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A.P. Kater et al.
Introduction
Although important progress has been made in the man- agement of chronic lymphocytic leukemia (CLL) in the last decades, treatment for elderly and unfit patients is still not optimized. Despite clear advantages of the chemotherapeu- tic drug chlorambucil in elderly patients, with respect to toxicity, oral administration and low costs, its efficacy as a single agent is low in CLL.
The CLL11 trial found that the progression-free survival of patients given combination treatment with chlorambucil and rituximab or chlorambucil and obinutuzumab was longer than that of patients given chlorambucil monothera- py (median progression-free survival: 15.4 months and 29.2 months, respectively, versus 11.1 months).1 Since the publi- cation of the findings of this trial, treatment with chloram- bucil and an anti-CD20 monoclonal antibody has become the standard, first-line therapy for elderly patients and those unfit for treatment with fludarabine, cyclophosphamide and rituximab (FCR).2 Nevertheless, relapses occur in virtu- ally all patients within 3.5 years.3 A more recent trial com- pared chlorambucil monotherapy with continuous treat- ment with the Bruton tyrosine kinase inhibitor ibrutinib and showed improved progression-free survival and overall survival in patients treated in the ibrutinib arm.4 Based on this study, ibrutinib also acquired a label for first-line treat- ment for previously untreated FCR-unfit patients. However, treatment with targeted inhibitors is not consid- ered curative, most likely because of the pronounced evolu- tionary capacity CLL cells resulting in the emergence of drug-resistant clones.5 Moreover, prolonged treatment with targeted inhibitors has significant medical, social, and eco- nomic costs. It is, therefore, necessary to optimize therapy for elderly and FCR-unfit patients and combine therapies with other mechanisms of action.
Lenalidomide is an oral immunomodulatory drug that has multiple mechanisms of action on the immune system. It alters the interaction between CLL cells and the protec- tive microenvironment and stimulates the cytotoxicity of natural killer cells against CLL cells. Lenalidomide restores the immunological synapse between T cells and CLL cells, reversing T-cell dysfunction and enhancing the ability of immune recognition of tumor cells. In addition, lenalido- mide directly affects cell proliferation through upregulation
of p21 activity. This effect is independent of the TP53 path- way and could thus be applicable for patients with TP53 dysfunction too.6-8
The overall response rates to lenalidomide as a single agent are low with few complete remissions (overall response rate range: 32%-72%, complete remission rate range: 0%-10%) in previously untreated or treated CLL patients.9-13 Addition of rituximab to lenalidomide resulted in an increased overall response rate of 78% with complete remissions in 11% of patients with relapsed/refractory CLL.14-16 Moreover, addition of rituximab seems to diminish tumor lysis syndrome and tumor flare reaction, which are distinct and difficult to manage toxicity profiles reported in CLL patients treated with lenalidomide.16
Given the key role of the microenvironment in chemore- sistance, addition of lenalidomide to chlorambucil and rit- uximab may result in further improvement of response rates.6 Furthermore, extended duration of treatment has been reported to improve both the overall response rate and quality of responses.16
Currently it is not known whether combination treat- ment with lenalidomide, rituximab and chlorambucil is fea- sible in terms of safety and efficacy. As such, we conducted a phase 1-2 study in which six cycles of triple therapy fol- lowed by six cycles of lenalidomide monotherapy were tested in elderly and FCR-unfit patients with advanced, pre- viously untreated CLL.
Methods
Study design and patients
This prospective, open-label study consisted of a phase 1 dose-finding part and a phase 2 efficacy part. Treatment-naïve patients diagnosed with immunophenotypically confirmed CLL, aged 65 – 80 years or 18 – 64 years with a Cumulative Illness Rating Scale score ≥7, in Binet C (Rai III-IV) stage, or with con- firmed active disease in Binet A or B (Rai 0-II) stage were enrolled.17 A complete list of inclusion and exclusion criteria is presented in Online Supplementary Table S1.
Treatment
All patients were treated with six cycles (every 28 days) of a combination of chlorambucil (p.o. cycles 1-6, days 1 – 7), ritux-
Figure 1. Schedule of phase 2 of the study. *or maximum tolerated dose
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haematologica | 2019; 104(1)