Page 170 - Haematologica - Vol. 105 n. 6 - June 2020

E.C. Rotbain et al.
In contrast to a clinical trial setting, inclusion of patients above 65 years and more patients with significant comor- bidities in our cohort40,41 may have reduced the impact of IGHV status as a prognostic factor.42-44 Clinical trial popula- tions in CLL studies exploring IGHV status and chemoim- munotherapy had a median age of 57-73 years,5,6,16,32 com- pared with 62-80 years in our study, further emphasizing the importance of assessing real-world data. The higher prevalence of elevated β2-microglobulin levels in the treat- ment groups with a higher median age in our study may reflect decreased renal function45,46 and thus the comorbid- ity of these patients, rather than more aggressive CLL. The impact of comorbidity and frailty in the real-world popula- tion reported here is also reflected by a 3-year OSt of 59% for patients treated with CD20-chlorambucil compared with over 80% in the CLL11 trial.8
Cancer patients for whom data registration is incom- plete have previously been found to have poorer out- come,47 which was also seen for patients with unknown IGHV status in the present study, when comparing both OSd and OSt in these patients with those of patients with mutated or unmutated IGHV. Patients with unknown IGHV status had a superior TFSd compared with that of U-CLL patients. This reflects that many patients with unknown IGHV status die, probably due to CLL-unrelat- ed causes, without ever receiving treatment for CLL.
The main strength of this study is its nationwide cohort, without the selection bias introduced in clinical trials, and the near completeness of data. Inherent in the retrospec- tive design of the study, patients were assigned therapy by the treating physicians based on clinical assessment of fit- ness and clinical guidelines, in line with the described age distribution. The discrepancy in baseline characteristics between the treatment groups is a weakness of our study, although we have adjusted for known dissimilarities between the groups. However, as stated above, factors such as number and type of subsequent lines of treat-
ments, and distribution of comorbidities across groups of patients, are unknown. Uneven distribution of these fac- tors could in part explain the discrepancy between our results and those of previous studies regarding the signifi- cance of IGHV status in relation to OSt. More patients were diagnosed with CLL during the latter half of the study period, likely due to earlier detection of CLL, lead- ing to a shorter follow-up time than anticipated. The short median follow-up time was also driven by the high mor- tality in this population, resulting in over half of the treat- ed patients dying during follow-up.
Conclusions
This population-based study demonstrates excellent OSt with FCR or BR for both U-CLL and M-CLL patients, indi- cating that patients who progress after first-line chemoim- munotherapy may be salvaged with second- or later-line treatments. In view of the long treatment-free period and the possibility of clinical cure for a substantial subgroup of M-CLL patients, intensive chemoimmunotherapy remains a valid treatment option and part of a personalized treat- ment landscape in CLL alongside targeted agents. Patients treated with chlorambucil-based regimens have a poor outcome; thus, improved supportive care and targeted treatment options, as seen in recent randomized con- trolled trials, are warranted for patients who are unfit for intensive chemoimmunotherapy.
Acknowledgments
We would like to thank Fanny Kullberg for her work in collect- ing information from medical records. This study was supported in part by grants from Janssen and Novo Nordisk Foundation. The funding sources had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.
References
1. Nabhan C, Chaffee KG, Slager SL, et al. Analysis of racial variations in disease char- acteristics, treatment patterns, and out- comes of patients with chronic lymphocyt- ic leukemia. Am J Hematol. 2016;91(7):677- 680.
2. Danish Lymphoma Group. National guid- lines for chronic lymphocytic leukaemia. Available at http://www.lymphoma.dk/ retningslinjer/2018.
3. da Cunha-Bang C, Simonsen J, Rostgaard K, et al. Improved survival for patients diag- nosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood Cancer J. 2016;6(11):e499.
4. HallekM,FischerK,Fingerle-RowsonG,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):1164-1174.
5. Fischer K, Bahlo J, Fink AM, et al. Long- term remissions after FCR chemoim- munotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.
6. Eichhorst B, Fink AM, Bahlo J, et al. First- line chemoimmunotherapy with ben- damustine and rituximab versus fludara- bine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocyt- ic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-infe- riority trial. Lancet Oncol. 2016;17(7):928- 942.
7. Cramer P, Isfort S, Bahlo J, et al. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospec- tive trials by the German CLL Study Group (GCLLSG). Haematologica. 2015;100(11): 1451-1459.
8. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29(7):1602-1604.
9. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176.
10. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed
chronic lymphocytic leukemia. N Engl J
Med. 2013;369(1):32-42.
11. International C. L. L. I. P. I. Working Group.
An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790.
12. da Cunha-Bang C, Christiansen I, Niemann CU. The CLL-IPI applied in a population- based cohort. Blood. 2016;128(17):2181- 2183.
13. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lym- phocytic leukemia. Blood. 1999;94(6):1840- 1847.
14. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggres- sive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
15. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247- 3254.
16. Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and ritux-
1628
haematologica | 2020; 105(6)