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  Conference on Retroviruses
and Opportunistic Infections
Boston USA
March 8-11, 2020
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Pomalidomide Clears Anal Cancer Precursor in High Proportion With or Without HIV
  "Clearance of HPV anal high-grade intraepithelial lesions with low-dose pomalidomide" CROI 2020, March 8-11, 2020, Boston
Mark Mascolini
Pomalidomide, an oral agent with immunomodulatory activity, completely or partially cleared the anal cancer precursor high-grade squamous intraepithelial lesions (HSIL) in almost 60% of men with or without HIV infection [1]. The 12-month study found that pomalidomide worked even in people with chronic extensive disease.
A derivative of thalidomide, pomalidomide has antiangiogenic and immunomodulatory activity and has been licensed since 2013 for treatment of relapsed and refractory multiple myeloma (https://www.pomalyst.com). Pomalidomide has no predicted interactions with antiretrovirals and has activity against other viral tumors including Kaposi sarcoma.
Australian SPACE Study researchers who conducted this trial noted that people with HIV run a much higher risk of anal cancer than the general population. HSIL progresses to anal cancer in about 1 in 400 HIV-positive people yearly, especially in people with persistent HSIL. High prevalence of human papillomavirus (HPV) infection in gay men with or without HIV underlies the heightened risk of HSIL and anal cancer in these groups. HSIL treatment relies on local therapies, and recurrence rates after successful therapy are high.
SPACE Study investigators set out to test a low dose of pomalidomide (2 mg daily for 21 of 28 days) for safety, ability to attain histologic clearance of anal HSIL, and durability over 12 months with no additional therapy.
Participants had to have grade 2 or 3 anal intraepithelial neoplasia (AIN) confirmed by biopsy at least 3 times over 12 months. They needed an undetectable viral load with antiretroviral therapy, adequate organ function, and the ability to tolerate thromboprophylaxis (usually aspirin). Participants received 6 cycles of pomalidomide (2 mg orally) with aspirin (150 mg) consisting of 21 days of treatment and 7 days of rest. The primary endpoint evaluation came at week 24, and follow-up with no therapy continued for another 24 weeks.
The 26 study participants included 10 people with HIV, who were younger than HIV-negative participants (median 48 versus 58 years). Everyone was a man and 25 of 26 participants were white. Four people with HIV and 5 without HIV smoked. Everyone had grade 3 HSIL for a median duration of 37 months. Nine of 10 people with HIV were taking antiretroviral therapy, and everyone had an undetectable viral load. Median CD4 counts were 700 in the HIV group and 830 in the HIV-negative group.
Adverse events were mild, self-limited, and not related to the 2 study withdrawals. Of the 3 serious adverse events, one was possibly related to treatment (a cardiac event in a person with a strong family history of heart disease). Researchers recorded grade 2 neutropenia in 16 people and grade 1 neutropenia in 16. Four people had grade 2 constipation and 12 grade 1 constipation. Grade 2 rash affected 2 people and grade 1 rash arose in 8. People with HIV maintained viral suppression.
After 6 months of treatment, 4 people with HIV and 4 without HIV had a complete HSIL response. Respective numbers of partial responses were 1 and 3. After 12 months (the last 6 months without treatment), 3 people with HIV and 5 without HIV had a complete HSIL response, while 3 with HIV and 4 without HIV had a partial response.
Treatment induced HPV-specific CD4 responses and immune activation, which support an immunologic mechanism of action for pomalidomide.
SPACE Study investigators concluded that low-dose pomalidomide "induced durable and continuing clearance of anal HSIL in people with and without HIV." The agent proved effective across multiple genotypes, even in people with chronic extensive disease. The researchers called for further study of pomalidomide for HPV-associated premalignancy.
1. Polizzotto M, Van Bockel D, Law C, et al. Clearance of HPV anal high-grade intraepithelial lesions with low-dose pomalidomide. Conference on Retroviruses and Opportunistic Infections (CROI). March 8-11, 2020. Boston. Abstract 70.