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Case Report/Case Series |

Clinical Activity of Lenalidomide in Visceral Human Immunodeficiency Virus–Related Kaposi Sarcoma FREE

Maud Steff, MD1,2; Véronique Joly, MD, PhD2,3; Julie Di Lucca, MD1,2; Judith Feldman, MD2,4; Samuel Burg, MD2,5; Laure Sarda-Mantel, MD2,5; Gilles Peytavin, MD, PhD6; Eduardo Marinho, MD2,7; Béatrice Crickx, MD, PhD1,2; Eric Raymond, MD, PhD2,8; Sylvie Lariven, MD2,3; Eve Maubec, MD1,2
[+] Author Affiliations
1Service de Dermatologie, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
2Université Paris Diderot Sorbonne Paris Cité, Paris, France
3Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
4Service de Médecine Interne, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
5Service de Médecine Nucléaire, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
6Service de Pharmacie, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
7Service d’Anatomie et Cytologie Pathologiques, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
8Service d’Oncologie Médicale, Hôpital Beaujon-Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
JAMA Dermatol. 2013;149(11):1319-1322. doi:10.1001/jamadermatol.2013.5751.
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Published online

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.

Figures in this Article

Kaposi 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 HIV-related KS whose disease progresses or who cannot tolerate chemotherapy, novel anticancer agents are warranted.

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%.68 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.

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 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 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).

Place holder to copy figure label and caption
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.

Graphic Jump Location

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 evaluation showed a partial response with major reduction of hypermetabolic abnormalities, especially disappearance of lung, hepatic, and pancreatic lesions.

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

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.

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 HIV-associated 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 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.

Accepted for Publication: May 21, 2013.

Corresponding Author: Maud Steff, MD, APHP, Hôpital Bichat, Service de Dermatologie, 46 rue Henri Huchard, 75018 Paris, France (maudsteff@hotmail.com).

Published Online: September 30, 2013. doi:10.1001/jamadermatol.2013.5751.

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, 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.

Conflict of Interest Disclosures: None reported.

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.
PubMed   |  Link to Article
Serraino  D, De Paoli  A, Zucchetto  A,  et al.  The impact of Kaposi sarcoma and non-Hodgkin lymphoma on mortality of people with AIDS in the highly active antiretroviral therapies era. Cancer Epidemiol. 2010;34(3):257-261.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Uldrick  TS, Whitby  D.  Update on KSHV epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett. 2011;305(2):150-162.
PubMed   |  Link to Article
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.
PubMed
Ben M’barek  L, Fardet  L, Mebazaa  A,  et al.  A retrospective analysis of thalidomide therapy in non-HIV-related Kaposi’s sarcoma. Dermatology. 2007;215(3):202-205.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Davies  F, Baz  R.  Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010;24(suppl 1):S13-S19.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

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.
PubMed   |  Link to Article
Serraino  D, De Paoli  A, Zucchetto  A,  et al.  The impact of Kaposi sarcoma and non-Hodgkin lymphoma on mortality of people with AIDS in the highly active antiretroviral therapies era. Cancer Epidemiol. 2010;34(3):257-261.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Uldrick  TS, Whitby  D.  Update on KSHV epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett. 2011;305(2):150-162.
PubMed   |  Link to Article
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.
PubMed
Ben M’barek  L, Fardet  L, Mebazaa  A,  et al.  A retrospective analysis of thalidomide therapy in non-HIV-related Kaposi’s sarcoma. Dermatology. 2007;215(3):202-205.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Davies  F, Baz  R.  Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010;24(suppl 1):S13-S19.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article

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