners Institute). These systems are members of the NCI-funded Cancer Research Network (CRN, https://crn.cancer.gov/) a consortium within the Health Care Systems Research Networks (HCSRN).

The HCSRN’s Virtual Data Warehouse (VDW) was the primary data source for this study.^19–21 The VDW is a series of standardized databases and content areas that include enrollment, demographic, tumor registry, pharmacy, vital sign, diagnosis, procedure, infusion, and benefit data. This system is populated with data on all services received for all members via EHR and claims data for members who receive care. Within the VDW, the Virtual Tumor Registry (VTR) contains data consistent with the North American Association of Central Cancer Registries (NAACCR) standards.²² VTR data is obtained from medical chart reviews of cancer patients by trained abstractors and includes data associated with health service use, clinical, treatment, and tumor characteristics. The VDW pharmacy files contain data on national drug code (NDC)-based prescription drugs dispensed from both outpatient pharmacies and infusion centers. Death information is obtained from the VTR, membership files, state-level death registries, and from Social Security Administration data.

Study Population

We included n=853 patients diagnosed with CML (International Classification of Diseases for Oncology [ICD-O-3] codes 9863, 9875, 9876) between January 1, 2000 and December 31, 2016. Eligibility was limited to patients’ first cancer diagnosis (sequence 00 or 01), who were 21 years or older at diagnosis, survived at least 1 month after diagnosis, and continuously enrolled in the 12 months following diagnosis. The follow-up period was defined as January 1, 2000 through December 31, 2017.

Study Measures

The primary outcome measure was the proportion of CML patients treated with any of the five FDA-approved oral TKIs (bosutinib, dasatinib, imatinib, nilotinib or ponatinib) in the 12 months following diagnosis. Additionally, we assessed the proportions of patients who received non-TKI oral agents (ruxolitinib, thalidomide, lenalidomide, chlorambucil, and ibrutinib), non-oral therapy, or no cancer therapy. Among patients who received an oral therapy agent (TKI or non-TKI), we calculated the proportion of use of each agent through the fourth-line setting. First-line therapy was defined as the first oral anti-cancer agent initiated within the first twelve months following diagnosis. Patients were classified as switching (to a second-, third, and fourth-line therapy) if they had evidence of cessation of the initial agent (no further prescriptions ordered or dispensed for the initial agent), followed by initiation of a different oral agent (i.e., a dispensing for another oral agent).

The date of treatment initiation was defined as the first date a patient received an oral agent, as measured by the initial dispensing date for a given agent. Duration of each distinct line of therapy was measured as the time between the date of treatment initiation (day of first dispensing) and the end date. The end date for each line of therapy was defined as the earliest of the following dates: discontinuation, plan disenrollment, death, the day before the first dispensing date of the new therapy (only for those who switched) or end of study period (12/31/2017). The date of discontinuation was defined by the last day of medication availability based on days supplied, before a gap in therapy coverage ≥60 days. Patients had to be enrolled for the entire 60-day gap (unless due to death) to be identified as discontinuing. Medication adherence was measured using proportion of days covered (PDC), defined as the total days’ supply of agent divided by the duration of each distinct line of therapy.^7,23 Time-to-treatment was defined as the number of days between CML diagnosis and treatment initiation (for first-line therapy) and, for those who switched therapy, the number of days between end date of previous therapy and date of initiation for the subsequent line of therapy.

Statistical Analysis

Descriptive statistics were used to characterize baseline patient variables and oral cancer agent use. Baseline patient variables included age at diagnosis, sex, race, Hispanic ethnicity, study site, year of diagnosis, vital status at end of follow-up period, the Quan adaptation of the Charlson Comorbidity Index score (e.g., excluding cancer diagnosis)²⁴, and duration of follow-up. We calculated the proportion of patients who received any oral cancer agent and the proportion who did not receive any oral therapy, overall and by year.

For those who received an oral agent, we calculated the proportion of patients who received each type of agent, overall and by year, during the study period. We also calculated the proportion of patients who received each type of oral agent by line of therapy. We described the most commonly used therapeutic sequence of oral agents received by patients, by total number of agents in the sequence.

We used multivariable logistic regression to estimate the likelihood of receiving any oral agent, adjusting for age at diagnosis, race, Hispanic ethnicity, study site, year of diagnosis, and Charlson Comorbidity Index score. All statistical tests assumed a two-sided alpha of 0.05. Analyses were conducted using SAS 9.4 (SAS Inc., Cary, NC).

Results

Among all patients with CML, 81% were treated with an oral agent (Table 1). Compared to those who did not receive an oral agent, patients who received oral therapy were more likely to be younger (70% <age 65 years at diagnosis versus 36%), non-white (24% versus 18%), Hispanic (12% versus 6%), diagnosed after 2005 (74% versus 53%), and have a Charlson Comorbidity Index of 0 (63% vs 42%).

Table 1.

Characteristics of Study Cohort

Characteristic	Received Oral Agent (n=694)		Did Not Receive Oral Agent (n=159)		p-value
Age at Diagnosis, years	n	%	n	%	<.0001
18–39	124	17.9	13	8.2
40–64	358	51.6	44	27.7
65–79	174	25.1	53	33.3
≥80	38	5.5	49	30.8
Mean age (s.d.), years	55.9 (15.6)		67.5 (17.5)		<.0001
Sex					0.71
Male	404	58.2	90	56.6
Female	290	41.8	69	43.4
Race					0.004
Asian	67	9.7	6	3.8
Black	62	8.9	10	6.3
American Indian/Alaskan Native/Native Hawaiian/Pacific Islander	16	2.3	<6	0.6
Other/Unknown	21	3.0	12	7.6
White	528	76.1	130	81.8
Ethnicity					0.08
Hispanic	81	11.7	9	5.7
Non-Hispanic/Unknown	613	88.3	150	94.3
Year of CML Diagnosis					<.0001
2000–2004	179	25.8	74	46.5
2005–2009	209	30.1	36	22.6
2010–2014	252	36.3	42	26.4
2015–2017	54	7.8	7	4.4
Charlson-Deyo Comorbidity Index					<.0001
0	438	63.1	67	42.1
1	128	18.4	40	25.2
≥2	128	18.4	52	32.7
Mean Charlson Comorbidity Index (s.d.)	0.8 (1.3)		1.3 (1.61)		<.0001
Mean Duration of Follow-up (s.d.), months	63.9 (49.3)		33.7 (43.1)		<.0001
Received Hydroxyurea	278	40.1	57	35.9	0.33

Notes: Table estimates based on n=853 patients diagnosed with CML between 2000–2017.

^*Charlson Comorbidity Index excludes all cancer diagnoses from the Index.

Abbreviations: CML=chronic myelogenous leukemia; s.d.=standard deviation. Cells with the value “<6” represent instances where there are less than six patients (but at least 1 patient) with the given variable value; HIPAA and data use agreements with participating sites prohibit us from reporting exact values in such instances. Oral agents included bosutinib, chlorambucil, dasatinib, ibrutinib, imatinib, lenalidomide, nilotinib, ponatinib, ruxolitinib, and thalidomide. Non-oral agents included: asparaginase, azacytidine, Bacillus of Calmette and Guerin (BCG), bendamustine, bevacizumab, busulfan, cetuximab, cyclophosphamide, cytarabine, daunorubicin, decitabine, docetaxel, doxorubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, melphalan, mitoxantrone, pegaspargase, pentostatin, rituximab, tocilizumab, topotecan, vincristine. P-value based on chi-square test (for categorical variables and t-test (for continuous variables) comparing patients who received an oral agent to those who did not receive an oral agent.

Figure 1 shows the swift decrease in use of non-oral therapies among patients with CML, from 100% in 2000 to 5% in 2005 and continuing thereafter (to <1% by 2017), alongside the rapid uptake of oral TKI agents following their FDA approval. In 2001, approximately 65% of patients received imatinib, rising to 98% of patients by 2005. Use of imatinib by patients began decreasing after 2005, from 97% in 2006 to 64% in 2017. Following the FDA approval of dasatinib in 2006, patient use of this agent increased from 4% (2006) to 26% by 2015. Similarly, use of nilotinib increased from 1% in 2007 to 17% in 2016, following its approval in 2007. Use of bosutinib remained near 1% between FDA approval in 2012 through 2017, with ponatinib at or below 1% following FDA approval in 2013.

Figure 1.

Trends in Treatment Use among Patients with CML.

Notes: Estimates based on n=853 patients diagnosed with CML between 2000–2017. Percentages in any given year may not add to 100%, since a patient may have used more than more therapy in a year. “Other” oral agents included: ruxolitinib, thalidomide, lenalidomide, chlorambucil, and ibrutinib. “Non-oral” therapy included asparaginase, azacytidine, Bacillus of Calmette and Guerin (BCG), bendamustine, bevacizumab, busulfan, cetuximab, cyclophosphamide, cytarabine, daunorubicin, decitabine, docetaxel, doxorubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, melphalan, mitoxantrone, pegaspargase, pentostatin, rituximab, tocilizumab, topotecan, vincristine.

Among those patients who received an oral agent as first-line therapy, 91% used imatinib, 6% dasatinib, 2% nilotinib, and 1% other oral agents (Table 2). Time-to-initiation of first-line therapy was shortest for those who received dasatinib (22.9 days) and the duration of first-line therapy was longest for patients who received imatinib (47 months). The PDC of first-line therapy was similar across oral agents, ranging from 0.85 with nilotinib to 0.93 with dasatinib. Approximately 28% of patients who received first-line therapy switched to a second-line oral agent, among which the most commonly used second-line agent was dasatinib (66%) followed by nilotinib (30%), imatinib (3%), and bosutinib (0.5%). Time-to-initiation of second-line therapy was shortest for imatinib (17.5 days) and duration of second-line therapy was longest for those who received dasatinib (27 months).

Table 2.

Patterns of Oral Anti-Cancer Agent Use among Patients with CML

Total number of patients who initiated line of therapy	Imatinib	Dasatinib	Bosutinib	Nilotinib	Ponatinib	Other
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
First-line (n=694)	630 (90.7)	41 (5.9)	n/a	14 (2.0)	n/a	9 (1.3)
Time to first-line therapy, days (mean/median)	67.1/12	22.9/12		228.6/51.5		476.6/91
Duration (mean, months)	46.72	20.92		23.72		3.85
PDC, (mean)	0.88	0.93		0.85		0.91
Second-line (n=196)	6 (3.1)	130 (66.3)	<6	59 (30.1)	n/a	n/a
Time to second-line therapy, days (mean/median)	17.5/0	97.2/3.5	0/0	121.5/6
Duration (mean, months)	22.36	27.74	22.16	25.96
PDC (mean)	0.91	0.84	1.00	0.83
Third-line (n=64)	18 (28.1)	6 (9.4)	<6	32 (50)	<6	n/a
Time to third-line therapy, days (mean/median)	116.4	26.8	173.3	22.8	39
Duration of third-line treatment (mean, months)	20.28/32.5	15.05/11.5	15.47/4.5	27.22/10.5	4.5/0
PDC (mean)	0.81	0.98	0.88	0.82	0.85
Fourth-line (n=17)	<6	6 (35.3)	<6	<6	<6	<6
Time to fourth-line therapy, days (mean/median)	149/149	16.8/13.5	705.6/443	31.7/16	18.5/18.5	398/398
Duration (mean, months)	4.30	25.72	5.89	26.70	15.21	1.67
PDC (mean)	1.00	0.87	0.91	0.65	0.98	1.00

Notes: Table estimates based on n=694 patients diagnosed with CML between 2000–2017 who received any oral anti-cancer agent. Cells with the value “<6” represent instances where there are less than six patients (but at least 1 patient) who received the respective agent; HIPAA and data use agreements with participating sites prohibit us from reporting exact values in such instances. “Other” oral agents included: ruxolitinib, thalidomide, lenalidomide, chlorambucil, and ibrutinib. Abbreviations: CML=chronic myelogenous leukemia; PDC=proportion of days covered.

Nearly one in every three patients who received second-line therapy switched to a third-line agent, among which nilotinib was most common (50%), followed by imatinib (28%), dasatinib (9%), bosutinib (6%), and ponatinib (6%). Patients who received nilotinib as the third-line therapy had the shortest time-to-initiation and longest duration of use. Patients who received dasatinib as third-line therapy had the highest PDC (0.98). About 27% of patients who received third-line therapy switched to fourth-line, with dasatinib the most commonly used fourth-line agent (35%). Each of the remaining agents were used by fewer than six patients.

The most common oral therapy sequences for patients who received up to four lines of therapy are presented in Table 3. Among patients who received first line therapy only, 65% of patients used imatinib as the first-line agent, 4% used dasatinib and 1% used nilotinib. For patients who received two lines of oral therapy (n=196), the most common sequence was imatinib followed by dasatinib (42%), then imatinib followed by nilotinib (17%), and dasatinib followed by nilotinib (4%). Among those who received three lines of oral therapy (n=64), 39% received imatinib-dasatinib-nilotinib and 11% received imatinib-dasatinib-imatinib, with fewer than six patients receiving imatinib-nilotinib-imatinib or imatinib-nilotinib-dasatinib. Among the patients who received a fourth-line oral therapy (n=17), the three most common sequences were imatinib-dasatinib-imatinib-dasatinib, imatinib-dasatinib-nilotinib-dasatinib, or imatinib-nilotinib-imatinib-nilotinib.

Table 3.

Most Common Oral Therapeutic Sequences among Patients with CML who Received up to Four Lines of Therapy

Line of therapy and number of patients who initiated line of therapy	Number of patients who received agent or sequence	Sequence of agents in treatment regimen
		1	2	3	4
First-line (n=694)	454	Imatinib
	25	Dasatinib
	10	Nilotinib
Second-line (n=196)	84	Imatinib	Dasatinib
	34	Imatinib	Nilotinib
	7	Dasatinib	Nilotinib
Third-line (n=64)	25	Imatinib	Dasatinib	Nilotinib
	7	Imatinib	Dasatinib	Imatinib
	<6	Imatinib	Nilotinib	Imatinib
	<6	Imatinib	Nilotinib	Dasatinib
Fourth-line (n=17)	<6	Imatinib	Dasatinib	Imatinib	Dasatinib
	<6	Imatinib	Dasatinib	Nilotinib	Dasatinib
	<6	Imatinib	Nilotinib	Imatinib	Nilotinib

Notes: Table estimates based on the n=694 patients diagnosed with CML between 2000–2017 who received any oral anti-cancer agent. The table is not exhaustive and only provides the three most common agents or sequences (or four if there were equal percentages of patients who received two sequences), for each line of therapy. Cells with the value “<6” represent instances where there are less than six patients (but at least 1 patient) who received the respective agent; HIPAA and data use agreements with participating sites prohibit us from reporting exact values in such instances. Abbreviations: CML=chronic myelogenous leukemia.

In multivariable regression analysis, age at diagnosis and Charlson Comorbidity Index were statistically significantly associated with receiving an oral agent (Supplemental Table 1). Specifically, patients who were older (Odds Ratio (OR)=0.96, 95% Confidence Interval (CI):0.95–0.97, p<0.001) and patients who had a greater comorbidity burden (OR=0.87, 95% CI:0.76–0.99, p=0.039) had lower odds of receiving an oral agent than those who were younger and had fewer comorbidities. Year of CML diagnosis was statistically significantly associated with greater odds of receiving an oral agent, with those patients diagnosed in more recent years having greater odds than those diagnosed earlier (OR=1.16, 95% CI:1.10–1.21, p<0.001). Sex, race, Hispanic ethnicity, and receipt of hydroxyurea were not found to be significantly associated with receipt of an oral agent in this population.

Discussion

Our study is the first to quantify the dramatic shift in treatment practices away from non-oral chemotherapy agents toward use of novel oral TKIs in a large cohort of patients treated for CML. In addition, we detailed patterns of switching and multiple lines of use for the majority of patients who initiated oral therapy. The patterns of oral agent use underscore the long length of time on treatment that many CML patients undergo (we found as long as 48 months for imatinib, i.e., 4 years), as well as the heterogeneity in the sequential use of different oral agents, with some patients receiving four lines of therapy. These findings from real-world community oncology settings address important questions, demonstrating widespread adoption of new anti-cancer agents following their FDA approval and the substitution effects on the use of older therapies.

We found that 81% of patients newly diagnosed with CML in our analysis received an oral agent between 2000–2017, with 99% of these patients receiving a TKI as their first-line agent. These estimates are higher than those previously reported in the few studies that assessed non-use of TKIs.^13,14 Using SEER-Medicare data, Winn and colleagues¹³ found that approximately 68% of eligible patients newly diagnosed with CML between 2007–2011 initiated TKI therapy within 180 days following diagnosis. Darkow and colleagues¹⁴ reported that 42% of patients newly diagnosed with CML between 1997–2009 initiated TKI therapy, using pharmacy and medical claims data from 45 large US employers. Although differences in study design and population preclude a direct comparison across studies, the high proportion reported in our study is based on estimates for patients diagnosed with CML via our tumor registry data linked to actual dispensing data. These data reflect contemporary treatment patterns for all five oral TKI agents currently FDA-approved as treatment options within our community practices. The cohort comprises patients under 65 years of age (70%) with a mean age of 55 and higher estimates may be due to prescribing practices when treating patients with fewer chronic conditions. Similarly, patients with more comorbid conditions were less likely to receive an oral anti-cancer agent, potentially related to greater physician or patient concerns about adverse events or toxicities.

Consistent with prior studies assessing the use of oral TKI agents for the treatment of CML across health care settings, imatinib was the predominant therapy used between 2001–2017,^6–12 overall and as a first-line therapy. Imatinib-treated patients also had the longest duration of therapy due to it being the earliest TKI drug approved. Of note, our study extends this prior research by showing the rapid decline in use of older, non-oral therapies between approximately 2000–2005 (from 100% to 5%, respectively) coinciding with the prompt uptake of imatinib from 65% (2001) to 98% (in 2005)—a clear substitution effect. We also observed a decrease in imatinib use beginning in 2006 (following FDA approval of dasatinib), a finding that reflects similar trends to those shown in a recent study by Cole and Dusetzina¹² who showed decreased use of imatinib as first-line therapy from approximately 100% between 2001–2005 to nearly 40% in 2014. Though imatinib use did not decrease below 60% in our study, these results collectively demonstrate a shift over time away from imatinib in the first-line setting toward dasatinib and nilotinib.

Our findings on the therapeutic sequences among patients with CML reflect long-term patterns of oral TKI use in community oncology practice and add to a paucity of literature,^25–30 particularly outside of the clinical trial setting.^7,10,11 Nearly 28% of patients who initiated a first-line oral agent switched to a second-line agent, consistent with findings from prior observational studies.^7,10,11 This is also consistent with expected secondary resistance estimates for imatinib, requiring a therapeutic switch.³¹ Dasatinib was the most common second-line agent used (66%) and nilotinib was the most common third-line agent used (50%), indicating imatinib-dasatinib (for first- to-second-line) and imatinib-dasatinib-nilotinib (for first- to third-line) as the specific sequences. These findings are consistent with prior research^7,26–28,30, follow the sequential drug approval years, and highlight the patterns of sequential oral TKI agents in real-world practice.

Limitations

This study has certain limitations that warrant consideration when interpreting results. First, our study was conducted among cancer patients enrolled in ten integrated health systems with standardized prescribing practices and our findings are most generalizable to similar populations. However, there are also strengths to this population, including the stability of the population over time and access to comprehensive tumor registry and electronic health record data. Second, we did not have access to data on presence of the BCR-ABL1 mutation, the phase of CML, cytogenic or molecular response to therapy; thus, we were not able to evaluate the association of these factors with therapy initiation, discontinuation, delays in therapy or switching. Third, we did not have access to data on reason for discontinuation or switching. However, we relied on the availability and ability to access comprehensive pharmacy, utilization, infusion, clinical and demographic information from the electronic health records of ten health care systems and report findings from a large sample size. Fourth, in estimating adherence with PDC, we relied on pharmacy data on medication dispensings, which does not guarantee that patients took the medication as directed and may lead to an overestimation of adherence. However, pharmacy records are considered to be more accurate than self-reported medication use.^32,33 Finally, we did not assess patient cost-sharing associated with oral TKI use, although this has been shown to be associated with treatment delays and discontinuation.³⁴

Conclusion

Our findings provide a comprehensive and longitudinal analysis of the treatment patterns among patients with CML across ten large U.S. health care systems. We highlight the rapid uptake of oral TKI agents over an 18-year period during which five novel agents were approved by the FDA to treat CML. The unique nature of CML and the approaches to treat the disease, characterized by extended treatment periods that may last patients’ entire remaining lives, present opportunities for future research to understand the primary reasons for treatment discontinuation and switching, as well as to assess the value of therapy for patients and the health care system. As the costs of oral anti-cancer medications reach new highs,^12,35 studies are warranted to assess the long-term health and financial outcomes among CML patients and if the continued benefits outweigh the risks of therapy.