Abstract
Background: CLL is a lymphoproliferative disease characterized by an accumulation of malignant lymphocytes due to a defect in apoptosis. CLL lymphocytes demonstrate increased NF-κB activity, which may play a role in mediating resistance to fludarabine. Additionally, several cytokines have been linked to enhanced CLL survival, including TNF-α, bFGF, and VEGF. Given thalidomide’s ability to inhibit these cytokines and NF-κB activity, we investigated whether thalidomide, either alone or in combination with fludarabine, is an effective treatment for pts with CLL previously treated with fludarabine.
Methods: CLL pts requiring therapy as defined by NCI-WG criteria and who were previously treated with fludarabine were eligible. Pts were randomized to receive either thalidomide alone (T) or in combination with fludarabine (FT). Thalidomide was started at a dose of 200 mg qHS and adjusted as tolerated. Pts assigned to FT started thalidomide prior to receiving fludarabine at a dose of 25 mg/m2 each day x 5 days x 6 cycles.
Results: 13 pts have been enrolled, 8 men/5 women, median age=60, (range 48–68), 4 pts refractory to fludarabine, randomized to receive either T (6) or FT (7). The median dose of thalidomide was 200 mg qHS (range 50–450). Of the 10 evaluable pts, there have been 1 CR (FT), 3 PRs (1T, 2FT), and 2 hematologic improvements (1T/1FT). Of interest, 5 pts on T developed tumor flares, characterized by fevers, increased size and tenderness of lymph nodes, increased lymphocyte counts, and decreased hemoglobin and platelet counts. These symptoms resolved with either continued treatment (3 pts) or temporarily discontinuing the thalidomide and re-introducing it at a dose of 50 mg (2 pts). Patients on T demonstrated hematologic improvement (HI) prior to decreases in lymph node size. Figs 1 and 2 illustrate two patients with tumor flares followed by marked HI, but only minimal improvement in LAD. Pt in fig 1 continued on T, while pt in fig 2 had T held for 4 weeks. Overall, therapy was tolerated, with grade 3 toxicities being: neuropathy(2)(requiring T dose reduction), sedation(1), catheter thrombosis(1), febrile neutropenia(1), infection(3), none requiring discontinuation of therapy.
Conclusion: Thalidomide demonstrates activity alone and in combination with fludarabine as treatment for CLL. Further data are required to see if FT can increase the response rate over historical controls for patients who relapse after fludarabine. The addition of F to T appears to ameliorate the development of a tumor flare.
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