Lenalidomide Plus Bendamustine and Rituximab Led to Increased Activity, Increased Toxicity in Older Patients With Untreated Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is associated with a median overall survival (OS) of five years, and for elderly patients – who comprise a majority of the MCL population – standard therapy is not defined. In a phase I/II trial by the Nordic Lymphoma Group, researchers found that adding the immunomodulatory agent lenalidomide to bendamustine and rituximab (L+BR) increased response rates and extended progression-free survival (PFS) compared with rates seen with BR alone in earlier clinical trials, but this combination also led to higher-than-expected rates of infections and second primary malignancies (SPMs).

“For older patients, who constitute the majority of the MCL population, there is no defined standard therapy,” the authors, led by Alexandra Albertsson-Lindblad, MD, from Skåne University Hospital in Lund, Sweden, explained. “The German STiL group compared BR and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in a randomized trial, with the conclusion that BR was associated with higher PFS and less toxicity, making this regimen preferable.”

Given that lenalidomide has demonstrated activity as first-line treatment for MCL, as well as relapsed/refractory MCL, Dr. Albertsson-Lindblad and investigators examined the safety and efficacy of L+BR as first-line treatment in 51 patients (median age = 71 years; range = 62-84 years) with MCL.

Patients were enrolled from 19 centers in Sweden, Norway, Denmark, and Finland between October 12, 2009, and May 22, 2013. All patients who had a confirmed stage II-IV MCL diagnosis were eligible for inclusion if they could not tolerate high-dose chemotherapy, had a World Health Organization performance status of 0-3, and had not received any previous treatment other than one cycle of chemotherapy and/or radiotherapy.

The multicenter, non-randomized, open-label study consisted of two phases: phase I was a dose-escalation stage to identify the maximum tolerated dose (MTD); phase II was an expansion cohort to measure survival outcomes.

In phase I, patients received L+BR induction therapy in six 28-day cycles:

  • Lenalidomide administered orally twice-daily on days 1-14 (following a 3+3 dose-escalation design with an initial dose of 5 mg in cycles 1-6, escalating 5 mg in each step, followed by 25 mg in cycles 7-13)
  • 90 mg/m2 of bendamustine administered intravenously (IV) on days 1-2
  • 375 mg/m2 of rituximab IV on day 1

This was followed by a 28-day maintenance cycle with single-agent lenalidomide administered orally twice daily on days one through 21 for a maximum of seven cycles (52 weeks).

The researchers determined the MTD to be lenalidomide 10 mg during cycles two through six, followed by 10 mg in cycles seven and eight and 15 mg in cycles nine through 13. Notably, a high number of adverse events (AEs) were observed in the first stages of phase I, prompting the researchers to amend the treatment protocol in the following ways:

  • Omitting lenalidomide during the first treatment cycle
  • Administering corticosteroids prior to every rituximab infusion and in cycle two
  • Administering antibiotic prophylaxis to all patients

Of the 50 patients included in the analysis (one patient was removed because of screen failure), 37 patients (73%) completed the induction phase (cycles 1-6), and 12 (24%) completed the maintenance phase (cycles 1-13). Most patients (n=36; 68%) received the MTD dose of L+BR.

After a median follow-up of 31 months (range = 13-59 months), the median PFS (primary endpoint of phase II) was 42 months (95% CI 31-53). “[This] is longer than the reported PFS of 35 months in the BR arm of MCL patients in the German STiL study,” the authors noted.

The median overall survival (OS) was 53 months, with a 73 percent three-year OS rate, and the overall response rate (ORR) was 80 percent based on intention to treat (TABLE).

In addition, compared with lymphocyte levels at baseline, lymphocyte levels after three months of L+BR treatment were significantly decreased (p<0.001). The researchers also found that 36 percent of evaluable patients had MRD-negativity in bone marrow after induction with L+BR, “suggesting that molecular remission can be achieved with this regimen,” the authors wrote.

However, these benefits seemed to come at the expense of an “unexpected high degree of severe adverse events” starting in phase I, most of which were allergic or cutaneous reactions.

“By omitting lenalidomide from cycle one and by adding corticosteroids in cycle two, the allergic reactions observed in the first cohorts could be prevented and the risk of severe cutaneous reactions was diminished, although not completely eradicated,” Dr. Albertsson-Lindblad and colleagues wrote.

The incidence of grade 3-5 infections was high (42%), they added, and led to treatment discontinuation in 10 percent of patients (n=5). Treatment discontinuation was related to:

  • Toxicity (n=28; 74%, 15 of which occurred during induction phase)
  • Progressive disease (PD; n=6; 16%, 5 of which occurred during the induction phase)
  • SPM (n=3; 8%)
  • Withdrawal of consent (n=1)

Twelve deaths were reported, six due to PD, three due to infection during induction phase, and two due to SPM (including lung cancer and chronic myelomonocytic leukemia).

“It is likely that the increased toxicity associated with lenalidomide addition outweighs a possible benefit in efficacy,” the authors concluded.

The study is limited by its non-randomized design and its use of data from previously reported clinical trials, rather than a comparator arm. The authors recommend long-term follow-up and analysis of additional treatment combinations to improve outcomes for this patient population.


Albertsson-Lindblad A, Kolstad A, Laurell A, et al. Lenalidomide-bendamustine-rituximab in untreated mantle cell lymphoma >65 years, the Nordic Lymphoma Group phase I+II trial NLG-MCL4. Blood. 2016 June 27. [Epub ahead of print]

TABLE. Response Rates per CT Scan and Bone Marrow Results
CT scan 3 months 6 months 6 weeks after therapy
ORR 88% 80% 64%






PR 20 8 1
PD 1 3 8
Not evaluated* 5 7 10
Total 50 50 50
CT = computed tomography; ORR = overall response rate; CR = complete remission; CRU = complete remission undetermined; PR = partial remission; PD = progressive disease

*Not evaluated included death of any cause, consent withdrawn, end of study due to anything other than PD, end of treatment due to any cause and not evaluated at this time point, not done due to other cause/missing data