Cancer Chemotherapy & Biotherapy: Principles & Practices, 4th Edition

Thalidomide and Its Analogs for the Treatment of Hematologic Malignancies, Including Multiple Myeloma and Solid Tumors

Paul Richardson

Constantine S. Mitsiades

Teru Hideshima

Kenneth Anderson

INTRODUCTION

Thalidomide was originally developed in the 1950s for the treatment of pregnancy-associated morning sickness. However, its extensive over-the-counter marketing in Europe was marked by the tragic consequences of teratogenicity and dysmelia (stunted limb growth),1 which triggered its subsequent withdrawal from the market.2, 3 In addition, the teratogenic properties of thalidomide raised among oncologists the hypothesis that the potent inhibitory effects of this drug on growing fetal tissues, combined with the pathophysiologic similarities linking tumor biology and fetal development, might be redirected towards applications in cancer treatment.4 In fact, in the early 1960s at least two clinical trials of thalidomide for patients with advanced cancers were reported.5, 6 In one of these trials, thalidomide was administered at daily doses of 300 to 2,000 mg in 71 patients with various types of cancers. No objective clinical responses were observed, except for resolution of a pulmonary metastasis in a patient with renal cell carcinoma.5 In the second trial, 21 patients with various types of advanced cancer (including 2 patients with multiple myeloma [MM]) received thalidomide at 600 to 2,000 mg daily doses, which led to palliation of symptoms in approximately one third of the patients, while 2 patients had minimal slowing of their tumor's growth.6 However, these results were not deemed sufficiently encouraging to warrant further clinical development efforts. Thalidomide was therefore not further pursued as a potential anticancer drug for several decades. In the meantime, however, the drug gradually emerged as a therapeutic agent for a range of medical conditions, on the basis of anecdotal clinical evidence and converging supporting research evidence suggesting potential beneficial pharmaco-immunologic effects.7 For instance, thalidomide was used, within the context of clinical trials or for compassionate use, for the treatment of severe erythema nodosum leprosum (ENL),8 Behçet's disease,9 graft versus host disease,10 and oral ulcers and wasting associated with HIV infection.11, 12 This reemergence of thalidomide was reflected by its FDA approval in 1998 for the short-term treatment of cutaneous manifestations of moderate to severe ENL, together with its use as maintenance therapy to prevent recurrence of cutaneous ENL.7 This FDA approval was of critical importance for the clinical applications of thalidomide, not only because it has since become a treatment of choice for ENL, but also because it allowed for off-label use of this medication for a wide spectrum of other disease states for which it was speculated that the immunomodulatory and antiangiogenic properties of thalidomide would be beneficial (Table 27.1).7, 13, 14 To prevent any occurrence of teratogenic effects, thalidomide is now administered under strict guidelines to prevent fetal exposure to the this medication.13

TABLE 27.1 POTENTIAL THERAPEUTIC USES OF THALIDOMIDE CURRENTLY UNDER INVESTIGATION

Cancer and related conditions
Solid tumors (e.g., brain, breast, renal cell carcinoma)
   Hematologic malignancies (e.g., MM and myelodysplastic syndromes [MDS])
Infectious diseases
   HIV/AIDS and related conditions
   Aphthous ulcerations
   Wasting syndrome
   Mycobacterial infections (e.g., tuberculosis)
Autoimmune diseases
   Discoid and systemic lupus erythematosus
   Chronic graft vs. host disease
   Inflammatory bowel disease
   Rheumatoid arthritis
   Multiple sclerosis
Dermatologic diseases
   Behçet's syndrome
   Prurigo nodularis
   Pyoderma gangrenosum
Other disorders
   Sarcoidosis
   Diabetic retinopathy
   Macular degeneration

The interest in the use of thalidomide in the oncologic setting was rekindled in the 1990s with the realization that tumor-associated vasculature is an important therapeutic target in a broad range of neoplasias and that thalidomide possesses substantial antiangiogenic properties in a wide range of in vivo and in vitro models of neovascularization.15, 16, 17, 18, 19, 20, 21, 22, 23

Indeed, thalidomide inhibited angiogenesis induced by bFGF in the rabbit cornea micropocket assay or by VEGF in a murine model of corneal vascularization.19,24 Based on these data from D'Amato, Folkman, et al. and the fact that thalidomide is transformed to active metabolites with antiangiogenic activity in humans,25 thalidomide was evaluated for the treatment of various neoplasias.26, 27, 28, 29, 30 Of particular note was the well-chronicled decision to test thalidomide, at the suggestion of an especially enlightened wife of a MM patient and on the basis of the studies by Folkman et al., in a compassionate use study of three patients with advanced MM at the University of Arkansas. The encouraging evidence of clinical activity in two of these three patients led to a larger phase II effort,31 which confirmed the clinical activity of thalidomide against MM and was followed by extensive clinical trials of thalidomide-based therapy for MM worldwide as well as other applications in a broad range of other hematologic malignancies and solid tumors. Despite the progress in its use and the fact that thalidomide does not have the classical patterns of toxicities associated with the use of conventional DNA- or microtubule-targeting chemotherapeutics, this is still a drug that is not completely devoid of any adverse effects. This has led to an effort to develop thalidomide analogs that are not only more potent than their parent compound in preclinical models but also retain the clinical activity of thalidomide without some of the serious side effects associated with its use.

In this chapter, we present a comprehensive review of the pharmacology of thalidomide and its analogs, a description of preclinical studies in MM to illustrate the complex putative mechanisms of action of thalidomide, and an overview of clinical studies that have confirmed the activity of thalidomide and its analogs against MM. Studies in other hematologic malignancies and the status of research in solid tumors and in other cancer-related applications are also discussed.

MECHANISM(S) OF ACTION OF THALIDOMIDE AND ITS IMMUNOMODULATORY DERIVATIVES (IMIDS)

Although it was originally hypothesized that the teratogenic and antitumor effects of thalidomide may have a common underlying mechanistic denominator, such as its antiangiogenic effect, the precise mechanisms responsible for the clinical activity of thalidomide remain to be completely elucidated. This can be attributed to a number of reasons: (a) the preclinical in vitro and in vivo studies of thalidomide that are necessary to dissect its mechanisms of action are difficult to perform because of the enantiomeric interconversion and spontaneous cleavage of the drug to multiple metabolites,32many of which have been incompletely characterized due to their short half-life; (b) the in vivo activity of thalidomide requires metabolic activation, mainly by the liver, which explains at least in part the discordance between the modest, at best, activity of thalidomide in in vitro assays of antitumor activity25, 33 and the potent in vivo effect; (c) the chemical structure of thalidomide does not offer readily recognizable clues regarding possible intracellular molecular targets that might explain its clinical activity or adverse events; and (d) the species-specific differences in the metabolism and other pharmacokinetic properties of thalidomide complicate the extrapolation of in vivo data from many animal models to the clinical setting in humans.24

In regards to the antitumor activity of thalidomide, the biggest wealth of mechanistic information has been acquired in the setting of MM, mainly because this is the disease setting in which thalidomide has demonstrated more impressive clinical activity. Despite the modest activity of thalidomide in antitumor assays in vitro,34 this drug is currently considered to confer its in vivo anti-MM effects via at least four distinct but potentially complementary types of activity: (a) direct antiproliferative/proapoptotic antitumor activity,34 probably mediated by one or more of its in vivo metabolites35; (b) indirect targeting of tumor cells by abrogation of protective effects conferred on MM tumor cells by bone marrow stromal cells via paracrine or autocrine secretion of cytokines and growth factor or via cell adhesion molecule–mediated interactions34; (c) antiangiogenic activity; and (d) immunomodulatory activity that contributes to enhanced antitumor immune response.36

The notion that thalidomide possesses direct antitumor effects in MM and other diseases is inferred from a series of converging pieces of evidence from preclinical and clinical studies. Despite the fact that the in vitro effects of thalidomide on proliferation and viability of MM cells are relatively modest,34thalidomide derivatives, such as lenalidomide (Revlimid, CC-5013 or IMID-1) and CC-4047 (Actimid),34, 35 have a far more potent in vitro antitumor effect through their antiproliferative and proapoptotic properties than the parent compound in assays performed in the absence of any other cell type (e.g., stromal, endothelial, or liver cells) that could facilitate either thalidomide metabolism or indirect effects on targets other than the tumor cells themselves.34, 35Therefore, the fact that at least some of the known in vivo thalidomide metabolites can have in vitro activity against tumor cells suggests that thalidomide may confer a direct in vivo antiproliferative/proapoptotic effect via its metabolites. The precise mechanism (or mechanisms) for this direct effect remains under investigation. Cell cycle analyses, by propidium iodide staining, of thalidomide- and lenalidomide-treated MM cell lines indicate G0/G1 growth arrest, subsequently followed by an increased sub-G1 peak, consistent with induction of MM cell death.34 Interestingly, clinically relevant doses of thalidomide derivatives, such as lenalidomide or CC-4047, trigger suppression of the transcriptional activity of NF-κB in MM cells.35 In view of the important role of NF-κB in MM, as well as other neoplasias, in the production of several intracellular antiapoptotic molecules, including the caspase inhibitors FLIP, XIAP, cIAP-2 or the antiapoptotic Bcl-2 family member A1/Bfl-1,37, 38, 39 this effect of thalidomide derivatives supports the notion that thalidomide exerts its in vivo effects, at least in part, by inhibition of NF-κB signaling in MM cells. It is also conceivable that because NF-κB protects MM cells from the proapoptotic effects of steroids or cytotoxic chemotherapeutics,35, 37, 38, 39 the effect of thalidomide on NF-κB activity can account for the ability of its combinations with dexamethasone or cytotoxic chemotherapeutics to achieve more potent in vivo antitumor responses than either agent alone.40, 41, 42, 43, 44, 45, 46, 47

Thalidomide and its derivatives critically modulate the adhesive interactions48 of MM cells with bone marrow stromal cells (BMSCs). The adhesion of MM cells to BMSCs triggers secretion of proliferative/antiapoptotic cytokines (e.g., IL-6).49, 50, 51 This event is mainly paracrinic, it is mediated by transcriptional activation of NF-κB in BMSCs,50 and it leads to attenuated sensitivity of MM cells against dexamethasone or cytotoxic chemotherapy.52 As a result of the effect of thalidomide and its immunomodulatory derivatives (IMiDs) in blocking this MM-stromal paracrine interaction, these agents significantly modify the proliferative and drug resistance properties of MM cells in the bone marrow microenvironment.

Another important property of thalidomide is that it selectively inhibits TNF-α production, while leaving the patient's immune system otherwise intact,53 which has led to its application in various disorders characterized by increased TNF-α secretion, such as ENL, Mycobacterium tuberculosis infection, graft versus host disease, and cancer- and HIV-related cachexia.

The precise mechanism mediating thalidomide-induced inhibition of TNF-α activity has not been fully elucidated, but it is apparently distinct from those of other TNF-α inhibitors, such as pentoxifylline and dexamethasone.54, 55 It has been proposed that thalidomide accelerates the degradation of TNF-α mRNA, thereby substantially (but not necessarily completely) suppressing the production of TNF-α protein.54, 56 Interestingly, thalidomide can decrease the binding of the transcription factor NF-κB to its consensus DNA-binding sites, which include not only the actual TNF-α gene57 but also other genes that are modulated by TNF-α in an NF-κB-dependent fashion.35 It has also been proposed that the antiangiogenic properties of thalidomide are mediated, at least in part, by inhibition of TNF-α signaling, in view of the proangiogenic effects of TNF-α itself.19 However, the absence of a major effect of TNF-α in experimental models of angiogenesis and the inability of (at least some) potent TNFα inhibitors to directly influence angiogenesis suggest that thalidomide's antiangiogenic effects cannot be attributed to TNF-α inhibition alone.19, 24

Thalidomide and its analogs influence factors that regulate tumor cell proliferation and osteoclast function, including interleukin (IL)-6, IL-1β, IL-10, and TNF-α.58 Thalidomide also decreases the secretion of vascular endothelial growth factor (VEGF), IL-6,59 and basic fibroblast growth factor (bFGF) by MM and/or BM stromal cells. These various mechanisms of action are summarized in Figure 27.1. Within the context of characterizing the mechanism underlying the teratogenic effects of thalidomide, D'Amato et al. observed its antiangiogenic properties,19, 24 which involved inhibition of the proangiogenic effects of β-FGF and/or VEGF in their models.19, 24, 60 Further in vitro studies have suggested that the antiangiogenic effect of thalidomide is due to its metabolites and not the parent compound.61

In regards to the immunomodulatory properties of thalidomide, its precise effects on immune effector cells (e.g., different subpopulations of lymphocytes) have not been consistent across the full spectrum of pertinent studies published to date.62, 63, 64 Although there is evidence that thalidomide does not directly suppress lymphocyte proliferation,48 there are data indicating differential effects on T-cell stimulation, shifts in T-cell responses, and inhibition of proliferation of already stimulated lymphocytes.63, 65, 66, 67, 68 Thalidomide also modifies the expression patterns of cell adhesion molecules on leukocytes, inhibits neutrophil chemotaxis, and modulates the production or function of various cytokines, including not only the inhibition of TNF-α signaling but also the inhibition of IL-12 production, the enhanced synthesis of IL-2, and the inhibition of IL-6.48, 53, 69, 70, 71, 72 Of particular note for the applications of thalidomide and lenalidomide in MM, thalidomide and its analogs (IMiDs) augment natural killer cell–mediated cytotoxicity in MM.36 Thalidomide and its IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3–stimulated T cells from MM patients, accompanied by an increase in interferon-γ and IL-12 secretion. Importantly, treatment of patient peripheral blood mononuclear cells (PBMCs) with thalidomide or its IMiDs triggers increased lysis of autologous MM cells. Furthermore, PBMCs from MM patients have demonstrated an increase in CD3-CD56+ natural killer cells in response to thalidomide/IMiD therapy.36

PHARMACOLOGY OF THALIDOMIDE

Thalidomide or α-N(phthalimido) glutarimide (C13O4N2H9) (gram molecular weight of 258.2)73 is a glutamic acid derivative that contains two amide rings and a single chiral center (see Fig.27.1).73 The currently available formulation of thalidomide consists, at physiologic pH, of a nonpolar racemic mixture of S(-) and R(+) isomers, which are cell membrane permeable.73, 74 The S isomer has been associated with thalidomide's teratogenic effect, while the R isomer has been linked with the sedative properties of the drug.24, 74, 75 Because of rapidly interconversion of these two isomers at physiologic pH in vivo, any efforts to generate formulations of only the R isomer have failed to neutralize the teratogenic potential of thalidomide.74, 76

Figure 27.1 Antitumor activity of Thal/IMiDs in the bone marrow milieu. Thal/IMiDs (A) induce G1 growth arrest and/or apoptosis in MM cell lines and patient cells resistant to conventional chemotherapy, (B) inhibit MM cell adhesion to BMSCs, (C) decrease cytokine production and sequelae, and (D) decrease angiogenesis in the bone marrow microenvironment.

TABLE 27.2 SINGLE–DOSE PHARMACOKINETIC PARAMETERS OF THALIDOMIDE IN HUMANS33

Population

Dose

Mean Apparent Pharmacokinetic Parameters

Tmax

T1/2(hr)

Vd (L)

Elderly patients with hormone refractory prostate cancer

200 mg

3.3*

6.5

66.9

800 mg

4.4*

18.3

165.8

Patients with HIV infection

300 mg

3.4

5.7

78.2

Healthy female volunteers

200 mg

5.8

4.1

53.0

Healthy male volunteers

200 mg

4.4

8.7

120.7

tmax, time to reach maximum concentrations; t1/2, elimination half-life; Vd, volume of distribution; HIV, human immunodeficiency virus.
*Median value.
Reproduced with permission from Stirling DI. The pharmacology of thalidomide. Semin Hematol 2000;37:5–14.

Pharmacokinetics

Pharmacokinetic studies of thalidomide in humans have been limited by the lack of suitable intravenous formulations due to its instability and poor water solubility. Therefore, current knowledge about thalidomide pharmacokinetics is based on animal studies and on clinical trials in human patients receiving oral thalidomide.

As shown in Table 27.2, the pharmacokinetic properties of thalidomide are variable, with the t1/2 falling in the range of 4 to 9 hours in most studies

Absorption

Oral administration of thalidomide at a dose of 100mg/kg in animal studies reportedly led to peak serum concentrations within 4 hours.77 The absorption of thalidomide in these studies appeared independent of administered doses. Subsequent studies in humans indicate a similar pharmacokinetic pattern, with approximately 4 hours mean time to reach peak concentration (Cmax) with a thalidomide dose of 200 mg.23, 24, 25, 29 In particular, single-dose thalidomide trials conducted in healthy volunteers, patients with HIV infection, and patients with hormone-refractory prostate cancer (see Table 27.2) have shown that the time to peak concentration in the peripheral blood ranges between 3 and 6 hours, suggesting slow absorption from the gastrointestinal tract.78, 79, 80 While the area under the curve (AUC) correlates with the thalidomide dose, the maximum concentration (Cmax) is highly variable, which also reflects the variability of GI absorption.81, 82 Correction for ideal body weight or body surface area does not lessen the variability.78, 79 This variability has further confounded efforts to delineate the pharmacokinetic properties of thalidomide in humans and define a dose-response relationship in therapeutic trials.

Distribution

In animal studies, thalidomide is widely distributed throughout most tissues and organs,77 without significant drug binding by plasma proteins.79, 80Thalidomide is detected in semen of rabbits following oral administration73, 83 and has been shown to be present in semen of patients after a period of 4 weeks of therapy, with levels that seem to correlate with serum levels.84

Metabolism

Thalidomide undergoes rapid and spontaneous nonenzymatic hydrolytic cleavage at physiologic pH, generating up to 50 metabolites, 5 of which are considered to be primary metabolites.25, 74, 76, 77, 85 The majority of these metabolites are unstable, and their rapid degradation under physiologic conditions has complicated the research efforts to characterize their biologic properties.86 Although in vitro studies in rat cells suggested that thalidomide induces cytochrome (CYP) 450 isoenzymes, subsequent evaluation of single- or multiple-dose pharmacokinetic parameters of oral thalidomide at 200 mg daily in healthy volunteers showed that thalidomide does not inhibit or induce its own metabolism over a 21-day period in humans. It is therefore thought that only limited metabolism of thalidomide occurs via the hepatic CYP 450 system.87, 88, 89 No induction of its own metabolism has been noted with prolonged use.90, 91Importantly, there appear to be substantial species-specific differences in the patterns and profiles of metabolites of thalidomide in mice versus humans.92, 93,94 This explains why the teratogenic effects of thalidomide in humans were not detected in preclinical murine models that preceded the first clinical applications of the drug,1, 2 and also why, in immunodeficient mouse models of MM, thalidomide exhibited antitumor activity only in the setting of xenotransplantation of the mice with human liver tissue.95

Figure 27.2 Mechanisms of action of IMiDs in augmentation of host immune response. IMiDs augment differentiation of Dendritic Cells (DC) by inhibiting secretion of IL-6 and VEGF from MM and/or BMSCs. IMiDs also stimulate natural killer cell activity by triggering IL-2 secretion from T cells mediated by the CD28/PI3-K/NF-AT2 signaling pathway.

Clearance

The primary mechanism of elimination of thalidomide occurs by the spontaneous hydrolysis in all body fluids, with an apparent mean clearance of 10 L/hour for the (R)-enantiomer and 21 L/h for the (S)-enantiomer in adult subjects.32 This leads to higher blood concentrations of the (R)-enantiomer than of the (S)-enantiomer. Thalidomide and its metabolites are rapidly excreted in the urine, while the nonabsorbed portion of the drug is excreted unchanged in feces, but clearance is primarily nonrenal, with mean terminal half-lives of the R and S isomers measured in healthy male human volunteers at 4.6 and 4.8 hours, respectively.77, 78, 81 After a single dose (200 mg daily), there was minimal intact drug excretion in urine over a 24-hour period.78 Studies of both single and multiple dosing of thalidomide in elder prostate cancer patients showed a significantly longer half-life at a higher dose (12,00 mg daily) than at a lower dose (200 mg daily).79 Conversely, no effect of increased age on elimination half-life was identified in the age range of 55 to 80 years.79 The effect of hepatic dysfunction on drug clearance has not been evaluated.

Drug Interactions

Thalidomide's interactions with other drugs have not been systematically characterized, except for studies that showed a lack of significant interaction with oral contraceptives.33 Animal studies suggest that thalidomide enhances the sedative effects of barbiturates and alcohol and the catatonic effects of chlorpromazine and reserpine.96 Conversely, the CNS stimulatory effects of medications such as methamphetamine and methylphenidate) appear to counteract the depressant effects of thalidomide.96

Adverse Effects

Generally, thalidomide is well tolerated at doses below 200 mg daily. Sedation and constipation are the most common adverse effects reported in cancer patients26, 30, 33, 60 (Table 27.3). The most serious adverse effect is a dose- and time-dependent peripheral sensory neuropathy.97 An increasing incidence of thromboembolic events in thalidomide-treated patients has been reported, but generally in the context of thalidomide combinations with other drugs, including steroids and particularly anthracycline-based chemotherapy. In fact, these thromboembolic complications, which rarely appear in single-agent thalidomide treatment of MM or other cancer patients, initially triggered closure of studies exploring a combination of thalidomide with liposomal doxorubicin (Doxil) and dexamethasone.98, 99 Possible cardiovascular effects of thalidomide include bradycardia and hypotension. The risk of these adverse cardiovascular events with thalidomide treatment appears to be higher among elderly patients with coronary disease receiving multiple antihypertensive medications.33 A recent report described for the first time a case of pulmonary hypertension in a MM patient receiving thalidomide.100

Safety data from current phase I and II clinical trials of thalidomide in the treatment of solid tumors, MM, and hematologic malignancies suggest peripheral neuropathy occurs in 10 to 30% of patients.27, 29, 30, 101 Thalidomide-related neuropathy is characterized as asymmetric, painful, peripheral paresthesia with sensory loss.14, 102, 103, 104, 105 It commonly presents with numbness of the toes and feet, muscle cramps, weakness, signs of pyramidal tract involvement, and carpal tunnel syndrome.14, 73 The risk of developing peripheral neuropathy during thalidomide increases with higher cumulative doses of the drug, especially in elderly patients.73 Although clinical improvement typically occurs upon prompt discontinuation of the drug, long-standing residual sensory loss has been documented.102, 103, 104, 105 It remains to be determined whether the incidence of thalidomide-induced peripheral neuropathy is indeed increased in cancer patients with a history of prior exposure to vinca alkaloids, bortezomib, or other drugs that can cause peripheral neuropathy. In the interim, particular caution and careful monitoring are necessary in cases of cancer patients with a prior history of neuropathy and/or when thalidomide is used in combination with other agents associated with development of neuropathy,33 especially since there has been little progress in defining effective strategies for alleviation of neuropathic symptoms.

TABLE 27.3 CLINICAL ADVERSE EVENTS REPORTED DURING THALIDOMIDE USE33

Neurologic
   Sedation
   Dizziness
   Mood changes
   Headaches
   Gastrointestinal
   Constipation
   Nausea
   Increased appetite
Dermatologic
   Exfoliative/erythrodermic cutaneous reactions
   Brittle fingernails
   Pruritus
Miscellaneous
   Xerostomia
   Weight gain
   Edema of the face/limbs
   Reduction in thyroid hormone secretion
   Hypotension

Reproduced with permission from Stirling DI. The pharmacology of thalidomide. Semin Hematol 2000;37:5–14.

Figure 27.3 Possible apoptotic signaling triggered by Thal/IMiDs and other agents. Thal/IMiDs predominantly induce caspase-8/ caspase-3 cleavage. Bortezomib triggers caspase-8 and -9 cleavage, and Dex triggers caspase-9 cleavage, suggesting rationally based combinations of Thal/IMiDs with these agents.

Pharmacology of Thalidomide Derivatives: Focus on Lenalidomide (CC-5013, Revlimid) and CC-4047 (Actimid)

Lenalidomide (or 3-(4′aminoisoindoline-1′-one)-1-piperidine-2,6-dione) is a thalidomide derivative with an empirical formula of C13H13N3O3 and a molecular weight of 259.25. It constitutes a lead compound in the new class of immunomodulatory thalidomide derivatives (IMiDs) and exhibits a constellation of pharmacological properties, including inhibition of inflammation, stimulation of T cells and natural killer cells, inhibition of angiogenesis and tumor cell proliferation, as well as modulation of hematopoietic stem cell differentiation.34, 36, 58, 106 It is an orally administered agent that has been tested in MM and myelodysplastic syndromes (MDS) as well as an expanding array of other clinical settings because of preclinical data suggesting more potent activity and less toxicity than its parent compound, along with a lack of teratogenic effects. The results of single- and multiple-dose studies of lenalidomide administration in healthy male volunteers33 indicate that this drug is rapidly absorbed following oral administration, with peak plasma levels occurring between 0.6 and 1.5 hours postdose. Coadministration with food delays absorption somewhat but does not alter its actual extent, and the pharmacokinetic disposition of lenalidomide is linear. The Cmax and AUC values increase proportionately with increasing dose, both over a single-dose range of 5 to 400 mg and after multiple dosing with 100 mg daily.33 The t1/2increases with dose, from approximately 3 hours at the 5-mg dose to approximately 9 hours at the 400-mg dose (the higher dose is believed to provide a better estimate of the t1/2 due to the prolonged elimination phase). Steady-state levels of lenalidomide are achieved by day 4 of administration, and there is no evidence of disproportionate drug accumulation with multiple dosing. Approximately 70% of the orally administered dose of lenalidomide is excreted by the kidney. Ongoing studies are characterizing in detail the adverse event profile of lenalidomide use and are addressing the potential for drug interactions with other agents. The latter consideration is particularly important because the clinical experience with thalidomide to date indicates that the adverse events with this new class of agents may be heavily influenced by a broad range of factors, including not only medications administered concomitantly but also “recall” effects of prior exposure to agents causing neurotoxicity; toxicity patterns may also be influenced by the pathophysiology of each disease (e.g., preliminary indication of a higher rate of neuropathy in thalidomide-treated patients with MM versus other disease) and the presence of comorbidities (e.g., possible aggravation of neuropathy in diabetic patients). Therefore, more extensive clinical experience will be required to conclusively determine whether lenalidomide is completely devoid of some of thalidomide's side effects when combined with other drugs and/or used in heavily pretreated patient populations. This is particularly important, because recent studies indicate that other immunomodulatory thalidomide analogs, such as CC-4047 (Actimid), are also active against MM in vivo107 but maintain thalidomide's potential for teratogenicity108 and result in a higher incidence of thromboembolic events than either lenalidomide or thalidomide alone,109 suggesting important differences in the pharmacological properties of different thalidomide derivatives.

Figure 27.4 Dex augments Thal/IMiDs-induced growth inhibition in MM. MM.1S cells were treated with DMSO control, Thal (1 µM), and Revlimid µM) in the presence of different concentration of Dex for 48 hours. Cell growth was assessed by [3H]-thymidine uptake.

Figure 27.5 Revlimid augments bortezomib-induced cytotoxicity in MM cell lines and patient tumor cells.A: MM.1S cells were pretreated with or without 1 µM Revlimid for 48 hours, and then a subtoxic concentration of Bortezomib (3 nM) was added for an additional 24 hours. Revlimid potentiated the apoptotic effect of Bortezomib. B: CD138+ tumor cells are treated with control or with 10 or 20 nM bortezomib in the presence or absence of 5 µM Revlimid for 24 hours. Cell toxicity was assessed by MTT assay.

CLINICAL STUDIES OF THALIDOMIDE AND ITS DERIVATIVES IN MM

Despite efforts to improve the outcome of MM patients with the use of high-dose chemotherapy and stem cell transplantation, MM remains incurable, necessitating development of more effective therapies based on novel therapeutic targets and corresponding conceptual frameworks that depart from conventional cytotoxic chemotherapy.110, 111 One such approach involves the inhibition of angiogenesis, an approach based on multiple observations that hematologic malignancies, such as MM, are associated with intense neovascularization of bone marrow.23, 112 Even though the bone marrow sinusoids in normal individuals are endowed with extensive networks of vascular support, the homing of MM cells (or malignant cells from other hematologic neoplasias) to the bone marrow is associated with further increase in its microvascular density (MVD), especially in more advanced cases of his disease.112, 113, 114 This may suggest that the role of bone marrow neoangiogenesis in hematologic malignancies is related less to the sustaining of a sufficient blood supply to tumor cells (since such a supply is always readily available to cells in the bone marrow) than to the generating of a local microenvironment where the activated endothelium of bone marrow neovessels can further support the proliferation, survival, and drug resistance of tumor cells. Nonetheless, because of the extensive data that established neoangiogenesis as a key component in the growth, progression, and metastatic spread of solid tumors,115 along with the evidence that increased bone marrow blood vessel formation parallels the progression of hematologic malignancies,31, 112, 114, 116, 117, 118 MM and other hematologic neoplasias have frequently been the focus of clinical applications of proposed antiangiogenic therapies.

Vacca and colleagues reported that the extent of bone marrow angiogenesis has high positive correlation with the labeling index (LI) of bone marrow plasma cells as well as disease activity in patients with MM,112 a finding consistent with subsequent studies confirming extensive bone marrow vascularization in MM.31, 114, 117, 118 They also observed that a poor prognosis correlates with elevated levels of angiogenic cytokines, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), and increased bone marrow levels of mast cells, which secrete a variety of angiogenic factors.112, 117,118, 119 Collectively, these observations provided a rationale for the use of antiangiogenic drugs to treat MM and other hematologic neoplasias.

Figure 27.6 Effect of Revlimid, rapamycin, and combination on patient MM cells. A dose-dependent increase in the percentage of apoptotic patient MM cells, evidenced by Apo 2.7 staining of bright CD38 positive cells, was noted after exposure to combination Revlimid and rapamycin treatment.

Thalidomide therapy for advanced refractory MM was initiated after an encouraging original experience in two patients treated at the University of Arkansas. This prompted a larger phase II study of single-agent thalidomide in 84 patients with relapsed and refractory MM.31 In this heavily pretreated patient population, 76 of 84 enrolled patients (90%) had relapsed after receiving high-dose chemotherapy; 42% harbored MM tumor cells with deletion of chromosome 13, a cytogenetic abnormality that signifies unfavorable prognosis in patients receiving cytotoxic chemotherapy–based regimens;31, 120 21% of patients had greater than 50% infiltration of their bone marrow by malignant plasma cells; and 15% had a plasma cell labeling index (PCLI) greater than 1%, which signifies an increased proliferative rate of the malignant plasma cells.

The primary endpoint of this trial was paraprotein response, and additional endpoints included time to response, time to disease progression, event-free survival, overall survival, and improvement in other laboratory parameters. Single-agent thalidomide was administered for a median of 80 days (range, 2 to 465), at a starting dose of 200 mg orally (PO) at nighttime, with subsequent dose escalation by 200 mg every 2 weeks up to a maximum of 800 mg. Most patients received thalidomide daily doses up to 400 mg (86%), with fewer attaining 600 mg/day (68%) and 800 mg/day (55%). Response, which was defined as greater than 25% reduction in serum or urine levels of paraprotein, was seen in 27 patients (32%). Importantly, paraprotein levels in the serum or urine were decreased by greater than 90% in eight patients (including two with complete remission), with median time to paraprotein response of approximately 2 months. In 78% of responding patients, decreases in plasma cell infiltration of bone marrow and increased hemoglobin values were observed. Interestingly, however, bone marrow microvascular density was not significantly decreased, even among responders to treatment.

In this first experience of thalidomide treatment in MM, adverse events were reported to be generally mild to moderate, with increasing incidence at higher dose levels. Constipation was frequent but manageable with administration of laxatives. Peripheral neuropathy, characterized by paresthesia or numbness, was reported by 12% of patients receiving 200 mg daily. However, its frequency was increased to 28% of patients receiving 800 mg daily. Other mild to moderate side effects included weakness, fatigue, and somnolence, which were reported by 34% of patients receiving 200 mg daily and 43% of those treated at the 800-mg dose level. More severe adverse events were infrequent (occurring in ≤ 10% of patients), and hematologic effects were rare. However, nine patients discontinued thalidomide due to drug intolerance. One responding patient died suddenly on day 37 of treatment, most likely due to sepsis, but a possible relationship to thalidomide could not be ruled out. The incidence of myelosuppression was low, with significant leucopenia, anemia, and/or thrombocytopenia occurring in fewer than 5% of patients. After 12 months of follow-up, Kaplan-Meier estimates of the mean event-free and overall survival for all patients were 22% and 58%, respectively.

Subsequent studies from other centers confirmed that thalidomide is active in MM. In a phase II trial at the MD Anderson Cancer Center, thalidomide was administered in 43 evaluable patients with MM resistant to conventional therapies.121 Eleven of 43 patients (26%) achieved partial response or better, defined by greater than 50% reduction of serum M-protein and/or greater than 75% reduction of Bence-Jones protein.

In a smaller study from Mayo Clinic, 16 heavily pretreated MM patients received an oral thalidomide dose of 200 mg/day for two weeks, increased by 200 mg/day every 2 weeks to a maximum of 800 mg/day.122 Four patients (25%) achieved partial responses, lasting between 2 to 10 months. Adverse effects included constipation (25%), excessive sedation (25%), fatigue (25%), and rash (19%). In a multicenter phase II study of relapsed MM patients after high-dose chemotherapy and stem cell transplantation, oral thalidomide was administered with a dose escalation from 200 to 600 mg/day over 12 weeks and a subsequent maintenance phase of 200 mg/day for up to 1 year.97 The 12-week progression-free survival rate was 67% (95% CI, 48 to 86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28 to 60%), with a median duration of 6 months. Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Responses were observed both at lower doses and in patients who completed the dose escalation. These results suggest that the optimal thalidomide dose varies among patients and that the relationship of dose to adverse, dose-limiting toxicity is unpredictable. The dose of thalidomide therapy should be based on the individual patient tolerance.97 Other reports from Europe have confirmed response rates to thalidomide (at dose ranges of 200 to 800 mg daily) ranging between 36 to 51% in both relapsed and refractory settings.123, 124

The significant clinical activity of single-agent thalidomide in refractory and relapsed MM, provided a stimulus for trials of combinations of thalidomide with chemotherapy and dexamethasone in view of their nonoverlapping toxicities and different mechanisms of action.

Initial clinical experience incorporating thalidomide into the DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatinum) regimen revealed a notable capacity to induce complete responses in patients with plasma cell leukemia and MM.125 Low-dose thalidomide in combination with dexamethasone and also in combination with Biaxin has been reported to be active in relapsed disease in a number of studies,45 although the effect of Biaxin appears to involve a change in the metabolism of dexamethasone. The combination of dexamethasone and thalidomide has been evaluated in both relapsed and refractory disease as well as in newly diagnosed, previously untreated patients. The importance of addressing such a question in the context of prospective, controlled trials was highlighted by occasional reports of life-threatening toxic epidermal necrolysis associated with the thalidomide-dexamethasone combination.73 However, a recently reported large phase III randomized trial by ECOG comparing thalidomide in combination with dexamethasone versus high-dose dexamethasone alone showed a significant advantage for the combination (response rate 68% vs. 44%, P < .0001). However greater toxicity was observed in the combination arm, including deep venous thrombosis and pulmonary embolism in 16% of patients receiving both drugs. Moreover, there are now extensive reports of thrombotic events resulting from thalidomide treatment when thalidomide is combined not only with dexamethasone but also with anthracyclines, including liposomal doxorubicin (Doxil).126, 127 Because of the significantly lower incidence of thromboembolic events in the setting of thalidomide monotherapy, it is conceivable that thalidomide and/or its metabolites cause a modest increase of hypercoagulability, which is significantly enhanced when the drug is combined with other potentially prothrombotic, antiangiogenic agents.99

Therefore, while thalidomide treatment is associated with a promising response rate, its administration is not devoid of significant adverse events, which can, in some cases, be very serious, particularly when thalidomide is administered in combination with other drugs. Dose reductions of thalidomide (or other components of combination therapies), careful selection of patients who will receive these combinations, and comprehensive monitoring of patients may reduce the incidence of such events.

Another approach that has successfully been employed involves the development of thalidomide derivatives that not only are more potent in regards to a least some of the biologically activities of the parent compound but also have fewer side effects.128 The original efforts to develop such thalidomide analogs yielded two classes of derivatives, the phosphodiesterase type 4 inhibitors, which inhibit TNF-α signaling but have little effect on T-cell activation (so-called selective cytokine-inhibitory drugs, or SelCIDs), and another group of nonphosphodiesterase type 4 inhibitors known as immunomodulatory drugs (IMiDs), which not only inhibit TNFα but also markedly stimulate T-cell proliferation and interferon-γ production.

As described previously, the IMiDs appear to have significantly greater potency than thalidomide, and perhaps a more favorable toxicity profile. On this basis, phase I, II, and III studies of CC-5013 (also known as CDC-5013 or lenalidomide) have been performed in patients with refractory or relapsed MM, with favorable clinical results.128 The first oncologic setting in which lenalidomide was tested was a phase I dose-escalation study of lenalidomide (at 5, 10, 25, and 50 mg PO daily) in 27 patients (median age, 57 years; range, 40 to 71 years) with relapsed and refractory relapsed MM. In 24 evaluable patients, no dose-limiting toxicity (DLT) was observed in patients treated at any dose level within the first 28 days; however, grade 3 myelosuppression developed after day 28 in all 13 patients at the 50-mg daily dose level. In 12 patients, dose reduction to 25 mg/day was well tolerated and was therefore considered to represent the maximal tolerated dose (MTD). Importantly, no significant somnolence, constipation, or neuropathy was seen in any cohort of that study. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 patients (90% CI, 52 to 85%), including 11 patients(46%) who had received prior thalidomide treatment. Stable disease (<25% reduction in paraprotein) was observed in an additional 2 patients (8%). Therefore, 17 (71%) of 24 patients (90% CI, 52 to 85%) demonstrated benefit from treatment with lenalidomide.128

These encouraging results provided the stimulus for additional studies of lenalidomide in MM. A phase II multicenter, randomized, controlled, open-label study was conducted comparing oral lenalidomide at either 30 mg once daily or 15 mg twice daily for a total of 6 cycles, each comprising 3 weeks on lenalidomide therapy and 1 week off. That trial showed that a dose of 30 mg once daily is better tolerated than the twice daily regimen and that lenalidomide administered as a part of a 3 weeks on and 1 week off schedule is highly active has a response rate of approximately 35%, has a manageable adverse event profile, results in very little significant neuropathy (<5%), and has a very low incidence of thrombosis (even when combined with dexamethasone). In patients in whom dexamethasone was added to the IMiD, responses were seen in about 40% of cases.

In a phase III trial, a lenalidomide and dexamethasone combination is being compared with dexamethasone plus placebo in relapsed or refractory MM patients. Two randomized studies of high-dose dexamethasone and lenalidomide have now been completed and preliminary results are very encouraging with high response rates that appear remarkably durable, as compared to high dexamethasone and placebo. Toxicities were significant however and notable for a high rate of DVT/PE (~14%) which had not been seen with lenalidomide alone.200, 201

Finally, a second immunomodulatory thalidomide derivative, CC-4047, has recently entered clinical trials for use in the treatment of MM and other neoplasias. In a phase I dose-escalation study107 conducted in 24 patients with relapsed and relapsed refractory MM patients, the MTD was identified as 2 mg daily. Neutropenia was the major dose-limiting toxicity and was observed in 58% of patients. Grade 3 deep vein thrombosis was seen in 4 of 24 patients (16%). Other side effects were mild; these included rash, neuropathy, constipation, edema, and hypotension. Importantly, treatment resulted in minor responses (>25% reduction in paraprotein) or better in two thirds of patients, with 4 (16%) of 24 assessable patients achieving complete remission. CC-4047 administration was associated with T-cell activation, with increased RO expression on CD4+ and CD8+ cells, and a concomitant fall in resting CD45RO+ cells seen. Moreover, there were significant increases in serum levels of serum IL-2 receptor and IL-12, possibly indicating activation of T cells.107 Overall, the results of early CC-4047 clinical studies show important evidence of the antitumor activity of IMiDs as a drug class. Further studies of this orally bioavailable agent in patients with MM and prostate cancer are underway.

CLINICAL STUDIES OF THALIDOMIDE AND THALIDOMIDE DERIVATIVES IN OTHER HEMATOLOGIC NEOPLASIAS OR IN SOLID TUMORS

Other Plasma Cell Dyscrasias

The encouraging clinical results seen with thalidomide and its analogs in MM raised the possibility that MM is more thalidomide responsive than other neoplasias because of pathophysiological features intrinsic to the plasma cell lineage. This suggests by extension that thalidomide may also be active against other plasma cell dyscrasias, including Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma). Indeed, single-agent thalidomide administered in the context of a small phase II study led to a 25% response rate,129 while a combination of low-dose thalidomide (200 mg daily), dexamethasone (40 mg once weekly), and clarithromycin (500 mg twice daily) showed activity in two trials.41 In primary systemic amyloidosis, a phase I/II trial of single-agent thalidomide showed hematologic improvement in 5 of 11 patients130 and disease stabilization in 3 patients. However, as in other reports, substantial toxicities were observed, especially at higher doses of thalidomide.131 Overall, while thalidomide may be active in some patients who have Waldenström's macroglobulinemia and are refractory to other standard regimens, the use of thalidomide and IMiDs is still investigational for patients with plasma cell dyscrasias other than MM.

Myelodysplastic Syndromes

The increased angiogenesis noted in bone marrow biopsies of at least some cases of myelodysplastic syndromes (MDS) provided the original basis for evaluation of thalidomide as a therapeutic agent for MDS. Bertolini et al. reported clinical responses in 2 of 5 thalidomide-treated MDS patients, with concomitant decreases in bFGF and VEGF in responding patients.132 In larger studies of 83, 30, and 34 MDS patients, hematologic improvement (e.g., transfusion independence) was observed in approximately 30% of evaluable patients in the first two trials and in 19 of 29 patients (65%) in the third trial.133,134, 135 Higher platelet counts and lower blast percentage at baseline appeared to be associated with higher probability of response to thalidomide. Additional studies have also documented normalization of counts, with cytogenetic responses, in 3 thalidomide-treated patients with MDS.136 However, improvement in nonerythroid lineages is not commonly seen,133 and dose escalation beyond 200 mg daily causes cumulative neurological toxicity without necessarily conferring better hematological responses. Indeed, the North Central Cancer Treatment Group study N998B evaluated the tolerance and activity of an alternate thalidomide schedule of 200 mg daily with escalation to a maximum daily dose of 1,000 mg; there was extensive early patient withdrawal from the study (after a median of less than 2.5 months) due to toxicity.137 Combination of darbepoetin with thalidomide in patients with MDS was associated with increased thromboembolic events in a small study.138 However, when tolerated, prolonged drug treatment appears necessary to maximize hematological benefit, since the median time to erythroid response is 16 weeks (range, 12 to 20 weeks), with an erythropoietic response rate of 29% among the patients who completed the minimum 12 weeks of thalidomide treatment in one of the large MDS studies.133 Subsequent institutional studies have confirmed the ability of thalidomide to lower transfusion requirements. Given the necessity for prolonged administration, its use appears best suited for treatment of patients with lower risk disease.134, 139, 140 Investigation of the overall clinical benefit of low-dose thalidomide in MDS is nearing completion in a national randomized, placebo-controlled phase III trial.

The encouraging clinical experience with thalidomide in the treatment of MDS, as well as the favorable profile of manageable side effects of thalidomide analogs in MM, provided a strong impetus for testing lenalidomide in MDS patients.141, 142 Furthermore, lenalidomide inhibits the VEGF-induced trophic response of myeloblasts and endothelial cells while augmenting heterotypic adhesion of hematopoietic progenitors to bone marrow stroma to promote sustained growth arrest and preferential extinction of myelodysplastic clones.143 In a cohort of 25 MDS patients with symptomatic or transfusion-dependent anemia who completed 8 or more weeks of treatment with lenalidomide, 16 (62%) of patients experienced an erythroid response according to International Working Group (IWG) criteria, with 12 patients experiencing sustained transfusion inde pendence or a 2 g/dL or greater rise in hemoglobin levels.141, 142 Hematopoietic-promoting activity was greater among patients with low-risk or Int-1–risk MDS, with 15 of 21 (71%) experiencing hematological benefit. Erythroid responses to lenalidomide were associated with complete or partial (>50%) reduction in the proportion of abnormal metaphases in 9 of 13 informative patients, as well as improved primitive progenitor outgrowth and reduced grade of cytological dysplasia. Myeloid and platelet toxicity was dose limiting but occurred at all dose levels; it depended on cumulative drug exposure and necessitated either dose reduction or treatment interruption. These preliminary data suggest that lenalidomide is a promising oral agent that may find its clinical niche in the management of ineffective erythropoiesis in MDS patients, and confirmatory trials have recently been completed, with impressive activity in patients with a 5q variant of MDS. Although thalidomide therapy is associated with improvements in cytopenias in patients with MDS, more data are still needed on effects of the drug on the clonal tumor cell population, cytogenetic responses, and progression of MDS to acute myeloid leukemia (AML). Randomized trials are currently ongoing to determine the role of thalidomide and lenalidomide in MDS.

Myelofibrosis with Myeloid Metaplasia

The increased microvascular density in the bone marrow of patients with myelofibrosis/myeloid metaplasia (MMM)144 also prompted evaluation of thalidomide in this clinical setting. Several studies have shown145, 146, 147, 148, 149 that thalidomide offers, in variable percentages of patients, improvement in hematologic parameters, including increased platelet counts and hemoglobin levels, decreases in spleen size (though usually of moderate degree), increased bone marrow megakaryopoiesis, and decreased bone marrow angiogenesis.145 Interestingly, however, some of the patients treated with 200 to 400 mg/day developed significant myeloproliferative reactions, including marked leucocytosis and thrombocytosis,147, 148 the precise etiology of which has not been elucidated. Other studies of thalidomide in MMM150, 151 showed improved hemoglobin levels, decreased transfusion requirements or transfusion independence in 29% of patients, increased platelet counts in 38% of patients with moderate to severe thrombocytopenia, and decreased size of spleen in 41% of patients. On the other hand, more than 60% of patients discontinued the drug within 6 months of starting thalidomide therapy due to side effects, and almost 20% of patients had myeloproliferative reactions with leukocytosis and/or thrombocytosis. However, thalidomide appeared to maintain its clinical activity in MMM even when the daily thalidomide dose was reduced to as low as 50 mg, while most of the side effects appeared to occur at higher doses, suggesting that lower dosing may improve the therapeutic ratio. Furthermore, it appears that the combination of low-dose thalidomide (50 mg daily) with oral prednisone (starting at 0.5 mg/kg per day and tapered over 3 months) is not only well tolerated but also leads to durable objective responses, including improvement in terms of anemia, thrombocytopenia, and spleen size in 62%, 50%, and 19%, respectively, of 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic splenomegaly).152, 153 Further trials of thalidomide and lenalidomide in MMM are underway.

Acute Myelogenous Leukemia

The use of thalidomide in acute leukemias was based not only on the putative antiangiogenic effects of this drug and the increased microvascular density of bone marrow of leukemic patients23 but also on in vitro data suggesting that thalidomide or its derivatives can trigger differentiation or cell death of leukemia cell lines.154 A phase I/II dose-escalating trial of AML patients139, 140 showed that thalidomide (200 to 400 mg daily for at least 1 month) led to a greater than 50% reduction of blasts in bone marrow, along with improvement in peripheral blood counts, for a median response duration of 3 months (range, 1 to 8 months). Responses were associated with significant decreases in microvascular density and plasma bFGF levels.37, 38, 39, 139, 140 Overall, however, more data will be required to define the role, if any, that thalidomide should have in the therapeutic management of AML.

Non-Hodgkin's Lymphoma

Similar to other hematologic neoplasias, and despite their ready access to the general circulation, neoplastic lesions of non-Hodgkin's lymphoma (NHL) also present increased microvascular density,155 while increased serum levels of VEGF and bFGF correlate with poor prognosis.156 Results from a phase II study of thalidomide (starting dose of 200 mg daily, with dose escalation by 200 mg every week up to a maximum of 800 mg) in 19 patients with recurrent NHL (including patients with small lymphocytic lymphoma; follicular small cleaved, large B-cell lymphoma; mantle-cell lymphoma; mucosa-associated lymphoid tumors (MALTs); and peripheral T-cell lymphoma) and Hodgkin's disease without CNS involvement showed that 1 patient (5%) with recurrent gastric mucosa–associated lymphoid tissue lymphoma achieved a complete response and 3 patients (16%) achieved stable disease,157suggesting that thalidomide has limited single-agent activity in heavily pretreated patients with recurrent or refractory lymphoma. There are also case reports of clinical activity of thalidomide for the treatment of angioimmunoblastic lymphadenopathy,158, 159 but more data will be needed to derive a more conclusive picture on the role of thalidomide, if any, in NHL. A recent phase I/II clinical trial combining thalidomide with fludarabine in treatment-naive CLL patients showed overall response rate of 100% (compared with historical data of response rates of up to ~60% with fludarabine-based regimens), with complete remissions in 55% of patients. At a median follow-up of 15+ months none of the patients had relapsed and median time to disease progression had not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg per day, concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity.202 More extensive phase II evaluation of the clinical efficacy of this regimen is ongoing.

Clinical Studies of Thalidomide in the Treatment of Solid Tumors and Other Cancer-Related Indications

Kaposi's Sarcoma

Kaposi's sarcoma (KS) was another tumor type that appeared to be a reasonable setting for clinical testing of thalidomide, not only because of the increased vascularity of its lesions but also because of the fortuitous clinical findings of improvement of KS lesions in patients receiving thalidomide for HIV-related oral ulcers. In a phase II trial of male HIV-positive patients with histopathologically diagnosed KS, thalidomide (100 mg PO once nightly for 8 weeks) achieved partial responses in 6 of 17 patients,160 while a reduction in HHV-8 DNA load to undetectable levels was observed in 3 of the responding patients. These results 161 were also subsequently confirmed in other phase II trials.162 However, because most patients with HIV-related KS also receive concomitant antiretroviral therapy, caution is warranted in the interpretation of the results, in particular, the degree to which the observed activity reflects the effects of thalidomide. Thalidomide has also shown clinical benefit in non-HIV-related KS, for example, following allogeneic stem cell transplantation,163 another area of active ongoing investigation.

Renal Cell Cancer

Multiple studies have attempted to address the role of thalidomide in the management of renal cell carcinoma (RCC), a tumor driven by genetic changes (e.g., VHL mutations and constitutive activation of HIF-1a transcriptional activity)164 that induce angiogenesis. These studies have either involved low-dose thalidomide treatment (≤200 mg daily)115, 165 or higher doses (e.g., 600 mg daily or intrapatient escalation to daily doses as high as 1,200 mg),166, 167, 168,169 mostly in patients with metastatic RCC. The results have been variable, including partial responses in 3 to 16% of patients, disease stabilization in 16 to 45% of patients, and side effects similar to those seen in other clinical settings. The combination of thalidomide with other immunomodulatory agents, such as IL-2170, 171 or IFN-α, has attracted interest, but the thalidomide–IFN-α combination has led to serious adverse events, including seizures and visual disturbances.172 Therefore, the precise role of these combinations in the therapeutic management of RCC is uncertain.

Other Solid Tumors

Thalidomide has demonstrated sporadic evidence of activity in a variety of solid tumors, including gliomas,173, 174, 175, 176, 177 melanoma,115, 178, 179 and prostate cancer,180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190 but not in breast carcinoma.191

Graft versus Host Disease (GVHD)

The immunomodulatory and anti-inflammatory properties of thalidomide have stimulated interest in the field of GVHD, and over the last decade thalidomide has become established as an adjunctive treatment for chronic GVHD (cGVHD).192 Vogelsang et al. first demonstrated thalidomide to be safe and effective in 23 patients with cGVHD refractory to conventional treatment and in 21 patients with high-risk GVHD, with complete responses observed in 7 of 23 patients (30%) who were given the drug as salvage treatment and in 7 of 21 patients (33%) who were given it as primary therapy.193 The median duration of therapy was 240 days, sedation and constipation were the major side effects, and 4 patients discontinued medication because of peripheral neuropathy. Subsequent reports confirmed these results both in adults and in children, with the best responses seen in patients with predominantly mucocutaneous involvement by cGVHD.194, 195 In a larger phase II trial by Parker and colleagues, thalidomide was used as salvage therapy in 80 patients who had refractory cGVHD and had failed to respond to prednisone or prednisone and cyclosporin.10 Sixteen patients (20%) had a sustained response, with 9 achieving complete responses and 7 partial responses. The median duration of response was 16 months, and most responses were again seen in patients with isolated mouth, skin, and liver GVHD but without severe sclerodermatous manifestations. It should be noted that patients were maintained on prednisone and cyclosporine during thalidomide therapy, and 36% of patients had thalidomide discontinued because of side effects, including sedation, constipation, and neuropathy.


Additional side effects included skin rash and neutropenia, which had not been previously reported in the past studies of cGVHD, and these resulted in discontinuation of the drug in a small number of patients. In a more recent study, response to thalidomide in refractory cGVHD was seen in 38% of patients, and the treatment was well tolerated. However, a separate randomized, placebo-controlled trial found that the duration of thalidomide treatment was too short to assess its efficacy in controlling cGVHD because of side effects, including neutropenia and neuropathy, which led to early discontinuation.196 At this stage, thalidomide therefore appears to have activity against cGVHD, but whether it should be used for first-line treatment of cGVHD remains to be determined.28

Cachexia

Clinical trials of thalidomide in patients with cachexia secondary to terminal cancer are underway, based on encouraging preliminary reports.197 Interestingly, a recent report has also described beneficial effects of the combination of thalidomide and irinotecan for the treatment of metastatic colorectal cancer, in which abrogation of dose-limiting gastrointestinal toxicity, including diarrhea and nausea, was seen.198 Finally, studies in the palliative care setting have also looked at the role of thalidomide in chronic nausea, insomnia, and profuse sweating as well as an adjunct in pain control, with symptomatic benefit reported.199

CONCLUSION

The tragic experience of the early years of thalidomide use fortunately did not deter a more carefully monitored emergence of its use in diseases where its diverse immunomodulatory and antiangiogenic properties could be beneficial. Importantly, through a combination of careful preclinical study, serendipity, and thoughtful clinical development, thalidomide has become more than a merely promising agent. It is an integral part of the therapeutic management of MM and MDS, but is also used for nonmalignant conditions such as erythema nodosum leprosum (ENL). Importantly, the development of thalidomide derivatives, with more refined biological properties and attenuated potential for specific side effects compared with the parent compound, represents a promising new direction for clinical applications of this class of drugs. It may in fact be appropriate to revise our thinking about thalidomide analogs and view them, not as minor variations of the parent compound, but as a diverse group of structurally related but functionally distinct agents; such revision is indicated, for example, by the different pharmacological and clinical properties of thalidomide and lenalidomide (CC-5013). Even though it remains unclear which of the proposed biological activities of thalidomide and its derivatives account for its effects in MM or other diseases (e.g., their antiangiogenic activity, direct antitumor activity, modulation of tumor-stromal adhesive interactions, or immunomodulatory activity), it is clinically apparent that thalidomide has major activity in patients with MM and MDS. In contrast, the accumulating clinical experience in solid tumors is less encouraging, but patients with certain tumor types may benefit, most likely in the context of thalidomide-containing combination therapies. The uses of thalidomide for the management of certain treatment-related complications (e.g., cGVHD) or for relief of symptoms related to advanced malignancy or its treatment (e.g., cachexia, diarrhea)197, 198, 199 are also noteworthy. The emergence of thalidomide derivatives with considerable potential for improved efficacy and less toxicity provides an exciting platform for future therapies in a wide array of cancers and also non-neoplastic disease settings.

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FOOTNOTE

Disclosure: Dr. Paul Richardson and Dr. Kenneth Anderson are members of the Speakers' Bureau for Celgene Corp. Kenneth Anderson is a member of the Advisory Board of Celgene Corp.