At the end of 6 months of low-dose pomalidomide (Pomalyst), more than half of men who have sex with men had partial or complete clearance of long-standing, grade 3 anal lesions from human papillomavirus, irrespective of HIV status; the number increased to almost two-thirds when they were checked at 12 months, according to a 26-subject study said in video presentation of his research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
“Therapy induced durable and continuous clearance of anal HSIL [high-grade squamous intraepithelial lesions]. Further study in HPV-associated premalignancy is warranted to follow up this small, single arm study,” said study lead Mark Polizzotto, MD, PhD, head of the therapeutic and vaccine research program at the Kirby Institute in Sydney.
HPV anal lesions, and subsequent HSIL and progression to anal cancer, are prevalent among men who have sex with men. The risk increases with chronic lesions and concomitant HIV infection.
Pomalidomide is potentially a less painful alternative to options such as freezing and laser ablation, and it may have a lower rate of recurrence, but it’s expensive. Copays range upward from $5,000 for a month supply, according to GoodRx. Celgene, the maker of the drug, offers financial assistance.
Pomalidomide is a derivative of thalidomide that’s approved for multiple myeloma and also has shown effect against a viral lesion associated with HIV, Kaposi sarcoma. The drug is a T-cell activator, and since T-cell activation also is key to spontaneous anal HSIL clearance, Dr. Polizzotto and team wanted to take a look to see if it could help, he said.
The men in the study were at high risk for progression to anal cancer. With a median lesion duration of more than 3 years, and at least one case out past 7 years, spontaneous clearance wasn’t in the cards. The lesions were all grade 3 HSIL, which means severe dysplasia, and more than half of the subjects had HPV genotype 16, and the rest had other risky genotypes. Ten subjects also had HIV, which also increases the risk of anal cancer.
Pomalidomide was given in back-to-back cycles for 6 months, each consisting of 2 mg orally for 3 weeks, then 1 week off, along with a thrombolytic, usually aspirin, given the black box warning of blood clots. The dose was half the 5-mg cycle for Kaposi’s.
The overall response rate – complete clearance or a partial clearance of at least a 50% on high-resolution anoscopy – was 50% at 6 months (12/24), including four complete responses (4/15, 27%) in subjects without HIV, as well as four in the HIV group (4/9, 44%).
On follow-up at month 12, “we saw something we did not expect. Strikingly, with no additional therapy in the interim, we saw a deepening of response in a number of subjects.” The overall response rate climbed to 63% (15/24), including 33% complete response in the HIV-free group (5/15) and HIV-positive group (3/9).
Some did lose their response in the interim, however, and the study team is working to figure out if it was do to a recurrence or a new infection.
A general pattern of immune activation on treatment, including increased systemic CD4+ T-cell responses to HPV during therapy, supported the investigator’s hunch of an immunologic mechanism of action, Dr. Polizzotto said.
There were four instances of grade 3 neutropenia over eight treatment cycles, and one possibly related angina attack, but other than that, adverse reactions were generally mild and self-limited, mostly to grade 1 or 2 neutropenia, constipation, fatigue, and rash, with no idiosyncratic reactions in the HIV group or loss of viral suppression, and no discontinuations because of side effects.
The men in the study were aged 40-50 years, with a median age of 54 years; all but one were white. The median lesion involved a quarter of the anal ring, but sometimes more than half.
The work was funded by the Cancer Institute of New South Wales, the Australian National Health and Medical Research Council, and Celgene. Dr. Polizzotto disclosed patents with Celgene and research funding from the company.
SOURCE: Polizzotto M et al. CROI 2020. Abstract 70
