Lenalidomide:anovelanticancerdrugwithmultiplemodalitiesChristine Galustian† & Angus Dalgleish†St Georges University of London, Division of Cellular and Molecular Medicine, Department of Oncology, Cranmer Terrace, Tooting, London
Over the past 5 years, lenalidomide (Revlimid®, Celgene Co., Summit, NJ, USA), a member of a class of drugs termed immunomodulatory drugs, has emerged as a significant weapon in the arsenal of cancer-therapeutics. It is a lead therapeutic in multiple myeloma and del-5q myelodysplastic syndromes and has also been trialed for acute leukaemia and chronic lymphocytic leukaemia, relapsed or refractory Hodgkin’s lymphoma, T-cell non-Hodgkin’s lymphoma, prostate cancer, non-small cell lung cancer, malignant melanoma, renal cancer, advanced ovarian and peritoneal carcinoma. The most significant development for lenalidomide has been its FDA approval (US and Europe) for previously treated multiple myeloma in combination with dexamethasone. The following review describes key clinical and mechanistic breakthroughs that have made lenalidomide a leading cancer therapeutic.
Current therapies for treatment of multiple myeloma, myelodysplatic syndromes (MDS) and chronic lymphocytic leukaemia (CLL) are based on cytotoxic or antiproliferative agents such as bortezomib, doxorubicin and mephelan for multiple myeloma; chlorambucil, fludarabine, cyclophosphamide and CHOP (cyclophosphamide, doxorubicin (adriamycin) and vincristine combinations) for CLL; and methyltranferase inhibitors (azacitidine) and haematopoiesis stimulators (recombinant erythropoietins) and immunosuppressants (cyclosporine) for MDS.
More specifically targeted therapies such as the small-molecule inhibitors, imatinib (ABL) and monoclonal antibodies, rituximab (CD20), and alemtuzumab (CD52) are also available for CLL and multiple myeloma. However, all of the agents have single modes of action, which although effective, target few of the pathways that are involved in these diseases. The requirement for multi-modal therapy in these diseases has resulted in the trial of agents such as thalidomide and its analogues such as lenalidomide, which are anti-metastatic, anti-angiogenic and also augment antitumour immunity.
2. Chemistryandpharmacokineticsoflenalidomide
Lenalidomide and the related compound pomalidomide are 4-amino-gultaramide derivatives of thalidomide in which an amino group was added to the fourth carbon of the phthaloyl ring of the parent compound (Figure 1). Both agents also exist as a racemic mixture of the active S(-) and R(+) forms. Like thalidomide, they are both administered in FDA approved daily oral dosing every 21 – 28 days of monthly cycles. Elimination of the drugs is through the renal route; therefore, caution is recommended in dosing patients with impaired creatinine clearance. After oral administration, the half-lifes of lenalidomide and pomalidomide are
1. Overview of the market
2. Chemistry and pharmacokinetics
of lenalidomide
3. Clinical efficacy of lenalidomide
4. Regulatory affairs
5. Pharmacodynamics of
lenalidomide
6. Expert opinion
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3 and 7 h, respectively [1,2]. In contrast to thalidomide, which has dose limiting toxicity due to somnolence, constipation and peripheral neuropathy, both lenalidomide and pomali-domide have less commonly observed neurosedative toxicity. Dose-limiting neutropenia and thrombocytopenia are the most common toxicities seen with these drugs. Venous thromboembolism has been reported in various trials, and is increased when haemopoeitic agents such as erythropoeitin are also used, but is rarer when the drug is used singly (for example in a recent MDS study in which incidence was only 3.4% [3]). The incidence is markedly reduced when aspirin is given concomitantly.
3. Clinicalefficacyoflenalidomide
3.1 ClinicalstudiesonmultiplemyelomaResults from Phase I and II studies in the relapsed setting show lenalidomide alone to have significant activity with responses seen in 14 – 29% of patients [4]. Activity has been shown to increase markedly when lenalidomide is combined with dexamethasone: two randomised Phase III trials in North America and Europe [5,6] have demonstrated that the combination regimen provides greater efficacy than with dexamethasone alone, with combined response rates of 59 versus 21 – 24% for dexamethasone, and complete response (CR) rates of 13 – 17 versus 1 – 4%. Inclusion criteria in these trials were that patients had had at least 3 cycles of therapy for myeloma. Patients who were resistant to high doses of dexamethasone (200 mg) were excluded from this trial. Median time to progression was doubled from 4.7 to 11.1 months and overall survival times were also increased from 20.2 to 29.6 months. More recent trials
have shown more promising data, for example, in studies with patients in long term therapy (> 4 years). 11 out of 15 patients had partial or complete responses to lenalidomide therapy either given alone, or with dexamethasone [7]. Mono-therapy with lenalidomide seems to give similar percentages of partial/complete responses in this study. A further investigation in newly diagnosed myeloma suggests that low dose dexamethasone plus lenalidomide gives better survival rates after 1 year than standard dose dexamethasone plus lenalidomide (96 versus 88%) [8]. Combination therapy with lenalidomide, bortezomib and dexamethasone in refractory myeloma has shown very promising initial results in 33 patients with > 55% partial response and 36% with very good partial responses or complete responses [9].
The main adverse effects seen in these two Phase III trials were neutropenia, thrombocytopenia, infection and anaemia, which occurred in 25 – 35, 9.7 – 13, 16 and 8 – 13% of patients, respectively. Deep vein thrombosis occurred in 13.5 and 4% of patients in the MM009 and MM010 trials, respectively. Patients at present on combinations of lenalidomide and dexamethasone are given prophylactic aspirin to reduce this effect.
3.2 MdsMDS are disorders in which bone marrow function is abnormal and there is insufficient production of mature blood cells often leading to severe and refractory anaemia (reviewed in [10]). Bone marrow failure can occur in around 30% of patients. Chrosomal (cytogenetic) abnormalities are detected in > 50% of patients with MDS. Patients with low- and intermediate-1-risk MDS with interstitial deletions in the long arm of chromosome 5 (deletion 5Q) alone, or in combination
with other cytogenetic abnormalities, represent 20 – 30% of the MDS patient population.
The haematological activity of lenalidomide in lower-risk MDS, and its potential toxic reactions were initially demonstrated in an open study with 43 patients experiencing transfusion-dependent or symptomatic anaemia [11]. These patients had either failed previous treatment with erythro-poietin or were unlikely to respond to cytokine therapies owing to high erythropoietin and extensive transfusions. Lenalidomide was used at a dose of 25 or 10 mg per day, or 10 mg daily for 21 days out of every 28-day cycle for 16 weeks. The erythroid response rate was 56%, with 24 out of 43 patients responding: 20 of these 24 patients achieved transfusion independence. There was an 83% response rate in patients with the 5q chromosomal deletion compared to 57% in patients with a normal karyotype, and 12% in patients with other cytogenetic abnormalities. In the 20 patients with karyotypic abnormalities, 10 (50%) had a complete remission (with a restoration of normal karyotype and disappearance of dysplasia), including 9 of 12 patients with deletion 5q. Lenalidomide response times were also quicker for the deletion 5q patients (8 versus 11.2 weeks). The most common side events were neutropenia (55%) and thrombocytopenia (44%).
This trial led to multi-centre studies in transfusion-dependent, low- or intermediate-1 risk MDS patients either with deletion 5q (trial MDS-003) [12] or those without the 5q deletion (trial MDS-002) [13]. In the MDS-003 trial, 148 patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily for 24 weeks. The transfusion response rate was 76%, with 99 (67%) patients achieving transfusion-independence. Responding patients increased their haemoglobin to a median of 13.4 g/dl. Transfusion independence was obtained with a median of 4.6 weeks, and the median duration was greater than 104 weeks after follow up. Among 85 evaluable patients, 62 (73%) had cytogenetic improvement and 38 (45%) had complete cytogenetic remission.
In the second multi-centre Phase II trial (MDS-002) in patients without the 5q deletion, with identical doses of lenalidomide, > 80% of study participants had a heavy transfusion burden at the start of the study. Among 215 patients treated, the transfusion response rate was 43%, with 26% achieving transfusion-independence. Based on these results, lenalidomide was approved for use in the US by the FDA in December 2005 for the treatment of IPSS low- or intermediate-1 risk MDS patients with deletion 5q, at a dose of 10 mg daily.
3.3 EffectsoflenalidomideonCLLB-cell CLL is the most common leukaemia in the Western world and results from accumulation of mature B lymphocytes mainly in the blood and bone marrow because of faulty apoptosis [14]. The activity of lenalidomide was studied in patients with relapsed/refractory CLL [15]. Lenalidomide was given at 10 mg daily with dose escalation up to 25 mg daily.
The study showed 3 (7%) patients with CR, 1 nodular partial remission (PR) and 10 patients with PR giving an overall response rate of 32%. When measuring plasma levels of angiogenic factors, inflammatory cytokines and cytokine receptors at baseline, day 7 and day 28, there was a dramatic increase in median IL-6, IL-10, IL-2 and TNF-R1 levels on day 7, whereas no changes were observed in median (VEGF) levels (20 patients studied). Therefore, lenalidomide as a continuous treatment has antitumour activity in heavily pretreated patients with CLL when given continuously. However, in contrast to MDS or multiple myeloma patients in whom 25 mg daily of lenalidomide can be administered, 10 mg daily of lenalidomide is the maximal recommended dose in CLL, as complete responses seen at this dose and higher doses (25 mg daily) can lead to tumour flare reactions, which are not related to clinical responsiveness [16], but this is thought to be manageable when patients are given starting doses of 10 mg daily [17]. Thus, lenalidomide’s tolerability and optimal dose may be disease specific [18]. In a study of patients with CLL, small lymphocytic leukaemia and mantle cell lymphoma, it was also shown that toxicity was decreased by alternating thalidomide with lenalidomide, which allowed longer immunomodualtory drug (IMiD) treatment and good response rates [19]. Other major adverse effects seen in CLL patients include fatigue, neutropenia in 40 – 70% of patients and anaemia [15,20]. The mechanism of action of lenalidomide in CLL patients is still unclear, but there are new data showing that CLL cells can inhibit immune synapse formation in CD4+ and CD8+ T cells, both in autologous patient cell populations and in healthy donor T cells exposed to the CLLs, leading to an impaired response to APCs (antigen-presenting cells), and lenalidomide treatment of CLLs can reverse the suppression of synapse formation by CLLs [21]. Also, there is evidence that lenalidomide does not directly kill CLL cells but does affect the anti-apoptotic effects of nurse-like cells on CLLs in the CLL microenvironment [22].
3.4 OthercancersLenalidomide has been trialed in a number of other cancers with a good degree of success. For example, in a completed Phase I trial of mantle cell lymphoma at 20 mg after 2 cycles, 5 out of 6 patients achieved responses including one CR, one PR, and three minor responses [23]. In a Phase I trial of aggressive relapsed/refractory non-Hodgkin’s lymphoma, objective responses were seen in 28% of patients [24]. Osteonectin, cyclin D1 and p21kip correlate with non-Hodgkin’s lymphoma cell lines sensitivity to lenalidomide [25]. In a study of 18 patients with small lymphocytic lymphoma, 4 (22%) patients had a complete or partial response [26]. In 12 patients with acute leukaemia, CRs were seen in 2 patients [27].
In solid tumour trials, promising data has also been shown: 55% of patients with prostate cancer had reduction of PSA of > 98% [28] and in 18 patients with rapidly
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progressive thyroid cancer, a 67% response was seen with 22% of patients having PR [29].
4. Regulatoryaffairs
As previously mentioned, lenalidomide has been FDA approved in the US and Europe for previously treated multiple myeloma in combination with dexamethasone. It is also approved for use in patients with transfusion-dependent anaemia owing to low or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality with or without further cytogenetic abnormalities. Lenalidomide is available only under a special restricted distribution program, RevAssistSM, similar to the S.T.E.P.S.® program instituted for Thalomid®, to insure no foetal exposure, owing to the teratogenic properties associated with these drugs.
5. Pharmacodynamicsoflenalidomide
Lenalidomide affects many cell pathways and processes as discussed below (Figure 2).
5.1 AntitumoureffectsInitial efforts to understand the anticancer properties of lenalidomide and its analogues in myeloma and MDS have focused on direct antitumour activities such as increased apoptosis and inhibition of tumour cell proliferation. Lenali-domide and pomalidomide inhibit proliferation of a number of multiple myeloma cell lines including Sultan and RPMI8266 and, furthermore, render doxorubicin and dexamethasone resistant subtypes of these cell lines sensitive to these agents [30]. Lenalidomide and pomalidomide have been shown to inhibit the proliferation of two B-lymphoma cell lines but have no effect on normal B cells and increase proliferation of CD34 progenitors [31]. Lenalidomide, thalidomide and pomalidomide trigger activation of caspase-8, enhance multiple myeloma cell sensitivity to FAS-induced apoptosis and downregulate NF-κB, cellular inhibitor of apoptosis 2 and FLICE inhibitory protein [32]. In MDS del(5)(q31), lenalidomide inhibits growth of del(5q) erythroid progenitors and upregulates SPARC, a tumour suppressor gene, which may play a role in the pathogenesis of the 5q- syndrome and activin A, with a role in apotosis of erythropoietic cells [33].
5.2 EffectsonimmunefunctionThe effects of lenalidomide and its analogues on immune function have been reported since the early 90s and more recently, long-term responses and responses in patients’ low tumoural mass seen with lenalidomide in different trials point toward its immunological mechanism(s).
5.2.1 T-cell costimulationThe IMiDs® immunomodulatory drugs thalidomide, lenali-domide and pomalidomide have been shown to act as T-cell costimulatory molecules. In contrast to their well documented
anti-inflammatory effects on LPS stimulated monocytes [34-36], in which there is a decrease in the secretion of TNF-α, T cells activated through CD3 or IL-2 have enhanced proliferation when co-treated with the IMiDs thalidomide, lenalidomide or pomalidomide [37]. This proliferation is concomitant with increased secretion of proinflammatory cytokines such as IL-2, IFN-γ, and IL-12 from CD4 and CD8 T cells that have been stimulated to become TH1 type T cells (using IL-12).
Lenalidomide alone does not induce cell cycle changes in T cells; however, following CD3 ligation on T cells, lenalidomide enhances G1 to S transition compared with CD3 ligation alone [37]. Lenalidomide also induces significant CD3 T-cell proliferation in the presence of immature DCs, or mature DCs. The mechanisms by which the costimulatory effects are thought to occur are through CD28: CTLA-4–Ig, which blocks costimulation through the B7-CD28 pathway, inhibits T-cell proliferation induced by immature and mature DCs and lenalidomide partially overcomes this inhibitory effect of CTLA-4–Ig. Lenalidomide can induce CD28 phosphorylation and also augments NF-κB activation on anti-CD28 activated T cells. The IMiDs immunomodulatory compounds enhance AP-1-driven transcriptional activity two- to fourfold after 6 h of T-cell stimulation, and their relative potencies for AP-1 activation correlate with potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells [38]. IL-2 production from stimulated T cells is increased through rises in PKC-θ activation and enhanced DNA-binding activity of AP-1 but not NF-κB [39].
5.2.2 Effects on T-regulatory cellsThe IMiDs immunomodulatory compounds have been assessed for their activity against naturally occurring regulatory T cells. These cells are of the CD4 lineage and express very high levels of CD25 (Interleukin 2 receptor) [40]. They also are characterised by expression of FOXP3, a protein of the FORKHEAD box family, which leads to inhibition of IL-2 mediated proliferation and renders T cells suppressive to other activatory cell types such as activatory CD4 T-cells, CD8 cytotoxic T-cells and natural killer (NK) cells [41]. Both lenalidomide and pomalidomide, but not thalidomide, inhibit expression and function of these cells [42,43]. This finding is critical as T-regulatory cells are in tumour infiltrating populations in patients with ovarian, breast, pancreatic and colorectal cancers [44-46], and indicate poor prognosis in patients with gastric and oesophageal cancers [47]. Furthermore, in ovarian cancer, a high CD8:T regulatory cell ratio is a good prognostic indicator [48,49]. T regulatory cells are also raised in patients with multiple myeloma [50] non-Hodgkin’s lymphoma [51] and CLL [52], which can respond to lenalidomide treatment.
5.2.3 Effects on NK cells and NKT cellsNK cells comprise around 10% of the lymphocyte population in normal individuals and are important for recognition and removal of cells virally infected or cancer cells. They recognise cells with missing major histocompatibility complex (MHC)
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class I. NK cells are critical in antitumour immunity (reviewed in [53]). Davies et al. have shown that IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with thalidomide/IMiDs immunomodulatory compounds demon-strated significantly increased lysis of multiple myeloma cell lines [78]. More recently, Zhu et al. showed pro-apoptotic effects of lenalidomide and pomalidomide on tumour cells in a co-culture model of PBMC and tumour cells using K562 and RAJI tumour targets, in which increased apoptosis was induced by preincubating the PBMC population with the drugs before addition to the target cells [54]. The NK population within the PBMCs was shown to be responsible for mediating the apoptosis of K562 cells. Lenalidomide can also enhance NK and monocyte cytotoxicity toward target cells through an increase in antibody-dependant cell cytotoxicity (ADCC) when the target cells are treated with rituximab (anti-CD20 monoclonal antibody) [55]. This effect is dependant on the presence of antibody and on IL-2 or IL-12. Lenalidomide and pomalidomide combined with IgG1-isotype antibodies enhance ADCC through enhanced IL-12 cytokine signalling and increased effector cell granzyme B and FasL expression [56]. The effect was seen with non-Hodgkin’s lymphoma target lines in vitro and with B-cell CLLs derived from patients previously treated with fludarabine and cyclophosphamide. Enhanced NK cell Fc-γ receptor signalling is associated with enhanced phosphorylated
extracellular signal-related kinase levels leading to enhanced effector function.
However, it is possible that the IMiDs immunomodulatory compounds effects on NK cells is indirect and occurs through increased IL-2 cytokine production in T cells costimulated by the IMiDs immunomodulatory compounds. IMiDs immunomodulatory compounds facilitate nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 through activation of phosphoinositide-3 kinase signalling, with resulting IL-2 secretion [57]. IMiDs immunomodulatory compounds enhance both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells [57].
Natural killer T (NKT) cells are CD1d-restricted glycolipid reactive innate lymphocytes that provide protection from pathogens and tumours. These cells mediate antitumour effects through direct effects on tumour cells, cytokine production, antiangiogenesis and activation of other cells, notably dendritic cells and NK cells [58]. Lenalidomide enhances antigen-specific expansion of NKT cells in response to the NKT ligand -galactosylceramide α-GalCer) in patients with myeloma and in healthy donors and. NKT cells activated in the presence of lenalidomide have greater ability to secrete interferon-ϒ and patients with multiple myeloma or MDS del5Q treated with lenalidomide have an increase in their NKT cells in vivo [59].
Apoptosis/growth arrestLenalidomide
MonocytesNK cells
T cellsTumour cells e.g. Multiple
myeloma
Apoptosis/necrosis/growth
arrest
Endothelial cellangiogenesis
Inhibition ofangiogenesis
Inhibition ofBFGF/VEGF
Co-stimulation of CD3/increase of IFN-γEnhanced killing of
5.3 EffectsonangiogenesisAngiogenesis, the formation of new blood vessels from existing vasculature, plays a crucial role in tumour progression [60]. New blood vessels are required for tumour growth beyond 1 – 2 mm3; therefore, inhibition of angiogenesis has become an important target for cancer treatment [61]. Increased angiogenesis in the bone marrow of patients with multiple myeloma is a poor prognostic feature [62,63], Neovascularisation in multiple myeloma is mediated by various angiogenic growth factors released by tumour cells and the bone marrow micro-environment such as VEGF, basic fibroblastic-growth factor and hepatocyte-growth factor. IMiDs immunomodulatory compounds can inhibit in vivo angiogenesis in xeno- transplantation models such as Hodgkin’s lymphoma [64], melanoma [65], cervical cancer [66] and colorectal cancer. Lenalidomide has anti-angiogenic activity shown in the rat mesenteric-ring assay [67]. A key inhibitory mechanism in this study has been inhibition of AKT phosphorylation. Other inhibitory mechanisms put forward by the IMiDs immuno-modulatory compounds include inhibition of endothelial cell migration, adhesion and capillary-tube formation, endothelial cell apoptosis in 3D collagen cultures [68], and inhibition of key pro-angiogenic growth factors such as VEGF, basic fibroblastic-growth factor and HIF [69,70]. It is not yet been determined whether inhibition of angiogenesis by lenalidomide and the IMiDs immunomodulatory compounds are crucial to responses in multiple myeloma and other diseases as some studies showed a lack of decreases in proangiogeneic cytokines in thalidomide treated multiple myeloma patients [71,72] and the drugs display anti-angiogenic activity in vitro independently of immunomodulatory effects [73].
5.4 EffectsonmetastasisandcellmigrationMetastasis is critical for cancer progression being present in > 30% of patients at initial diagnosis. The process is complex, involving cell migration from the primary site, cell adhesion and growth in new organs. Thalidomide and
lenalidomide inhibit metastasis in mouse xenograft models of cancers such as Hodgkin’s lymphoma [64] and ocular melanoma [74], The mechanisms for metastasis inhibition are unclear, but so far, with thalidomide, it has been shown that migration [75], inhibition of cell adhesion molecules such as ICAM-1 and LFA-1 [76] and β2 and β3 integrins [75], and gap-junction function are involved [77]. It is believed that increased antitumour responses mediated by NK cells and dendritic cells caused by lenalidomide may augment metastasis inhibition in vivo [64,78], but because direct anti-invasive and anti-adhesive effects occur in vitro, the drug can inhibit steps involved in metastasis irrespective of immune function.
6. Expertopinion
Based on the current wealth of data on lenalidomide, its has great potential as a leading cancer drug. Unlike most existing anticancer therapeutics, lenalidomide and its IMiD™ immuno-modulatory compounds analogues have several mechanisms of action encompassing many signalling pathways, which has the advantage of potentially decreasing drug resistance. A range of immunostimulatory effects have been reported in a number of effector-cell types suggesting a powerful mechanism for the drugs antitumour activities. Studies are now focusing on the molecular mechanisms of action of the compound, which is being facilitated by state of the art genomic and proteomic array technologies. These future studies will define the gene and protein targets of the lenalidomide and the IMiD immunomodulatory compounds analogues and allow more focused therapies in combination with other known and novel therapeutics.
Declarationofinterest
A research grant has been awarded to AG Dalgleish from the Celgene corporation.
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AffiliationChristine Galustian† & Angus Dalgleish†Author for correspondenceSt Georges University of London, Division of Cellular and Molecular Medicine, Department of Oncology, Cranmer Terrace, Tooting, London Tel: +44 208 725 0954; Fax: +44 208 725 0158; E-mail: [email protected]
