Lenalidomide monotherapy for R/R MCL demonstrates efficacy and predictable safety profile in long-term analysis of three phase II trials

In the American Journal of Hematology, last month Thomas E. Witzig, MD, from the Mayo Clinic, Rochester, MN, US, and colleagues published a report consolidating data from three phase II trials (NHL-002, NHL-003, and MCL-001) to ultimately provide long-term efficacy and safety data for the immunomodulatory agent lenalidomide in the treatment of Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL).

  • NHL-002 (NCT00179660) was conducted between August 2005 and September 2006 at 8 centers in the US and Canada, and included 15/49 patients (31%) with R/R MCL
  • NHL-003 (NCT00413036) occurred between November 2006 and March 2008 at 48 centers based in Western Europe (n=28), the US (n=17), and Canada (n=3), and included 57/217 patients (26%) with R/R MCL
  • MCL-001 (EMERGE; NCT00737529) was a global, multicenter, open-label trial of lenalidomide monotherapy in 134 patients with R/R MCL. This trial took place between January 2009 and March 2013 at 45 centers based in the US (n=18), Europe (n=18), Asia (n=8), and Colombia (n=1)

In all three studies, oral lenalidomide monotherapy was given at a dose of 25mg/day on days 1–21 of each 28-day cycle as tolerated for up to 52 weeks in NHL-002 or until disease progression in NHL-003 and MCL-001. Lenalidomide was administered at a 10mg dose for patients with moderate renal insufficiency characterized by creatinine clearance ≥30 to <60mL/min (MCL-001 only). The primary outcome measure for all three studies was best Overall Response Rate (ORR), in addition to Duration of Response (DoR) in the MCL-001 trial.

Key Highlights:
Patient disposition and baseline characteristics:
  • In total, 206 patients (pts) with R/R MCL included in the current analysis
  • Median age = 67 years (33–84); 63% of pts (n=130) were ≥65 years
  • MCL stage III/IV disease = 91% of pts (n=187)
  • Eastern Cooperative Oncology Group performance status 0–1 = 88% of pts (n=181)
  • High (≥6.2) MIPI = 34% of pts (n=71)
  • Elevated lactate dehydrogenase = 42% of pts (n=87)
  • High tumor burden = 52% of pts (n=108); bulky disease = 30% of pts (n=62)
  • Median number of prior therapies = 4 (range, 1–13); 75% had received ≥3 prior therapies
  • Prior therapies included regimens containing anthracyclines (96%; n=198), bortezomib (76%; n=157), and rituximab (98%; n=201)
  • Median time from last prior therapy = 3.3 months (range, 1–58.5)
  • ORR = 33%; CR/CRu = 11% (n=11); PR = 22% (n=46); SD = 32% (n=65); PD = 24% (n=50)
  • Median Time To Response (TTR): in all responders = 2.2 months (range, 1.6–24.2); in CR/CRu pts = 2.0 months (range, 1.6–20.9)
  • Median DoR: in all responders = 16.6 months (95% CI, 11.1–29.8); in CR/CRu pts = 28.1 months (95% CI, 11.0–NR); in PR pts = 11.1 months (range, 6.5–26.7)
  • Median PFS = 5.5 months (95% CI, 3.7–7.4)
  • Median OS = 24.4 months (95% CI, 19.0–30.0)
  • In post-bortezomib pts (n=157):
    • ORR = 31% (n=48); CR/CRu = 9% (n=14); PR = 22% (n=34); SD = 31% (n=48); PD = 25% (n=39)
    • Median TTR = 2.3 months (range, 1.6–15.9)
    • Median DoR = 16.6 months (95% CI, 8.9–28.1)
    • Median PFS = 4.5 months (95% CI, 3.7–7.2)
    • Median OS = 21.5 months (95% CI, 13.7–28.4)
  • ORR with lenalidomide monotherapy in the combined cohort was consistent across patient subgroups according to baseline demographics, clinical characteristics, or type of prior therapy
  • Average daily dose of lenalidomide: all MCL pts = 21mg; post-bortezomib pts = 20mg
  • Median duration of treatment: all MCL pts = 106 days; post-bortezomib pts = 101 days
  • Proportion of pts who received ≥12 cycles of lenalidomide = 26%
  • Proportion of pts who experienced dose interruption/reduction due to AEs: in all MCL pts = 59%; in post-bortezomib pts = 58%
  • Proportion of pts who discontinued lenalidomide due to AEs = 13%
  • Myelosuppression was the most common grade 3–4 toxicity
  • Incidence of grade 3–4: neutropenia = 42%; thrombocytopenia = 28%; anemia = 11%; febrile neutropenia = 6%
  • Most common non-hematologic toxicities: fatigues (7%), diarrhea (6%), dyspnea (5%), and pneumonia (4%)
  • Other AEs of interest: deep vein thrombosis (grade ≥3, 3%; 1 dose interruption), pulmonary embolism (2%, resolved without interruption), tumor flare reaction (14 pts in total; grade I–II, 7%)
  • In total, 113 pts died during, or within 30 days of last dose, of treatment with lenalidomide
  • Most common causes of death: MCL (n=78), other known causes (n=22), unknown causes (n=11), and toxicity (n=2)
  • Invasive Secondary Primary Malignancies (SPM) reported in 13 pts (6%) and included hematologic malignancies in 3 pts (1 AML; 1 MDS; 1 MDS to AML) and solid tumors in 10 pts
  • Median time to onset of invasive SPM = 15.4 months (range, 1.2–52.1)

The authors concluded that this long-term data indicates that lenalidomide monotherapy achieved a “noteworthy” ORR of 33% and has a “consistent, predictable, and manageable” toxicity profile demonstrated across numerous phase II trials in heavily pre-treated, advanced-stage patients with R/R MCL. The authors emphasized the importance of understanding the long-term outcomes and toxicities of novel agents, which are becoming more frequently used as first-line therapy for the treatment of MCL.


Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post-bortezomib). The purpose of this report is to provide longer follow-up on the MCL-001 study (follow-ups were 6.8 [NHL-002], 7.6 [NHL-003], and 52.2 [MCL-001] months). The 206 relapsed MCL patients treated with single-agent lenalidomide (25 mg/day PO, days 1-21 every 28 days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow-up of X, the combined best overall response rate was 33% (including 11% with complete remission [CR]/unconfirmed CR). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response of 16.6 months (95% CI: 11.1%-29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event. Overall, single-agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.

  1. Witzig T.E. et al. Long-Term Analysis of Phase II Studies of Single-Agent Lenalidomide in Relapsed/Refractory Mantle Cell Lymphoma. American Journal of Hematology. 2017 Jul 11. DOI: 10.1002/ajh.24854. [Epub ahead of print].