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. 2014 Jun;5(3):91–101. doi: 10.1177/2040620714532124

Lenalidomide in relapsed or refractory mantle cell lymphoma: overview and perspective

Madhav Desai 1,2, Kate Newberry 3, Zhishuo Ou 4, Michael Wang 5,6, Liang Zhang 7,✉
PMCID: PMC4031905  PMID: 24883181

Abstract

Lenalidomide, a novel immunomodulatory agent, was approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome and relapsed multiple myeloma. Data from preclinical studies paved the way for clinical trials of lenalidomide in mantle cell lymphoma (MCL). Initial phase I and II clinical trials of lenalidomide alone and as part of combination regimens in patients with relapsed/refractory MCL have shown promising results. Its immunomodulatory, T cell costimulatory, anti-inflammatory and anti-angiogenic actions working together in the tumor cell microenvironment seem to be responsible for its enhanced antitumor efficacy. Lenalidomide’s nature of action and safety profile favor it over other agents studied in relapsed/refractory MCL. This review summarizes the data from preclinical and clinical studies of lenalidomide in relapsed/refractory MCL and compares the results with those of other novel agents being used for relapsed/refractory MCL.

Keywords: immunomodulatory agents, lenalidomide, mantle cell lymphoma

Introduction

Mantle cell lymphoma (MCL) was considered almost incurable until it was discovered that thalidomide, an almost forgotten compound till then, can in fact achieve better remission rates in relapsed cases of MCL with fewer toxicities [Damaj et al. 2003; Kaufmann et al. 2004]. Thalidomide was first introduced in the late 1950s, but it was not used for decades after it was found to cause severe birth defects, including phacomelia. In the 1990s, it was found that thalidomide has anti-angiogenic properties which renewed interest by researchers in this agent as a treatment for cancer. Subsequent studies showed that thalidomide possesses antitumor effects and can be used to treat various cancers [Kumar et al. 2002].

Although thalidomide possesses anti-angiogenic, anticancer and immunomodulatory effects, including inhibition of tumor necrosis factor-α (TNFα), treatment is associated with some severe side effects, including peripheral neuropathy and venous thromboembolism [Chaudhry et al. 2002; Mileshkin et al. 2006, Palumbo et al. 2011]. Besides this, intense monitoring is required to prevent pregnancy, due to its teratogenic effects. Therefore, research was driven to generate novel thalidomide analogs with enhanced antitumor, anti-angiogenic and immunomodulatory effects and better tolerability profile [Aragon-Ching et al. 2007]. This led to the generation of a novel class of thalidomide analogs known as immunomodulators (IMiDs), with enhanced immunological and anticancer properties but lacking the severe toxicities associated with thalidomide [Bartlett et al. 2004; Knight, 2005; Aragon-Ching et al. 2007]. Lenalidomide is one of the IMiDs that has shown promising antitumor efficacy in a wide range of malignancies, especially B-cell hematological malignancies [Chanan-Khan and Cheson, 2008]. Lenalidomide (Revlimid®) is a structural analog of thalidomide that possesses an additional amino (NH2) group at position 4 of the phthaloyl ring and removal of the carbonyl (C=O) at position 2. Lenalidomide was approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of myelodysplastic syndrome (MDS) with 5q deletion, with or without other cytogenetic abnormalities. It was subsequently approved for use in combination with dexamethasone to treat relapsed/refractory multiple myeloma (MM). Because of its efficacy in myeloma, lenalidomide is also being studied in other B cell malignancies, including MCL, with promising initial results.

MCL is an aggressive variant of B cell non-Hodgkin’s lymphoma (NHL) and its incidence in the US has been rising steadily during the past three decades [Zhou et al. 2008]. It carries a poor prognosis compared to other NHL subtypes with a median overall survival (OS) of 5–7 years with recent advances [Perez-Galan et al. 2011]. Median age at diagnosis is 68 years and most patients are diagnosed at an advanced stage of the disease [Zhou et al. 2008]. There is no standard consensus for treating MCL. The most common frontline chemotherapy is R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) or R-HyperCVAD (rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone alternating with cytarabine and methotrexate) [Lenz et al. 2005; Romaguera et al. 2010; Kluin-Nelemans et al. 2012]. The highest complete response (CR) rate for newly diagnosed MCL remains 34–61% [Lenz et al. 2005; Nickenig et al. 2006; Delarue et al. 2008; Geisler et al. 2008; Damon et al. 2009]. However, this comes at the expense of several hematological and nonhematological toxicities. Stem cell transplantation has improved outcomes, but it is not curative in all the patients [Khouri et al. 1998]. In addition, many patients are not eligible for stem cell transplantation due to their advanced age or associated comorbid conditions.

Although recent advances in treatment have slightly increased remission rates; recurrence and relapse are very common. Relapse is also a major cause of death in patients with MCL. Despite the fact that intensive frontline regimens and salvage programs can achieve an overall response rate (ORR) of nearly 90%, the majority of patients still relapse [Herrmann et al. 2009]. Bortezomib, a first generation proteasome inhibitor, was the first drug approved by the FDA for use in MCL patients who have received at least one prior therapy. The response rates still remain low and many patient relapse while on bortezomib, as we will see later. This emerging need for novel chemotherapeutic options that could induce prolonged responses and increase survival with fewer side effects led to thorough research into lenaliodomide in MCL patients. Extensive research led to FDA approval of lenalidomide for MCL patients whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Recently, ibrutinib (Bruton’s tyrosine kinase inhibitor) has been approved for treatment of relapsed MCL as well. In this review, we discuss the preclinical and clinical experience with lenalidomide as a promising therapeutic option for patients with relapsed and/or refractory MCL.

Mechanism of action of lenalidomide in MCL

In vitro and in vivo experimental studies have shown that lenalidomide works through multiple mechanisms, including direct tumor cytotoxicity, inhibition of angiogenesis and osteoclastogenesis, and disruption of stromal cell-derived signals from the tumor microenvironment [Chanan-Khan and Cheson, 2008]. In addition, lenalidomide acts as an immunomodulator by activating immune cells, especially natural killer (NK) and T cells. Compared with thalidomide, lenalidomide exerts superior anti-inflammatory and immunomodulatory actions [Aragon-Ching et al. 2007].

Lenalidomide stimulates proliferation and activation of antitumor T cells effective against MCL cells [Gaidarova et al. 2008]. Lenalidomide inhibits interleukin-1β (IL-1β) and TNF-α induced activation of IκB kinase (IKK) from nuclear factor-κB (NF-κB), preventing its nuclear translocation and induction of genes that function in metastasis, angiogenesis, cellular proliferation, inflammation and protection from apoptosis [Keifer et al. 2001]. Further, lenalidomide exhibits significant anti-angiogenic effects including interaction with tumor microenvironment, endothelial cells and vascular endothelial growth factor (VEGF) [Dredge et al. 2002, 2005; Vallet et al. 2008]. Recently it was also found that tumor lymphangiogenesis contributes to the progression of lymphomagenesis and that lenalidomide is effective in decreasing MCL growth specifically and metastasis by inhibiting recruitment of MCL-associated macrophages [Song et al. 2013].

Hernandez-Ilizaliturri and colleagues first studied the combination of lenalidomide and rituximab in aggressive lymphoma [Hernandez-Ilizaliturri et al. 2005]. They found that in vitro lenalidomide induced growth inhibition and apoptosis of lymphoma cells. In the mouse model, lenalidomide enhanced the antitumor effects of rituximab and augmented NK cell function. In addition, the combination increased the median survival of the lymphoma-bearing mice compared with rituximab alone. Lenalidomide has also been shown to increase recruitment of NK cells to tumor sites which is mediated by stimulation of dendritic cells and modification of the cytokine microenvironment that causes augmentation of rituximab-associated antibody-dependent cellular cytotoxicity (ADCC) [Reddy et al. 2008]. Lenalidomide potentiates the effects of rituximab more strongly than thalidomide [Richardson et al. 2010]. It also increases peripheral blood mononuclear cell (PBMC) mediated cytotoxicity. This enhanced PBMC activity can lead to tumor cell apoptosis. Increase of NK cells and NK-T cells from the PBMC population play an essential role in this process [Zhu et al. 2008]. Lenalidomide delayed the tumor growth and improved the survival of MCL-bearing mice when used with dexamethasone as well as rituximab [Zhang et al. 2009; Qian et al. 2011]. Lenalidomide also enhanced dexamethasone-induced G0/G1 arrest. The combination of lenalidomide with dexamethasone as well as with rituximab induces apoptosis of lymphoma cells through mitochondrial signaling pathways. Lenalidomide sensitizes tumor cells and enhances rituximab-mediated cytotoxicity of MCL cells. Daily treatment with lenalidomide increased NK cells by 10-fold in MCL-bearing SCID mice [Zhang et al. 2009]. The combination of lenalidomide and rituximab enhances the NK-cell mediated synapse formation and cell killing which can become dysfunctional as part of immune evasion by lymphoma cells [Gaidarova et al. 2009]. Additionally, lenalidomide induces capping of CD20 and cytoskeleton proteins of malignant B cells which increases their immune recognition by rituximab and its overall activity [Gaidarova et al. 2010]. Moros and colleagues studied the activity of lenalidomide in in vitro and in vivo models of bortezomib-resistant MCL and showed that single-agent lenalidomide is preferentially effective in MCL cases resistant to bortezomib by targeting C-Myc-driven tumorigenesis [Moros et al. 2012]. Lenalidomide has also shown to partially overcome resistance exerted by lymphoma cells towards other chemotherapeutic agents like rituximab and bortezomib [Reddy et al. 2006, Moros et al. 2012].

In summary, lenalidomide has antitumor activity in MCL as a single agent as well as in combination, mainly with rituximab. Preclinical success led to study of its efficacy and safety in clinical trials. Lenalidomide has been studied in clinical trials as a single agent and in combination with other agents with proven activity in MCL as described below.

Activity of single-agent lenalidomide in MCL

Table 1 reports the published data on activity of lenalidomide in relapsed MCL patients from phase II clinical trials of single-agent lenalidomide in patients with relapsed and/or refractory NHL. Lenalidmide has not been studied as a monotherapy in front-line settings of MCL.

Table 1.

Clinical experience with single agent lenalidomide in MCL.

Study Dose No. of patients Prior lines of therapy ORR CR/ uCR Median PFS, months Median DOR, months Most common grade 3/4 adverse events
Lenalidomide in relapsed/refractory MCL
NHL-002 [Habermann et al. 2009] 25 mg/d PO; days 1–21 15 4 (2–7) 53% 20% 5.6 13.7 Neutropenia (40%), thrombocytopenia (33%)
NHL-003 [Zinzani et al. 2013] 25 mg/d PO; days 1–21 57 3 (1–13) 35% 12 8.8 (5.5-23) 16.34 (7.1 to NR) Neutropenia (46%), thrombocytopenia (30%)
Eve et al. [2012] 25 mg/d PO, days 1–21 for 6 cycles followed by 15 mg maintenance 26 3 (2–7) 31% 8% 14.6 (7.3–21.9) 22.2 (0–53.6) Neutropenia (62%), thrombocytopenia (42%), infection (42%)
Lenalidomide in bortezomib-resistant MCL
EMERGE [Goy et al. 2013] 20 mg/d PO, days 1–21 134 4 (2–10) 28% 8% 4 (3.6–5.6); OS 19 (12.5–23.9) 16.6 (7.7–26.7) Neutropenia (43%), Thrombocytopenia (28%)
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CR, complete response; DOR, duration of response; MCL, mantle cell lymphoma; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PO, by month; uCR – unconfirmed CR.

NHL-002 was the first trial studying single-agent lenalidomide in patients with relapsed/refractory aggressive NHL [Wiernik et al. 2008]. In this multicenter phase II study, lenalidomide was administered as 25 mg per day orally for day 1 to 21 of a 28-day cycle. Lenalidomide receiving patients (n = 49) had an ORR of 35% with a median duration of response (DOR) of 6.2 months. Median progression-free survival (PFS) was 4 months. Activity and safety data among MCL patients has been published separately with a longer follow up [Habermann et al. 2009]. ORR among 15 patients with relapsed/refractory MCL was 53%; 20% of them had a CR. Median PFS among MCL patients was 5.6 months.

The subsequent clinical trial, NHL-003, an international phase II study, enrolled 217 patients with relapsed/refractory aggressive NHL and reported an ORR of 35%, with a median PFS of 3.7 months and median DOR or 10.6 months [Witzig et al. 2011]. Zinzani and colleagues recently presented long-term safety and efficacy data of MCL patients from the NHL-003 trial. Among 57 patients with relapsed/refractory MCL, 35% had a response and 12% had a CR with a median DOR of 8.8 (5.5–23) months. The median PFS among MCL patients was 16.4 (7.1 to not reached) months [Zinzani et al. 2013]. Vose and colleagues analyzed data from the NHL-002 and NHL-003 trials and showed that the potential of achieving a response to lenalidomide appears to be independent of prior history of stem cell transplantation (SCT) [Vose et al. 2013]. In this retrospective analysis, lenalidomide had an ORR of 63% [CR/unconfirmed CR (uCR) 26%] in patients with relapsed and/or refractory MCL who had at least one SCT done prior to receiving lenalidomide in both trials. Eve and colleagues studied a slightly different lenalidomide regimen in a phase II multi-center study among 26 patients with relapsed refractory MCL [Eve et al. 2012]. Patients received 25 mg per day of lenalidomide for 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. The study demonstrated an ORR of 31% with a median DOR of 22.2 months. Median PFS was 3.9 months without maintenance lenalidomide and 14.6 months with maintenance lenalidomide, providing evidence for further study of lenalidomide in maintenance settings to achieve a longer disease-free period.

Lenalidomide showed activity in bortezomib-resistant cells as we saw earlier. Goy and colleagues conducted a phase II, multicenter, single-arm, open-label study (MCL-001 ‘EMERGE’ study) to study the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed on or were refractory to bortezomib, a proteasome inhibitor approved in treatment of relapsed/refractory MCL (n = 134) [Goy et al. 2013]. Single-agent lenalidomide demonstrated a response among 28% of subjects with a median DOR of 16.6 [95% confidence interval (CI) 7.7–26.7] months. Median time to response was 2.2 months and median time to progression was 5.4 (3.7–7.5) months by central review. Median PFS was 4 (3.6–5.6) months and OS was 19 (12.5–23.9) months. The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (28%) and anemia (11%). This was the first clinical study to demonstrate activity of lenalidomide in bortezomib-resistant patients providing way for larger phase III study for its approval for bortezomib-resistant MCL patients.

Lenalidomide is better tolerated than its parent compound thalidomide [Richardson et al. 2002]. Previous clinical trials in relapsed/refractory NHL using lenalidomide as a single agent have reported the following hematological and nonhematological toxicities: grade 3/4 hematologic adverse events occurring in at least 5% of patients include neutropenia, thrombocytopenia, leukopenia, anemia and febrile neutropenia; and grade 3/4 nonhematological adverse events were rarely reported and were manageable [Wiernik et al. 2008; Witzig et al. 2011]. Among all grade 3 or 4 toxicities, neutropenia is the most common hematological toxicity (40–46%) [Goy et al. 2013]. However, the incidence of febrile neutropenia is lower (2–6%) [Reeder et al.; Witzig et al. 2011; Wang et al. 2012]. Thrombocytopenia also is common (28–30%), but did not culminate into serious events in any studies. All hematological toxicities were manageable and reversible upon discontinuation of lenalidomide. Thalidomide is associated with a high incidence of peripheral neuropathy [Mileshkin et al. 2006], but recent studies of lenalidomide have shown that the incidence of grade 3/4 neuropathy in lenalidomide-naïve patients is very low (0.4–1%). In addition, lenalidomide maintenance did not significantly increase the incidence of grade 3/4 peripheral neuropathy [Wang et al. 2008; Attal et al. 2012].

Activity of lenalidomide in combination regimens in MCL

As lenalidomide enhanced the antitumor activity of other agents in preclinical studies and as it showed promising activity as a single-agent in MCL, interest was driven to study lenalidomide in combination with other active agents for treating MCL. Lenalidomide has been combined with dexamethasone, rituximab and bortezomib in respective clinical trials (Table 2).

Table 2.

Clinical experience with lenalidomide in combination with other agents for MCL.

Study/regimen Dosing No. of patients Prior lines of therapy ORR CR/uCR Survival Median DOR, months Median follow up Most common grade 3/4 adverse events
Lenalidomide in combination regimen in relapsed/refractory MCL
LEN+DEXA [Zaja et al. 2012] LEN: 25 mg/d PO, days 1–21 33 3 (2–7) 52% 24% Median PFS: 12 months 18 N/A Neutropenia (53%), leukopenia (25%), thrombocytopenia (22%)
DEX: 40 mg/day on days 1, 8, 15, 22 (for maximum of 12 cycles) Median OS: 20 months
LEN+RTX [Wang et al. 2012] LEN: 20 mg/day PO, days 1–21 52 2 (1–4) 57% 36.4% Median PFS: 11.1 months 18.9 N/A Neutropenia (29 pt), lymphopenia (16 pt), leucopenia (13 pt), thrombocytopenia (10 pt)
RTX: 375 mg/m2 IV, 4 weekly doses – cycle 1 only Median OS: 24.3 months
LEN+BTZ [Morrison et al. 2012] LEN: 20 mg/d PO, days 1–14 53 1 (1–5) 40% 15% 1-year EFS 25%, 1-year PFS 41%, 1-year OS 67% N/A 2.3 years Thrombocytopenia (13%/21%), fatigue (21%/0), Neuropathy (17%/0)
BTZ: 1.3 mg/m2 IV days 1, 4, 8, 11 (maximum 8 cycles)
Lenalidomide in combination regimen in MCL
LEN+RTX+BTZ [Flinn et al. 2012] LEN: 10 mg/day PO, days 1–14 22 0 (0–1) 82% 32% 18-month PFS: 61%; 18-month OS: 79% N/A 16 (1–38) months Neutropenia (23%)
RTX: 375 mg/m2, days 1, 8, 15 of cycle 1 and then day 1 of subsequent cycles Rash (32%)
BTZ: 1.3 mg/m2 IV, days 1, 4, 8, 11 (maximum 6 cycles) Neuropathy (18%)
Thrombocytopenia (18%)
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BTZ, bortezomib; CR, complete response; DEX, dexamethasone; DOR, duration of response; EFS, event-free survival; IV, intravenously; LEN, lenalidomide; MCL, mantle cell lymphoma; N/A, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PO, by mouth; RTX, rituximab; uCR, unconfirmed CR.

To study the synergistic effects of lenalidomide in combination with rituximab demonstrated in preclinical studies, Wang and colleagues conducted a phase I/II clinical trial using this combination to investigate its efficacy in patients with relapsed and/or refractory MCL [Wang et al. 2012]. The maximum tolerated dose of lenalidomide when given in combination with rituximab was determined to be 20 mg in phase I. A total of 44 patients were enrolled in phase II, with an ORR of 57% and a median OS of 24.3 months. The median PFS was twice as long (11.1 months) with the lenalidomide–rituximab combination compared with lenalidomide alone (5.6 and 5.7 months) [Wiernik et al. 2008, Witzig et al. 2011, Wang et al. 2012]. Most common grade 3/4 adverse events were neutropenia (n = 29), lymphopenia (n = 16), leucopenia (n = 13 and thrombocytopenia (n = 10). These findings are promising and should be validated in a larger phase III clinical trial. Zaja and colleagues studied the combination of lenalidomide and dexamethasone among 33 patients with relapsed refractory MCL; 52% of the subjects had a response while 24% had a CR with a median DOR of 18 months. Median PFS was 12 months and median OS was 20 months [Zaja et al. 2012]. They reported slightly higher incidence of grade 3/4 neutropenia (53%) when lenalidomide was used in combination with dexamethasone, but this is likely due to this specific combination, as other studies using the lenalidomide–dexamethasone combination reported a similar adverse event profile, with an incidence of neutropenia near to 40% [Weber et al. 2007]. The incidence of thromboembolism was high in studies of lenalidomide in combination with dexamethasone in patients with myeloma and MDS [Carrier et al. 2011], which resulted in the FDA issuing a precautionary warning regarding thromboembolic events (deep vein thrombosis and pulmonary embolism) on the drug label. However, thromboembolic adverse events have not been seen in recent studies of lenalidomide either alone or in combination with other regimens in patients with MCL or other NHL. The high incidence of thromboembolic events reported in myeloma has been suggested to be associated with its use in combination with dexamethasone [Menon et al. 2008].

Morrison and colleagues conducted a phase II trial to investigate safety and efficacy of combination of lenalidomide with bortezomib (Alliance/CALGB 50501) [Morrison et al. 2012]. Although a higher ORR was expected, only 40% of patients responded with a 1-year PFS of 41%, while producing significant toxicity leading to treatment discontinuation in 32% of participants. Most common grade 3/4 toxicities (>10%) were thrombocytopenia (13/21), fatigue/aesthenia (21/0) and neuropathy (17/0; grade 2: 36%). Since this response was similar to that seen with single-agent lenalidomide and incidence of higher toxicity with this regimen, the authors do not recommend further studies with similar dose and schedule of combination of lenalidomide and bortezomib.

Flinn and colleagues studied combination of rituximab, lenalidomide and bortezomib in first- or second-line treatment of patients with MCL in a phase I/II trial [Flinn et al. 2012]. The maximum tolerated dose (MTD) of lenalidomide (10mg) in combination with bortezomib and rituximab was less than lenalidomide and bortezomib combination in MM as per study. In phase II, patients received 10 mg lenalidomide by mouth (PO) (daily on days 1–14), bortezomib 1.3 mg/m2 intravenously (IV) (days 1, 4, 8 and 11) and rituximab 375 mg/m2 (days 1, 8 and 15 of cycle 1; 375 mg/m2 on day 1 of subsequent cycles). ORR was 82% with 32% of patients having a CR. Those who did not received prior treatment, ORR was 75%. At the median follow up of 16 months, 18-month PFS was 61%. Grade 3/4 events were rash (32%), thrombocytopenia (23%), neutropenia (18%) and neuropathy (18%). The authors suggest that, given the incidence of neuropathy, subcutaneous or less frequent IV dosing of bortezomib is worthy of investigation rather than the twice-weekly IV bortezomib used in this study. The LENA-BERIT trial studied lenalidomide, bendamustine and rituximab as first-line therapy for patients >65 years with MCL [Jerkeman et al. 2011]. The results of the phase I portion reported that addition of lenalidomide to the rituximab–bendamustine regimen leads to increased toxicity in elderly patients with MCL, although it is associated with very high response rate (ORR 100%, n = 10).

Discussion

Managing relapsed/refractory MCL has always been a challenge, with many options being evaluated to date. Bortezomib was the first agent approved by the FDA for use in relapsed/refractory MCL followed by lenalidomide and ibrutinib, successively. The largest prospective phase II study of bortezomib in relapsed/refractory MCL (n = 155) showed an ORR of 33%, with 8% CR/uCRs and a median DOR of 9.2 months [Fisher et al. 2006]. Subgroup analyses of MCL cases from NHL-002 and NHL-003 reported ORR of 35–53% [Habermann et al. 2009; Zinzani et al. 2013]. We speculate that response rates with lenalidomide as a single agent are better than bortezomib, with fewer toxicities, especially peripheral neuropathy.

Single-agent lenalidomide also comparatively exhibits better efficacy than single-agent rituximab. When used as a single agent in relapsed/refractory MCL, rituximab showed an ORR in 27–34% (n = 104) [Foran et al. 2000; Ghielmini et al. 2005]. When lenalidomide and rituximab were combined, the combination was more effective than either agent alone [Wang et al. 2012]. Furthermore, there were very few grade 3/4 adverse events and all were manageable, with no patients discontinuing the study due to adverse events. Because the combination of lenalidomide and dexamethasone has been effective as a treatment for relapsed/refractory myeloma, the combination was tested in patients with relapsed/refractory MCL as well with an ORR of 52% and CR of 24% (n = 33). Investigators used a higher lenalidomide dose (25 mg/m2) and achieved comparatively lower response rates compared with a recent trial of lenalidomide–rituximab [Zaja et al. 2012]. From the available data, we can say that lenalidomide–rituximab might be better tolerated than lenalidomide–dexamethasone.

Combination of bendamustine and rituximab has also been studied with ORRs of 92% (n = 12) and 75% (n = 16), respectively [Rummel et al. 2005; Robinson et al. 2008]. Although the response rate and efficacy are higher with the bendamustine-containing regimen, the toxicity profile of the alkylating agent, which is cytoreductive and causes significant hematoxicity, is expected to be higher than that of lenalidomide. In addition, the higher response rates found in these studies have not been confirmed in larger randomized trials.

Temsirolimus, a mammalian target of rapamycin (mTOR) kinase inhibitor, has been studied as a single agent and in combination with other agents in MCL. In phase II trials, single agent temsirolimus has been studied with different dosing regimens: 250 mg intravenously every week with ORR of 38% [Witzig et al. 2005] and 25 mg intravenously every week with ORR of 41%. [Ansell et al. 2008]. In both studies, temsirolimus had significant dose-dependent hematological toxicities, especially thrombocytopenia (grade 3/4 thrombocytopenia: 66% with 250 mg; 39% with 25 mg regimen). Subsequently, a randomized, open-label phase III study was performed to evaluate temsirolimus in two dosing levels compared with investigator’s choice therapy (n = 162) [Hess et al. 2009]. Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly was shown to have ORR of 22%, median PFS of 4.8 months and median OS of 12.8 months compared with investigator’s choice therapy. Based on these results, temsirolimus gained approval for the treatment of patients with relapsed MCL in the European Union. Another study investigated the combination of temsirolimus with rituximab in relapsed/refractory MCL (n = 71), which achieved an ORR of 59% and CR of 19%. For the rituximab refractory group, the ORR was 52% [Ansell et al. 2011]. While the response rate for this regimen is comparable to those of the lenalidomide–rituximab combination, there were fewer CRs with the temsirolimus–rituximab combination. Furthermore, there were more grade 3 and 4 toxicities with the temsirolimus–rituximab combination, particularly thrombocytopenia and neutropenia in rituximab-refractory group.

As a novel modality, investigators are studying biologic therapy as a first-line approach in MCL patients. Recently, Ruan and colleagues published preliminary data from a phase II multicenter trial of lenalidomide and rituximab in MCL patients who are recently diagnosed and not received any chemotherapy [Ruan et al. 2013]. Among 31 enrolled patients, 77% achieved ORR and 40% CR at a median follow-up of 12 months. A total of 23 (87%) patients remain on study for further follow up and maintenance treatment assessment. Medial time to objective response was 2.8 months. Grade 3/4 adverse events were neutropenia (39%), rash (23%) and thrombocytopenia (13%). The authors believe that response rates may further improve with additional follow up on continued treatment. Biological therapy should be further explored in front-line settings with agents like lenalidomide and ibrutinib in MCL to improve outcomes.

FDA recently approved the Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, in the management of MCL in patients who have received at least one therapy on the basis of multi-center, international, single-arm trial enrolling 111 patients with relapsed or refractory MCL [Wang et al. 2013]. Ibrutinib (560 mg, once daily) achieved response rates of 68% with CR of 21% at a median follow up of 15.3 months. Grade 3 or greater hematological adverse events were few: neutropenia (16%), thrombocytopenia (11%) and anemia (10%). Estimated 18-month OS was 58% and estimated median PFS was 13.9 months (95% CI: 7 to not reached). This was a breakthrough in MCL history considering once oral dosing, tolerability and higher response rates.

At the current moment, we have novel and better modalities coming to existence in the MCL field. Ibrutinib and lenalidomide both seem to be the potential future therapies for these patients. It is difficult to compare lenalidomide against ibrutinib in absence of comparative trials. In fact, it would be interesting to know if the combination modality is superior to the current approaches – specifically standard chemotherapy.

Conclusion

Considering the poor prognosis of MCL and frequent relapse/refractory disease, novel agents with higher efficacy and better tolerability are sorely needed early in the course of the disease. Lenalidomide is a potential agent with immune-enhancing effects as evidenced in preclinical studies and further validation in recent clinical trials leading to its approval. Good overall tolerability and ability to further enhance the antitumor efficacy of the established immunotherapeutic agent, rituximab, put lenalidomide at the forefront for early consideration in relapsed and/or refractory MCL. Current evidence is definitely in favor for the extensive study of lenalidomide in combination, as maintenance regimen and even in front-line settings for MCL. Temsirolimus has been approved in the European Union, but considering its heavy toxicity profile, lenalidomide and rituximab may be a preference with the new addition of another biologic agent, ibrutinib, for further investigation as a therapeutic choice. As we quoted earlier, lenalidomide with ibrutinib and/or rituximab would be a therapeutic choice in the future. We highly recommend future phase II clinical trials of lenalidomide in combination with ibrutinib or other novel agents in relapsed and/or refractory setting of MCL in order to achieve better response rates and increase overall survival of this group of patients. Early biologic approach in chemotherapy of naïve MCL patients with immunomodulatory agents and ibrutinib should also be explored further.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

Contributor Information

Madhav Desai, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS, USA.

Kate Newberry, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Zhishuo Ou, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Michael Wang, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Liang Zhang, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit Number: 0429, Houston, TX 77030, USA.

References

  1. Ansell S., Inwards D., Rowland K., Jr., Flynn P., Morton R., Moore D., Jr., et al. (2008) Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 113: 508–514 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ansell S., Tang H., Kurtin P., Koenig P., Inwards D., Shah K., et al. (2011) Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol 12: 361–368 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aragon-Ching J., Li H., Gardner E., Figg W. (2007) thalidomide analogues as anticancer drugs. Recent Pat Anticancer Drug Discov 2: 167–174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Attal M., Lauwers-Cances V., Marit G., Caillot D., Moreau P., Facon T., et al. (2012) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366: 1782–1791 [DOI] [PubMed] [Google Scholar]
  5. Bartlett J., Dredge K., Dalgleish A. (2004) The evolution of thalidomide and its imid derivatives as anticancer agents. Nat Rev Cancer 4: 314–322 [DOI] [PubMed] [Google Scholar]
  6. Carrier M., Le Gal G., Tay J., Wu C., Lee A. (2011) Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 9: 653–663 [DOI] [PubMed] [Google Scholar]
  7. Chanan-Khan A., Cheson B. (2008) Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 26: 1544–1552 [DOI] [PubMed] [Google Scholar]
  8. Chaudhry V., Cornblath D., Corse A., Freimer M., Simmons-O’Brien E., Vogelsang G. (2002) Thalidomide-induced neuropathy. Neurology 59: 1872–1875 [DOI] [PubMed] [Google Scholar]
  9. Damaj G., Lefrere F., Delarue R., Varet B., Furman R., Hermine O. (2003) Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia 17: 1914–1915 [DOI] [PubMed] [Google Scholar]
  10. Damon L., Johnson J., Niedzwiecki D., Cheson B., Hurd D., Bartlett N., et al. (2009) Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol 27: 6101–6108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Delarue R., Haioun C., Ribrag V., Brice P., Delmer A., Tilly H., et al. (2008) RCHOP and RDHAP followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): final results of a phase II study from the GELA. ASH Annual Meeting Abstracts 112: 581 [Google Scholar]
  12. Dredge K., Horsfall R., Robinson S., Zhang L., Lu L., Tang Y., et al. (2005) Orally Administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and AKT phosphorylation in vitro. Microvasc Res 69: 56–63 [DOI] [PubMed] [Google Scholar]
  13. Dredge K., Marriott J., Macdonald C., Man H., Chen R., Muller G., et al. (2002) Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 87: 1166–1172 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Eve H., Carey S., Richardson S., Heise C., Mamidipudi V., Shi T., et al. (2012) Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol 159: 154–163 [DOI] [PubMed] [Google Scholar]
  15. Fisher R., Bernstein S., Kahl B., Djulbegovic B., Robertson M., De Vos S., et al. (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24: 4867–4874 [DOI] [PubMed] [Google Scholar]
  16. Flinn I., Mainwaring M., Peacock N., Shipley D., Arrowsmith E., Savona M., et al. (2012) Rituximab, lenalidomide, and bortezomib in the first-line or second-line treatment of patients with mantle cell lymphoma a phase I/II trial. ASH Annual Meeting Abstracts 120: 2748 [Google Scholar]
  17. Foran J., Cunningham D., Coiffier B., Solal-Celigny P., Reyes F., Ghielmini M., et al. (2000) Treatment of mantle-cell lymphoma with rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response. Ann Oncol 11(Suppl. 1): 117–121 [PubMed] [Google Scholar]
  18. Gaidarova S., Corral L., Gleizer E., Young D., Brady H., Bennett B., et al. (2008) Lenalidomide enhances anti-tumor effect of {gamma}{delta} T cells against mantle cell lymphoma. ASH Annual Meeting Abstracts 112: 2616 [Google Scholar]
  19. Gaidarova S., Corral L., Glezer E., Schafer P., Lopez-Girona A. (2009) Treatment of MCL cells with combined rituximab and lenalidomide enhances NK-mediated synapse formation and cell killing. ASH Annual Meeting Abstracts 114: 1687 [Google Scholar]
  20. Gaidarova S., Mendy D., Heise C., Aukerman S., Daniel T., Chopra R., et al. (2010) Lenalidomide induces capping of CD20 and cytoskeleton proteins to enhance rituximab immune recognition of malignant B-cells. ASH Annual Meeting Abstracts 116: 2845 [Google Scholar]
  21. Geisler C., Kolstad A., Laurell A., Andersen N., Pedersen L., Jerkeman M., et al. (2008) Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112: 2687–2693 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ghielmini M., Schmitz S., Cogliatti S., Bertoni F., Waltzer U., Fey M., et al. (2005) Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 23: 705–711 [DOI] [PubMed] [Google Scholar]
  23. Goy A., Sinha R., Williams M., Kalayoglu Besisik S., Drach J., Ramchandren R., et al. (2013) Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 31: 3688–3695 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Habermann T., Lossos I., Justice G., Vose J., Wiernik P., Mcbride K., et al. (2009) Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 145: 344–349 [DOI] [PubMed] [Google Scholar]
  25. Hernandez-Ilizaliturri F., Reddy N., Holkova B., Ottman E., Czuczman M. (2005) Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 11: 5984–5992 [DOI] [PubMed] [Google Scholar]
  26. Herrmann A., Hoster E., Zwingers T., Brittinger G., Engelhard M., Meusers P., et al. (2009) Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27: 511–518 [DOI] [PubMed] [Google Scholar]
  27. Hess G., Herbrecht R., Romaguera J., Verhoef G., Crump M., Gisselbrecht C., et al. (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27: 3822–3829 [DOI] [PubMed] [Google Scholar]
  28. Jerkeman M., Kolstad A., Laurell A., Raty R., Gronbaek K., Pedersen L., et al. (2011) Lenalidomide, bendamustine, and rituximab as first-line therapy for patients > 65 years with mantle cell lymphoma: results from the phase I portion of the Nordic Lymphoma Group MCl4 (LENA-BERIT) trial. ASH Annual Meeting Abstracts 118: 2700 [Google Scholar]
  29. Kaufmann H., Raderer M., Wohrer S., Puspok A., Bankier A., Zielinski C., et al. (2004) Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood 104: 2269–2271 [DOI] [PubMed] [Google Scholar]
  30. Keifer J., Guttridge D., Ashburner B., Baldwin A., Jr. (2001) Inhibition of NF-kappa B activity by thalidomide through suppression of ikappab kinase activity. J Biol Chem 276: 22382–22387 [DOI] [PubMed] [Google Scholar]
  31. Khouri I., Romaguera J., Kantarjian H., Palmer J., Pugh W., Korbling M., et al. (1998) Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16: 3803–3809 [DOI] [PubMed] [Google Scholar]
  32. Kluin-Nelemans H., Hoster E., Hermine O., Walewski J., Trneny M., Geisler C., et al. (2012) Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367: 520–531 [DOI] [PubMed] [Google Scholar]
  33. Knight R. (2005) IMiDs: a novel class of immunomodulators. Semin Oncol 32: S24–30 [DOI] [PubMed] [Google Scholar]
  34. Kumar S., Witzig T., Rajkumar S. (2002) Thalidomide as an anti-cancer agent. J Cell Mol Med 6: 160–174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lenz G., Dreyling M., Hoster E., Wormann B., Duhrsen U., Metzner B., et al. (2005) Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23: 1984–1992 [DOI] [PubMed] [Google Scholar]
  36. Menon S., Rajkumar S., Lacy M., Falco P., Palumbo A. (2008) Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 112: 1522–1528 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mileshkin L., Stark R., Day B., Seymour J., Zeldis J., Prince H. (2006) Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol 24: 4507–4514 [DOI] [PubMed] [Google Scholar]
  38. Moros A., Saborit-Villarroya I., Perez-Galan P., Martinez A., Campo E., Colomer D., et al. (2012) Activity of lenalidomide in vitro and in vivo models of bortezomib-resistant mantle cell lymphoma involving the modulation of c-myc/p27 axis. Cancer Res 72(8 Suppl): abstract 1942: [Google Scholar]
  39. Morrison V., Jung S.-H., Johnson J., Lacasce A., Blum K., Bartlett N., et al. (2012) Salvage therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: initial results of a phase II trial (ALLIANCE/CALGB 50501). ASH Annual Meeting Abstracts 120: 3696 [Google Scholar]
  40. Nickenig C., Dreyling M., Hoster E., Pfreundschuh M., Trumper L., Reiser M., et al. (2006) Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer 107: 1014–1022 [DOI] [PubMed] [Google Scholar]
  41. Palumbo A., Cavo M., Bringhen S., Zamagni E., Romano A., Patriarca F., et al. (2011) Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 29: 986–993 [DOI] [PubMed] [Google Scholar]
  42. Perez-Galan P., Dreyling M., Wiestner A. (2011) Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 117: 26–38 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Qian Z., Zhang L., Cai Z., Sun L., Wang H., Yi Q., et al. (2011) Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia Res 35: 380–386 [DOI] [PubMed] [Google Scholar]
  44. Reddy N., Hernandez-Ilizaliturri F., Czuczman M. (2006) The use of the immunomodulatory drug, lenalidomide (Revlimid(r)) as a novel strategy to overcome acquired antibody resistance in rituximab-resistant non-Hodgkin’s lymphoma (NHL) cell lines. AACR Meeting Abstracts 2006: 154-a [Google Scholar]
  45. Reddy N., Hernandez-Ilizaliturri F., Deeb G., Roth M., Vaughn M., Knight J., et al. (2008) Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol 140: 36–45 [DOI] [PubMed] [Google Scholar]
  46. Reeder C., Witzig T., Zinzani P., Vose J., Buckstein R., Haioun C., et al. (2009) Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: results from an international study (NHL-003). J Clin Oncol 27(Suppl. 15): abstract 8569. [Google Scholar]
  47. Richardson P., Schlossman R., Weller E., Hideshima T., Mitsiades C., Davies F., et al. (2002) Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100: 3063–3067 [DOI] [PubMed] [Google Scholar]
  48. Richardson S., Eve H., Copplestone J., Dyer M., Rule S. (2010) Activity of thalidomide and lenalidomide in mantle cell lymphoma. Acta Haematol 123: 21–29 [DOI] [PubMed] [Google Scholar]
  49. Robinson K., Williams M., Van Der Jagt R., Cohen P., Herst J., Tulpule A., et al. (2008) Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 26: 4473–4479 [DOI] [PubMed] [Google Scholar]
  50. Romaguera J., Fayad L., Feng L., Hartig K., Weaver P., Rodriguez M., et al. (2010) Ten-year follow-up after intense chemoimmunotherapy with rituximab-hypercvad alternating with rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol 150: 200–208 [DOI] [PubMed] [Google Scholar]
  51. Ruan J., Martin P., Shah B., Schuster S., Smith S., Furman R., et al. (2013) Combination biologic therapy without chemotherapy as initial treatment for mantle cell lymphoma: multi-center phase II study of lenalidomide plus rituximab. Blood 122: 247 [Google Scholar]
  52. Rummel M., Al-Batran S., Kim S., Welslau M., Hecker R., Kofahl-Krause D., et al. (2005) Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol 23: 3383–3389 [DOI] [PubMed] [Google Scholar]
  53. Song K., Herzog B., Sheng M., Fu J., Mcdaniel J., Ruan J., et al. (2013) Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. Cancer Res 73: 7254–7264 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Vallet S., Palumbo A., Raje N., Boccadoro M., Anderson K.C. (2008) Thalidomide and lenalidomide: mechanism-based potential drug combinations. Leuk Lymphoma 49: 1238–1245 [DOI] [PubMed] [Google Scholar]
  55. Vose J., Habermann T., Czuczman M., Zinzani P., Reeder C., Tuscano J., et al. (2013) Single-agent lenalidomide is active in patients with relapsed or refractory aggressive non-Hodgkin lymphoma who received prior stem cell transplantation. Br J Haematol 162: 639–647 [DOI] [PubMed] [Google Scholar]
  56. Wang M., Dimopoulos M., Chen C., Cibeira M., Attal M., Spencer A., et al. (2008) Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 112: 4445–4451 [DOI] [PubMed] [Google Scholar]
  57. Wang M., Fayad L., Wagner-Bartak N., Zhang L., Hagemeister F., Neelapu S., et al. (2012) Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 13: 716–723 [DOI] [PubMed] [Google Scholar]
  58. Wang M., Rule S., Martin P., Goy A., Auer R., Kahl B., et al. (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369: 507–516 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Weber D., Chen C., Niesvizky R., Wang M., Belch A., Stadtmauer E., et al. (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357: 2133–2142 [DOI] [PubMed] [Google Scholar]
  60. Wiernik P., Lossos I., Tuscano J., Justice G., Vose J., Cole C., et al. (2008) Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 26: 4952–4957 [DOI] [PubMed] [Google Scholar]
  61. Witzig T., Geyer S., Ghobrial I., Inwards D., Fonseca R., Kurtin P., et al. (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23: 5347–5356 [DOI] [PubMed] [Google Scholar]
  62. Witzig T., Vose J., Zinzani P., Reeder C., Buckstein R., Polikoff J., et al. (2011) An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol 22: 1622–1627 [DOI] [PubMed] [Google Scholar]
  63. Zaja F., De Luca S., Vitolo U., Orsucci L., Levis A., Salvi F., et al. (2012) Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers. Haematologica 97: 416–422 [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Zhang L., Qian Z., Cai Z., Sun L., Wang H., Bartlett J., et al. (2009) Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol 84: 553–559 [DOI] [PubMed] [Google Scholar]
  65. Zhou Y., Wang H., Fang W., Romaguer J., Zhang Y., Delasalle K., et al. (2008) Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer 113: 791–798 [DOI] [PubMed] [Google Scholar]
  66. Zhu D., Corral L., Fleming Y., Stein B. (2008) Immunomodulatory drugs revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 57: 1849–1859 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zinzani P., Vose J., Czuczman M., Reeder C., Haioun C., Polikoff J., et al. (2013) Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 Study. Ann Oncol 24: 2892–2897 [DOI] [PMC free article] [PubMed] [Google Scholar]

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