ALL-TRANS-RETINOIC ACID FOR THE TREATMENT OF AIDS-RELATED KAPOSIS-SARCOMA - RESULTS OF A PILOT PHASE-II STUDY

Retinoids have anti-tumor activity in several malignant and premaligna nt conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have an ti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients w ith mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were tre ated with all-trans retinoic acid (tRA). Poor tolerance was observed a t the initial starting dose of 150 mg/m(2), and thus subsequent patien ts were treated using a weekly dose escalation, starting with 45 mg/m( 2) (given daily, in subdivided doses), to the target dose of 150 mg/m( 2) (given daily in three subdivided doses). Nearly half (46%) of the p atients had extensive mucocutaneous disease with over 25 lesions. No p atient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm(3) or greater (strata I); and 17 had under 200/ mm(3) CD4 lymphocyte (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m(2); there was no significant dif ference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vo miting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to thera py was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three respond ers had baseline CD4 lymphocyte counts <200/mm(3). Three additional pa tients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease sta bilization of 16 weeks or greater. In evaluable patients, the median t ime to disease progression was 22 weeks and the overall median surviva l in all patients was 27.3 months. No significant changes in CD4 lymph ocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in s oluble IL-2 receptor levels while on tRA (p=0.037). We conclude that t RA has activity in patients with mucocutaneous AIDS-related Kaposi's s arcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.