HEMORRAGIA DIGESTIVA BAIXA POR DOENÇA HEMORROIDÁRIA TRATADA COM GRAMPEADOR PPH

HEMORRAGIA DIGESTIVA BAIXA POR DOENÇA HEMORROIDÁRIA TRATADA COM GRAMPEADOR PPH

VOLUME 26 䡠 NUMBER 9 䡠 MARCH 20 2008 JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E Lenalidomide for the Treatment of B-Cell Malig...

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VOLUME

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JOURNAL OF CLINICAL ONCOLOGY

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A R T I C L E

Lenalidomide for the Treatment of B-Cell Malignancies Asher A. Chanan-Khan and Bruce D. Cheson From the Roswell Park Cancer Institute, Buffalo, NY; and Georgetown University Hospital, Washington, DC. Submitted September 25, 2007; accepted November 30, 2007; published online ahead of print at www.jco.org on February 19, 2008. Supported in part by the Jerra Barit Myeloma Research Fund (A.C.-K.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Asher A. Chanan-Khan, MD, Elm & Carlton St, Buffalo, NY 14263; e-mail: [email protected] © 2008 by American Society of Clinical Oncology 0732-183X/08/2609-1544/$20.00

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Lenalidomide is a novel anticancer agent that has made a major impact in the treatment of patients with B-cell malignancies. A more potent analog of thalidomide, lenalidomide was developed to enhance immunomodulatory properties with improved safety profile. Its antitumor activity seems mediated through modulation of both the cytokine and cellular tumor cell microenvironment. Preclinical as well as clinical observations demonstrate that lenalidomide downregulates production of various critical prosurvival cytokines in the tumor microenvironment while concurrently promoting activation of T- and natural killer (NK) cell-mediated antitumor response. Early clinical investigations noted its efficacy in relapsed and/or refractory multiple myeloma patients. Subsequently, larger randomized studies confirmed the clinical benefit of lenalidomide when added to dexamethasone compared with dexamethasone alone in previously treated myeloma patients resulting in its recent approval by the US Food and Drug Administration. Consequently, the role of lenalidomide in other B-cell malignancies has been investigated, with impressive results in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. This review summarizes the data from various clinical investigations and highlights the impact of lenalidomide in the management of patients with B-cell malignancies. J Clin Oncol 26:1544-1552. © 2008 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2007.14.5367

INTRODUCTION

During the last decade, thalidomide, the parent compound of a new class of anticancer drugs called immunomodulating agents (IMiDs) has demonstrated impressive antitumor activity in diverse malignant disorders. Singal et al first reported clinical benefit from thalidomide in patients with relapsed or refractory multiple myeloma.1 These findings were not only confirmed by several other investigators,2,3 but initiated a drug discovery phase for more potent and potentially less toxic analogs of thalidomide.4 This process resulted in the development of lenalidomide, currently the lead compound available in the IMiD class. Lenalidomide was designed to enhance immunologic and anticancer properties while potentially decreasing neurotoxic and teratogenic adverse effects of the parent compound thalidomide.4,5 The US Food and Drug Administration first approved lenalidomide for the treatment of patients with myelodysplastic syndrome with deletion (5q⫺). However, the activity of thalidomide in multiple myeloma (MM) led to extensive clinical investigations of lenalidomide in MM and other B-cell malignancies including chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). This review will focus on results from clinical inves-

tigations that continue to define the role of this new compound in B-cell malignancies. MECHANISM OF ACTION OF LENALIDOMIDE

The second generation of IMiDs (lenalidomide and pomalidomide) was synthesized on the structural backbone of thalidomide molecule. Lenalidomide was developed by adding an amino group (NH2-) at position 4 of the phthaloyl ring and removal of the carbonyl group (C ⫽ O) of the 4-amino–substituted phthaloyl ring. These structural changes were designed to enhance its immunomodulatory and antitumor activity.4 Despite the clinical activity of the IMiDs in various malignant diseases, the exact mechanism of their antitumor activity remains elusive. It is possible that the antitumor activity of lenalidomide is mediated through multiple mutually exclusive processes that primarily depend on the type of tumor cells and their microenvironment. Several investigators have reported antiproliferative and proapoptotic effects of lenalidomide on tumor cells in vitro.6,7 Furthermore, in vivo studies demonstrated enhanced antimyeloma effect of lenalidomide compared with thalidomide.8 Interestingly, we observed no direct proapoptotic effect of lenalidomide in vitro in primary tumor cells obtained from B-CLL patients despite significant antileukemic effects in in vivo.9

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Immunomodulating Agents for B-Cell Malignancies

An important effect of lenalidomide is its ability to modulate production of various cytokines in tumor microenvironment. Lenalidomide is reported to downregulate key prosurvival cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF); cytokines that enrich the malignant microenvironment favoring tumor cell survival and proliferation and resistance to therapy (Fig 1).10-12 Downstream from VEGF signaling is the phosphatidyl inositol-3⬘ (PI3)-kinase/Akt signaling pathway which is important in proliferation and survival of various cancers including MM. Lenalidomide inhibits Akt phosphorylation at Ser473 and Thr308, suggesting that the antiproliferative and antiangiogenic effect of lenalidomide may relate to downregulation of VEGF signaling through the Akt pathway.6,13,14 Lenalidomide may also affect other components of the tumor microenvironment, including the immune cellular compartment. Preclinical observations demonstrate its activation of immune effector cells (T and NK cells)15,16 stimulating T-cell proliferation and increased production of IL-2 and interferon (IFN)-␥ through T-cell receptor activation.15,17 Also, activation and proliferation of NK cell has been reported with lenalidomide.18,19 We observed that while lenalidomide failed to directly induce apoptosis in primary B-CLL cells obtained from patients, in vitro exposure of tumor cells to lenalidomide resulted in upregulation of costimulatory molecules (CD80, CD86, and CD40) as well as Fas ligand (CD95).9 These immunophenotypic changes in tumor cells may explain the robust immune response clinically presenting as a tumor flare reaction and resulting in an immune-mediated antitumor response.19 These properties of lenalidomide, which collectively alter the tumor cell environment and shift the balance from an antiapoptotic to

Lenalidomide ↓ ICAM ↓ VEGF ↓ TNF-α

a proapoptotic microenvironment (Fig 1), form the basis for its clinical investigation in patients with B-cell malignancies.

MULTIPLE MYELOMA

Relapsed or Refractory MM Anderson et al first reported the antitumor activity of lenalidomide in a preclinical MM model.20 This observation resulted in clinical investigations of lenalidomide in patients with relapsed or refractory disease.21 Although no dose-limiting toxicity (DLT) was observed when lenalidomide was escalated from 5 to 50 mg/d within the first 28 days, grade 3 myelosuppression was noted after 28 days in all 13 patients at the 50-mg dose level. The maximum tolerated dose (MTD) of lenalidomide was thus established at 25 mg/d. Antimyeloma activity (at least 25% reduction in paraprotein concentration) was observed in 71% of patients. In a multicenter, randomized study, Richardson et al22 investigated two dosing schedules of lenalidomide. Patients were randomly assigned to receive either 30 mg once daily or 15 mg twice daily for 21 of 28 days. The overall response rate (ORR) in the two arms was 24% and 29%, respectively. Dexamethasone was added to lenalidomide in patients whose remained stable or progressed after two cycles. Addition of dexamethasone resulted in a response in an additional 29% of patients (Table 1).22 Notably, patients on the twice-daily schedule showed no significant increase in grade 3/4 myelosuppression (69% v 80%; P ⫽ .3) and a significantly shorter time to occurrence of grade 3/4 myelosuppression (1.8 v 5.5 months; P ⫽ .05) compared with the once-daily schedule.

Stromal Cell

Tumor Cell

Lenalidomide ↓ Proliferation ↑ Apoptosis ↓ pAkt ↓ pErk

TNF-α Lenalidomide ↑ CD95 (Fas) ↑ CD80 ↑ CD86 ↑ CD83 ↑ CD40

VEGF

Lenalidomide ↓ VEGF ↓ TNF- α ↓ PDGF PDGF ↓ IL-10 ↓ TGF- β

TNF-α

IL-10

T - Cell

Lenalidomide T-cell activation T-cell proliferation ↑ CD178 (Fas ligand) ↓ CD40L

Fig 1. Effect of lenalidomide on tumor cell and its microenvironment. ICAM, intercellular adhesion molecule; VEGF, vascular endothelial growth factor; TNF, tumor necrosis factor; PDGF, plateletderived growth factor; IL, interleukin; TGF, transforming growth factor; NK, natural killer.

TGF- β

Lenalidomide Activates NK cells NK cell proliferation

NK Cell

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Chanan-Khan and Cheson

Table 1. Clinical Experience of Lenalidomide in B-Cell Malignancies % Study

Disease

Clinical Phase

Regimen

MM Richardson21 Richardson22

MM-r/r MM-r/r

I II

Knop83 Richardson32 Richardson33 Morgan31 Baz30 Weber23

MM-r/r MM-r/r MM-r/r MM-r/r MM-r/r MM-r/r

I/II I II II I/II III

Dimopoulous24

MM-r/r

III

Rajkumar16 Palumbo29 CLL Chanan-Khan58 Ferrajoli59 NHL Wang72

MM-nd MM-nd

II I

L (5-50 mg QD) L (30 mg QD) L (15 mg BID) RAD RV RVD RCD DVdR LD D LD D LD R-MP

CLL CLL

II II

MCL

I

Wiernik84 Witzig70 WM Treon77

NHL-aggressive NHL-indolent

II II

WM

II

L (25 mg QD 3 week on, 1 week off weeks 1-48) ⫹ rituximab (375 mg/m2/wk on weeks 2-5 and 13-16)

AL

II

L (15 mg QD 3 week on, 1 week off)

Amyloidosis Seldin78

No. of Patients

ORR

CR/nCR

27 67 35 23 38 19 21 52 170 171 176 175 34 54

71* 24 29 78 58 53 62 75 59.4 21.1 59.1 23.9 91 81

NR 6 0 74 6 5 5 29 22 2.6 17 4.0 6 23.8

L (25 mg QD) 21 of 28 days L (10 mg QD) escalated to maximum of 25 mg QD

45 44

57.5 32

18 7

L (5-25 mg QD) 3 of 4 weeks ⫹ rituximab (375 mg IV) weekly ⫻ 4 weeks L (25 mg QD) 3 of 4 weeks L (25 mg QD) 3 of 4 weeks

15

33

7

41 27

34 26

12 7

8

37

0

43

60

24

Abbreviations: MM; multiple myeloma, CLL; chronic lymphocytic leukemia, CR; complete response, nCR; near CR, L; lenalidomide, MCL; mantle cell lymphoma, nd; newly diagnosed, NHL; non-Hodgkin’s lymphoma, ORR; overall response rate, r/r; relapsed or refractory, RAD; revlimid/doxorubicin/dexamethasone, RCD; revlimid/cyclophosphamide/dexamethasone, DVdR; doxorubicin/vincristine/low-dose dexamethasone/revlimid, WM; Waldenström macroglobulinemia. *At least 25% reduction in paraprotein.

These encouraging observations set the stage for two large, randomized, multicenter, double-blind, placebo-controlled clinical trails, the MM-009 (in the United States) and MM-010 (conducted internationally).23,24 The design of these two clinical trials was identical: MM patients who experienced failure with at least one prior therapy were randomly assigned to receive dexamethasone (40 mg/d on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles, and thereafter only on days 1 through 4 of each treatment cycle) in combination with placebo or lenalidomide 25 mg/d for 21 days of a 28-day cycle. The primary end point of the studies was time to progression (TTP), with secondary end points including ORR, safety, and overall survival. A total of 353 and 351 patients were enrolled on the MM-009 and MM-010 studies, respectively. Patients received a median of three prior therapies, with more than 60% experiencing progression after at least two prior antimyeloma regimens. The ORR to lenalidomide plus dexamethasone in MM009 and MM-010 was 61% and 59% compared with 21% and 24% with dexamethasone plus placebo, respectively (P ⬍ .001). Importantly, the TTP in the two studies was 11.1 and 11.3 months for the combination armscomparedwith4.7monthswiththecontrolarm(P⬍.001).Median overall survival was longer than 29.6 months in MM-009, and has not yet been reached in the MM-010 study.23,24 Subset analysis of pooled data from these two clinical trials demonstrated efficacy of lenalidomide in 1546

relapsed/refractory myeloma patients despite prior exposure to thalidomide.25 Similar results from these two studies established the efficacy of lenalidomide in MM. Table 2 summarizes the commonly reported grade 3 and 4 toxicities in these clinical trials. Previously Untreated MM The observation that the ORR of lenalidomide/dexamethasone in MM-009 and MM-010 was higher among patients who received one versus two or more prior therapies (65% and 66% v 59% and 57% respectively) stimulated interest in exploring this agent in less heavily treated patients.26 Rajkumar et al27 first investigated the clinical activity of lenalidomide combined with high-dose dexamethasone in 34 treatment-naı¨ve myeloma patients, with an ORR of 91%. Consequently, the Eastern Cooperative Oncology Group (ECOG) is conducting a large, randomized, multicenter clinical trial investigating lenalidomide in treatment-naı¨ve myeloma patients. Patients are randomly assigned to lenalidomide (25 mg/d for 21 days) with high-dose dexamethasone (40 mg/d on days 1 to 4, 9 to 12, and 17 to 20) or low-dose dexamethasone (40 mg/d on days 1, 8, 15, and 22). Patients were to continue therapy until disease progression, when they would again be randomly assigned to thalidomide (200 mg/d) with low- or high-dose dexamethasone. Although response rates are not available, the overall JOURNAL OF CLINICAL ONCOLOGY

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Immunomodulating Agents for B-Cell Malignancies

survival at 1 year was significantly higher with low-dose (96.5%) compared with high-dose dexamethasone, (86%; P ⬍ .001), respectively. As a result, the data monitoring committee recommended early release of the survival results, with all patients switching to lowdose dexamethasone.28 Therefore, clinical experience with lenalidomide to date demonstrates that early use in MM patients is associated with a higher rate of clinical responses and, possibly, improved survival. Although the exact reason for this observation remains undetermined, the maximum benefit of lenalidomide may be harnessed more effectively before immunosuppressive therapies or high-dose chemotherapy and stem-cell transplantation. Future clinical trials with correlative studies focused on patients’ immune repertoire and clinical outcome will help determine the optimal clinical setting for lenalidomide-based therapies. Novel Combinations With Lenalidomide Combination regimens to improve on the outcome with lenalidomide are under investigation (Table 1). Palumbo et al29 studied the combination of lenalidomide (21 days every 4 to 6 weeks) with melphalan/prednisone (4 days every 4 to 6 weeks) regimen in a phase I study. In four cohorts, the dose of melphalan and lenalidomide was escalated from 0.18 to 0.25 mg/kg/d and 5 to 10 mg, respectively, whereas the prednisone dose was maintained at 2 mg/kg/d. The MTD was 0.18 mg/kg/d of melphalan and 10 mg/d of lenalidomide. Grade 3 to 4 adverse events included neutropenia (58%), thrombocytopenia (21%), and febrile neutropenia (3%). Impressively, 81% of patients achieved at least a partial remission (47.6% a very good partial remission [VGPR]) with immunofixation-negative complete response (CR) recorded in 23.8%. Knopp et al combined lenalidomide with doxorubicin and dexamethasone (RAD) and reported an ORR of 78%, whereas addition of lenalidomide to DVd (doxorubicin/ vincristine/low-dose dexamethasone) resulted in a 75% ORR 75%.30 RCD (revlimid/cyclophosphamide/dexamethasone), a multidrug oral regimen, is reported to have an ORR of 62% in relapsed or refractory patients (Table 1).31 In a phase I trial, Richardson et al32 combined lenalidomide (5 to 20 mg per day for 14 of 21 days) with bortezomib (1.0 and 1.3 mg/m2 on days 1, 4, 8, and 11). MTD was defined as lenalidomide 15 mg and bortezomib 1.0 mg/m2. The objective response rate (CR and partial and minor responses) was 58%. Dexamethasone (40 mg on the day of/after bortezomib) was added to the combination at disease progression and resulted in an ORR of 71%.32 Preliminary result of an ongoing phase II study of this regimen and demonstrated ORR and CR rate of 53% and 5%, respectively (Table 1).33 This regimen in now being investigated in treatment-naı¨ve patients.

CHRONIC LYMPHOCYTIC LEUKEMIA

Recent reports of combinations of cytotoxic agents (eg, fludarabine, pentostatin) with monoclonal antibodies (rituximab, alemtuzumab) suggests an improvement not only in complete and overall response rates, but also with a suggestion of survival prolongation.34-36 Nevertheless, relapse is inevitable, and CLL remains incurable. Development of novel therapeutic strategies based on an evolving understanding of

the biology of the disease remains an important goal. A hallmark of the CLL cell is its inherent resistance to apoptosis, related in large part to the Bcl-2 family of proteins. Overexpression of the antiapoptotic protein Bcl-2 in CLL is associated with an aggressive clinical course, chemotherapy resistance, and shortened survival.37-39 Although initially thought to be causative, overexpression of Bcl-2 may be induced by the interaction of CLL cells with the malignant microenvironment.40,41 Abnormal cytokine networks clearly exist within the B-CLL microenvironment.42-45 The inherent ability of CLL cells to secrete prosurvival cytokines (VEGF, TNF-␣, and IL-6) and express corresponding receptors results in formation of a paracrine/autocrine growth-promoting loop.42,44,46 In addition, abnormal expression of these cytokines in the microenvironment also modulates T-cell and NK-cell dysfunction.47-49 In fact, CD4⫹ T cells are reported to support the survival of CLL cells.50,51 These abnormalities seem to be induced by the CLL cell itself through contact-dependent interactions.52 Consistent with this, CLL cells downregulate expression of the CD80 (B7-1) and CD86 (B7-2) costimulatory ligands, which may blunt antitumor T-cell activation and possibly induce anergy.53,54 Thus, aberrant prosurvival cytokine networks plus a prosurvival T-cell interaction/compromised antitumor T-cell and NK responses lead to unchecked growth of the B-CLL clone, as well as resistance to standard therapy. The microenvironment is now recognized as a potential therapeutic target in CLL such that disruption of cytokine networks and/or alteration of the interaction between the CLL and the immune system from prosurvival to antitumor may open novel strategies for treating CLL. Lenalidomide for Relapsed or Refractory CLL We and others have reported that thalidomide has antileukemic activity in patients with CLL.55-57 In a phase I study of previously untreated patients, thalidomide (100-300 mg/d for 6 months) was combined with fludarabine (25 mg/m2/day for 5 days, every 4 weeks for six cycles). No DLT was observed. ORR and CR rates were 100% and 55%, respectively.55 Kay et al reported stabilization of disease in 84% of CLL patients with a median TTP of 8.5 months.56 These observations lead to a single-institution phase II study at Roswell Park Cancer Institute (Buffalo, NY), in CLL patients progressing, or refractory to at least one prior therapy administering lenalidomide for 21 days of a 28-day cycle. Among the first 29 patients, the starting dose of lenalidomide was 25 mg/d, whereas the subsequent 16 patients started lenalidomide at 10 mg/d and the dose at 5 mg every 2 weeks as tolerated to a maximum of 25 mg/d. The study design allowed patients to continue therapy until disease progression, unacceptable toxicity, or progression. Patients with progressive disease during treatment with lenalidomide were then treated with rituximab in addition to lenalidomide, at a dose of 375 mg/m2 (on days 1, 8, and 15 of cycle 1 and on days 1 and 15 of each subsequent treatment cycle) for a total of six cycles. Forty-five patients with a median of four (range, one to 10) prior therapies were enrolled, 64% with Rai stage III/IV, 51% were fludarabine refractory, and 29% had Zap-70⫹ cells.58 In another phase II study, Ferrajoli et al59 used a starting dose of 10 mg every day for 4 weeks followed by a dose escalation of 5 mg every 28 days to a maximum of 25 mg/d to treat 44 patients with a median of 51-15 prior therapies, a median ␤2 microglobulin level of 4.3 mg/dL (range, 1.6 to 10.1 mg/dL), advanced Rai stage in 45%, fludarabine refractory in 27%, and prior alemtuzumab 1547

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Chanan-Khan and Cheson

in 51%. Other unfavorable features including unmutated IgVH gene and unfavorable cytogenetic abnormalities were observed in 88% and 59% of the patients, respectively. Toxicity of Lenalidomide in CLL The most common toxicity reported in the Roswell Park study was grade 1/2 fatigue (73%). The incidence of grade 3/4 neutropenia and thrombocytopenia was 70% and 45%, respectively, with only 15% of patients developing neutropenic infections (Fig 2). In the University of Texas M.D. Anderson Cancer Center (Houston, TX) experience,59 the incidence of grade 3/4 neutropenia and thrombocytopenia was 39% and 15%, respectively, in 325 courses of treatment. The incidence of fatigue was 1%. Differences in toxicity between studies may reflect the lower starting dose of lenalidomide in the latter study. Tumor flare reaction is an important adverse effect of lenalidomide observed uniquely in patients with CLL. It is characterized by the sudden onset of tender swelling of disease-involved lymph nodes with overlying inflammation of the skin, enlargement of liver and/or spleen, low-grade fever, rash, and, rarely, with a rise in the peripheral-

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Fig 2. Important (A) grade 1/2 and (B) grade 3/4 toxicity reported in two phase II clinical trial of lenalidomide in relapsed/refractory chronic lymphocytic leukemia patients. RPCI, Roswell Park Cancer Institute (Buffalo, NY) ; MDA, The University of Texas M.D. Anderson Cancer Center (Houston, TX). 1548

Len/Dex (n ⫽ 353)

Dex/Placebo (n ⫽ 350)

Adverse Effect

No.

%

No.

%

Neutropenia Infection* Thrombocytopenia Venous thromboembolism†

125 55 46 46

35 16 13 13

12 32 22 14

3 9 6 4

Abbreviations: Len, lenalidomide; Dex, dexamethasone; NOS, not otherwise specified. *Infection includes terms of “infection NOS,” “pneumonia NOS,” “upper respiratory tract infection NOS,” “upper respiratory infection viral NOS,” “sepsis NOS,” “bacterial infection NOS,” “urinary tract infection NOS,” “pharyngitis,” “nasopharyngitis,” “febrile neutropenia,” “oral candidiasis,” “oral fungal infection NOS,” “pneumonia primary atypical,” “sinusitis fungal,” “herpes simplex,” herpes zoster,” “encephalitis herpes,” “herpes viral infection NOS,” “pneumonia cytomegalovirus,” and “viral infection NOS.” †Venous thromboembolism includes terms of “deep-vein thrombosis,” “pulmonary embolism,” and “pulmonary infarction.”

blood white cell count. The median duration of the flare reaction in the Roswell Park study was 14 days, with most patients experiencing the flare only during the first cycle.58 In neither of the two studies was the flare reaction the cause of termination of therapy. We were able to effectively manage the flare reaction with nonsteroidal antiinflammatory therapy (ibuprofen 400 mg orally every 6 hours) with a minority of the patients requiring additional oral morphine sulfate for pain control.60 Additionally, low-dose steroids (eg, prednisone 10 to 20 mg daily) decreases the severity but not the frequency of tumor flare reaction.61 The incidence of flare reaction was significantly lower in the M.D. Anderson study. The differences between these studies may reflect disparities in patient populations (more heavily pretreated and prior treatment with alemtuzumab) or variation in starting dose (25 v 10 mg). In the Roswell Park experience, tumor flare correlated with clinical response; all but one patient who achieved a complete response had grade 3 or worse flare reaction. Ongoing studies will further clarify the importance of flare reaction. Although no deaths were attributed to tumor flare in either trial, this adverse event can be severe and, especially in the context of concurrent tumor lysis syndrome, has been fatal in some CLL patients treated with lenalidomide.62 It is, therefore, important to recognize that this adverse effect of lenalidomide in CLL patients may be associated with morbidity and mortality and can mimic tumor progression. Our experience demonstrates that continued treatment of disease with lenalidomide concurrently with effective management of pain symptoms will eventually result in tumor reduction and a clinical response.

0

a

Proportion of Patients (%)

B

Table 2. Commonly (ⱖ10%) Reported Grade 3/4 Adverse Effects of Lenalidomide in Patients With Multiple Myeloma Treated in MM-009 and MM-010 Studies

Response The clinical efficacy of lenalidomide in patients with relapsed or refractory CLL has now been confirmed in two independent clinical trials. The overall response in the Roswell Park study was 57.5% (updated results) with a complete response rate of 18%.63 The median time to best response was 5.9 months (range, 1.6 to 18.3 months) with a median progression-free survival of 19.4 months (range, 1.2 to 38⫹ months). Complete responses observed JOURNAL OF CLINICAL ONCOLOGY

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Immunomodulating Agents for B-Cell Malignancies

in this study were associated with undetectable minimal residual disease by flow cytometry and polymerase chain reaction for immunoglobulin heavy chain gene. The overall response in the M.D. Anderson study was 32% with a 7% complete response rate. With a median follow-up of 11 months, the median duration of response was 12⫹ months.59 Notably, clinical responses were observed even in patients with high-risk cytogenetics, Zap-70⫹ patients or those were fludarabine refractory.64,65 Additionally, patients in the Roswell Park study who developed disease progression while on lenalidomide responded when rituximab was added to lenalidomide (ORR ⫽ 71%), suggesting additive benefit. Correlative Studies Correlative investigations were conducted on pretreatment primary tumor cells to study the effect of lenalidomide on the tumor cell as well as its microenvironment. We observed that exposure to lenalidomide failed to induce a direct proapoptotic effect on these CLL cells in vitro despite an obvious antileukemic effect in corresponding patients.9 Nevertheless, treatment with lenalidomide resulted in modulation of the CLL cell phenotype with upregulation of costimulatory molecules (including CD80, CD86, and CD40).9 This change in surface expression of costimulatory molecules concurrently with increase in circulatory NK cells may explain the immediate immune recognition phenomenon clinically presenting as the flare reaction that is associated with antileukemic effects in vivo.19 Lenalidomide for Previously Untreated CLL Single-agent lenalidomide is currently being studied as initial therapy of CLL at the Princess Margaret Hospital (Toronto, Ontario, Canada). Preliminary results demonstrate high response rate (ORR ⫽ 75%) even at a lower dose investigated. Other investigators are exploring it in combination with chemotherapy.66 DanaFarber Cancer Institute (Boston, MA) investigators are initiating a phase I dose escalation trial of lenalidomide in combination with a fludarabine/ rituximab. In an effort to develop a nonchemotherapy induction regimen the CLL Research Consortium is starting a pilot study of lenalidomide in combination with rituximab for treatment-naı¨ve patients. The oral availability of lenalidomide makes it attractive for maintenance after cytoreductive therapy. Thus, a clinical trial of lenalidomide maintenance after chemoimmunotherapy (fludarabine/rituximab) induction in previously untreated CLL patients has recently been initiated at The Georgetown University Hospital (Washington, DC) and Roswell Park Cancer Institute, while researchers at the Mayo Clinic (Rochester, MN) will be investigating the impact of lenalidomide maintenance after induction with PCR (pentostatin/ cyclophosphamide/rituximab) regimen. Lenalidomide has clearly demonstrated antileukemic activity in CLL with several clinical trials initiated in treatment-naı¨ve or relapsed/ refractory CLL patients. These studies are investigating variable dosing schedule as well as combination with currently available chemotherapy or immunotherapy. Combination with novel agents is also being explored such as with bendamustine at Georgetown University. Results from these clinical investigations should further define the role of lenalidomide in CLL.

NON-HODGKINⴕS LYMPHOMA

The impressive clinical activity of lenalidomide in patients with multiple myeloma and CLL as well as the antitumor activity of this drug in preclinical lymphoma model system prompted its investigation in patients with NHL. Lenalidomide induced growth arrest and apoptosis of lymphoma cell lines67 as well as enhancing NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) of rituximab.68 In addition, using a lymphoma xenograft mouse model HernandezIlizaliturri et al69 demonstrated that IMiD molecules enhanced the antitumor activity of rituximab, resulting in improved survival of tumor-bearing animals. Aggressive NHL Wiernik et al reported preliminary results of lenalidomide monotherapy in patients with relapsed or refractory non-Hodgkin’s lymphoma. Lenalidomide (25 mg/d) was administered on days 1 to 21 of a 28-day cycle and continued for 52 weeks as tolerated or until disease progression. Patients with various aggressive histologic subtypes (including diffuse large B-cell, follicular center cell, mantle cell, and transformed NHL) were enrolled. Forty-one of the 50 patients were assessable for response. Clinical responses were observed in all lymphoma subtypes. The ORR was 34% (n ⫽ 14) including five patients with CR unconfirmed (CRu), with a median progression-free survival in patients achieving a CRu of more than 239 (⬎ 191 to ⬎ 373 days) days.70 An ongoing multicenter clinical trial is further investigating clinical efficacy of single agent lenalidomide in patients with aggressive NHL. Indolent NHL Witzig et al reported a phase II study of lenalidomide (25 mg/d for 21 of 28 days) in patients with relapsed or refractory indolent NHL.70 Among 27 assessable patients with a median of three (range, one to 17) prior therapies, the ORR was 26% (n ⫽ 7) including two CRs, whereas the overall clinical benefit (stable disease or better response) was observed in 59% of the patients.70 A large, randomized, multicenter clinical trial conducted by the Cancer and Leukemia Group B (CALGB) is investigating the clinical benefit of lenalidomide versus lenalidomide/rituximab in patients with relapsed follicular NHL. Mantle-Cell Lymphoma Kaufman et al first reported the clinical efficacy of thalidomide combined with rituximab in patients with relapsed/refractory mantlecell lymphoma (MCL). The ORR and CR rate in this study was 81% and 31%, respectively with a median progression-free survival of 20.4 months.71 On the basis of these findings, a phase I clinical trial of lenalidomide (5 to 25 mg) in combination with rituximab was initiated for MCL. The MTD was 20 mg/d, 21 of 28 days. The DLT was prolonged neutropenia. Thirteen of 15 patients were assessable and had a median of three1-4 prior therapies. Although there were no responses in the 10- and 15-mg dose cohorts, five of six patients in the 20-mg cohort responded including a complete response.72 On the basis of the important single-agent activity of lenalidomide and bortezomib in MCL,73,74 CALGB is currently conducting a phase II trial of the combination of the two agents in patients with relapsed or refractory MCL. 1549

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WALDENSTRO¨M MACROGLOBULINEMIA AND AMYLOIDOSIS

Thalidomide has demonstrated clinical activity in Waldenstro¨m macroglobulinemia (WM) either alone75 or in combination regimen.76 Coleman et al reported an ORR and CR rate of 93% and 20%, respectively, when thalidomide was added to dexamethasone and clarithromycin.76 On the basis of these observations, Treon et al77 initiated a phase II clinical trial of lenalidomide (25 mg/d, 3 weeks on and 1 week off on weeks 1 to 48) in combination with rituximab (375 mg/m2/wk on weeks 2 to 5 and 13 to 16) in patients with WM. Among eight assessable patients, three achieved a partial response. An important adverse effect observed was the acute decrease in hematocrit (median, 4.2%) within the first 2 weeks of therapy. Final results of this study will help define the toxicity profile of lenalidomide in WM, whereas future studies are warranted to optimize dose and schedule. In a phase II study, Seldin et al78 reported the clinical efficacy of single-agent lenalidomide in patients with AL amyloidosis. Lenalidomide was administered at a dose of 15 mg/d for 21 days of a 28-day cycle. Among the 43 patients enrolled the, ORR (complete and partial responses) was 60%, with 24% achieving a complete remission.78

CONCLUSION

IMiDs are a novel class of anticancer drugs that have demonstrated antitumor activity in various malignant disorders. Of this class, most recent attention has focused on the more active agent, lenalidomide. Although the exact antitumor mechanisms of lenalidomide remain to be clearly defined, modulation of the tumor microenvironment through immune effector cell activation as well as perturbation of the cytokine milieu in the microenvironment have been demonstrated.9,12 Two large randomized multicenter phase III clinical trials have confirmed lenalidomide efficacy in MM patients.23,24 Subsequently, several clinical trials have confirmed its efficacy in combination with other antimyeloma agents in the relapsed/refractory setting and, more recently, in treatment-naı¨ve MM patients. It is important to note that, despite this encouraging experience, management of toxicities such as myelosuppression and venous thromboembolism (VTE) remains an important concern with lenalidomide therapy.79 In these two phase III clinical trials, the incidence of VTE among patients receiving lenalidomide with high-dose dexamethasone was 15% (MM-090)23 and 8.5% (MM-010).24 Because a similar experience was noted with thalidomide, this may be a class effect of these agents. As such, the current US Food and Drug Administration recommendation is to use prophylactic anticoagulation throughout the duration of lenalidomide treatment. Interestingly, in a recent report by Rajkumar et al28 on the ECOG frontline study, a decrease in incidence of VTE was observed with low-dose dexamethasone/lenalidomide versus high-dose dexamethasone/lenalidomide arm, 6.3% and 18.4%, respectively (P ⬍ .0001). Although the optimal prophylactic strategy remains undetermined, a reduced frequency has been reported with low-dose aspirin; weight-adjusted, low-dose warfarin sodium; or lowmolecular weight heparin.80 An important limitation of lenalidomide is the lack of safety profile in patients with compromised renal function. Since most of the drug (approximately 70%) is excreted unchanged in urine, patients with renal insufficiency are at higher risk of toxicity (especially myelosuppression).81 A recently concluded pharmacokinetic study demonstrated a significant decrease in total and 1550

renal clearance of lenalidomide in patients with moderate to severe renal failure.82 Although lenalidomide has already shifted the treatment paradigm in MM, reports from ongoing clinical trials are expected to further define its role in the management of treatment-naı¨ve patients or as maintenance therapy post– cytoreductive therapy. Two clinical trials of single-agent lenalidomide have demonstrated its efficacy in heavily pretreated relapsed or refractory B-CLL irrespective of poor prognostic factors such as high-risk cytogenetic abnormalities, Zap-70⫹, unmutated immunoglobulin status, or refractoriness to prior fludarabine. This observation has opened a new avenue in CLL therapeutics, with major impact on the development of future treatment regimens. Concurrently targeting the tumor cell itself either with chemotherapy, monoclonal antibodies or inhibitors of specific cell-survival signaling pathways and targeting the microenvironment with lenalidomide is a promising therapeutic strategy. Future clinical investigation will thus focus on defining the most optimal dose of lenalidomide in this patient population, especially when combined with chemotherapy. An important research question is the mechanism of tumor flare reaction and how to control it while maintaining an effective dose. Our preliminary observations that lenalidomide in CLL is modulating the tumor microenvironment,12 needs further evaluation because understanding the mechanism of action of lenalidomide can further help in defining its position in CLL therapeutics. In summary, although lenalidomide has made a major impact in the treatment of patients with B-cell cancers, ongoing clinical trials continue to investigate and define its role in additional clinical settings. Its unique immune stimulatory properties and oral bioavailability make it an interesting compound to incorporate in combination regimens with other antitumor agents. Future investigation should also focus on determining its mechanism of action in B-cell malignancies, optimizing efficacy, minimizing toxicity, and defining biomarkers of response.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Asher A. Chanan-Khan, Celgene (C); Bruce D. Cheson, Celgene (C) Stock Ownership: None Honoraria: Asher A. Chanan-Khan, Celgene Research Funding: Asher A. Chanan-Khan, Celgene Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Asher A. Chanan-Khan Manuscript writing: Asher A. Chanan-Khan, Bruce D. Cheson Final approval of manuscript: Asher A. Chanan-Khan, Bruce D. Cheson JOURNAL OF CLINICAL ONCOLOGY

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Immunomodulating Agents for B-Cell Malignancies

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61. Musial L, Miller K, Tonelli A, et al: Low-dose prednisone decreases the severity but not the frequency of lenalidomide associated tumor flare feaction (TFR) in chronic lymphocytic leukemia (CLL) patients. Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL 62. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al: Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 25:246s, 2007 (suppl; abstr 5047) 63. Chanan-Khan MK, Whitworth A, Lawrence D, et al: Clinical activity of lenalidomide in relapsed or refractory chronic lymphocytic leukemia (CLL) patients: Updated results of a phase II clinical trial. Leuk Lymph 48:S166, 2007 64. Ferrajoli A, Keating M, Wierda W, et al: Lenalidomide is active in patients with relapsed/refractory chronic lymphocytic leukemia carrying unfavorable chromosomal abnormalities. Blood 110: 754, 2007 65. Chanan-Khan A, Czuczman M, Padmanabhan S, et al: Clinical efficacy of lenalidomide in fludarabine-refractory chronic lymphocytic leukemia patients. Blood 24:5343-5349, 2006 66. Chen C, Paul H, Mariela P, et al: A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia. Blood 110: 2042, 2007 67. Corral L, Zhu D, Wang Y, et al: The IMiDs immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce growth arrest and apoptosis in NHL tumor cells in vitro. Blood 2006 (abstr 2388) 68. Wu L, Schafer P, Muller G, et al: Lenalidomide strongly enhances natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) of rituximab treated non-Hodgkins lymphoma cell lines in vitro. Blood 108:3714, 2006 (abstr) 69. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, et al: 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, 2005 70. Witzig TE, Vose J, Pietronigro D, et al: Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol 25:4285-4292, 2007 71. Kaufmann H, Raderer M, Wohrer S, et al: Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood 104:2269-2271, 2004 72. Wang M, Fayad L, Hagemeister F, et al: A phase I/II study of lenalidomide (Len) in combination with rituximab (R) in relapsed/refractory mantle cell

lymphoma (MCL) with early evidence of efficacy. J Clin Oncol 25:18s, 2007 (suppl; abstr 7522) 73. O’Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676-684, 2005 74. Goy A, Younes A, McLaughlin P, et al: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:667-675, 2005 75. Dimopoulos MA, Zomas A, Viniou NA, et al: Treatment of Waldenstrom’s macroglobulinemia with thalidomide. J Clin Oncol 19:3596-3601, 2001 76. Coleman M, Leonard J, Lyons L, et al: BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenstrom’s macroglobulinemia. Leuk Lymphoma 43:1777-1782, 2002 77. Treon SP, Patterson CJ, Hunter ZR, et al: Phase II Study of CC-5013 (Revlimid) and Rituximab in Waldenstro¨m’s macroglobulinemia: Preliminary Safety and Efficacy Results. Blood 2006 (abstr 2443) 78. Sanchorawala V, Wright DG, Rosenzweig M, et al: Durable responses to lenalidomide in patients with AL amyloidosis: Follow up of a phase II trial. Blood 109:492-496, 2007 79. Rajkumar SV, Blood E: Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 354:2079-2080, 2006 80. Miller KC, Padmanabhan S, Dimicelli L, et al: Prospective evaluation of low-dose warfarin for prevention of thalidomide associated venous thromboembolism. Leuk Lymphoma 47:2339-2343, 2006 81. Niesvizky R, Naib T, Christos PJ, et al: Lenalidomide-induced myelosuppression is associated with renal dysfunction: Adverse events evaluation of treatment-naive patients undergoing front-line lenalidomide and dexamethasone therapy. Br J Haematol 138:640-643, 2007 82. Chen N, Lau H, Kong L, et al: Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol 47:1466-1475, 2007 83. Knop S, Gerecke C, Topp M, et al: RAD (Revlimid, adriamycin, dexamethasone) is a new treatment for relapsed multiple myeloma. Haematologica 2007 (abstr PO-658) 84. Wiernik PH, Lossos IS, Tuscano J, et al: Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory aggressive non-Hodgkin lymphoma. J Clin Oncol 25: 457s, 2007 (suppl; abstr 8066)

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