今日の臨床サポート

Kaposi肉腫

著者: 加藤哲朗 日比谷クリニック/東京医科大学病院感染症科

監修: 味澤篤 がん・感染症センター 都立駒込病院

著者校正/監修レビュー済:2022/08/17
患者向け説明資料

概要・推奨   

  1. カポジ肉腫のリスクは、CD4陽性リンパ球数が減少するほど増加し、特にCD4陽性リンパ球数が200個/μL未満で急激に増加する(推奨度1)
  1. 肺のカポジ肉腫は予後不良である(推奨度2)
  1. リポゾーム化ドキソルビシンはカポジ肉腫に有効である(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
加藤哲朗 : 特に申告事項無し[2022年]
監修:味澤篤 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、新たな治療方法に関する研究について加筆した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. カポジ肉腫はAIDS患者に発生する代表的な悪性腫瘍である。主に皮膚や粘膜および消化管や肺などの内臓臓器に発生する。
  1. 原因はヒトヘルペスウイルス8(human herpes virus-8: HHV-8)であり、潜伏感染していたHHV-8が免疫力の低下に伴ってカポジ肉腫を発症すると考えられている[1]
  1. HIV感染者において、CD4陽性リンパ球数が500個/μL未満で発症リスクが増加し、特に200個/μL未満でのリスクが高い[2]
  1. 疫学的な特徴として、カポジ肉腫患者のほとんどが男性同性間性的接触者(MSM)であることが挙げられる。
 
  1. カポジ肉腫のリスクは、CD4陽性リンパ球数が減少するほど増加し、特にCD4陽性リンパ球数が200個/μL未満で急激に増加する(推奨度1O)
  1. まとめ:カポジ肉腫はCD4陽性リンパ球数が高値でも発症しうるが、CD4陽性リンパ球数が200個/μL未満で特にリスクが増加する。
  1. 研究内容:Lodiらは1986年~2006年で555例のカポジ肉腫患者を対象とした研究で、CD4陽性リンパ球数が200個/μL未満の患者、200~349個/μL、350~499個/μLの患者では、CD4陽性リンパ球数が500個/μL以上の患者と比してカポジ肉腫の発生リスクがそれぞれ18.9倍、3.6倍、4.1倍であった[2]
問診・診察のポイント  
HIV感染症のリスクの確認:
  1. リスクの高い性行為歴、特に同性間性交渉歴

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文献 

G Rezza, M Andreoni, M Dorrucci, P Pezzotti, P Monini, R Zerboni, B Salassa, V Colangeli, L Sarmati, E Nicastri, M Barbanera, R Pristerà, F Aiuti, L Ortona, B Ensoli
Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.
J Natl Cancer Inst. 1999 Sep 1;91(17):1468-74.
Abstract/Text BACKGROUND: The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV.
METHODS: We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided.
RESULTS: Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84).
CONCLUSIONS: Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.

PMID 10469747
Sara Lodi, Marguerite Guiguet, Dominique Costagliola, Martin Fisher, Andrea de Luca, Kholoud Porter, CASCADE Collaboration
Kaposi sarcoma incidence and survival among HIV-infected homosexual men after HIV seroconversion.
J Natl Cancer Inst. 2010 Jun 2;102(11):784-92. doi: 10.1093/jnci/djq134. Epub 2010 May 4.
Abstract/Text BACKGROUND: Despite the success of combination antiretroviral therapy (cART) in reducing the incidence of Kaposi sarcoma, HIV-infected individuals who have responded to treatment continue to be diagnosed with Kaposi sarcoma. We examine factors associated with the incidence of Kaposi sarcoma among cART-treated HIV-infected homosexual men and changes in their survival after its diagnosis over calendar time.
METHODS: Data were from HIV-infected homosexual men with well-estimated dates of HIV seroconversion (ie, change in status from being HIV negative to having HIV antibodies detected). Incidence of Kaposi sarcoma was calculated. We used Kaplan-Meier methods to determine survival after Kaposi sarcoma diagnosis in three calendar periods: before 1996, 1996-2000, and 2001-2006. Poisson models were used to examine the effect of risk factors such as current and nadir CD4 cell count (ie, the lowest CD4 cell count ever recorded for a person), duration of infection, and age at diagnosis for Kaposi sarcoma incidence in cART-treated men. All statistical tests were two-sided.
RESULTS: Among the 9473 men, 555 were diagnosed with Kaposi sarcoma in the period 1986-2006, of whom 319 died. The percentage surviving 24 months after Kaposi sarcoma diagnosis rose statistically significantly during the study period from 35% (95% confidence interval [CI] = 29% to 42%) before 1996 to 84% (95% CI = 76% to 90%) in 1996-2000 and to 81% (95% CI = 70% to 88%) in 2001-2006 (P < .001). Seventy men were diagnosed with Kaposi sarcoma after starting cART. Current (ie, within 6 months) CD4 cell count was associated with incidence of Kaposi sarcoma among cART-treated men (rate ratios [RRs] = 18.91, 95% CI = 8.50 to 42.09, for CD4 level category <200 cells per cubic millimeter; RR = 3.55, 95% CI = 1.40 to 9.00, for 200-349 cells per cubic millimeter; and RR = 4.11, 95% CI = 1.74 to 9.70, for 350-499 cells per cubic millimeter; all compared with > or = 500 cells per cubic millimeter). After adjustment for current CD4 cell count, HIV infection duration, age, or nadir CD4 cell count was not associated with Kaposi sarcoma incidence.
CONCLUSIONS: Among cART-treated HIV-infected homosexual men, current CD4 cell count was the factor most strongly associated with the incidence of Kaposi sarcoma. Survival estimates after Kaposi sarcoma diagnosis have improved over time.

PMID 20442214
H Katano, Y Sato, T Kurata, S Mori, T Sata
High expression of HHV-8-encoded ORF73 protein in spindle-shaped cells of Kaposi's sarcoma.
Am J Pathol. 1999 Jul;155(1):47-52. doi: 10.1016/S0002-9440(10)65097-3.
Abstract/Text Human herpesvirus 8 (HHV-8) has been demonstrated previously in Kaposi's sarcoma (KS) tissues by immunohistochemistry, in situ polymerase chain reaction, and in situ hybridization. The HHV-8-encoded protein ORF73 is a 222- or 234-kd protein named latent nuclear antigen (LNA) or latency-associated nuclear antigen (LANA) that is identified in HHV-8-infected cell lines by immunofluorescence assay. In the present study, a rabbit antibody against a recombinant ORF73 protein was developed. Immunofluorescent staining of a HHV-8-infected cell line, TY-1, showed that the staining pattern of the anti-ORF73 antibody overlapped completely the LANA staining pattern obtained using KS patients' sera. Immunoblotting analysis showed that the anti-ORF73 antibody reacted specifically with 222- and 234-kd proteins that were present in TY-1 and BCBL-1 cell lysates. Immunohistochemistry using a catalyzed signal amplification system demonstrated that the anti-ORF73 antibody reacted exclusively with the majority of KS spindle-shaped cells, showing a nuclear dot-like staining pattern. Some of the ORF73 protein-positive cells also expressed CD34 and vimentin but not CD68 or factor-VIII-related antigen. These data indicate that the anti-ORF73 antibody recognizes LANA and that most KS cells are infected with HHV-8 in the latent phase. Our findings also suggest that ORF73 protein plays an important role in the pathogenesis of KS.

PMID 10393835
H T Turoglu, M F Akisik, S Y Naddaf, W S Omar, J S Kempf, H M Abdel-Dayem
Tumor and infection localization in AIDS patients: Ga-67 and Tl-201 findings.
Clin Nucl Med. 1998 Jul;23(7):446-59.
Abstract/Text Examples of Ga-67 and Tl-201 scans in AIDS patients performed at St. Vincent's Hospital and Medical Center of New York are presented. Use of these methods is the adopted approach at this institution in AIDS patients for localizing sites of tumor or infection involvement. A Ga-67 scan is the most common nuclear medicine examination performed on AIDS patients. Sequential Tl-201 and Ga-67 scans have a role in differentiating Kaposi's sarcoma from malignant lymphoma and opportunistic infections. For intracranial lesions, Tc-99m MIBI or Tl-201-201-201-201 chloride can differentiate malignant from benign inflammatory lesions.

PMID 9676950
B Holkova, K Takeshita, D M Cheng, M Volm, C Wasserheit, R Demopoulos, A Chanan-Khan
Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi's sarcoma treated with chemotherapy.
J Clin Oncol. 2001 Sep 15;19(18):3848-51. doi: 10.1200/JCO.2001.19.18.3848.
Abstract/Text PURPOSE: Kaposi's sarcoma (KS) is the most common AIDS-related malignancy. Pulmonary involvement by KS (PKS) has carried a poor prognosis with median reported survival ranging from 3 to 10 months. We studied whether the introduction of highly active antiretroviral therapy (HAART; triple antiretroviral therapy including a protease inhibitor and two reverse transcriptase inhibitors) has been associated with improved survival for AIDS patients with PKS.
PATIENTS AND METHODS: A retrospective study was performed of 37 consecutive patients with PKS and human immunodeficiency virus infection in the tumor registry at a large municipal hospital in New York City between 1994 to 1997. There were 16 patients from 1994 to 1995 (pre-HAART period) and 21 patients from 1996 to 1997 (post-HAART period). The primary end point was survival, which was defined as time from start of chemotherapy until death from any cause.
RESULTS: Patients were analyzed by the date of diagnosis (pre- v post-HAART period) and whether or not they received HAART. Kaplan-Meier analysis showed significantly better survival in patients diagnosed in the post-HAART period (P =.0025). Additional Kaplan-Meier analysis indicated that patients on HAART had substantially better survival (P <.0001). Cox multivariate analyses showed that HAART therapy was associated with a reduced risk of death (hazard ratio = 0.09; 95% confidence interval, 0.03 to 0.69).
CONCLUSION: In patients with AIDS-associated PKS and undergoing chemotherapy, administration of HAART was associated with increased survival.

PMID 11559722
Abstract/Text AIDS-related Kaposi's sarcoma (KS) occurs principally in homosexual or bisexual men infected with the newly identified human herpes virus-8, also called KS-associated herpes virus. Unlike classical forms of the disease, AIDS-associated KS is a multicentric entity that frequently involves lymph nodes and the GI tract. KS may also occur in the lung, commonly in the setting of extensive mucocutaneous disease and very rarely as an isolated event. The exact incidence of intrathoracic KS in patients with AIDS is unknown. Before the advent of highly active antiretroviral therapy (HAART), pulmonary KS had been reported in approximately 10% of patients with AIDS, 25% of patients with cutaneous KS, and in roughly 50% of postmortem examinations of patients with AIDS, KS, and respiratory infections. In the HAART era, the incidence of KS has declined precipitously in North America and Europe but not in third world countries where HAART is largely unavailable. Pulmonary KS may cause radiographic infiltrates and respiratory symptoms that mimic a variety of other infectious and neoplastic processes. An aggressive diagnostic evaluation of patients who have this condition is essential because chemotherapy and radiation therapy may provide significant palliation, particularly if used in conjunction with HAART. This review briefly explores the changing epidemiology of KS. The pathology and pathogenesis of KS is also reviewed, along with the clinical and radiographic presentation, diagnosis, and management of pulmonary KS.

PMID 10767252
M Bower, M Nelson, A M Young, C Thirlwell, T Newsom-Davis, S Mandalia, T Dhillon, P Holmes, B G Gazzard, J Stebbing
Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.
J Clin Oncol. 2005 Aug 1;23(22):5224-8. doi: 10.1200/JCO.2005.14.597.
Abstract/Text PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens.
PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively.
RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS.
CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

PMID 16051964
Chad J Achenbach, Robert D Harrington, Shireesha Dhanireddy, Heidi M Crane, Corey Casper, Mari M Kitahata
Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection.
Clin Infect Dis. 2012 Feb 1;54(3):424-33. doi: 10.1093/cid/cir802. Epub 2011 Nov 17.
Abstract/Text BACKGROUND: The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs.
METHODS: We examined patients in the University of Washington Human Immunodeficiency Virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics, and immunologic changes in patients with and without IRIS.
RESULTS: Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7%-16%) developed paradoxical IRIS in the first year on ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs 7% [1/15], P < .01). Patients with mucocutaneous KS and tuberculosis-IRIS experienced greater median increase in CD4(+) cell count during the first 6 months of ART compared with those without IRIS (+158 vs +53 cells/μL, P = .04, mucocutaneous KS; +261 vs +113, P = .04, tuberculosis).
CONCLUSIONS: Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in >10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality.

PMID 22095568
D W Northfelt, B J Dezube, J A Thommes, B J Miller, M A Fischl, A Friedman-Kien, L D Kaplan, C Du Mond, R D Mamelok, D H Henry
Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial.
J Clin Oncol. 1998 Jul;16(7):2445-51. doi: 10.1200/JCO.1998.16.7.2445.
Abstract/Text PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS).
PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes.
RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin.
CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

PMID 9667262
Timothy Cooley, David Henry, Margaret Tonda, Steven Sun, Martin O'Connell, Wayne Rackoff
A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma.
Oncologist. 2007 Jan;12(1):114-23. doi: 10.1634/theoncologist.12-1-114.
Abstract/Text BACKGROUND: Despite a decreased incidence of AIDS-related Kaposi's sarcoma (KS) due to the advent of highly active antiretroviral therapy, approximately 15% of AIDS patients still develop AIDS-related KS. This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin for the treatment of AIDS-related KS.
METHODS: This was a double-blind, multicenter study that randomized patients with AIDS-related KS to six cycles of pegylated liposomal doxorubicin (20 mg/m2; n = 60) or liposomal daunorubicin (40 mg/m2; n = 19) every 2 weeks. Clinical benefit was assessed using patient questionnaires and monitoring of KS-associated symptoms. Tumor responses were assessed using imaging techniques, direct measurement of skin lesions, and photographs, when possible.
RESULTS: Clinical benefit was observed in 48/60 patients (80%) receiving pegylated liposomal doxorubicin and was maintained for a median of 62 days (range, 28-107 days). Clinical benefit was achieved by 12/19 patients (63.2%) receiving liposomal daunorubicin and was maintained for a median of 55 days (range, 28-84 +days). Clinical benefit correlated with tumor response. Tumor responses were achieved by 55.0% of patients receiving pegylated liposomal doxorubicin and 31.6% of patients receiving liposomal daunorubicin. Response rates were similar within each treatment group when only those patients without changes in antiretroviral therapy during treatment were considered. Adverse events associated with pegylated liposomal doxorubicin were neutropenia (30%), nausea (28.3%), and asthenia (16.7%).
CONCLUSIONS: Pegylated liposomal doxorubicin is safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit, tumor response, or both.

PMID 17227906
Mary Cianfrocca, Sandra Lee, Jamie Von Roenn, Anil Tulpule, Bruce J Dezube, David M Aboulafia, Richard F Ambinder, Jeannette Y Lee, Susan E Krown, Joseph A Sparano
Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy.
Cancer. 2010 Aug 15;116(16):3969-77. doi: 10.1002/cncr.25362.
Abstract/Text BACKGROUND: Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined.
METHODS: Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m2 intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m2 iv every 3 weeks. The KS Functional Assessment of HIV (FAHI) quality of life instrument was used before and after every other treatment cycle.
RESULTS: The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P=.024) and swelling (P<.001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P=.49), median progression-free survival (17.5 months vs 12.2 months; P=.66), and 2-year survival rates (79% vs 78%; P=.75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P=.077).
CONCLUSIONS: Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the HAART era.

Copyright (c) 2010 American Cancer Society.
PMID 20564162
Giuseppe Badalamenti, Lorena Incorvaia, Laura Algeri, Annalisa Bonasera, Alessandra Dimino, Raimondo Scalia, Alessandra Cucinella, Giorgio Madonia, Federica Li Pomi, Antonio Galvano, Valerio Gristina, Francesca Toia, Adriana Cordova, Viviana Bazan, Antonio Russo
Safety and effectiveness of gemcitabine for the treatment of classic Kaposi's sarcoma without visceral involvement.
Ther Adv Med Oncol. 2022;14:17588359221086829. doi: 10.1177/17588359221086829. Epub 2022 Mar 26.
Abstract/Text Background: Classic Kaposi's sarcoma (CKS) is a rare, multifocal, endothelial cell neoplasm that typically occurs in elderly people with previous infection by human herpes virus-8. Prospective trials are rare, and the choice of drugs relies on prospective trials performed on HIV-associated Kaposi's sarcoma (KS). Pegylated liposomal anthracyclines and taxanes are considered the standard first- and second-line chemotherapy, respectively. Despite the indolent biologic behavior, the natural history is characterized by recurrent disease. This condition of chronic administration of cytotoxic drugs is often associated with immediate/long-term adverse events.
Methods: This was an observational, retrospective study to evaluate the effectiveness and safety of gemcitabine in patients with CKS. From January 2016 to September 2021, the patients were treated with gemcitabine 1000 mg/m2 on days 1 and 8, with cycles repeated every 21 days. The treatment was administered as first or second line.
Results: Twenty-seven (27) patients were included in the study. Twenty-one (21) out 27 patients (77.8%) achieved a partial response (PR), including 8 patients with major response (MR) (29.6%) and 13 patients with minor response (mR) (48.2%); 2 (7.4%) showed a complete response (CR), 3 (11.1%) a stable disease (SD), and 1 (3.7%) a progressive disease (PD). Tumor responses were generally rapid, with a median time to first response of 4 weeks (range, 3-12 weeks). Patients who responded had disease improvement with flattening of the skin lesions, decrease in the number of lesions, and substantial reduction in tumor-associated complications. Median duration of response was 19.2 months. Common adverse events were grades 1/2 thrombocytopenia, and grade 1 noninfectious fever. No patient discontinued treatment as a result of adverse events.
Conclusion: Our study showed that gemcitabine is effective and well tolerated, acts rapidly on cutaneous lesions, and allows substantial symptom palliation, without dose-limiting toxicity. Gemcitabine represents a safe and effective option for the treatment of CKS.

© The Author(s), 2022.
PMID 35356263
Ramya Ramaswami, Mark N Polizzotto, Kathryn Lurain, Kathleen M Wyvill, Anaida Widell, Jomy George, Priscila Goncalves, Seth M Steinberg, Denise Whitby, Thomas S Uldrick, Robert Yarchoan
Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection.
Clin Cancer Res. 2022 Mar 1;28(5):840-850. doi: 10.1158/1078-0432.CCR-21-3364.
Abstract/Text PURPOSE: Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.
PATIENTS AND METHODS: Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.
RESULTS: Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%-87%. Twelve of 18 HIV-positive (67%; 95% CI, 41-87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%-97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6-15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.
CONCLUSIONS: Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.

©2021 American Association for Cancer Research.
PMID 34862247
Erin G Reid, Kelly Shimabukuro, Page Moore, Richard F Ambinder, Jack D Bui, Semi Han, Otoniel Martínez-Maza, Dirk P Dittmer, David Aboulafia, Elizabeth Yu Chiao, Toby Maurer, Robert Baiocchi, Ronald Mitsuyasu, William Wachsman, AIDS Malignancy Consortium (AMC)
AMC-070: Lenalidomide Is Safe and Effective in HIV-Associated Kaposi Sarcoma.
Clin Cancer Res. 2022 Jun 13;28(12):2646-2656. doi: 10.1158/1078-0432.CCR-21-0645.
Abstract/Text PURPOSE: Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS.
EXPERIMENTAL DESIGN: The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia.
RESULTS: Fifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription.
CONCLUSIONS: Lenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and <10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS. See related commentary by Henry and Maki, p. 2485.

©2022 American Association for Cancer Research.
PMID 35247913
Thomas S Uldrick, Kathleen M Wyvill, Pallavi Kumar, Deirdre O'Mahony, Wendy Bernstein, Karen Aleman, Mark N Polizzotto, Seth M Steinberg, Stefania Pittaluga, Vickie Marshall, Denise Whitby, Richard F Little, Robert Yarchoan
Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy.
J Clin Oncol. 2012 May 1;30(13):1476-83. doi: 10.1200/JCO.2011.39.6853. Epub 2012 Mar 19.
Abstract/Text PURPOSE: Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS.
PATIENTS AND METHODS: Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately.
RESULTS: Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2).
CONCLUSION: Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.

PMID 22430271
Thomas S Uldrick, Priscila H Gonçalves, Kathleen M Wyvill, Cody J Peer, Wendy Bernstein, Karen Aleman, Mark N Polizzotto, David Venzon, Seth M Steinberg, Vickie Marshall, Denise Whitby, Richard F Little, John J Wright, Michelle A Rudek, William D Figg, Robert Yarchoan
A Phase Ib Study of Sorafenib (BAY 43-9006) in Patients with Kaposi Sarcoma.
Oncologist. 2017 May;22(5):505-e49. doi: 10.1634/theoncologist.2016-0486. Epub 2017 Mar 24.
Abstract/Text LESSONS LEARNED: Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated.
BACKGROUND: We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity.
METHODS: Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed.
RESULTS: Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p = .08) suggests other metabolites may be increased.
CONCLUSION: Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib. The Oncologist 2017;22:505-e49.

© AlphaMed Press; the data published online to support this summary is the property of the authors.
PMID 28341759
Susan E Krown, Debasmita Roy, Jeannette Y Lee, Bruce J Dezube, Erin G Reid, Raman Venkataramanan, Kelong Han, Ethel Cesarman, Dirk P Dittmer
Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium study.
J Acquir Immune Defic Syndr. 2012 Apr 15;59(5):447-54. doi: 10.1097/QAI.0b013e31823e7884.
Abstract/Text PURPOSE: The mammalian target of rapamycin is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mammalian target of rapamycin-dependent signaling.
METHODS: Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phosphoribosomal S6 protein, and phospho-Akt expression. Interleukin 6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored.
RESULTS: Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of 4 subjects whose biopsies were studied at ≥day 50 showed decreased phosphoribosomal S6 protein staining.
CONCLUSIONS: Rapamycin seems safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations but may be exploited to achieve therapeutic benefit.

PMID 22067664
Julie Delyon, Lucie Biard, Marion Renaud, Matthieu Resche-Rigon, Jérôme Le Goff, Stéphane Dalle, Valentine Heidelberger, Laetitia Da Meda, Laurie Toullec, Guislaine Carcelain, Samia Mourah, Sophie Caillat-Zucman, Vincent Allain, Maxime Battistella, Céleste Lebbe
PD-1 blockade with pembrolizumab in classic or endemic Kaposi's sarcoma: a multicentre, single-arm, phase 2 study.
Lancet Oncol. 2022 Apr;23(4):491-500. doi: 10.1016/S1470-2045(22)00097-3. Epub 2022 Mar 10.
Abstract/Text BACKGROUND: Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment.
METHODS: We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0-1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants.
FINDINGS: 30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1-24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44-90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths.
INTERPRETATION: In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma.
FUNDING: MSD France.

Copyright © 2022 Elsevier Ltd. All rights reserved.
PMID 35279271
Valérie Pourcher, Aude Desnoyer, Lambert Assoumou, Céleste Lebbe, Angélique Curjol, Anne-Geneviève Marcelin, Fanny Cardon, Séverine Gibowski, Dominique Salmon, Jean-Marie Chennebault, Isabelle Poizot-Martin, Gilles Peytavin, François Boué, Dominique Costagliola
Phase II Trial of Lenalidomide in HIV-Infected Patients with Previously Treated Kaposi's Sarcoma: Results of the ANRS 154 Lenakap Trial.
AIDS Res Hum Retroviruses. 2017 Jan;33(1):1-10. doi: 10.1089/AID.2016.0069. Epub 2016 Sep 7.
Abstract/Text Lenalidomide, an oral immunomodulating agent, has shown promising activity in HIV-infected individuals with Kaposi's sarcoma (KS). This single-arm, multicenter, open-label, Gehan's two-stage phase II trial evaluated the efficacy and safety of lenalidomide in HIV-infected patients with progressive KS despite previous chemotherapy (NCT01282047, ANRS 154 Lenakap trial). The primary endpoint was the rate of partial response (PR) or complete response (CR) at week 24, evaluated by both the study investigators and the patients using the Physical Global Assessment (PGA). AIDS Clinical Trials Group (ACTG) criteria for KS treatment evaluation were used as a secondary endpoint. The data and safety monitoring board recommended that enrollments be halted on April 24, 2013, because of lack of responses. We enrolled 12 antiretroviral-treated HIV-infected men with progressive KS despite previous chemotherapy. Their HIV plasma viral load was <50 copies/ml and their median CD4 cell count 444/mm3. One patient stopped taking lenalidomide because of hives at week 1 and a second patient died at week 7. The remaining 10 patients were assessable at week 24, when none had PGA-defined CR or PR and one had ACTG-defined PR. There were no additional PGA responses at week 48, but an additional three patients had ACTG responses, for a total of four patients with ACTG PR at week 48 (40%; 95% confidence interval: 12.2-73.8). Fourteen grade 3-4 adverse events were considered at least possibly related to lenalidomide during a total of 101 cycles. Lenalidomide was well tolerated in antiretroviral experienced patients with progressive KS previously treated with chemotherapy. The ACTG-defined response rate at week 48 was 40%, while it was 0% using PGA criteria.

PMID 27405442

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