Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era

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1 Published Ahead of Print on April 26, 2018, as doi: /haematol Copyright 2018 Ferrata Storti Foundation. Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era by Anthony Mato, Jordan Jahnke, Pengxiang Li, Maneesha Mehra, Vrushabh P. Ladage, Michelle Mahler, Scott Huntington, and Jalpa A. Doshi Haematologica 2018 [Epub ahead of print] Citation: Anthony Mato, Jordan Jahnke, Pengxiang Li, Maneesha Mehra, Vrushabh P. Ladage, Michelle Mahler, Scott Huntington, and Jalpa A. Doshi. Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era. Haematologica. 2018; 103:xxx doi: /haematol Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

2 Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era Anthony Mato 1, Jordan Jahnke 2, Pengxiang Li 2,3, Maneesha Mehra 4, Vrushabh P. Ladage 2, Michelle Mahler 5, Scott Huntington 6, Jalpa A. Doshi 2,3 1 Memorial Sloan Kettering Cancer Center, New York City, NY, USA; 2 Division of General Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3 Leonard Davis Institute of Health Economics, Philadelphia, PA; 4 Janssen Global Services, LLC, Raritan, NJ, USA; 5 Janssen Research & Development, Raritan, NJ, USA; 6 Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA Corresponding author: Jalpa A. Doshi, PhD, University of Pennsylvania, 1223 Blockley Hall, Philadelphia, PA Tel jdoshi@pennmedicine.upenn.edu d

3 Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries, with a median age at diagnosis of 72 years. 1 Until 2014, chemoimmunotherapy combinations were the mainstay treatment, particularly for physically fit patients. 2, 3 However, older individuals or those with comorbid conditions may be less likely to tolerate standard CLL chemoimmunotherapy combinations. It is important to establish a baseline understanding of real world CLL treatments and outcomes prior to the introduction of novel agents, which would allow for a better understanding of unmet needs, particularly among older patients in the pre-novel therapy era, and also inform future comparative effectiveness studies. 4 Current literature provides limited data about real world treatment patterns and survival among older CLL patients. To address these gaps in the literature, we utilized comprehensive prescription and medical insurance claims linked with cancer registry data to analyze both first-line and second-line treatment patterns as well as survival outcomes in older adults newly diagnosed with CLL, in the time period ( ) that immediately predated FDA approval of novel agents. We also stratified outcomes by age (66-74 younger seniors vs. 75 years older seniors ). Our retrospective cohort study used SEER-Medicare linked data to compare treatment patterns, time-to-treatment initiation, and overall and CLL-specific survival from first-line and second-line treatments, among Medicare beneficiaries aged >65 years who were newly diagnosed with CLL between 2007 and The SEER registries capture newly diagnosed cancer patients, covering about 28% of the U.S. population. 5 The SEER-Medicare files utilized in our study included all SEER patients from 2007 through 2011 who had fee-for-service Medicare claims (inpatient, outpatient, d

4 physician, skilled nursing facility care, home health, hospice, pharmacy [Part D] claims) linked from 2007 through Our final study sample consisted of 3,214 newly diagnosed CLL patients. Initial treatment pattern outcomes consisted of the percentage of patients receiving a CLL treatment, mean time to first-line treatment initiation, and the type of treatment regimen initiated. A full list of CLL treatments may be found in Appendix Table 1. Time to firstline treatment initiation was defined as the time elapsed between the index (diagnosis) date and the date of the first claim for a CLL treatment. Type of treatment regimen was categorized as chlorambucil monotherapy, rituximab monotherapy, rituximab-containing chemoimmunotherapy combination, or other chemotherapy. A therapy was considered part of the first-line treatment regimen if it was received within 60 days of the initial drug claim. 6, 7 We also examined second-line treatments, defined as re-initiation of at least one or all of the agents in the first-line treatment regimen following a treatment-free interval of > 180 days, or the addition of a new treatment that was not part of the first-line treatment regimen. The second-line treatment start date was defined as the date on which the re-initiated therapy was administered or filled or the date on which the new treatment was added. Time to second-line treatment initiation was defined as the time elapsed between the index (diagnosis) date and the start of the second-line treatment date. Survival outcomes included OS (overall survival) and CLL-specific survival from first-line and second-line CLL treatment. We also examined 1-year and 2-year OS rates. CLL-specific survival was defined as the net survival measure representing cancer d

5 survival in the absence of other causes of death. Kaplan-Meier estimates were used to examine OS from first-line and second-line treatment dates among patients receiving these treatments. 8 Cox regressions examined factors associated with OS and CLLspecific survival from the first treatment date and second-line treatment date among treated patients. 9 (Appendix Table 4) Appendix Table 2 provides the sample characteristics for Medicare patients newly diagnosed with CLL, by age group. Over a median follow up of 36.1 months from CLL diagnosis, 1,047 (32.6%) of the overall patient sample received first-line treatment, with lower rates of treatment in the older seniors group (29.0% v 38.3%; P<.001). However, the older seniors group had a shorter median time to first treatment (4.4 v 6.8 months; P<.001). Rituximab-containing chemoimmunotherapy combinations were the most common treatment approaches overall (utilized in nearly half of patients receiving first-line treatment), yet significant differences were observed in the distribution of treatment approaches between the two age groups (P<.001). For example, a higher proportion of the older seniors group (vs. younger group) received monotherapy with either chlorambucil (21.0% v 9.0%) or rituximab (30.3% v 20.0%). Twelve percent of patients received second-line treatment; again, rates were lower in the older seniors group (10.7% v 14.2%; P=.004). Among patients receiving second-line treatment, the median time from CLL diagnosis to initiation of the secondline treatment was 21.8 months. Similar to the findings for first-line treatment, rituximabcontaining chemoimmunotherapy combinations were the most common second-line treatments (40.8%). d

6 The median OS from first-line treatment initiation and second-line treatment initiation was 52.4 months and 33.7 months, respectively. Estimated 1-year and 2-year OS rates after first-line treatment initiation were 81.4% and 69.3%, respectively (Table 3). OS rates after second-line treatment initiation were 71.8% at 1 year and 57.5% at 2 years. Patients in the older seniors group had a 1-year OS rate of 77.0% and 2-year OS rate of 62.7%, whereas those in the younger seniors group had a 1-year OS rate of 87.0% and 2-year OS rate of 79.0%. Similar patterns were observed for OS rates from the time of second-line treatment. Unadjusted Kaplan-Meier curves for OS from firstand second-line treatments are shown in Figure 1. Regression analyses were run, controlling for a series of variables (listed in Appendix Table 4). Among patients receiving first-line treatment, older age was associated with worse OS (HR,1.81; 95% CI,1.46 to 2.24). Additionally, male sex, Northeast location relative to the West, Medicare Part D low-income subsidies, higher NCI comorbidity index score 10, and presence of disability were associated with worse OS. Receipt of rituximab monotherapy (HR, 0.69; 95% CI, 0.51 to 0.91) or rituximabcontaining chemoimmunotherapy combinations (HR, 0.64; 95% CI, 0.49 to 0.84), compared to chlorambucil monotherapy, were associated with better OS after first-line treatment. As with first-line treatment, older age was associated with worse OS among patients receiving second-line treatment. Among patients receiving first-line treatment, older age (HR,1.81; 95% CI,1.34 to 2.44), male sex, receiving Medicare Part D low-income subsidies, and higher NCI comorbidity index score were associated with worse CLL-specific survival outcomes. Receipt of rituximab or rituximab-containing chemoimmunotherapy combinations d

7 compared to chlorambucil monotherapy was associated with better CLL-specific survival outcomes. Similarly, older age was associated with worse CLL-specific survival among patients receiving second-line treatment (HR, 1.86; 95% CI, 1.15 to 2.99). Our study provides detailed observational data regarding treatment patterns and outcomes of CLL patients treated in the pre-novel therapy era with both first-line and second-line treatments. Such data will be an important baseline for future evaluations of novel therapies. We found that approximately one-third of newly diagnosed elderly CLL patients received first-line treatment, over a median follow-up of 3 years. Among those who received CLL treatment, approximately 37% progressed to a relapse/refractory phase, with a median time to second-line treatment of 22 months. Rituximab combination therapies were common for both first-line and second-line treatment. In our study 21% of older seniors received chlorambucil as a first-line treatment. Of note, patients aged 75 years were less likely to initiate treatment compared to younger seniors. When they did initiate treatment, they were more likely to receive monotherapy with chlorambucil or rituximab. These findings may be related to data from clinical trials suggesting a minimal benefit of adding rituximab to chlorambucil monotherapy or to fludarabine and cyclophosphamide in patients older than 65 years. 11, 12 Given that novel therapies including ibrutinib 13 and the combination of the glycoengineered anti-cd20 antibody obinutuzumab and chlorambucil 14 have shown superior outcomes as compared to chlorambucil monotherapy in clinical trials 13, 14 these agents may represent promising new therapies for current and future patients similar to those included in our study. e

8 In addition to having lower rates of treatment, treated patients aged 75 years had significantly lower OS as compared to younger seniors, and this discrepancy persisted even after controlling for socioeconomic, clinical, and treatment characteristics. This older population is prone to a greater incidence and severity of comorbidities, as well as disease and infection-related death, all of which may lead to delays in therapy initiation and poorer outcomes ,18 OS rates among all treated patients were modest (median 52.4 months for first-line therapy and 33.7 months for second-line therapy). Although our study does not permit causal inferences, we observed that rituximab monotherapy and rituximab-containing chemoimmunotherapy combinations were associated with favorable survival outcomes when compared to chlorambucil monotherapy in the front-line setting. Our study had a few limitations. First, we utilized registry and claims data and did not have access to all relevant prognostic factors, such as β2-microglobulin, lactate dehydrogenase, white cell count, or molecular and genetic abnormalities (e.g., presence of Del(17p)/TP53 mutation) which could have influenced treatment choice or survival outcomes. Additionally, the SEER-Medicare registry does not contain staging information for leukemia patients and our markers for disease severity (e.g., patients with claims-based diagnoses of anemia and thrombocytopenia) may not have been an adequate proxy of severity for all the patients in our study. If these unmeasured confounders correlated with the variables (e.g. age group, treatment group) included in our multivariable survival model (appendix Table 4), our estimates would be biased. In this population-based study of Medicare beneficiaries diagnosed with CLL in the years prior to the novel therapy era, we observed modest overall and CLL-specific e

9 survival among patients treated in both first-line and relapse-refractory contexts. Older seniors had lower rates of treatment, were more commonly treated with monotherapies, and had poorer disease-specific and OS outcomes compared to younger patients. As longitudinal data on novel therapies continue to accumulate, future studies should examine CLL outcomes to correlate how results obtained in recent landmark clinical trials translate into clinical practice. e

10 Acknowledgements: This study was funded by research funding from Janssen Inc. to JAD. The authors wish to thank Amy R. Pettit, PhD, consultant and Adjunct Fellow, University of Pennsylvania Center for Public Health Initiatives, for her feedback on the manuscript and assistance with editing. The authors would like to thank Molly Fanning, BA, Marian Bergkamp, BA, and Manuela Casuriaga, BA from the University of Pennsylvania for assistance with formatting the manuscript. Portions of this work were previously presented during the poster session of the 2016 American Society of Hematology Meeting on Hematologic Malignancies, September 16-17, 2016, Chicago, IL, and the 2016 American Society of Hematology Annual Meeting and Exposition, December 3-6, 2016, San Diego, CA. Author contributions: A.M., J.A.D., S.H., and P.L. conceived and designed the study; J.J. and P.L. performed the statistical analysis; and all authors interpreted the data, wrote the manuscript, and critically reviewed the final version of the manuscript. Conflict-of-interest disclosure: At the time of the study, A.M. reported having received research funding and consultancy fees from Gilead, AbbVie, Pharmacyclics, and TG Therapeutics; research funding from Acerta, Regeneron, Portola, and DTRM; and consultancy fees from Janssen, Celgene, and Kite.At the time of our study, M.M. and M.M. were under the employment of Johnson & Johnson and held stock in Johnson & Johnson. S.H. reported receiving honoraria from Pharmacyclics and consulting and traveling fees from Celgene and Janssen. J.A.D. reported serving as a consultant for Alkermes, Forest Laboratories (now Allergan), Ironwood Pharmaceuticals, Shire, and e

11 Vertex Pharmaceuticals; and had received research funding from AbbVie, Biogen, Humana, Janssen, PhRMA, Pfizer, Regeneron, Sanofi, and the National Pharmaceutical Council. J.A.D. s spouse holds stock in Merck and Pfizer. J.J., P.L., and V.P.L. have no conflicts to report. dd

12 REFERENCES 1. National Cancer Institute. Chronic lymphocytic leukemia/small lymphocytic lymphoma. Accessed 27 October Eichhorst B, Fink A, Busch R, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, openlabel, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7): Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18): Nabhan C, Mato AR. Economic modeling of the cost of chronic lymphocytic leukemia therapy: It is about the model. J Clin Oncol. 2017;35(16): National Cancer Institute. Overview of the SEER program. Accessed 27 October Danese MD, Griffiths RI, Gleeson M, et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood. 2011;117(13): dd

13 7. Satram-Hoang S, Reyes C, Hoang KQ, Momin F, Skettino S. Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and Medicare database. Ann Hematol. 2014;93(8): Bland JM, Altman DG. Survival probabilities (the Kaplan-Meier method). BMJ. 1998;317(7172): Andersen PK, Gill RD. Cox's regression model for counting processes: A large sample study. The Annals of Statistics. 1982;10(4): Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11): Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet. 2010;376(9747): Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114(16): Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25): Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12): dd

14 15. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood. 2008;111(10): Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1): Nabhan C, Mato A, Flowers CR, et al. Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: Prospective evaluation on 455 patients treated in the United States. BMC Cancer. 2017;17(1): Stauder R, Eichhorst B, Hamaker ME, et al. Management of chronic lymphocytic leukemia (CLL) in the elderly: A position paper from an international Society of Geriatric Oncology (SIOG) task force. Ann Oncol. 2017;28(2): dd

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18 Appendix Appendix Table 1. FDA-Approved Drugs for Chronic Lymphocytic Leukemia Included in the Study Generic Name Brand Name Route(s) of First FDA Medicare Coverage Administration Approval Date 1 alemtuzumab Campath IV B May bendamustine Treanda IV B/D October chlorambucil Luekeran Oral D March cladribine Leustatin IV B February cyclophosphamide Cytoxan IV/Oral B/D November cytarabine Depocyt IV B August doxorubicin Doxil IV B June fludarabine Fludara IV B April ibrutinib Impruvica Oral D November idelalisib Zydelig Oral D July lenalidomide Revlimid Oral D October obinutuzumab Gazyva IV B November ofatumumab Arzerra IV B October oxaliplatin Eloxatin IV B August pentostatin Nipent IV B October rituximab Rituxan IV B November vincristine Oncovin IV B July

19 Appendix Figure 1. Sample Selection Flowchart 14,230 patients diagnosed with CLL/SLL (First Primary Site), patients missing diagnosis month excluded 13,809 patients diagnosed with CLL/SLL (First Primary Site), ,332 patients below age 66 excluded 10,477 patients diagnosed with CLL/SLL (First Primary Site), patients not enrolled in fee-for-service Medicare Parts A and B in the 12 months before or 6 months after index date excluded 9,725 patients diagnosed with CLL/SLL (First Primary Site), ,937 patients enrolled in an HMO (vs. fee-forservice Medicare) in the 12 months before or 6 months after index date excluded 6,788 patients diagnosed with CLL/SLL (First Primary Site), ,574 patients without Medicare Part D coverage in the 6 months post-index date excluded 3,214 patients diagnosed with CLL/SLL (First Primary Site),

20 Appendix Table 2. Sample Characteristics for Elderly Medicare Patients Newly Diagnosed with Chronic Lymphocytic Leukemia, by Age Group All CLL patients Age <75 Age 75 Characteristic (N = 3,214) (n = 1,243) (n = 1,971) P Age, mean (SD) n % n % n % Male 1, <.001 Race.547 White 2, , , Non-white Region <.001 Northeast Midwest South West 1, Part D Low-Income Subsidy status.003 None 2, , Full or Partial Specific comorbidities Anemia/thrombocytopenia <.001 Cognitive <.001 Cardiovascular 2, , <.001 Infection <.001 Musculoskeletal 1, Renal failure NCI comorbidity index, mean (SD) <.001 Claims-based disability status* <.001 Year of CLL diagnosis *Claims-based prediction for disability status, a proxy measure for the Eastern Cooperative Oncology Group (ECOG) performance status scale 3

21 Appendix Table 3. Characteristics of Medicare Patients Newly Diagnosed with Chronic Lymphocytic Leukemia, by Treatment Status All CLL Patients (N = 3,214) CLL Patients Initiating First- Line Treatment (n = 1,047) CLL Patients Initiating Second- Line Treatment (n = 387) Age Characteristics n % n % n % <75 years 1, years 1, Gender, male 1, Race White 2, Non-white Region Midwest Northeast South West 1, Part D Low-Income Subsidy Status None 2, Full or Partial Specific comorbidities Cognitive Cardiovascular 2, Infection Musculoskeletal 1, Renal failure Anemia/Thrombocytopenia NCI comorbidity index, mean (SD) Claims-based disability status* Year of CLL diagnosis First-line treatment Chlorambucil only N/A Rituximab only N/A Rituximab containing chemoimmunotherapy combination N/A Other chemotherapy N/A Second-line treatment 4

22 Chlorambucil only N/A N/A Rituximab only N/A N/A Rituximab containing chemoimmunotherapy combination N/A N/A Other chemotherapy N/A N/A *Claims-based prediction for disability status, a proxy measure for the Eastern Cooperative Oncology Group (ECOG) performance status scale 5

23 Appendix Table 4. Multivariate Cox Regression Results for Overall and CLL-Specific Survival Characteristics Overall Mortality from First-Line Treatment Date (N = 1,047) Overall Mortality from Second-Line Treatment Date (N = 387) CLL-Specific Mortality from First-Line Treatment Date (N = 1,047) CLL-Specific Mortality from Second-Line Treatment Date (N = 387) Age, years <75 Reference Reference Reference Reference (1.46 to 2.24) 1.53 (1.1 to 2.13) 1.81 (1.34 to 2.44) 1.86 (1.15 to 2.99) Male 1.56 (1.28 to 1.91) 1.47 (1.06 to 2.03) 1.42 (1.07 to 1.88) 1.40 (0.89 to 2.19) Race White Reference Reference Reference Reference Non-white 1.01 (0.74 to 1.38) 0.88 (0.53 to 1.47) 1.14 (0.75 to 1.75) 0.79 (0.37 to 1.66) Region Midwest 1.17 (0.85 to 1.60) 1.07 (0.64 to 1.77) 1.27 (0.84 to 1.92) 1.26 (0.66 to 2.41) Northeast 1.52 (1.18 to 1.96) 1.68 (1.13 to 2.51) 1.21 (0.83 to 1.75) 1.28 (0.69 to 2.38) South 1.08 (0.84 to 1.39) 1.06 (0.70 to 1.61) 1.05 (0.74 to 1.49) 1.33 (0.77 to 2.32) West Reference Reference Reference Reference Part D Low-Income Subsidy status None Reference Reference Reference Reference Full or partial 1.31 (1.03 to 1.67) 1.33 (0.89 to 1.98) 1.21 (0.86 to 1.68) 1.32 (0.77 to 2.25) NCI comorbidity score 1.15 (1.05 to 1.27) 1.11 (0.94 to 1.30) 1.13 (0.99 to 1.29) 1.18 (0.96 to 1.46) Disabled 1.66 (1.16 to 2.37) 1.68 (0.83 to 3.42) 1.62 (0.99 to 2.65) 1.83 (0.72 to 4.63) Comorbidities Anemia/thrombocytopenia 1.00 (0.80 to 1.24) 1.07 (0.74 to 1.55) 1.01 (0.75 to 1.37) 1.09 (0.65 to 1.81) Cognitive 1.03 (0.79 to 1.34) 0.77 (0.49 to 1.23) 1.04 (0.73 to 1.50) 0.53 (0.27 to 1.07) Cardiovascular 1.31 (1.00 to 1.71) 1.11 (0.73 to 1.68) 1.37 (0.94 to 2.00) 1.17 (0.66 to 2.07) Infection 1.04 (0.73 to 1.48) 1.20 (0.64 to 2.23) 1.09 (0.68 to 1.75) 1.58 (0.73 to 3.44) Musculoskeletal 1.24 (0.79 to 1.94) 0.66 (0.45 to 0.98) 0.80 (0.59 to 1.08) 0.64 (0.37 to 1.12) Renal failure 1.25 (0.80 to 1.97) 1.23 (0.50 to 3.03) 0.92 (0.45 to 1.85) 0.40 (0.05 to 3.27) Time to treatment (months) 1.00 (0.99 to 1.01) 1.01 (1.00 to 1.02) 0.98 (0.97 to 0.99) 0.98 (0.96 to 1.00) First line treatment group Chlorambucil only Reference Reference Reference Reference Rituximab only 0.69 (0.51 to 0.91) 0.96 (0.58 to 1.60) 0.56 (0.38 to 0.84) 0.92 (0.44 to 1.90) Rituximab containing 0.64 (0.49 to 0.84) 1.39 (0.85 to 2.27) 0.64 (0.44 to 0.92) 1.74 (0.89 to 3.41) chemoimmunotherapy combination Other chemotherapy 0.86 (0.61 to 1.21) 1.19 (0.66 to 2.16) 0.90 (0.57 to 1.42) 1.14 (0.50 to 2.57) Second line treatment group Chlorambucil only N/A Reference N/A Reference Rituximab only N/A 0.73 (0.39 to 1.35) N/A 0.70 (0.30 to 1.61) Rituximab containing N/A 1.00 (0.54 to 1.85) N/A 1.10 (0.48 to 2.49) chemoimmunotherapy combination Other chemotherapy N/A 1.41 (0.75 to 2.63) N/A 1.79 (0.80 to 4.03) Year of diagnosis 2007 Reference Reference Reference Reference (0.80 to 1.37) 1.31 (0.85 to 2.04) 0.89 (0.62 to 1.27) 1.01 (0.57 to 1.80) (0.63 to 1.11) 1.18 (0.74 to 1.88) 0.59 (0.40 to 0.87) 0.68 (0.36 to 1.28) (0.64 to 1.21) 1.32 (0.75 to 2.31) 0.56 (0.36 to 0.87) 0.73 (0.35 to 1.54) (0.47 to 1.06) 2.16 (1.12 to 4.15) 0.35 (0.19 to 0.65) 0.66 (0.22 to 1.99) 6