Characterization of IMiDs (Immunomodulating Agents) Induced “Flare Reaction” in Patients with Chronic Lymphocytic Leukemia (CLL) and Correlation with Changes in Serum Cytokine Levels.

Introduction: Several cytokines (including TNF-alpha, IL-6 and VEGF) are reported to play a critical role in the pathogenesis of CLL cells. Targeting the tumor microenvironment through modulation of the cytokine milieu thus is a potential way to treat CLL. In 2 separate clinical studies we investigated the role of IMiDs (thalidomide and lenalidomide) either in combination with standard chemotherapy (thalidomide + fludarabine, FT) or single agent (lenalidomide, L) in pts with previously untreated or relapsed/refractory CLL, respectively. In these studies we observed tumor flare reaction not previously reported. In this report we describe the clinical characteristics of this side effect, its management and correlation with changes in serum cytokine levels. Flare Reaction (FR): CLL pts treated with IMiDs were noted to have tender increase in lymph nodes size starting within 24–48 hours of initiating therapy with or without erythema and rash. Some patients also increased their total white cell as well as absolute lymphocyte count (ALC).

Results: A total of 48 pts (20 on FT and 28 on lenalidomide) are collectively treated on 2 clinical trials. Median age was------, -----had limited stage (0-II) and ----- has advance Rai stage (III, IV). ------(%) on the FT and 22 (78.5%) on the L developed a FR, which was noted as early as 24 hours after initiation of therapy (median 48 hours). Most pts resolved FR by day 14. A comparison of serum cytokine level at day 0 and 7 was done in 10 pts (9 with FR) treated with L. An increase in TNF-a (n=4), MIG (n=6), IP-10 (n=8), IL-8 (n=7) and IL-10 (n=6) was noted at day 7.

Management: FR was treated with ibuprofen 400 mg q 6 hr with addition of oral morphine (or agents of equivalent potency) for improved pain control.

Conclusion: FR is a new side effect noted in CLL pts treated with IMiDs that is fairly well managed by anti-inflammatory agent along with aggressive pain control. Higher incidence is noted with L. There seems to be no correlation of FR with clinical response to therapy. Identification of the FR is important to avoid confusion with disease progression. An increase in levels of inflammatory cytokine was noted in all pts treated with L which may explain the underlying mechanism of this phenomenon.