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Real-world results of first-line therapy in CLL
with CLL do not have a treatment indication at the time of diagnosis. Cytogenetic status was only available in 58% of the patients. The analysis was not mandatory until 2010 according to the national guidelines while FISH was more commonly performed in the later time period (2010-2013). Notably, university hospitals performed FISH significantly more often, and the older the patient the more rarely was the analysis performed.
The vast majority (80%) were treated according to the national guidelines. Notably, compliance to national guidelines was associated with better response, and PFS and OS (univariate analysis). However, patients included in clinical trials had an even better ORR and OS but a shorter PFS. This may partly be due to our conservative approach on how to interpret response, i.e. if not all vari- ables for a complete or partial response where available responses were considered to be of a lower grade. As patients in studies may have been more thoroughly eval- uated, variables for response were possibly more avail- able; this may have resulted in a higher response rate for these patients. Also, selection bias or more effective regi- mens and a more thorough follow up in clinical trials (which may detect progression at an earlier stage) may have influenced the results.
The different types of treatments used may at least partly reflect the development of therapies over time. In fact, FCR was used much more in the later time period and B/BR, which was not introduced until the end of the study period, was used less. Even though CLB use declined during the study period, approximately one- third of all patients still received first-line CLB as late as 2013, although with significant regional differences. Regarding FCR and BR, the response rate was slightly lower than in prospective first-line clinical studies6,8,9 and for CLB it was slightly higher.10,34 As expected, and in line with recently published data,8,32 FCR was more common- ly used in younger patients and CLB was the most fre- quently used treatment overall and in the elderly. The median age for CLB-treated patients did not increase over time, possibly indicating that more modern treatments, such as B/BR, were not always used in patients over 65 years of age. OS differed between the two time periods (2007-2009 vs. 2010-2013), but this difference was not sig- nificant. This is in line with our previous findings regard- ing second-line therapy in the Stockholm region,1 where no improvement in OS over the years was seen.
Real-world treatment outcome may differ from that in clinical trials and when compared to data from prospec- tive trials,6,8,9 patients in this study showed a relatively low ORR and short PFS and OS, despite an 80% compli- ance to national guidelines.
In line with previous data, del(17p)14-16 was a negative predictive marker but also type of treatment, age and per- formance status were independently associated with poorer PFS and OS. Patients in this report were compara- tively old versus those in trials,6,8,32 and as many as 39% received CLB and CLB treatment was associated with poorer outcome. In addition, cytogenetic status, the strongest predictor of outcome, was unknown in almost half the patients. These factors may at least partly explain the differences in our results and those reported in tri- als.6,8,32 Notably, patients treated with single CLB in clini- cal trials34-36 showed an even shorter PFS; this may be due to a more thorough evaluation in trials. Also, patients treated with B/BR showed a comparatively poor out-
come.8 However, these regimens were used only in the elderly, and only FCR and FC showed better outcomes. The difference in OS between the time periods was not significant (P=0.07), and this may possibly be influenced by the low use of FCR and by the fact that bendamustine became available only at the end of the time period. IGHV mutation status is still optional in the Swedish guidelines, probably explaining the low number of patients analyzed. Thus, the power of the analysis was insufficient for the multivariate analysis. However, our findings for the whole population was in line with previ- ous reports37 in showing a significant impact on outcome.
The infection rate6,8,10,34 was comparable to previous clinical studies with an expected higher infection rate for FCR. Our study showed an incidence of RT in line with previous data.32,38-40 However, our study did not, in con- trast to previous data,38,41 show any association between treatment with fludarabine and RT. The slightly lower incidence of RT within the CLB group may be because the median time to transformation was three years, and the patients in this group were older and had a shorter median OS.
Our study indicates that type of hospital may possibly have an impact on outcome but could not confirm previ- ous findings23 regarding outcome in urban versus rural regions. The possible differences between type of hospi- tals may derive from the fact that FISH analysis was more often performed at university hospitals, and the wide- spread use of the regularly up-dated Swedish National Guidelines may have minimized the difference between regions as 80% were treated according to guidelines. The regional usage of chlorambucil varied between 27-49%. We still have no explanation for this. Elderly patients and those with a poorer performance status might also be on concomitant medication with ASA or statins, i.e. those with certain comorbidity. This may explain why con- comitant ASA or statins showed a significant association in univariate but not in multivariate analysis.42 Also, in some previous reports, ASA or statins do not appear to affect outcome.43,44
A limitation of the study is its retrospective nature and the lack of data from recent years during which different regimens have been used and novel therapies have become available. For example, part of the study was per- formed before bendamustine was introduced as first-line treatment in CLL and before a CD20 antibody was added to CLB. For a more complete understanding of real-world outcome in CLL patients, an analysis of the outcome of treatment of relapse is warranted. As this requires a longer follow up, we have started a separate project for further investigation. Despite these limitations, in rela- tion to today’s standard-of-care treatment, the results are still important.
In summary, our results provide additional information representative of real-world outcome of first-line CLL treatment and provide an important context within which to evaluate the findings obtained from clinical tri- als of new drugs. We show that outcome in real-world situations differs from that in clinical trials, and that sin- gle-agent CLB treatment, as well as age and performance status, were independent factors for poor outcome in multivariate analysis. Notably, the older the patient the more rarely was FISH analysis performed and the more often CLB was chosen as treatment. As CLL and related complications seem to be the major cause of death in
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