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Editorials
responses were seen in 83% of the patients treated, the median progression-free survival was 49 months, and the 3- year overall survival rate was 95%.
Early monotherapy trials showed that lenalidomide is associated with a unique toxicity profile in patients with CLL, causing tumor lysis syndrome, tumor flare reaction, myelosuppression, and, in particular, neutropenia, skin rash, and diarrhea.1,2 Particularly severe events, including deaths, were reported in trials with no dose escalation4 or rapid dose escalation,5 and tumor lysis syndrome occurred in patients with bulky lymphadenopathy despite proper prophylaxis.1 After these early experiences, trials with lenalidomide employed stepwise dose escalation strategies with low starting doses (usually 2.5 mg/day), as in the study presented by Kater et al., and managed tumor flare reactions with non-steroidal anti-inflammatory drugs and corticos- teroids. Moreover, careful patient selection is recommend- ed. The population included in the study by Kater et al. mainly consisted of older but fit patients: 98% were 65 years or older, 87% had a Cumulative Illness Rating Scale score of 6 or lower, and all had a glomerular filtration rate of 60 mL/min or higher at the time of entry into the study.
In the last decade, several lenalidomide-containing com- bination regimens have been evaluated in patients with treatment-naïve CLL. When lenalidomide was combined with rituximab in the frontline setting, the treatment was generally well tolerated, with the most common grade 3-4 toxicities being neutropenia, anemia, infections, increased transaminase levels, and skin rash.6,7 However, when differ- ent partners, such as chemotherapy agents or targeted drugs, were tested in combination with lenalidomide, some trials documented excessive toxicities that led to early ter- mination of the studies. For instance, a phase 1 study inves- tigating the combination of lenalidomide with fludarabine and rituximab was closed early because of unpredictable reactions and unexpectedly persistent myelosuppression, even when very low doses of fludarabine and lenalidomide were given, which made treatment delivery difficult.8 Instead, induction treatment with low-dose lenalidomide together with reduced-dose FCR was demonstrated to be safe.9 In the relapse setting, lenalidomide was evaluated in association with rituximab and ibrutinib; the study investi- gating this approach showed a high incidence of persistent severe neutropenia that occurred despite growth factor sup- port.10 This unfavorable toxicity profile, together with poor preliminary efficacy data, discouraged further evaluation of this combination. The combination of lenalidomide with rituximab and idelalisib also showed unacceptable liver tox- icity in patients with relapsed or refractory indolent lym- phoma.11
Regarding efficacy, the single-arm design of the study by Kater et al. does not allow a direct comparison of the triple combination with chlorambucil and rituximab. Acknowledging the limitations of cross-trial comparisons, however, the efficacy of the proposed regimen compares positively with that of chlorambucil plus anti-CD20 mono- clonal antibodies. In a study conducted by Strati et al.,7 the combination of lenalidomide plus rituximab produced an overall response rate of 73% in treatment-naïve patients, with a complete remission (CR)/CR with incomplete hema- tologic recovery (CRi) rate of 35%, a median time to treat- ment failure of 22 months, and a 4-year overall survival rate
of 90%. The same treatment combination was explored in a multicenter study, which showed an overall response rate of 88%, of which 15% were CR/CRi, and a median pro- gression-free survival of 19 months.6
It is essential to put the data presented by Kater and col- leagues into perspective by considering recent changes in the treatment landscape of CLL brought about by the avail- ability of new targeted drugs, such as BTK inhibitors, PI3K inhibitors, and Bcl-2 antagonists, which have also been studied in older patients. In a recent update of the phase III RESONATE-2 trial of ibrutinib, which enrolled patients aged 65 years and older with previously untreated CLL and without del(17p), researchers reported that at a median fol- low-up time of 29 months, the overall response rate was 92%, the median duration of progression-free survival had not been reached, and the 24-month progression-free sur- vival rate was 89%.12 Patients carrying abnormalities on chromosome 17 represent a subset of CLL patients with a particularly poor prognosis. In the cohort presented by Kater et al., eight (17%) patients had del(17p), and their pro- gression-free survival rate was lower than that of patients without del(17p) (38% versus 59% at 3 years). Notably, in a phase II study that evaluated ibrutinib in a cohort of treat- ment-naïve CLL patients with TP53 aberrations, the esti- mated 5-year progression-free survival rate was 74.4%.13
That being said, a credit that pertains exclusively to lenalidomide is the role this drug has had in elucidating tumor-microenvironment interactions in CLL. Phenotypic and functional immune defects are known to be associated with CLL; these defects confer an increased risk of infec- tions and autoimmune phenomena and foster leukemia cell proliferation and survival. Several studies have shown that treatment with lenalidomide modulates the cross-talk between tumor cells and various components of the tumor microenvironment. Examples of these effects include the ability to normalize CD3+ T-cell and Treg numbers in vivo14,15 and to restore immunological synapse formation.16 The antitumoral activities of lenalidomide also appear to be attributable to a direct effect on neoplastic cells; lenalido- mide not only enhances immune recognition, but also induces CRBN-mediated upregulation of p21 in vitro17 (Figure 1).
The recent progresses in immunotherapy approaches that exploit the ability to engineer the T-cell receptor, such as chimeric antigen receptor (CAR) T-cell therapy, may revi- talize interest in the use of immunomodulatory agents, including lenalidomide, in CLL. Immune dysfunctions are thought to be responsible for the lower efficacy of these approaches in CLL than in other lymphoproliferative dis- eases. Apheresis products from CLL patients and the derived CAR T-cell products exhibit an exhausted pheno- type and tend to have reduced potency. It has been demon- strated that certain features of the apheresis product, such as the predominance of early memory/naïve T cells and low expression of exhaustion markers, correlate with effi- cacy.18 It has also been reported that ibrutinib may correct some of the T-cell defects that hinder CAR T-cell produc- tion and enhance in vivo function.19 The ability of lenalido- mide to enhance CAR T-cell activity has been explored in a mouse model of B-cell lymphoma20 and provides a rationale for future investigations of the immunomodulatory proper- ties of lenalidomide and its derivatives in CLL.
haematologica | 2019; 104(1)
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