Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia

Abstract

Purpose: Lenalidomide is a novel therapeutic agent with uncertain mechanism of action that is clinically active in myelodysplastic syndrome (MDS) and multiple myeloma (MM). Application of high (MM) and low (MDS) doses of lenalidomide has been reported to have clinical activity in CLL. Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence.

Patients and methods: Four patients with relapsed CLL were treated with lenalidomide (25 mg/d for 21 days of a 28-day cycle). Serious adverse events including tumor flare and tumor lysis are summarized. In vitro studies examining drug-induced apoptosis and activation of CLL cells were also performed.

Results: Four consecutive patients were treated with lenalidomide; all had serious adverse events. Tumor flare was observed in three patients and was characterized by dramatic and painful lymph node enlargement resulting in hospitalization of two patients, with one fatal outcome. Another patient developed sepsis and renal failure. In vitro studies demonstrated lenalidomide-induced B-cell activation (upregulation of CD40 and CD86) corresponding to degree of tumor flare, possibly explaining the tumor flare observation.

Conclusion: Lenalidomide administered at 25 mg/d in relapsed CLL is associated with unacceptable toxicity; the rapid onset and adverse clinical effects of tumor flare represent a significant limitation of lenalidomide use in CLL at this dose. Drug-associated B-cell activation may contribute to this adverse event. Future studies with lenalidomide in CLL should focus on understanding this toxicity, investigating patients at risk, and investigating alternative safer dosing schedules.

Fig 1

Patient 4 computed tomography scan of the neck: (A) at the start of lenalidomide therapy; (B) on day 24 of cycle 1.

Fig 2

Pretreatment cervical lymph node and excised tonsil following lenalidomide treatment. These studies demonstrate increased Ki67 expression and CD3, CD4, CD8, granzyme B positive cells following lenalidomide treatment.

Fig 3

(A) Treatment of CLL cells ex vivo with lenalidomide (0.5 μmol/L) for 48 and 72 hours does not promote loss of viability in vitro. (B) Treatment of CLL cells ex vivo with lenalidomide results in dose dependent upregulation of the CD40 antigen. (C) Representative histograms show CD40 and CD86 expression increase on CLL cells after 48 hours 0.5 μM lenalidomide treatment in vitro. (D) CLL cell mRNA expression of CD40, but not CD86, is significantly increased after 24 hours of 0.5 μM lenalidomide treatment in vitro.

Fig 4

CLL cells from patients 1, 2, and 3 were treated in vitro with 0.5 μM lenalidomide for 48 hours. Results shown are increase in percent of CD40 and CD86 positive cells relative to media control that is greatest in patient 1 and 3 who both had tumor flare.