Research
Case Report/Case Series
Clinical Activity of Lenalidomide in Visceral Human Immunodeficiency Virus–Related Kaposi Sarcoma Maud Steff, MD; Véronique Joly, MD, PhD; Julie Di Lucca, MD; Judith Feldman, MD; Samuel Burg, MD; Laure Sarda-Mantel, MD; Gilles Peytavin, MD, PhD; Eduardo Marinho, MD; Béatrice Crickx, MD, PhD; Eric Raymond, MD, PhD; Sylvie Lariven, MD; Eve Maubec, MD
IMPORTANCE Curative treatment of aggressive Kaposi sarcoma (KS) with conventional
chemotherapy in human immunodeficiency virus (HIV)–infected patients remains difficult. The administration of thalidomide, an immunomodulatory drug with antiangiogenic effects, is limited by its toxicity. This engenders interest in evaluating thalidomide analogues such as lenalidomide with better toxicity profiles. To our knowledge, we describe for the first time a patient with visceral KS successfully treated with lenalidomide. OBSERVATIONS A man with advanced visceral HIV-related KS progressing after 11 months of highly active antiretroviral therapy (HAART) and 2 lines of conventional chemotherapy (pegylated liposomal doxorubicin and docetaxel) was treated with lenalidomide on a compassionate use basis. He showed a rapid partial response without any substantial adverse effect but experienced relapse after 5 months of treatment, in a context of virologic failure. CONCLUSIONS AND RELEVANCE Similar to our observation, good partial response without toxic effects has been reported in 3 patients with only skin involvement. Because immune reconstitution syndrome may occur in HIV-infected patients with KS undergoing HAART, KS improvement may be partly explained by immune recovery. An ongoing US phase 1/2 trial will better evaluate the efficacy and tolerance of lenalidomide in patients with HIV-related KS with and without visceral involvement.
Corresponding Author: Maud Steff, MD, APHP, Hôpital Bichat, Service de Dermatologie, 46 rue Henri Huchard, 75018 Paris, France (maudsteff @hotmail.com).
JAMA Dermatol. 2013;149(11):1319-1322. doi:10.1001/jamadermatol.2013.5751 Published online October 2, 2013.
K
aposi sarcoma (KS) is a highly angioproliferative tumor caused by the human herpesvirus 8. Human immunodeficiency virus (HIV)–related KS usually displays aggressive clinical behaviors and is often associated with early occurrence of lymph node and visceral metastases. Kaposi sarcoma was the most frequent cancer in HIV-infected patients before the use of highly active antiretroviral therapy (HAART). Although the frequency of KS has decreased following the introduction of HAART, KS remains the second most frequent cancer in HIV-infected patients1 and is acknowledged as being the immediate cause of 5% of deaths in patients with AIDS receiving HAART.2,3 When HIV infection is diagnosed concomitantly with KS, HAART, including protease inhibitors, may be the first treatment step to slow tumor progression. However, a combination of HAART with chemotherapy can also be used in patients with visceral and/or rapidly progressive disease. 4 Drugs used in conventional chemotherapies include liposomal doxorubicin, paclitaxel, and oral etoposide, yielding antitumor activity but also displaying dose-limiting hematological toxicity.5 For patients with HIVrelated KS whose disease progresses or who cannot tolerate chemotherapy, novel anticancer agents are warranted. jamadermatology.com
Author Affiliations: Author affiliations are listed at the end of this article.
In recent years, thalidomide, a drug with potent antiangiogenic properties, has been proposed for the treatment of patients with HIV-related and non–HIV-related KS. In those patients, thalidomide treatment was associated with partial response rates ranging from 27% to 47%, but the frequency of withdrawal owing to toxic effects was 23% to 35%.6-8 Thus, there is an interest in evaluating thalidomide analogues such as lenalidomide that have better toxicity profiles. Herein, we describe the outcome of a patient with visceral HIV-related KS successfully treated with lenalidomide.
Report of a Case In November 2010, a 49-year-old African man presented with cutaneous nodular tumors, lymphedema of the left lower limb, and palpable left inguinal lymph nodes in the context of HIV infection. Tumor biopsies confirmed pathological features of typical KS. Serum CD4 cell counts were 79 cells/μL, and HIV viral load was 200 000 copies/mL. The patient was first treated with HAART (darunavir + ritonavir + etravirine + raltegravir potassium). Despite an increase of CD4 count to 112 cells/μL JAMA Dermatology November 2013 Volume 149, Number 11
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Figure 1. Gangrene Extension After Conventional Chemotherapy
After 2 lines of conventional chemotherapy, the gangrene extended to all left toes, with leg and foot ulcers causing life-threatening bleeding.
Figure 2. Positron-Emission Tomography With Computed Tomography (PET/CT) Scan Before LenalidomideTreatment
Before treatment with lenalidomide, a PET/CT scan showed visceral extent of the Kaposi sarcoma, with diffuse bone marrow, lymph node, lung, hepatic, and pancreatic metastases.
and a decrease in HIV viral load to less than 55 copies/mL in February 2011, the skin lesions of the lower limb worsened. At this time, a computed tomographic scan of chest, abdomen, and pelvis showed only left inguinal and external iliac lymph 1320
Figure 3. Positron-Emission Tomography With Computed Tomography (PET/CT) Scan After Lenalidomide Treatment
After 2 cycles of lenalidomide, PET/CT scan evaluation showed a partial response with major reduction of hypermetabolic abnormalities, especially disappearance of lung, hepatic, and pancreatic lesions.
node involvement. Six cycles of pegylated liposomal doxorubicin were delivered every 28 days. Despite this chemotherapy, in August 2011, he presented with extended ulcers on the left leg and dry gangrene of the second, third, fourth, and fifth left toes. Evaluation of his KS showed visceral involvement with diffuse bone marrow, lung, hepatic, and pancreatic metastases that were confirmed by pathologic analysis. This patient underwent 2 cycles of docetaxel treatment and experienced dose-limiting clinical and biological adverse effects consisting of Common Terminology Criteria for Adverse Events grade 3 diarrhea, grade 4 neutropenia, and grade 3 anemia. After this second-line chemotherapy, in September 2011, the gangrene extended to all left toes, with leg and foot ulcers causing life-threatening bleeding (Figure 1). Lifesaving transfemoral amputation had to be performed. A positron-emission tomography with computed tomography (PET/CT) scan confirmed visceral progression (Figure 2). At the time of progression, the serum CD4 cell count was 469 cells/μL and the HIV viral load was 124 copies/mL. Lenalidomide was then introduced on a compassionate use basis at 1 daily oral dose of 25 mg for 21 days every 28 days. In November 2011, after 2 weeks of treatment, evidence of clinical benefit was already observed, consisting of the regression of lymphedema of the left thigh, healing of the amputation stump, and an improvement of the patient’s general condition (Figure 3). After 2 cycles of lenalidomide treatment, the patient’s Eastern Cooperative Oncology Group performance status substantially improved from 4 to 2 and almost complete disappearance of lymphedema and inguinal lymph nodes was observed, along with a rapid epithelialization of the amputation stump. Furthermore, PET/CT scan
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Lenalidomide in Visceral Kaposi Sarcoma
Case Report/Case Series Research
evaluation showed a partial response with major reduction of hypermetabolic abnormalities, especially disappearance of lung, hepatic, and pancreatic lesions. The partial response lasted 5 months, without any substantial adverse effect. In December 2011, a virologic failure was diagnosed (CD4 cell counts were 315 cells/μL and HIV viral load was 11 000 copies/mL). Genotypic resistance testing demonstrated resistance to an integrase inhibitor (raltegravir) and a nonnucleoside reverse transcriptase inhibitor (etravirine). In February 2012, 2 months after a switch to a CCR5 receptor antagonist (maraviroc), CD4 cell counts were 411 cells/μL and the HIV viral load was still 10 600 copies/mL. At this time, after 5 cycles of lenalidomide treatment, lymphedema of the left thigh and inguinal lymph nodes showed evidence of progression that was confirmed in March 2012 using PET/CT scan.
Discussion This patient presented with an extremely severe cutaneous and visceral KS involvement that did not respond to conventional chemotherapies. When the decision was made to introduce lenalidomide, the patient's life was under threat. After only 2 weeks of treatment, the clinical benefit was clear and the life expectancy was better. The first assessment after 2 cycles of lenalidomide treatment showed an objective partial response that lasted 5 months. Lenalidomide, an analogue of thalidomide, is an immunomodulatory drug, with antiangiogenic, direct effects on tumor and stroma cells, and immune-stimulatory properties.9 Lenalidomide is currently registered for the treatment of patients with multiple myeloma who have already received at least 1 other therapy and for those with myelodysplastic syndrome with chromosome 5q deletion. To our knowledge, only 3 cases of HIVassociated KS have been previously successfully treated with lenalidomide, all reported in 1 article by Martinez et al.10 After failure of conventional chemotherapies, these 3 patients showed KS lesions limited to the skin without visceral involvement. Similar to our observation, no substantial adverse effects were reported during treatment (8-24 months). Partial responses were observed after 1 and 2 months and were maintained for 12 and 14 months in 2 patients with no toxic effects. The initial worsening during the first months of HAART could be considered a paradoxical immune reconstitution inflammatory syndrome (IRIS). Achenbach et al11 showed that paradoxical IRIS occurred in the first year of HAART in 29% of patients with KS, starting a median of 2 to 3 months after
ARTICLE INFORMATION Accepted for Publication: May 21, 2013. Published Online: October 2, 2013. doi:10.1001/jamadermatol.2013.5751. Author Affiliations: Service de Dermatologie, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Steff, Di Lucca, Crickx, Maubec); Université Paris Diderot Sorbonne Paris Cité, Paris, France (Steff, Joly, Di Lucca, Feldman, Burg, Sarda-Mantel, Marinho, Crickx, Raymond, Lariven, Maubec); Service de Maladies Infectieuses jamadermatology.com
HAART initiation. The median duration of visceral KS IRIS was 206 days.11 Our patient did not fulfill the clinical criteria required to meet the definition of paradoxical IRIS: he did not have clinical localized cutaneous or lymph node inflammation or any radiologic or histopathological inflammatory manifestation. However, we cannot totally exclude the role of immune reconstitution in disease progression. Improvement in KS with lenalidomide treatment may be partly explained by immune system recovery. However, the quick improvement in KS after the introduction of lenalidomide, like in the 3 cases reported by Martinez et al,10 leads us to believe that lenalidomide played at least a major role. Lenalidomide seems to be a particularly interesting anticancer drug for HIV-related KS because the use of other anticancer treatment in patients with HIV infection can be limited by adherence, toxicity, and by pharmacokinetic interactions with antiretroviral therapy. In this case, an increased viral load was observed during lenalidomide treatment; thus, lenalidomide may have interfered with HIV plasma viral loads. The majority of lenalidomide is eliminated by renal excretion. Although no interaction of lenalidomide with tubular renal secretion has been demonstrated, viral load monitoring during lenalidomide treatment would be of interest if further development of lenalidomide is considered. Even if lenalidomide was better tolerated than thalidomide, frequent adverse events have been reported for lenalidomide in combination with dexamethasone, such as neutropenia, asthenia, constipation, muscle cramps, thrombopenia, anemia, diarrhea, and skin rash. There is also a substantial risk of deep venous thrombosis and pulmonary embolism. Because of structural similarity with thalidomide, the potential for teratogenicity of lenalidomide limits its use in female patients of childbearing potential if no contraception is used. Furthermore, patients must be closely monitored for potential neurotoxic effects. The US Food and Drug Administration recently warned the public of an increased risk of second primary cancers in patients with newly diagnosed multiple myeloma who received lenalidomide. In clinical trials conducted with lenalidomide for myeloma, patients had an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma. Therefore, despite encouraging evidence of activity such as that reported in our patient, further clinical evaluation of lenalidomide in KS is to be restricted to clinical trials. An ongoing phase 1/2 trial in the United States (NCT01057121) will better evaluate the efficacy and tolerance of lenalidomide in patients with HIV-related KS with and without visceral involvement.
et Tropicales, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Joly, Lariven); Service de Médecine Interne, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Feldman); Service de Médecine Nucléaire, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Burg, Sarda-Mantel); Service de Pharmacie, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Peytavin); Service d’Anatomie et Cytologie Pathologiques, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
(Marinho); Service d’Oncologie Médicale, Hôpital Beaujon-Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France (Raymond). Author Contributions: Drs Steff and Maubec had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Steff, Raymond, Maubec. Acquisition of data: Steff, Joly, Di Lucca, Feldman, Burg, Sarda-Mantel, Peytavin, Crickx, Raymond. Analysis and interpretation of data: Steff, Di Lucca,
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Burg, Sarda-Mantel, Marinho, Crickx, Raymond, Lariven, Maubec. Drafting of the manuscript: Steff, Di Lucca, Burg, Peytavin, Raymond, Maubec. Critical revision of the manuscript for important intellectual content: Steff, Joly, Feldman, Sarda-Mantel, Marinho, Crickx, Raymond, Lariven, Maubec. Obtained funding: Di Lucca. Administrative, technical, or material support: Burg, Sarda-Mantel, Peytavin. Study supervision: Joly, Crickx, Raymond, Lariven, Maubec.
lymphoma on mortality of people with AIDS in the highly active antiretroviral therapies era. Cancer Epidemiol. 2010;34(3):257-261. 3. Sodqi M, Marih L, Lahsen AO, et al. Causes of death among 91 HIV-infected adults in the era of potent antiretroviral therapy [in French]. Presse Med. 2012;41(7-8):e386-e390. 4. Martellotta F, Berretta M, Vaccher E, Schioppa O, Zanet E, Tirelli U. AIDS-related Kaposi’s sarcoma: state of the art and therapeutic strategies. Curr HIV Res. 2009;7(6):634-638.
REFERENCES
5. Uldrick TS, Whitby D. Update on KSHV epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett. 2011;305(2):150-162.
1. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762.
6. Little RF, Wyvill KM, Pluda JM, et al. Activity of thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol. 2000;18(13):2593-2602.
2. Serraino D, De Paoli A, Zucchetto A, et al. The impact of Kaposi sarcoma and non-Hodgkin
7. Ben M’barek L, Fardet L, Mebazaa A, et al. A retrospective analysis of thalidomide therapy in
Conflict of Interest Disclosures: None reported.
non-HIV-related Kaposi’s sarcoma. Dermatology. 2007;215(3):202-205. 8. Fife K, Howard MR, Gracie F, Phillips RH, Bower M. Activity of thalidomide in AIDS-related Kaposi’s sarcoma and correlation with HHV8 titre. Int J STD AIDS. 1998;9(12):751-755. 9. Davies F, Baz R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010;24(suppl 1):S13-S19. 10. Martinez V, Tateo M, Castilla MA, Melica G, Kirstetter M, Boué F. Lenalidomide in treating AIDS-related Kaposi’s sarcoma. AIDS. 2011;25(6):878-880. 11. Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Clin Infect Dis. 2012;54(3):424-433.
NOTABLE NOTES
Religion and the Skin: Devotional Dermatoses Barry Ladizinski, MD; Kachiu C. Lee, MD, MPH
Various dermatologic conditions have been described in association with religious practices.1 Allergic contact dermatitis (ACD) to potassium dichromate in leather straps of tefillin (phylacteries) is commonly reported in observant Jewish males who put on tefillin during morning prayer. Among Hindu women, ACD has been reported from bindi (the red adhesive disc worn on the forehead) and kumkum (red powder used for religious markings), and contact depigmentation has been reported from bindi’s adhesive (para-tertiary-butylphenol). A foreign body granuloma developed on the forehead of 4-year-old Hindu boy who wore his mother’s bindi for 8 months. ACD has also been reported from a wooden cross necklace worn by a Christian man and from ceremonial perfume used by a Muslim man.1 Dermatoses secondary to increased pressure or friction incurred during prolonged periods of prayer are also commonly reported. “Prayer marks” or “prayer nodules” are asymptomatic, hyperpigmented, lichenified, nodular callosities that are found on the forehead, knees, ankles, and dorsa of the feet in Muslim men, who pray 5 times daily. Similarly, “pew blisters” or “prayer blisters” were reported in a Catholic woman who developed bullae on both knees from repeated kneeling in church. An Israeli study described 13 Orthodox Jewish male Yeshiva students with asymptomatic elongated, hyperpigmented, hyperkeratotic patches on the bony protuberances of the dorsal spine that developed from repeated swaying against a rigid backboard during prayer (davening). The skin findings were consistent with friction hypermelanosis, which the authors termed “davener’s dermatosis.”1 Cutaneous infections are common among religious individuals who live or pray in shared spaces. Over 80% of Muslim men who worship at various mosques in Durban, South Africa, were found to have tinea pedis or unguium, and dermatophytes and yeast were isolated from the floors and carpets in all of the mosques.2 Orf was reported in 9 Muslim individuals following contact with sheep and goats during the Sacrifice
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Feast in Turkey, and impetigo was prominent in a study of Hajj pilgrims in Saudi Arabia. An outbreak of methicillin-resistant Staphylococcus aureus skin infections was reported in an unspecified religious community in Pennsylvania. Other reports of religion-associated dermatoses include a Catholic woman with celiac disease who developed dermatitis herpetiformis following ingestion of a gluten-containing wafer during communion and 12 Taoist disciples with second- and third-degree plantar burns after walking over burning coals during a firewalking cleansing ceremony.1 Traction alopecia of the frontal scalp and submandibular beard has been reported in Sikh men, who are forbidden from cutting their hair and thus tie the hair into tight knots.1 Vitamin D deficiency has been reported in Orthodox Jewish, Muslim, and Seventh Day Adventist communities, as they customarily wear clothing that allows minimal exposure to sunlight. This type of dress can serve also serve a protective role, as one study found lower rates of malignant melanoma in Orthodox Jews when compared with non-Orthodox Jews.3 Author Affiliations: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Ladizinski); Department of Dermatology, Brown University, Providence, Rhode Island (Lee). Corresponding Author: Barry Ladizinsk, MD, Johns Hopkins Bloomberg School of Public Health, 300 N Charles St, Ste 304, Baltimore, MD 21201 (
[email protected]). 1. Feit NE, Weinberg JM, DeLeo VA. Cutaneous disease and religious practice: case of allergic contact dermatitis to tefillin and review of the literature. Int J Dermatol. 2004;43(12):886-888. 2. Raboobee N, Aboobaker J, Peer AK. Tinea pedis et unguium in the Muslim community of Durban, South Africa. Int J Dermatol. 1998;37(10):759-765. 3. Vardi G, Modan B, Golan R, Novikov I, Shafir R. Orthodox Jews have a lower incidence of malignant melanoma: a note on the potentially protective role of traditional clothing. Int J Cancer. 1993;53(5):771-773.
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