Phase II Study of Thalidomide in Escalating Doses for Follicular (F-NHL) and Small Lymphocytic Lymphoma (Sll): CALGB Study 50002.

Background: Thalidomide has marked activity in both untreated and heavily pretreated myeloma. Its activity in part is believed to be due to inhibition of bFGF and VEGF induced angiogenesis. Elevated levels of bFGF in serum and urine have correlated with decreased survival in lymphoma possibly through up-regulation of BCL-2.

Methods: 25 patients (pts) with previously treated F-NHL and SLL were registered and treated on this multi-institutional study from July 2001–April 2004 to evaluate the efficacy and safety of oral thalidomide in this patient group. Pts had B-cell SLL (7: 36.8%), F-NHL grade 1 (7: 36.8%), grade 2 (3: 15.8%) and grade 3 (2: 10.1%) NHL. Pts were eligible for entry with up to 3 prior chemotherapy (CT) and 2 immunotherapy (IT) regimens provided performance status was ≥ 1. Pts with new onset of B-symptoms, rising LDH, rapid tumor growth or greater than one year from initial diagnosis were required to undergo repeat lymph node biopsy to exclude recent transformation. Pts with CNS involvement, prior peripheral neuropathy >gr 1, HIV+, and pregnant or nursing women were also excluded. Pts were required to have Cr <2 x ULN, AST/ALT <2.5 x ULN and an ANC > 750. Median age at study entry was 60 years (36–87). Prior therapy was evaluated in 20 pts and 17/20 had received multi-agent CT while 12/20 pts received prior IT. Thalidomide was initiated at a dose of 200 mg daily and escalated by 100 mg daily every 1–2 weeks as tolerated with a maximal dose of 800 mg/d. If ≥ gr 2 peripheral neuropathy or ≥ gr 3 somnolence or mood changes occurred, the dose was held for one week and restarted at 50% of the prior daily dosage.

Results: The median daily dose was 400 mg (range 50–800 mg). There was 1 complete response (CRu-residual abnormality) in a pt with SLL and one partial response in a pt with F-NHL grade 1 (ORR 8%: 95%CI: 1–26%). 16 pts had progressive disease during therapy and 2 died of disease soon after stopping therapy due to adverse events. One patient continues on therapy without progression of disease to date. The remaining 4 pts were taken off of therapy prior to the first 3 month evaluation. The reason for withdrawal was pt refusal (2) and adverse events (2). The median event free survival was 2.6 months (95% CI:1.4–4.4 mos) with a median overall survival of 23.3 months. Toxicity information on 24/25 pts revealed 4 (17%) with grade 4 neutropenia with 1/4 febrile as well. The most common grade 3 toxicities were anemia (13%), dyspnea (13%), fatigue (8%) and neurologic toxicities consisting of somnolence, dizziness, depression and anxiety (21%). Peripheral sensory neuropathy was reported as gr 2 in 8% and gr 3 in 8%. However, 38% of pts were reported as experiencing gr 2 fatigue. There were no grade 5 toxicities.

Conclusion: These phase II trial results in a pretreated pt population demonstrate that, despite an acceptable toxicity profile, thalidomide has only minimal efficacy in F- NHL and SLL.