- Email: [email protected]
Comparison of selective retinoic acid receptor– and retinoic X receptor–mediated efficacy, tolerance, and survival in cutaneous t-cell lymphoma
REPORTS
Comparison of selective retinoic acid receptore and retinoic X receptoremediated efficacy, tolerance, and survival in cutaneous T-cell lymphoma Christiane Querfeld, MD,a Steven T. Rosen, MD,b Joan Guitart, MD,a Alfred Rademaker, PhD,c Bing B. Fung,c William Posten, MD,a and Timothy M. Kuzel, MDb Chicago, Illinois Primary cutaneous T-cell lymphomas are non-Hodgkin’s lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Se´zary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy. The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/ Se´zary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity. In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy. (J Am Acad Dermatol 2004;51:25-32.)
M
ycosis fungoides (MF) and Se´zary syndrome (SS) represent the most common types of primary cutaneous T-cell lymphoma (CTCL), comprising 50% of all cutaneous
From the Departments of Dermatologya and Medicine,b Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, and Department of Preventive Medicine, Feinberg School of Medicine,c Northwestern University. Supported by the American Cancer Society (Dr Kuzel is a Clinical Career Development Award Recipient). Disclosure: Drs Guitart, Kuzel, and Rosen received honoraria for speakers for Ligand Pharmaceuticals. Drs Kuzel and Guitart are clinical investigators for studies with Ligand Phamaceuticals. This study was presented at the 12th Meeting of the European Academy of Dermatology, Barcelona, Spain, October 17, 2003. Accepted for publication: November 4, 2003. Reprint requests: Timothy M. Kuzel, MD, Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 N St Clair, Suite 850, Chicago, IL 60611. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.058
Abbreviations used: ATRA: CR: CTCL: FDA: MF: NCI: PD: PR: RAR: RXR: SS:
all-trans-retinoic acid complete response cutaneous T-cell lymphoma Food and Drug Administration mycosis fungoides National Cancer Institute progressive disease partial response retinoic acid receptor retinoic X receptor Se´zary syndrome
lymphomas.1 Clinically, MF is characterized by the development of patches, plaques, or tumors and staging is determined according to the TNM classification system.2 SS is the erythrodermic and more aggressive variant of CTCL with a leukemic component.3 Treatment of MF is regarded as palliative and therapy has encompassed a variety of modalities, including skin-targeted and systemic therapies.4 Retinoids, which are available as topical and systemic 25
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formulations, are compounds structurally related to vitamin A. The biological effects of retinoids are triggered through specific retinoid families, retinoic acid receptor (RAR) and retinoic X receptor (RXR).5-9 The benefits of retinoids in CTCL have been established by extensive clinical experience. However, the response rates were modest and duration short.10-17 Retinoids have also been combined with other treatment modalities including interferon alfa, psoralen-UVA, and radiation, but the results have not been found to be significantly better than monotherapy.18-23 Combinations of psoralen-UVA and retinoids achieved clinical response with less exposure to UVA, but have been shown to be inferior to psoralen-UVA plus interferon alfa.24 Dramatic biologic effects of all-trans retinoic acid (ATRA) were initially demonstrated for patients with acute promyelocytic leukemia and AIDS-related Kaposi’s sarcoma.25,26 In addition to the ability of ATRA to induce apoptosis, it was shown that it enhances IL-12 and interferon gamma production, and cell-mediated immunity in vitro, and, thus, might exert its effects in reconstitution of the T-helper cell 1 cytokine response.27,28 The potential for efficacy in CTCL with this agent led us to conduct a phase II trial for patients who have relapsed.29 In contrast, bexarotene is a new selective RXR agonist. These RXRs function as ligand-activated transcription factors that control gene expression leading to induction of apoptosis, and control of cell growth and differentiation, presumably different from RARs.30-32 Bexarotene has been studied in several clinical trials for patients with refractory earlyand advanced-stage disease.33,34 At recommended dosage, it is associated with significant side effects, particularly hyperlipidemia and hypothyroidism.35,36 In this retrospective study, we summarize and compare our phase II experience with the RAR agonist, ATRA, with our clinical use of the RXR agonist, bexarotene, for patients with MF/SS who have relapsed.
II trial. Eligible patients were at least 18 years of age with a diagnosis of MF/SS that was confirmed by skin biopsy. Patients were required to be refractory to or relapsed from at least 1 previously received treatment. Other eligibility criteria included: no systemic therapies or topical treatments for 4 weeks before study entry; no previous treatment with oral cisretinoid derivatives; Eastern Cooperative Oncology Group performance status of # 2; and preserved renal (creatinine # 2 mg/dL) and hepatic (bilirubin # 2 mg/dL) function. Also ineligible were: pregnant or lactating women; women of childbearing age who were not able to use contraception; and patients with active infections, other severe illness, central nervous system involvement, or hematologic findings with a decreased leukocyte count ( # 3.0 3 103/L) or decreased platelet count ( # 7.5 3 104/L). Patients were treated with bexarotene, after its approval by the Food and Drug Administration (FDA), for advanced/relapsed CTCL. Patient data were abstracted after institutional review board approval for chart review was obtained.
PATIENTS AND METHODS
Drug administration A total of 33 patients were treated with ATRA (provided by the Cancer, Therapeutic, and Evaluation Branch at the National Cancer Institute [NCI] in Bethesda, MD) orally with a daily dosage of 45 mg/ m2 in 2 divided doses. A minimum treatment of 2 months was required to determine the efficacy of ATRA. Treatment in responding patients was not permitted for more than 2 years. A total of 19 patients received daily bexarotene orally with a starting dosage of 300 mg/m2. Treatment was continued until disease progression or development of intolerable toxicity occurred. Adverse events were categorized
Patient selection Between 1991 and 2003, 52 patients were retrospectively identified from the records at the multidisciplinary cutaneous lymphoma clinic at the Feinberg School of Medicine of Northwestern University, Chicago, Ill. In all, 33 patients received ATRA between 1991 and 1999, and 19 patients received bexarotene between 2000 and 2003. All patients were staged according to the TNM classification. Patients treated with ATRA were required to sign an informed consent approved by the institutional review board before treatment in an institutional phase
Baseline and study tests Pretreatment tests included: medical history; complete physical examination with tumor assessment; skin biopsy specimens for routine histopathologic evaluation; skin and blood immunophenotyping; electrocardiogram; chest radiograph; complete blood cell count with differential; renal and liver function tests; prothrombin time; partial thromboplastin time; Se´zary cell count; human T-cell leukemia virus I/II serology; lipid profile; urinalysis; b-human chorionic gonadotropin in premenopausal women; computed tomographic scans; and lymph node biopsy of clinically abnormal lymph nodes. Evaluation during the study included history, physical examination, assessment of index lesions, and laboratory tests as indicated at baseline weekly for the first 4 weeks, then monthly and at the end of the study.
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as grade I to IV using NCI common toxicity criteria. Treatment was discontinued for patients who experienced grade III or IV toxicity, then restarted with a 25% to 50% dose reduction after resolution of side effects. Response classification A complete response (CR) was defined as no evidence of disease, including cutaneous and extracutaneous manifestations, for a minimum of 4 weeks. Suggestive cutaneous lesions or lymphadenopathy required a biopsy to determine the pathologic status. Patients with SS had to achieve normal peripheral blood counts. Partial response (PR) required at least 50% improvement for a minimum of 4 weeks. Patients with circulating Se´zary cells had to achieve a 50% reduction of the malignant cells. Stable disease reflected no significant changes of the disease. Progressive disease (PD) was defined as a $25% increase of cutaneous and/or visceral disease. Duration of response was defined as time of initial documentation of response to the time of documentation of progression. Time to progression reflected the time interval from study entry to the time of first observation of PD. Event-free survival was defined as interval between study entry and event. Events in event-free survival curves represented times at which a patient’s disease progressed, a patient’s course of treatment changed, complications occurred, or a patient died.
Table I. Demographics and characteristics of patients Characteristic
Age (yrs) Median Range Sex Male Female TNM stage IB IIA IIB III IVA IVB Prior treatment Median (range) Prior topical treatment \3 $3 Prior systemic treatment \3 [3
ATRA (n = 33)
Bexarotene (n = 19)
66 40-85
68 45-79
19 14
11 8
10 2 4 9 8 0
3 0 3 9 2 2*
4 (0-10)
5 (0-13)
26 (79%) 7 (21%)
13 (68%) 6 (32%)
20 (61%) 13 (39%)
9 (47%) 10 (53%)
ATRA, All-trans-retinoic acid. There were no statistically significant differences between groups. * One each with bone-marrow/liver metastasis.
RESULTS
equal in both groups. However, 84% of the patients treated with bexarotene represented advanced stages of disease (IIB-IVB) compared with 63% of patients who received ATRA (P = .20). The ATRAtreated group received a median of 4 prior therapies and the bexarotene-treated group received a median of 5 prior therapies (P value not significant). Among patients treated with ATRA, 26 (79%) were refractory to less than 3, and 7 (21%) to 3 or more prior topical therapies, whereas 20 (61%) were refractory to less than 3, and 13 (39%) to 3 or more prior systemic therapies. Of 19 patients, 13 (68%) treated with bexarotene were refractory to less than 3, and 6 (32%) to 3 or more prior topical treatments, whereas 9 (47%) to less than 3, and 10 (53%) to 3 or more prior systemic treatments.
Patient characteristics Baseline variables of 52 patients are summarized in Table I. In all, 33 patients were treated with ATRA and 19 patients were treated with bexarotene. Median follow-up time for the ATRA group was 43 months compared with 13.8 months for the bexarotene group. Patient age at presentation ranged from 40 to 85 years, with a median age of 66 years for the ATRA group and 68 years for the bexarotene group. Patients with tumor stages IB to IVB were
Response rates and duration of response No significant difference in the response categories was seen between the 2 treatment groups (Table II). Of 33 patients, 4 (12%) treated with ATRA achieved or maintained a response with a median duration of 20.5 months. Among these responders 1 patient (3%) achieved CR and 3 (9%) achieved PR. The patient who achieved CR was lost to follow-up at 36 months. One patient who attained PR relapsed at
Statistical methods All statistical analysis was on the basis of 52 enrolled patients. Baseline variables for each treatment group were summarized as determined statistically by Fisher’s exact test (categorical variables) and t test (continuous variables). Actuarial survival curves were calculated from the date of study entry according to the Kaplan-Meier method. Event-free survival curves were demonstrated from the date of study entry, also using the Kaplan-Meier method. P value was tested statistically by the log-rank test. A P value less than .05 was considered significant.
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Table II. Results of treatment
Follow-up (mos) Median (range) Best response CR PR SD PD Response duration (mos) Median Range Event-free survival (mos) Median Survival time (mos) Median Current status Alive Dead
ATRA (n = 33)
Bexarotene (n = 19)
43.0 (2-122)
13.8 (4-34)
1 3 10 19
(3%) (9%) (30%) (58%)
20.5 2-36
0 (0%) 4 (21%) 4 (21%) 11 (58%) 7.3 1.8-12
3.88
5.29
43.76
Not attained
10 23
13 6
Fig 1. Kaplan-Meier actuarial survival curves of patients treated with all-trans-retinoic acid (ATRA) and bexarotene. Median follow-up time of ATRA group was 43 months (range: 2-122) compared with 13.8 months (range: 4-34) of bexarotene group. Difference is not statistically significant (P = .99).
ATRA, All-trans-retinoic acid; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
2 months. In another patient who attained PR, despite clinical skin improvement, progression was monitored by increased Se´zary cell count at 15 months. The third patient who attained PR was lost to follow-up at 26 months. Of 19 patients, 4 (21%) who received bexarotene achieved and maintained a PR with a median duration of 7.3 months. Of 4 patients who achieved PR, 3 relapsed within 12 months. One patient who achieved a clinical CR of his skin had a stable elevated Se´zary cell count with progression at 11 months. Despite initial brief encouraging results, another patient developed PD at 1.75 months. He was discontinued from treatment at 1 month because of severe side effects, then at 2.5 months restarted with a 25% dose reduction. One patient, who was discontinued from treatment after worsening peripheral neuropathy, progressed at 3.5 months. Although 1 patient maintained a PR, she discontinued her medication for personal reasons at 12 months. In all, 3 patients with stable disease and 7 patients with PD noted a transient improvement of skin manifestations during the treatment. Outcome and survival Median follow-up time of the ATRA group was 43 months compared with 13.8 months of the bexarotene group (Table II). The overall median survival of all patients was 43.5 months (1-601 months). Kaplan-Meier survival curves were used to compare the median survival time between 33 patients treated with ATRA and 19 patients treated with bexarotene (Fig 1). Patients in the ATRA group
Fig 2. Kaplan-Meier event-free survival curves of patients treated with all-trans-retinoic acid (ATRA) and bexarotene. There is no statistically difference between treatment groups (P = .97).
had an overall median survival of 43 months. However, the median survival of the patients treated with bexarotene has not been reached. Differences in survival were not statistically significant between the treatment groups when corrected for length of follow-up (P = .99). There was no statistically significant difference in event-free survival time (3.88 months in patients treated with ATRA vs 5.29 months in patients treated with bexarotene; P = .97) (Fig 2). There was 1 patient in each therapy group who remained event-free during the observation time. A statistically significant difference was noted in patient survival status, most likely a result of the different length in follow-up time. Of patients, 23 (70%) in the ATRA cohort have died, 15 (46%) attributable to MF.
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Table III. Side effects associated with all-trans-retinoic acid and bexarotene administration with an incidence of $10% Side effect
ATRA (n = 33)
I Myalgia/arthralgia Headache Mucocutaneous -Pruritus Leukopenia -Neutropenia -Lymphopenia Gastrointestinal Infection Lipid/metabolic profile Hypothyroidism -Associated symptoms Neurologic Hepatotoxicity
12 31 7
6 20 2 6 6
II 6 2 3 7 1
2 3 8
III
Bexarotene (n = 19)
IV
I
II 1
III
IV 1
3 1
3
1 1
3 5 3 2
5 1 4
10
19 15 14 2
3 1
2 1 1 3 3
3
1
ATRA, All-trans-retinoic acid.
Other causes of death included cardiopulmonary disease, respiratory failure, and breast cancer. Only 6 of 19 patients (32%) among the bexarotene-treated group have died. All of these deaths were related to MF. Adverse effects Adverse events were categorized as grade I to IV according to the NCI common toxicities and were listed in Table III. In general, both treatments were well tolerated; the majority of patients developed mild (grade I) to moderate (grade II) side effects. However, the toxicity profile was different between these 2 retinoids. As with other retinoids, the most common side effects of ATRA were mucocutaneous involvement and hyperlipidemia. In contrast, the most common side effects reported for patients treated with bexarotene were hyperlipidemia, hypothyroidism with associated symptoms, and leukopenia. No severe impairment in hepatic function was detected in either group with only a mild elevation in liver transaminases seen in 6 patients treated with ATRA. In all, 31 patients treated with ATRA had dryness or erythema of the skin, lips, mouth, and eyes, whereas only 1 patient treated with bexarotene developed mild mucocutaneous dryness. Widespread pruritus was observed in 9 patients medicated with ATRA and in 14 medicated with bexarotene, but its relation to treatment versus disease remains unclear. A small number of patients in both treatment groups developed gastrointestinal symptoms including nausea, vomiting, and poor appetite, or musculoskeletal symptoms such as myalgia, arthralgia, and
pain. Transient mild headache was reported in 13 patients treated with ATRA and occurred moderately in 3 patients medicated with bexarotene. Hematologic findings including leukopenia, neutropenia, and lymphopenia occurred in 9 patients during treatment with bexarotene and in 1 patient treated with ATRA. However, 3 of 9 patients medicated with bexarotene developed grade III neutropenia and lymphopenia. Fever or sepsis was not associated with the neutropenia. There were 2 cases of herpes zoster and 1 case of superinfection of ulcerated tumor lesions for patients medicated with bexarotene. In all, 4 patients among those medicated with ATRA were treated for infections including pneumonia, urinary tract infection, and superficial skin infections. A total of 15 patients (45%) treated with ATRA developed hypertriglyceridemia (9 grade I and 6 grade II). One patient had grade IV hyperlipidemia, which resolved after 4 weeks of discontinuation from therapy. A total of 15 patients (80%) treated with bexarotene displayed elevated triglyceride levels, mostly grade II. In all, 3 patients developed grade III and 3 patients developed grade IV hypertriglyceridemia. After dose reduction and/or removal from therapy for 2 to 4 weeks, levels decreased to almost baseline. One patient developed a triglyceride level of 1470 mg/dl despite concomitant triple antilipid therapy. Withholding treatment resulted in an immediate recovery. No pancreatitis occurred. Lipidlowering agents were required in 18 (95%) of the patients medicated with bexarotene. Hypothyroidism occurred only for patients medicated with bexarotene. In all, 15 patients developed
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decreased thyrotropin and T4 levels. Associated symptoms including fatigue, general malaise, cold intolerance, weakness, and constipation, but resolved with hormone replacement.
DISCUSSION The results of our completed phase II study of ATRA for MF and the recently published experience with bexarotene, with its different pharmacokinetic and toxicity profile, provided a rational basis to compare the efficacy, toxicity, and survival between 2 cohorts of patients with MF/SS treated for more than 10 years at a single referral center. Small, nonrandomized, clinical trials with a variety of RAR-specific retinoids other than ATRA have been performed in the past in a limited number of patients with CTCL, reporting response rates between 44% and 67%.10-17 Criteria for response were usually limited to the appearance of the skin. ATRA has been widely and effectively used in the therapy of acute promyelocytic leukemia, but this is the first trial of its use for the treatment of MF/SS. Bexarotene is the first retinoid approved by the FDA for the treatment of cutaneous manifestations of refractory CTCL. In 2 multicenter phase II to III clinical trials it has been tested in patients with early and advanced stages of CTCL.33,34 Of patients with refractory early-stage CTCL, 54% responded to therapy at doses of 300 mg/m2/d with a CR rate of 7%. The overall response rate for patients with refractory advanced-stage CTCL was 45% at the same dosage. Our retrospective study did not demonstrate significant differences in response rates between the ATRA- and bexarotene-medicated groups. Patients with refractory stage IB through IVB disease treated with bexarotene had an overall response rate of 21% at recommended doses of 300 mg/m2 with a median duration of 7.3 months. The overall response rate to ATRA was 12% with a median duration of 20.5 months. One patient (3%) achieved and maintained a CR at 36 months. Compared with our ATRA-treated group, higher rates of PR and CR in RAR agonists have been previously reported. This might be related to the fact that patients in prior studies were not strictly limited to those with relapsed CTCL.11-14 In fact, most enrolled patients had not received or were exposed to less frequent therapy. In addition, different response criteria were often used with bias for a greater level of positive outcome. Usually, response was focused only on skin improvement, without rigorous systemic blood evaluation or biopsy specimens to prove histologic resolution. Compared with previously published data, our results also showed significantly lower rates of re-
sponse for bexarotene. The differences might be related to patient selection and sample size, but also may be a result of differences in response criteria. Prior studies have relied on a tool known as the physician’s global assessment that is heavily weighted toward the skin assessment. Despite clinical responses of cutaneous manifestations in our patients with advanced CTCL, we often could not detect an objective response on the basis of our response criteria, which included tests for evaluation of cutaneous and extracutaneous manifestations. Prior studies may also have overestimated the cutaneous improvement using a composite assessment scale for index cutaneous lesions defined in 8 grades including scale, erythema, and elevation of plaque, whereas a cutaneous response in our patients required at least a 50% reduction of area of lesions. Differences in dosage adjustments or protocol design might also have contributed to the different response rates. Once our patients were given the diagnosis of disease progression, despite cutaneous improvement, they were immediately switched to other therapeutic regimens and, therefore, were more likely to be classified as treatment failures. The overall survival and event-free survival times were not significantly different between our 2 treatment groups, suggesting a similar efficacy profile when used as a monotherapeutic agent. Adverse events were more common in ATRA with a broader spectrum, but usually mild (grade I) and to a lesser extent moderate (grade II) at presentation. Mucocutaneous symptoms, hyperlipidemia, and headache were the most common side effects. With the exception of hyperlipidemia, the toxic effects of bexarotene are distinct from ATRA-induced events. The most frequent bexarotene-related adverse events included hypothyroidism, cytopenia, and hyperlipidemia. These side effects are consistent with those previously reported, were generally manageable with oral medications or dose interruptions, and were totally reversible after discontinuation from treatment. A transient phenomenon with cutaneous improvement of erythema, pruritus, and subjective improvement in quality of life was observed in 10 patients with erythrodermic MF/SS when treated with bexarotene, despite the lack of an objective clinical response when extracutaneous manifestations were considered. The reason for the transient clinical response is not yet known. Possibly the immunomodulatory potency of bexarotene may cause a transient cutaneous T-helper cell 1 cytokine production that alters lymphocyte trafficking.37 Similarly, RAR retinoids in coculture with IL-2 have been shown to synergistically up-regulate the expression of the T-helper cell 1 cytokine interferon
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gamma, with ATRA as the most potent inducing agent.28 Thus, retinoids may not work in a traditional antineoplastic cytotoxic fashion, but rather may alter the distribution of the lymphocyte subsets from the skin compartment to the lymph nodes or blood. In conclusion, our data indicate that there does not appear to be significant differences in the modest response rates and survival times in patients with relapsed CTCL treated with the RAR-selective retinoid, ATRA, and the RXR-selective retinoid, bexarotene. Both have a favorable toxicity profile that can be managed with medications. The symptomatic toxicity profile caused by bexarotene seems to be limited to laboratory values and, hence, is symptomatically better tolerated. Our results demonstrate a relatively modest degree of efficacy for both compounds. In addition, the pharmacokinetic profile of ATRA is known to be inferior because of induction of its own metabolism through the P450 cytochrome pathway and possibly through up-regulation of cellular retinoic acidebinding proteins.38-40 Attempts to treat patients at the maximum tolerated dose have been limited by this phenomenon. Although RXR ligands are metabolized by hepatic cytochrome P450 as well, bexarotene may exert different effects through interaction with different isozymes.41 Pharmacokinetic studies on bexarotene did not result in autoinduction of its own metabolism.42 The optimal role for both retinoids may not be as monotherapeutic treatment options. Rather, immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using these agents in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.43 REFERENCES 1. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphoma study group of the European organization for research and treatment of cancer. Blood 1997;90:354-71. 2. Bunn PA, Lamberg SI. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treat Rep 1979;63:725-8. 3. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the international society for cutaneous lymphomas. J Am Acad Dermatol 2002;46:95-106. 4. Querfeld C, Guitart J, Kuzel TM, Rosen ST. Primary cutaneous lymphomas: a review with current treatment options. Blood Rev 2003;17:131-424. 5. Ivanova D, Gaudon C, Rossin A, Bourguet W, Gronemeyer H. RAR-RXR selectivity and biological activity of new retinoic acid analogues with heterocyclic or polycyclic aromatic systems. Bioorg Med Chem 2002;10:2099-102. 6. Chambon P. The retinoid signaling pathway: molecular and genetic analysis. Semin Mol Biol 1994;5:115-25. 7. Camacho LH. Clinical applications of retinoids in cancer medicine. J Biol Regul Homeost Agents 2003;17:98-114.
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25. Gupta V, Tabak D, Keating A. Acute promyelocytic leukemia: a case-based review. Hematology 2003;8:105-13. 26. Saiag P, Pavlovic M, Clerici T, Feauveau V, Nicolas JC, Emile D, et al. Treatment of early AIDS-related Kaposi’s sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial; Kaposi’s sarcoma ANRS study group (agence nationale de recherches sur le SIDA). AIDS 1998;12:2169-76. 27. Wang KC, Cheng AL, Chuang SE, Hsu HC, Su IJ. Retinoic acidinduced apoptoctic pathway in T-cell lymphoma: identification of four groups of genes with differential biological functions. Exp Hematol 2000;28:1441-50. 28. Fox FE, Kubin M, Cassin M, Niu Z, Trinchieri G, Cooper KD, et al. Retinoids synergize with interleukin-2 to augment IFN-g and interleukin-12 production by human peripheral blood mononuclear cells. J Interferon Cytokine Res 1999;19:407-15. 29. Siegel RS, Martone B, Guitart J, Samuelson E, Rosen S, Kuzel TM. Phase II trial of all-trans retinoic acid in the treatment of relapsed/refractory mycosis fungoides/Se´zary syndrome: proceedings of the American society of hematology. Blood 1999; 94:97a. 30. Nagpal S, Chandraratna RA. Recent developments in receptorselective retinoids. Curr Pharm Des 2000;6:919-31. 31. Wong SF. Oral bexarotene in the treatment of cutaneous T-cell lymphoma. Ann Pharmacother 2001;35:1056-65. 32. Zhang C, Hazarika P, Ni X, Weidner DA, Duvic M. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res 2002;8:1234-40. 33. Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent earlystage cutaneous T-cell lymphoma. Arch Dermatol 2001;137: 581-93. 34. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, et al. Bexarotene is effective and safe for treatment
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of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 2001;19: 2456-71. Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M. Optimizing bexarotene therapy for cutaneous Tecell lymphoma. J Am Acad Dermatol 2002;47:672-84. Liu S, Ogilvie KM, Klausing K, Lawson MA, Jolley D, Li D, et al. Mechanism of selective retinoid X receptor agonist-induced hypothyroidism in the rat. Endocrinology 2002;14388:2880-5. Lee BN, Duvic M, Tang CK, Bueso-Ramos C, Estrov Z, Reuben JM. Dysregulated synthesis of intracellular type 1 and 2 cytokines by T-cells of patients with cutaneous T-cell lymphoma. Clin Diagn Lab Immunol 1999;6:79-84. Kizaki M, Ueno H, Yamazoe Y, Shimada M, Takayama N, Muto A, et al. Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein. Blood 1996;87:725-33. Kizaki M, Ueno H, Matsushita H, Takayama N, Muto A, Awaya N, et al. Retinoid resistance in leukemic cells. Leuk Lymphoma 1997;25:427-34. Delva L, Cornic M, Balitrand N, Guidez F, Miclea JM, Delmer A, et al. Resistance to all-trans-retinoic acid (ATRA) therapy in relapsing acute promyeolocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993;82:2175-81. Howell SR, Shirley MA, Ulm EH. Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P 450. Drug Metab Disp 1998;26:234-9. Miller VA, Benedetti FM, Rigas JR, Verret AL, Pfister DG, Straus D. Initial clinical trial of a selective retinoid X receptor ligand, LGD 1069. J Clin Oncol 1997;15:790-5. Gorgun G, Foss F. Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox. Blood 2002;100: 1399-403.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the Journal of the American Academy of Dermatology for the preceding 5 years are maintained and are available for purchase from Elsevier Inc., until inventory is depleted. Please write to Elsevier Inc., Subscription Customer Service, 6277 Sea Harbor Dr, Orlando, FL 32887, or call 800-654-2452 or 407-345-4000 for information on availability and prices of particular issues.
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Comparison of selective retinoic acid receptore and retinoic X receptoremediated efficacy, tolerance, and survival in cutaneous T-cell lymphoma Christiane Querfeld, MD,a Steven T. Rosen, MD,b Joan Guitart, MD,a Alfred Rademaker, PhD,c Bing B. Fung,c William Posten, MD,a and Timothy M. Kuzel, MDb Chicago, Illinois Primary cutaneous T-cell lymphomas are non-Hodgkin’s lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Se´zary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy. The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/ Se´zary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity. In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy. (J Am Acad Dermatol 2004;51:25-32.)
M
ycosis fungoides (MF) and Se´zary syndrome (SS) represent the most common types of primary cutaneous T-cell lymphoma (CTCL), comprising 50% of all cutaneous
From the Departments of Dermatologya and Medicine,b Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, and Department of Preventive Medicine, Feinberg School of Medicine,c Northwestern University. Supported by the American Cancer Society (Dr Kuzel is a Clinical Career Development Award Recipient). Disclosure: Drs Guitart, Kuzel, and Rosen received honoraria for speakers for Ligand Pharmaceuticals. Drs Kuzel and Guitart are clinical investigators for studies with Ligand Phamaceuticals. This study was presented at the 12th Meeting of the European Academy of Dermatology, Barcelona, Spain, October 17, 2003. Accepted for publication: November 4, 2003. Reprint requests: Timothy M. Kuzel, MD, Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 N St Clair, Suite 850, Chicago, IL 60611. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.058
Abbreviations used: ATRA: CR: CTCL: FDA: MF: NCI: PD: PR: RAR: RXR: SS:
all-trans-retinoic acid complete response cutaneous T-cell lymphoma Food and Drug Administration mycosis fungoides National Cancer Institute progressive disease partial response retinoic acid receptor retinoic X receptor Se´zary syndrome
lymphomas.1 Clinically, MF is characterized by the development of patches, plaques, or tumors and staging is determined according to the TNM classification system.2 SS is the erythrodermic and more aggressive variant of CTCL with a leukemic component.3 Treatment of MF is regarded as palliative and therapy has encompassed a variety of modalities, including skin-targeted and systemic therapies.4 Retinoids, which are available as topical and systemic 25
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formulations, are compounds structurally related to vitamin A. The biological effects of retinoids are triggered through specific retinoid families, retinoic acid receptor (RAR) and retinoic X receptor (RXR).5-9 The benefits of retinoids in CTCL have been established by extensive clinical experience. However, the response rates were modest and duration short.10-17 Retinoids have also been combined with other treatment modalities including interferon alfa, psoralen-UVA, and radiation, but the results have not been found to be significantly better than monotherapy.18-23 Combinations of psoralen-UVA and retinoids achieved clinical response with less exposure to UVA, but have been shown to be inferior to psoralen-UVA plus interferon alfa.24 Dramatic biologic effects of all-trans retinoic acid (ATRA) were initially demonstrated for patients with acute promyelocytic leukemia and AIDS-related Kaposi’s sarcoma.25,26 In addition to the ability of ATRA to induce apoptosis, it was shown that it enhances IL-12 and interferon gamma production, and cell-mediated immunity in vitro, and, thus, might exert its effects in reconstitution of the T-helper cell 1 cytokine response.27,28 The potential for efficacy in CTCL with this agent led us to conduct a phase II trial for patients who have relapsed.29 In contrast, bexarotene is a new selective RXR agonist. These RXRs function as ligand-activated transcription factors that control gene expression leading to induction of apoptosis, and control of cell growth and differentiation, presumably different from RARs.30-32 Bexarotene has been studied in several clinical trials for patients with refractory earlyand advanced-stage disease.33,34 At recommended dosage, it is associated with significant side effects, particularly hyperlipidemia and hypothyroidism.35,36 In this retrospective study, we summarize and compare our phase II experience with the RAR agonist, ATRA, with our clinical use of the RXR agonist, bexarotene, for patients with MF/SS who have relapsed.
II trial. Eligible patients were at least 18 years of age with a diagnosis of MF/SS that was confirmed by skin biopsy. Patients were required to be refractory to or relapsed from at least 1 previously received treatment. Other eligibility criteria included: no systemic therapies or topical treatments for 4 weeks before study entry; no previous treatment with oral cisretinoid derivatives; Eastern Cooperative Oncology Group performance status of # 2; and preserved renal (creatinine # 2 mg/dL) and hepatic (bilirubin # 2 mg/dL) function. Also ineligible were: pregnant or lactating women; women of childbearing age who were not able to use contraception; and patients with active infections, other severe illness, central nervous system involvement, or hematologic findings with a decreased leukocyte count ( # 3.0 3 103/L) or decreased platelet count ( # 7.5 3 104/L). Patients were treated with bexarotene, after its approval by the Food and Drug Administration (FDA), for advanced/relapsed CTCL. Patient data were abstracted after institutional review board approval for chart review was obtained.
PATIENTS AND METHODS
Drug administration A total of 33 patients were treated with ATRA (provided by the Cancer, Therapeutic, and Evaluation Branch at the National Cancer Institute [NCI] in Bethesda, MD) orally with a daily dosage of 45 mg/ m2 in 2 divided doses. A minimum treatment of 2 months was required to determine the efficacy of ATRA. Treatment in responding patients was not permitted for more than 2 years. A total of 19 patients received daily bexarotene orally with a starting dosage of 300 mg/m2. Treatment was continued until disease progression or development of intolerable toxicity occurred. Adverse events were categorized
Patient selection Between 1991 and 2003, 52 patients were retrospectively identified from the records at the multidisciplinary cutaneous lymphoma clinic at the Feinberg School of Medicine of Northwestern University, Chicago, Ill. In all, 33 patients received ATRA between 1991 and 1999, and 19 patients received bexarotene between 2000 and 2003. All patients were staged according to the TNM classification. Patients treated with ATRA were required to sign an informed consent approved by the institutional review board before treatment in an institutional phase
Baseline and study tests Pretreatment tests included: medical history; complete physical examination with tumor assessment; skin biopsy specimens for routine histopathologic evaluation; skin and blood immunophenotyping; electrocardiogram; chest radiograph; complete blood cell count with differential; renal and liver function tests; prothrombin time; partial thromboplastin time; Se´zary cell count; human T-cell leukemia virus I/II serology; lipid profile; urinalysis; b-human chorionic gonadotropin in premenopausal women; computed tomographic scans; and lymph node biopsy of clinically abnormal lymph nodes. Evaluation during the study included history, physical examination, assessment of index lesions, and laboratory tests as indicated at baseline weekly for the first 4 weeks, then monthly and at the end of the study.
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as grade I to IV using NCI common toxicity criteria. Treatment was discontinued for patients who experienced grade III or IV toxicity, then restarted with a 25% to 50% dose reduction after resolution of side effects. Response classification A complete response (CR) was defined as no evidence of disease, including cutaneous and extracutaneous manifestations, for a minimum of 4 weeks. Suggestive cutaneous lesions or lymphadenopathy required a biopsy to determine the pathologic status. Patients with SS had to achieve normal peripheral blood counts. Partial response (PR) required at least 50% improvement for a minimum of 4 weeks. Patients with circulating Se´zary cells had to achieve a 50% reduction of the malignant cells. Stable disease reflected no significant changes of the disease. Progressive disease (PD) was defined as a $25% increase of cutaneous and/or visceral disease. Duration of response was defined as time of initial documentation of response to the time of documentation of progression. Time to progression reflected the time interval from study entry to the time of first observation of PD. Event-free survival was defined as interval between study entry and event. Events in event-free survival curves represented times at which a patient’s disease progressed, a patient’s course of treatment changed, complications occurred, or a patient died.
Table I. Demographics and characteristics of patients Characteristic
Age (yrs) Median Range Sex Male Female TNM stage IB IIA IIB III IVA IVB Prior treatment Median (range) Prior topical treatment \3 $3 Prior systemic treatment \3 [3
ATRA (n = 33)
Bexarotene (n = 19)
66 40-85
68 45-79
19 14
11 8
10 2 4 9 8 0
3 0 3 9 2 2*
4 (0-10)
5 (0-13)
26 (79%) 7 (21%)
13 (68%) 6 (32%)
20 (61%) 13 (39%)
9 (47%) 10 (53%)
ATRA, All-trans-retinoic acid. There were no statistically significant differences between groups. * One each with bone-marrow/liver metastasis.
RESULTS
equal in both groups. However, 84% of the patients treated with bexarotene represented advanced stages of disease (IIB-IVB) compared with 63% of patients who received ATRA (P = .20). The ATRAtreated group received a median of 4 prior therapies and the bexarotene-treated group received a median of 5 prior therapies (P value not significant). Among patients treated with ATRA, 26 (79%) were refractory to less than 3, and 7 (21%) to 3 or more prior topical therapies, whereas 20 (61%) were refractory to less than 3, and 13 (39%) to 3 or more prior systemic therapies. Of 19 patients, 13 (68%) treated with bexarotene were refractory to less than 3, and 6 (32%) to 3 or more prior topical treatments, whereas 9 (47%) to less than 3, and 10 (53%) to 3 or more prior systemic treatments.
Patient characteristics Baseline variables of 52 patients are summarized in Table I. In all, 33 patients were treated with ATRA and 19 patients were treated with bexarotene. Median follow-up time for the ATRA group was 43 months compared with 13.8 months for the bexarotene group. Patient age at presentation ranged from 40 to 85 years, with a median age of 66 years for the ATRA group and 68 years for the bexarotene group. Patients with tumor stages IB to IVB were
Response rates and duration of response No significant difference in the response categories was seen between the 2 treatment groups (Table II). Of 33 patients, 4 (12%) treated with ATRA achieved or maintained a response with a median duration of 20.5 months. Among these responders 1 patient (3%) achieved CR and 3 (9%) achieved PR. The patient who achieved CR was lost to follow-up at 36 months. One patient who attained PR relapsed at
Statistical methods All statistical analysis was on the basis of 52 enrolled patients. Baseline variables for each treatment group were summarized as determined statistically by Fisher’s exact test (categorical variables) and t test (continuous variables). Actuarial survival curves were calculated from the date of study entry according to the Kaplan-Meier method. Event-free survival curves were demonstrated from the date of study entry, also using the Kaplan-Meier method. P value was tested statistically by the log-rank test. A P value less than .05 was considered significant.
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Table II. Results of treatment
Follow-up (mos) Median (range) Best response CR PR SD PD Response duration (mos) Median Range Event-free survival (mos) Median Survival time (mos) Median Current status Alive Dead
ATRA (n = 33)
Bexarotene (n = 19)
43.0 (2-122)
13.8 (4-34)
1 3 10 19
(3%) (9%) (30%) (58%)
20.5 2-36
0 (0%) 4 (21%) 4 (21%) 11 (58%) 7.3 1.8-12
3.88
5.29
43.76
Not attained
10 23
13 6
Fig 1. Kaplan-Meier actuarial survival curves of patients treated with all-trans-retinoic acid (ATRA) and bexarotene. Median follow-up time of ATRA group was 43 months (range: 2-122) compared with 13.8 months (range: 4-34) of bexarotene group. Difference is not statistically significant (P = .99).
ATRA, All-trans-retinoic acid; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
2 months. In another patient who attained PR, despite clinical skin improvement, progression was monitored by increased Se´zary cell count at 15 months. The third patient who attained PR was lost to follow-up at 26 months. Of 19 patients, 4 (21%) who received bexarotene achieved and maintained a PR with a median duration of 7.3 months. Of 4 patients who achieved PR, 3 relapsed within 12 months. One patient who achieved a clinical CR of his skin had a stable elevated Se´zary cell count with progression at 11 months. Despite initial brief encouraging results, another patient developed PD at 1.75 months. He was discontinued from treatment at 1 month because of severe side effects, then at 2.5 months restarted with a 25% dose reduction. One patient, who was discontinued from treatment after worsening peripheral neuropathy, progressed at 3.5 months. Although 1 patient maintained a PR, she discontinued her medication for personal reasons at 12 months. In all, 3 patients with stable disease and 7 patients with PD noted a transient improvement of skin manifestations during the treatment. Outcome and survival Median follow-up time of the ATRA group was 43 months compared with 13.8 months of the bexarotene group (Table II). The overall median survival of all patients was 43.5 months (1-601 months). Kaplan-Meier survival curves were used to compare the median survival time between 33 patients treated with ATRA and 19 patients treated with bexarotene (Fig 1). Patients in the ATRA group
Fig 2. Kaplan-Meier event-free survival curves of patients treated with all-trans-retinoic acid (ATRA) and bexarotene. There is no statistically difference between treatment groups (P = .97).
had an overall median survival of 43 months. However, the median survival of the patients treated with bexarotene has not been reached. Differences in survival were not statistically significant between the treatment groups when corrected for length of follow-up (P = .99). There was no statistically significant difference in event-free survival time (3.88 months in patients treated with ATRA vs 5.29 months in patients treated with bexarotene; P = .97) (Fig 2). There was 1 patient in each therapy group who remained event-free during the observation time. A statistically significant difference was noted in patient survival status, most likely a result of the different length in follow-up time. Of patients, 23 (70%) in the ATRA cohort have died, 15 (46%) attributable to MF.
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Table III. Side effects associated with all-trans-retinoic acid and bexarotene administration with an incidence of $10% Side effect
ATRA (n = 33)
I Myalgia/arthralgia Headache Mucocutaneous -Pruritus Leukopenia -Neutropenia -Lymphopenia Gastrointestinal Infection Lipid/metabolic profile Hypothyroidism -Associated symptoms Neurologic Hepatotoxicity
12 31 7
6 20 2 6 6
II 6 2 3 7 1
2 3 8
III
Bexarotene (n = 19)
IV
I
II 1
III
IV 1
3 1
3
1 1
3 5 3 2
5 1 4
10
19 15 14 2
3 1
2 1 1 3 3
3
1
ATRA, All-trans-retinoic acid.
Other causes of death included cardiopulmonary disease, respiratory failure, and breast cancer. Only 6 of 19 patients (32%) among the bexarotene-treated group have died. All of these deaths were related to MF. Adverse effects Adverse events were categorized as grade I to IV according to the NCI common toxicities and were listed in Table III. In general, both treatments were well tolerated; the majority of patients developed mild (grade I) to moderate (grade II) side effects. However, the toxicity profile was different between these 2 retinoids. As with other retinoids, the most common side effects of ATRA were mucocutaneous involvement and hyperlipidemia. In contrast, the most common side effects reported for patients treated with bexarotene were hyperlipidemia, hypothyroidism with associated symptoms, and leukopenia. No severe impairment in hepatic function was detected in either group with only a mild elevation in liver transaminases seen in 6 patients treated with ATRA. In all, 31 patients treated with ATRA had dryness or erythema of the skin, lips, mouth, and eyes, whereas only 1 patient treated with bexarotene developed mild mucocutaneous dryness. Widespread pruritus was observed in 9 patients medicated with ATRA and in 14 medicated with bexarotene, but its relation to treatment versus disease remains unclear. A small number of patients in both treatment groups developed gastrointestinal symptoms including nausea, vomiting, and poor appetite, or musculoskeletal symptoms such as myalgia, arthralgia, and
pain. Transient mild headache was reported in 13 patients treated with ATRA and occurred moderately in 3 patients medicated with bexarotene. Hematologic findings including leukopenia, neutropenia, and lymphopenia occurred in 9 patients during treatment with bexarotene and in 1 patient treated with ATRA. However, 3 of 9 patients medicated with bexarotene developed grade III neutropenia and lymphopenia. Fever or sepsis was not associated with the neutropenia. There were 2 cases of herpes zoster and 1 case of superinfection of ulcerated tumor lesions for patients medicated with bexarotene. In all, 4 patients among those medicated with ATRA were treated for infections including pneumonia, urinary tract infection, and superficial skin infections. A total of 15 patients (45%) treated with ATRA developed hypertriglyceridemia (9 grade I and 6 grade II). One patient had grade IV hyperlipidemia, which resolved after 4 weeks of discontinuation from therapy. A total of 15 patients (80%) treated with bexarotene displayed elevated triglyceride levels, mostly grade II. In all, 3 patients developed grade III and 3 patients developed grade IV hypertriglyceridemia. After dose reduction and/or removal from therapy for 2 to 4 weeks, levels decreased to almost baseline. One patient developed a triglyceride level of 1470 mg/dl despite concomitant triple antilipid therapy. Withholding treatment resulted in an immediate recovery. No pancreatitis occurred. Lipidlowering agents were required in 18 (95%) of the patients medicated with bexarotene. Hypothyroidism occurred only for patients medicated with bexarotene. In all, 15 patients developed
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decreased thyrotropin and T4 levels. Associated symptoms including fatigue, general malaise, cold intolerance, weakness, and constipation, but resolved with hormone replacement.
DISCUSSION The results of our completed phase II study of ATRA for MF and the recently published experience with bexarotene, with its different pharmacokinetic and toxicity profile, provided a rational basis to compare the efficacy, toxicity, and survival between 2 cohorts of patients with MF/SS treated for more than 10 years at a single referral center. Small, nonrandomized, clinical trials with a variety of RAR-specific retinoids other than ATRA have been performed in the past in a limited number of patients with CTCL, reporting response rates between 44% and 67%.10-17 Criteria for response were usually limited to the appearance of the skin. ATRA has been widely and effectively used in the therapy of acute promyelocytic leukemia, but this is the first trial of its use for the treatment of MF/SS. Bexarotene is the first retinoid approved by the FDA for the treatment of cutaneous manifestations of refractory CTCL. In 2 multicenter phase II to III clinical trials it has been tested in patients with early and advanced stages of CTCL.33,34 Of patients with refractory early-stage CTCL, 54% responded to therapy at doses of 300 mg/m2/d with a CR rate of 7%. The overall response rate for patients with refractory advanced-stage CTCL was 45% at the same dosage. Our retrospective study did not demonstrate significant differences in response rates between the ATRA- and bexarotene-medicated groups. Patients with refractory stage IB through IVB disease treated with bexarotene had an overall response rate of 21% at recommended doses of 300 mg/m2 with a median duration of 7.3 months. The overall response rate to ATRA was 12% with a median duration of 20.5 months. One patient (3%) achieved and maintained a CR at 36 months. Compared with our ATRA-treated group, higher rates of PR and CR in RAR agonists have been previously reported. This might be related to the fact that patients in prior studies were not strictly limited to those with relapsed CTCL.11-14 In fact, most enrolled patients had not received or were exposed to less frequent therapy. In addition, different response criteria were often used with bias for a greater level of positive outcome. Usually, response was focused only on skin improvement, without rigorous systemic blood evaluation or biopsy specimens to prove histologic resolution. Compared with previously published data, our results also showed significantly lower rates of re-
sponse for bexarotene. The differences might be related to patient selection and sample size, but also may be a result of differences in response criteria. Prior studies have relied on a tool known as the physician’s global assessment that is heavily weighted toward the skin assessment. Despite clinical responses of cutaneous manifestations in our patients with advanced CTCL, we often could not detect an objective response on the basis of our response criteria, which included tests for evaluation of cutaneous and extracutaneous manifestations. Prior studies may also have overestimated the cutaneous improvement using a composite assessment scale for index cutaneous lesions defined in 8 grades including scale, erythema, and elevation of plaque, whereas a cutaneous response in our patients required at least a 50% reduction of area of lesions. Differences in dosage adjustments or protocol design might also have contributed to the different response rates. Once our patients were given the diagnosis of disease progression, despite cutaneous improvement, they were immediately switched to other therapeutic regimens and, therefore, were more likely to be classified as treatment failures. The overall survival and event-free survival times were not significantly different between our 2 treatment groups, suggesting a similar efficacy profile when used as a monotherapeutic agent. Adverse events were more common in ATRA with a broader spectrum, but usually mild (grade I) and to a lesser extent moderate (grade II) at presentation. Mucocutaneous symptoms, hyperlipidemia, and headache were the most common side effects. With the exception of hyperlipidemia, the toxic effects of bexarotene are distinct from ATRA-induced events. The most frequent bexarotene-related adverse events included hypothyroidism, cytopenia, and hyperlipidemia. These side effects are consistent with those previously reported, were generally manageable with oral medications or dose interruptions, and were totally reversible after discontinuation from treatment. A transient phenomenon with cutaneous improvement of erythema, pruritus, and subjective improvement in quality of life was observed in 10 patients with erythrodermic MF/SS when treated with bexarotene, despite the lack of an objective clinical response when extracutaneous manifestations were considered. The reason for the transient clinical response is not yet known. Possibly the immunomodulatory potency of bexarotene may cause a transient cutaneous T-helper cell 1 cytokine production that alters lymphocyte trafficking.37 Similarly, RAR retinoids in coculture with IL-2 have been shown to synergistically up-regulate the expression of the T-helper cell 1 cytokine interferon
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gamma, with ATRA as the most potent inducing agent.28 Thus, retinoids may not work in a traditional antineoplastic cytotoxic fashion, but rather may alter the distribution of the lymphocyte subsets from the skin compartment to the lymph nodes or blood. In conclusion, our data indicate that there does not appear to be significant differences in the modest response rates and survival times in patients with relapsed CTCL treated with the RAR-selective retinoid, ATRA, and the RXR-selective retinoid, bexarotene. Both have a favorable toxicity profile that can be managed with medications. The symptomatic toxicity profile caused by bexarotene seems to be limited to laboratory values and, hence, is symptomatically better tolerated. Our results demonstrate a relatively modest degree of efficacy for both compounds. In addition, the pharmacokinetic profile of ATRA is known to be inferior because of induction of its own metabolism through the P450 cytochrome pathway and possibly through up-regulation of cellular retinoic acidebinding proteins.38-40 Attempts to treat patients at the maximum tolerated dose have been limited by this phenomenon. Although RXR ligands are metabolized by hepatic cytochrome P450 as well, bexarotene may exert different effects through interaction with different isozymes.41 Pharmacokinetic studies on bexarotene did not result in autoinduction of its own metabolism.42 The optimal role for both retinoids may not be as monotherapeutic treatment options. Rather, immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using these agents in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.43 REFERENCES 1. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphoma study group of the European organization for research and treatment of cancer. Blood 1997;90:354-71. 2. Bunn PA, Lamberg SI. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treat Rep 1979;63:725-8. 3. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the international society for cutaneous lymphomas. J Am Acad Dermatol 2002;46:95-106. 4. Querfeld C, Guitart J, Kuzel TM, Rosen ST. Primary cutaneous lymphomas: a review with current treatment options. Blood Rev 2003;17:131-424. 5. Ivanova D, Gaudon C, Rossin A, Bourguet W, Gronemeyer H. RAR-RXR selectivity and biological activity of new retinoic acid analogues with heterocyclic or polycyclic aromatic systems. Bioorg Med Chem 2002;10:2099-102. 6. Chambon P. The retinoid signaling pathway: molecular and genetic analysis. Semin Mol Biol 1994;5:115-25. 7. Camacho LH. Clinical applications of retinoids in cancer medicine. J Biol Regul Homeost Agents 2003;17:98-114.
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