Anti-Tumour TreatmentFront-line treatment of CLL in the era of novel agents
Introduction
One of the most common B-cell malignancies in the Western world is Chronic lymphocytic leukaemia (CLL),with an annual incidence of 4.2 new cases per 100,000 [1]. It also has a clinical course which is highly heterogeneous. The course can be aggressive and rapidly progressing or more indolent [2].
Treating CLL is a challenge. It primarily affects the elderly, and as clinical trials have traditionally excluded older patients, it is difficult to extrapolate their findings into clinical practice [3], [4]. In addition, at diagnosis, CCL patients are old (median age 72 years) and tend to be unfit and burdened with comorbidities; as such, they will have a reduced capacity to withstand the toxicities associated with chemotherapy [4], [5].
This review examines the considerations involved in the selection of first-line treatments for unfit or elderly patients, which constitute the majority of CLL patients. It discuss the challenges associated with chemoimmunotherapy and examines the potential benefit of the use of targeted agents.
Section snippets
Selecting the appropriate first line treatment
The approach to treating CLL is judged based on weighing the potential benefits to the individual patient versus the risk associated with the available therapies [6]. However, there are a number of other factors [6].
The first is the stage of the disease. Fortunately, treatment does not have to be commenced immediately following a diagnosis of CLL. Current recommendations indicate that newly diagnosed patients with asymptomatic early-stage disease should simply be monitored until signs of
Current first-line treatment options
In 2015, the European Society for Medical Oncology (ESMO) included novel targeted agents (ibrutinib, idelalisib ± rituximab) into their clinical practice guidelines for CLL. These were intended to be used as first-line therapeutic options for patients harbouring del17p, a second-line or later-treatment option in patients experiencing a relapse within 24–36 months following chemoimmunotherapy, or refractory disease [1]. A new introduction in the updated 2016National Comprehensive Cancer Network
Novel agents in first-line treatment
The data concerning the efficacy and tolerability for chemoimmunotherapy and with the influx of targeted agents, it is questionable whether FCR should remain the standard of care in treatment-naïve patients who are fit, or chlorambucil plus CD20 regimens in those who are unfit.
Research suggests that B-cell receptor (BCR) activation plays a role in the pathogenesis of CLL [44], [45]. Ibrutinib is a Bruton’s tyrosine kinase(BTK) inhibitor, and idelalisib a phosphatidylinositol 3-kinase δ (p110δ)
Can targeted agents change current standards in first-line treatment ?
For many years, FCR was the first-line treatment of choice for young or fit CLL patients without 17p- or TP53 mutations, while combined chlorambucil + anti-CD20 therapy was only used for elderly or unfit patients without the two mutations [1]. However, only FCR can provide long-term disease remission as first-line treatment [22]: there is a clear lack of front-line treatments that can offer durable remission for older or unfit patients.
Targeted agents possessing durable remission and modest
The future for targeted agents in CLL
The position of targeted agents in the first-line setting remains unknown. It is possible that FCR should be reserved as first-line treatment for those such as younger patients with longer life expectancy who have the greatest potential to derive a survival benefit; targeted agents, with their unprecedented survival benefits, should be offered to elderly/unfit patients. However, it is arguably the case that the most effective option should be used first in all patients, to enable rapid
Conflicts of interest
TR received grants and personal fees from GlaxoSmithKline, Roche, Janssen, Pharmacyclics, Abbvie and Gilead; SS received honoraria for consultant or advisory board member from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche and Sanofi; AT received honoraria for consultant or advisory board, travel support from Janssen, Gilead and Hoffman-La Roche.
Acknowledgements
We thank Edward Lowczowski from the Medical University of Lodz for editorial assistance. The study was supported in part by grant funding from the Medical University of Lodz, Lodz, Poland: No. 503/8-093-01/503-01.
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