ABSTRACT
Chemoimmunotherapy (CIT) had long been used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) until 2014 when the first novel agent, ibrutinib, was approved in the United States. Numerous novel therapies have since become available. Nevertheless, as novel therapies have largely replaced CIT in CLL/SLL, its impact on survival has yet to be examined on the population level. In this study, we used the SEER (Surveillance, Epidemiology, and End Results) database to compare survival in patients with CLL/SLL before and after the approval of the first novel therapy. We included 9913 patients who started treatment within 2 years of CLL/SLL diagnosis. In the multivariable analyses, the overall survival improved significantly (hazard ratio [HR]: 0.86, 95% confidence interval: 0.81, 0.92), and death from CLL/SLL and other cancer (subdistribution‐HR: 0.69 and 0.77) also decreased significantly. Nevertheless, CLL/SLL remains the main cause of death during the novel agent era.
Keywords: cause of death, chronic lymphocytic leukemia/small lymphocytic lymphoma, novel agents, overall survival
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common subtype of non‐Hodgkin lymphoma, affecting > 200,000 patients in the United States [1]. Traditional chemoimmunotherapy had been the standard treatment in CLL/SLL before novel agents became available. Ibrutinib [2], a covalent Bruton tyrosine kinase inhibitor (cBTKi), was the first novel drug approved for relapsed/refractory CLL/SLL in 2014. In the trial which led to this approval, ibrutinib was associated with a progression‐free and overall survival of 75% and 83%, respectively, at 26 months in a heavily pretreated, chemotherapy‐refractory cohort [2].
Ever since, the treatment landscape of CLL/SLL has been substantially transformed. Two second‐generation cBTKi, acalabrutinib [3, 4] and zanubrutinib [5, 6], and the B‐cell lymphoma‐2 (BCL‐2) inhibitor, venetoclax [7] have been approved in CLL/SLL. Due to the superiority in both efficacy and safety over chemoimmunotherapy [4, 5, 7, 8], these regimens have been authorized as frontline therapies. Pirtobrutinib and lisocabtagene maraleucel have also been approved for relapsed/refractory diseases [9, 10].
The impact of access to cBTKi and BCL2 inhibitor on survival outcomes in CLL/SLL has not been examined on a population level. We hypothesize that the overall survival (OS) has improved with a decrease in mortality from CLL/SLL since the approval of these drugs.
In this analysis, we used the SEER (Surveillance, Epidemiology, and End Results) database, which covers ∼50% of the population in the United States [11]. We included 9913 adult patients diagnosed with CLL/SLL between the Years 2008 and 2019 (excluding 2013–2014) who required treatment within 2 years of diagnosis. Most patients included in this study were men (66%) and White (85%), with close to 80% diagnosed at the age of 60 or older. We defined the pre‐novel agent (pre‐NVA) era as the years of CLL/SLL diagnosis between 2008 and 2012 (N = 4876), and the novel agent (NVA) era during 2015–2019 (N = 5037). We considered the Years 2013–2014 as a “wash‐out” period for the use of novel agents [12]. The distributions of age, sex, and race were similar between the two treatment eras (Appendix 1: Table A1).
Patients in this analysis were followed until death, loss of follow‐up, or December 31, 2022, whichever occurred first. The median follow‐up for the overall population was 7.5 years (12.5 and 5.4 years for the pre‐NVA and NVA cohorts, respectively). We used the Kaplan–Meier method to estimate the 5‐year OS in the two cohorts. Given the relatively short duration of follow‐up in the NVA cohort, we applied the flexible parametric regression method to extrapolate the median OS in the two cohorts [13]. In the multivariable analysis, patients with follow‐up > 5 years were censored at the end of the 5th year to adjust for the imbalanced durations of follow‐up between the two cohorts. We used the proportional hazard Cox regression model to compare the OS between the NVA and pre‐NVA eras. We adjusted age (20–49, 50–59, 60–69, 70–79, 80+), sex, race (White, non‐White), and area of residence (metropolitan, non‐metropolitan), and reported hazard ratio (HR) with 95% confidence interval (CI).
The 5‐year OS rate was 61.0% and 65.3%, respectively, for the pre‐NVA and NVA cohorts (Figure 1). The estimated median OS was 7.1 and 8.3 years, respectively, in the two cohorts. The estimated and observed OS curves overlap for both cohorts, respectively (Appendix 2: Figure A1). In the multivariable analysis, the OS was significantly improved during the NVA era, compared with the pre‐NVA era (HR: 0.86, 95% CI: 0.81 to 0.92, p value < 0.001). In the sensitivity analysis of using the initiation of therapy as the beginning of follow‐up, the results were very similar (HR: 0.86, 95% CI: 0.79–0.93).
FIGURE 1.
Overall survival in chronic lymphocytic leukemia/small lymphocytic lymphoma needing therapy within 2 years of diagnosis before and after the approval of novel agents. CLL, chronic lymphocytic leukemia; OS, overall survival.
We classified causes of death (COD) into the following categories: (1) CLL/SLL, (2) cardiovascular disease (CVD), (3) infection, (4) cancer other than CLL/SLL, and (5) other cause. For the NVA era, we estimated the percentage of death within 5 years due to each cause. In the multivariable analysis, we censored patients with longer follow‐up at the end of the 5th year. We performed competing risk analysis to compare mortality from each cause, respectively, between the two eras. We adjusted for age, sex, race, and area of residence, and computed sub‐distribution of HR (sub‐HR) with 95% CI using the Fine‐Gray method [14].
During the NVA era, CLL/SLL remains the leading COD among patients requiring therapy within 2 years of diagnosis, accounting for close to two fifths of deaths within 5 years after the diagnosis, followed by other cancer, other cause, and CVD (Figure 2A). In the multivariable analysis, compared with the pre‐NVA era, patients diagnosed during the NVA era were less likely to die from CLL/SLL (sub‐HR: 0.69, 95% CI: 0.62–0.76), or other cancer (sub‐HR: 0.77, 95% CI: 0.67–0.88). The latter was not driven by myeloid neoplasm (similar between two eras, results not shown). Mortality due to CVD (sub‐HR: 1.17, 95% CI: 0.98–1.40) and infection (sub‐HR: 0.94, 95% CI: 0.67–1.32), respectively, were similar between the two treatment eras (Figure 2C,D). Similar trend was observed in the 3‐year cumulative incidence of different COD based on the calendar period of diagnosis (Figure 2B).
FIGURE 2.
Causes of death in CLL/SLL. (A) Composite of causes of death within 5 years after CLL diagnosis in the novel agent era. (B) Stacked 3‐year cumulative incidence of different causes of death over calendar years of diagnosis. (C) Cumulative incidence (non‐stacked) of different causes of death during the pre‐novel agent era 2008–2012. (D) Cumulative incidence (non‐stacked) of different causes of death during the novel agent era 2015–2019. CLL, chronic lymphocytic leukemia; CVD, cardiovascular disease.
Our large, population‐based analysis showed a lower 5‐year mortality in patients requiring treatment within 2 years of diagnosis since the approval of novel agents for CLL/SLL. Despite the statistically significant increase in OS, the numerical difference between the two eras appears marginal (4.3%). This is possibly explained by the relatively short follow‐up in the NVA cohort, patients requiring therapy within 2 years are likely enriched for adverse biology that is not fully overcome by novel agents, and the availability of effective therapies for later lines, e.g., pirtobrutinib and lisocabtagene Maraleucel. The OS benefit is supported by the gain of extrapolated median OS by more than 1 year since the availability of novel agents. Nevertheless, longer follow‐up remains needed.
Our study also demonstrated that mortality due to CLL/SLL and other cancers decreased significantly since 2014. These findings were overall consistent with the improved efficacy and safety of the novel agents. Mortality from CVD and infection did not show substantial decrease, which underscores the importance of primary prevention for CVD and intensive supportive care intervention to decrease the infectious risk even during the NVA era. Despite improvement in treatment efficacy, CLL/SLL remained the leading cause of death. These findings are consistent with results from a registry study from the Netherlands [15] and a single‐center retrospective analysis [16].
Our study has several limitations. Firstly, we were not able to consider unobserved confounders in this retrospective analysis, including molecular data on risk stratification. Secondly, potential lead time bias for this indolent disease may not be fully adjusted. However, the age distributions at diagnosis were similar between the two cohorts (Appendix 1: Table A1), and our analysis focused on patients requiring therapy within 2 years of diagnosis, which helped decrease lead time bias. Thirdly, detailed treatment information is not available in the SEER database, which precluded further analysis to quantify OS benefit attributed to each agent. Fourthly, there might be misclassification in COD [17, 18]. Fifthly, the SEER data and practice changes are often behind drug approvals. The improvement in survival found in our analysis did not reflect the impact of pirtobrutinib and lisocabtagene maraleucel. Lastly, the follow‐up remains relatively short for the NVA era and does not include most COVID pandemic, which could impact findings related to infection.
In summary, in this large, population‐based study, we observed significant improvement in 5‐year OS since the approval of novel agents for CLL/SLL. Despite a decrease in CLL/SLL‐related death, CLL/SLL remains the leading COD in this population. Studies that include all CLL/SLL patients with longer follow‐up are needed to examine the overall CLL/SLL population (versus patients needing early treatment) and impact from the more recently approved novel regimens.
Author Contributions
Mengyang Di: conceptualization, investigation, writing – original draft, formal analysis, data curation, writing – review and editing. Scott F. Huntington: investigation, writing – review and editing. Jenna M. Voutsinas: investigation, writing – review and editing, data curation, formal analysis. Vicky Q. Wu: investigation, writing – review and editing. Chaitra S. Ujjani: investigation, writing – review and editing. Scott D. Ramsey: investigation, writing – review and editing. Jennifer J. Huang: investigation, writing – review and editing. Ajay K. Gopal: investigation, writing – review and editing. Mazyar Shadman: investigation, writing – original draft, writing – review and editing, conceptualization.
Funding
The authors have nothing to report.
Conflicts of Interest
M.D. reports institutional research funding: Schrodinger, BeOne, Regeneron, Eli Lilly, AbbVie, Dren Bio; honorarium/consultancy: Genentech, BeOne, AbbVie, Incyte, Merck. S.F.H. reports consulting from Beigene, Janssen, Pharmacyclics, AbbVie, AstraZeneca, Flatiron Health Inc., Novartis, SeaGen, Genetech, Merck, TG Therapeutics, ADC Therapeutics, Epizyme, Lilly, Ipsen, Servier, Arvinas, and Thyme Inc.; research funding from Celgene, DTRM Biopharm, and TG Therapeutics. V.Q.W. reports consulting for Century Therapeutics. C.S.U. reports consulting: Abbvie, Allogene, Astrazeneca, Atara, Ascentage, Beigene, Bristol Myer Squibb, Genentech Janssen, Pharmacyclics and institutional research funding from Eli Lilly/Loxo, Abbvie, Adaptive Biotechnologies, Astrazeneca. S.D.R. reports employment, leadership, and stock and other ownership interests from Curta Consulting; research funding, travel, accommodations, and expenses from Bayer. J.J.H. reports honoraria from Eisai Inc., consultancy from AbbVie, and institutional research funding from BMS and BeOne. A.K.G. reports research funding from Merck, I‐Mab bio, IgM Bio, Takeda, Gilead, Astra‐Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab; Consultancy/Honoraria: Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I‐Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius‐Kabi, Scitek; Stock Options: Compliment Corporation. M.S. reports consulting, advisory boards, steering committees or data safety monitoring committees: Abbvie, Genentech, AstraZeneca, Genmab, Janssen, Beigene, Bristol Myers Squibb, Morphosys/Incyte, Kite Pharma, Eli Lilly, Mustang Bio, Fate therapeutics, Nurix and Merck. He also reports institutional research funding from Mustang Bio, Genentech, AbbVie, Beigene, AstraZeneca, Genmab, Morphosys/Incyte and Vincerx. Stock options: Koi Biotherapeutics. Employment: Bristol Myers Squibb (spouse).
Acknowledgments
The authors have nothing to report.
Appendix 1.
TABLE A1.
Baseline characteristics on patients diagnosed during two treatment eras.
| 2008–2012 (N = 4876) | 2015–2019 (N = 5037) | Overall (N = 9913) | |
|---|---|---|---|
| Age at diagnosis, year | |||
| 20–49 | 363 (7.4%) | 330 (6.6%) | 693 (7.0%) |
| 50–59 | 895 (18.4%) | 840 (16.7%) | 1735 (17.5%) |
| 60–69 | 1354 (27.8%) | 1455 (28.9%) | 2809 (28.3%) |
| 70–79 | 1317 (27.0%) | 1486 (29.5%) | 2803 (28.3%) |
| 80+ | 943 (19.3%) | 919 (18.2%) | 1862 (18.8%) |
| Sex | |||
| Male | 3183 (65.3%) | 3332 (66.2%) | 6515 (65.7%) |
| Female | 1693 (34.7%) | 1705 (33.8%) | 3398 (34.3%) |
| Race | |||
| White | 4182 (85.8%) | 4267 (84.7%) | 8449 (85.2%) |
| Black | 501 (10.3%) | 553 (11.0%) | 1054 (10.6%) |
| Asian or Pacific Islander | 151 (3.1%) | 154 (3.1%) | 305 (3.1%) |
| American Indian/Alaska Native | 23 (0.5%) | 16 (0.3%) | 39 (0.4%) |
| Area of residence | |||
| Metropolitan | 4131 (84.7%) | 4377 (86.9%) | 8508 (85.8%) |
| Nonmetropolitan | 744 (15.3%) | 659 (13.1%) | 1403 (14.2%) |
Appendix 2.
FIGURE A1.
The comparisons between the estimated and observed Kaplan–Meier curves of overall survival. (A) The pre‐novel agent cohort. (B) The novel agent cohort.
Data Availability Statement
The data that support the findings of this study are available in Surveillance, Epidemiology, and End Results Program at https://seer.cancer.gov/. These data were derived from the following resources available in the public domain: Surveillance, Epidemiology, and End Results Program, https://seer.cancer.gov/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available in Surveillance, Epidemiology, and End Results Program at https://seer.cancer.gov/. These data were derived from the following resources available in the public domain: Surveillance, Epidemiology, and End Results Program, https://seer.cancer.gov/.