Page 170 - 2019_04-Haematologica-web

S.E. Sylvan et al.
Introduction
Methods
Chronic lymphocytic leukemia (CLL) is the most com- mon leukemia in the Western world. In Sweden, the inci- dence is approximately 500 patients per year. The median age at diagnosis is approximately 70 years.1-4 The clinical course is extremely heterogeneous. At diagnosis, most patients are asymptomatic and the disease may be indo- lent for a long time. However, many patients show dis- ease progression after a few years. When the disease requires treatment, strategies should be individualized.5 Chemoimmunotherapy with fludarabine in combination with cyclophosphamide and rituximab (FCR) resulted in an overall response rate (ORR) of about 90% and improved overall survival (OS),6 and represents the stan- dard treatment in fit patients younger than 65 years. Yet, FCR is less well tolerated in patients over 65 years7 and these patients may instead benefit from bendamustine in combination with rituximab (BR) which has shown response rates similar to those achieved with FCR but with less toxicity.8,9 For elderly fragile patients, chloram- bucil in combination with a CD20 monoclonal anti- body10,11 could be an alternative; whether BR is to be pre- ferred in old unfit patients remains uncertain.12
The presence of TP53 aberrations [del(17p) or TP53 mutation] is strongly associated with chemotherapy refractoriness, early relapse,13,14 and, until recently, a very dismal prognosis.14-16 Hence, evaluation of TP53 status is strongly recommended before treatment initiation. Brutons’s tyrosine kinase (BTK) inhibitor ibrutinib17-19 has offered new options both for these patients and for relapsed/refractory CLL,20 with an ORR of 85% report- ed,17,18 and is considered the best available option for patients with TP53 disruptions.3,20,21 New treatments are costly and frequently accepted by regulatory agencies based on trials conducted in selected groups of patients with PFS, not OS, as end point. Hence, long-term results, including OS estimates, in real-life treated patients are important to determine the optimal therapy for patients with CLL.22
Previous data from the United States23 suggest that type of area (rural or urban) and type of hospital may influence response and survival especially in patients with high-risk CLL. However, Swedish results may differ due to the fact that almost all patients are treated within public health care. This means that most treatment decisions are taken at therapy conferences and we have a widespread usage of yearly up-dated national CLL guidelines.3
The Swedish Cancer Registry and the Swedish National CLL-Registry give us a unique opportunity to identify all patients diagnosed with CLL for an in-depth analysis of every single patient file. This provides a com- plete record of all patients treated within a defined time period on a nation-wide basis. Thus, this study provides high-quality real-world results on CLL first-line treatment that may be used as quality assurance and may help to interpret the cost-effectiveness of new drugs for health- care providers. It may also serve as a control for clinical trials, selecting patients based on inclusion/exclusion cri- teria. Given this, the aim of this study was to investigate the outcome following first-line therapy in a well-defined population of consecutive CLL patients, in a setting with complete follow up.
This was a retrospective observational study. All patients diagnosed with CLL according to the World Health Organization criteria from 2007 to 2013 were identified from the National Cancer Registry. A representative physician from each of Sweden’s six health-care regions reviewed all the patient files in the region to identify patients who had received first-line CLL treatment due to progressive, symptomatic CLL. Patients who had started therapy before the end of 2013 were included in order to obtain sufficient follow up. Their files were analyzed in detail from the date of diagnosis until death or until the end of the study period (2017), whichever came first. Patients who had only received treatment for autoimmune hemolysis or idio- pathic thrombocytopenic purpura (ITP) not related to progres- sive CLL were excluded. As this was a retrospective observa- tional study, ethics committee approval (2013/952-31/3) was obtained; in Sweden no informed patient consent was required. The study was performed in accordance with the ethical princi- ples of the Declaration of Helsinki24 and in compliance with national laws.
Data acquisition and study procedure
Data on patients’ characteristics, treatment, outcome and tox- icity were recorded on case record forms (CRFs). Information on participation in clinical trials, type of hospital (county/rural, regional or university) where the main body of treatment was given, where the decision on treatment was taken, geographical region, and whether choice of first-line therapy was compliant to the actual Swedish national CLL guidelines3 was also record- ed. Furthermore, concomitant medication with acetylsalicylic acid (ASA) or statins were recorded since these drugs appear to induce apoptosis on CLL cells25,26 and may improve outcome in FCR-treated CLL.27 Data were incorporated in a specially devel- oped version of the Information Network for Cancer Care (INCA) database and systematically cross-checked and validated for accuracy. Treatment response was evaluated according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.28 Major infections (grade III-V) and other serious adverse events (SAE) according to the NCI CTCAE 3.0 were recorded. Richter transformation (RT) and secondary tumors were also recorded. The Swedish Cause of Death Registry was used to validate records of death.29
Statistical analysis
End points in this study were evaluated according to the IWCLL criteria28 and included: ORR, duration of response (DOR), PFS, OS and safety. In the analysis of PFS, time was cal- culated from the start date of first-line therapy to the date of progression or date of death, whichever came first. In the analy- sis of OS, time was calculated from the date of first-line therapy to the date of death. For event-free patients, time was calculated to the date of last clinical visit.
The Kaplan-Meier method was used to estimate and graphi- cally display OS and PFS. Proportional hazards regression was used to estimate the effect of risk factors on time to failure. Results from these models are presented as hazard ratios (HR) together with 95% confidence intervals (CI). Reported P-values from these models refer to Wald tests.
As FISH analysis was not implemented in the national guide- lines until 2010, and cytogenetic status is a strong prognostic and predictive marker,14-16 patients were grouped into an earlier treatment period (2007-2009) and a later period (2010-2013). Multivariate analyses were restricted to the latter cohort. Analysis of the impact of IGHV mutation status did not provide
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haematologica | 2019; 104(4)