Lenalidomide Associated Tumor Flare Reaction Correlates with Clinical Response in Patients with Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia
Authors: Sher Taimur , Patel Mehul , Whitworth Amy , Miller Kena , Musial Laurie , Lawrence David , Padmanabhan Swaminathan , Ailawadhi Sikander , Wilding Gregory , DePaolo Dawn , Bangia Naveen , Czuczman Myron S. , Wallace Paul K. , Lee Kelvin P. , Khan Asher Chanan 
Published: April 2020

INTRODUCTION: We have previously reported that in patients with B-CLL, lenalidomide induces a tumor flare reaction (TFR) that is clinically characterized by painful, tender enlargement of disease involved lymph nodes, spleen and/or liver along with low grade fever. The underlying mechanism as well as the impact of TFR on treatment outcomes remains unknown. We analyzed data from our phase II clinical trial in which the clinical efficacy of lenalidomide alone was investigated in patients with relapsed or refractory B-CLL and correlated the severity of TFR with clinical efficacy.

METHODS: Forty five patients with relapsed refractory CLL, enrolled in a phase II study were divided into two groups; group A consisted of first 29 patients who were treated with 25 mg of lenalidomide for 21 days of a 28 day cycle without any prophylaxis for tumor flare reaction, group B consisted of subsequent 16 patients who received 10 mg per day of lenalidomide initially with subsequent escalations of 5 mg every 1–2 weeks to a maximum dose of 25 mg along-prednisone prophylaxis (20 mg/day for 5 days followed by 10 mg/day for 5 days) was given to this group during cycle 1 only.

RESULTS: Thirty of the 45 patients (67%) developed clinically significant TFR. Of these 20 (67%) were grade I, 7 (23%) grade II and 3 (10%) grade III. The median time to TFR was 6 days (range 0–56 days). The median time to resolution was 14 days (95% CI: 10–26 days). In over 90% of cases flare occurred only during first treatment cycle. Median age for those who either developed or did not develop flare reaction was 61 and 71 years respectively (p=0.004, 2-sided, Wilcoxon test). Nineteen patients (66%) in group A and 11 (69%) in group B developed TFR. Grade II/III flare was observed in 9 (47%) and 1 (9%) patients in group A and B, respectively (p=0.05). The median time to onset of TFR was 4 days in group A and 9 days in group B (p=0.01). The median duration of TFR was 13 and 28 days in groups A and B respectively (p=0.16). A total of 8 patients achieved molecular complete remission (mCR). All but 1 patient who achieved mCR had a flare reaction (p=0.24). The median progression free survival of patients with or without TFR was 19.9 and 19.4 months, respectively. There was a trend to improvement of progression free survival in group A patients compared to group B patients, 23 vs. 17.8 months, respectively (p=0.74, log rank test), however, this difference did not reach statistical significance. TFR reaction was managed by non-steroidal anti-inflammatory agent with or without oral morphine. Eleven of the 30 patients with TFR required treatment and only 3 patients received supplemental morphine. None of patient required discontinuation of lenalidomide for TFR.

CONCLUSION: Although the mechanism of TFR remains to be determined clinically it appears to be an immunologically mediated phenomenon that is uniquely seen in CLL patients. We observe that the occurrence and severity of TFR appears to correlate with clinical response to lenalidomide. Steroid prophylaxis decreases the severity but not the incidence of TFR. The effect on overall efficacy of steroid pre-treatment for prevention of TFR remains to be determined in larger cohort of patients.