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Lenalidomide, rituximab, cyclophosphamide, and dexamethasone combination is tolerable and effective in previously untreated iNHL

Mar 9, 2017

On 23 rdFebruary 2017, Allison Rosenthal, D.O., from the Mayo Clinic, Scottsdale, AZ, USA, and colleagues publishedthe results of a phase II trial in the American Journal of Hematology.

The trial ( NCT00784927) investigated the feasibility and response to lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) in patients with previously untreated, symptomatic low grade NHL. Between November 10 2008 and March 8 2013, 36 patients were enrolled at the Mayo Clinic and 33 were eligible for statistical analysis (FL n=8; MZL n=7; WM n=15; LPL n=1; and low grade B-cell lymphoma with plasmacytic differentiation n=1). The median age was 68 years (43–83 years).

Key Highlights:

  • Treatment
    • Rituximab 375mg/m 2IV on D1
    • Lenalidomide 20mg orally on D1–21
    • Cyclophosphamide 250mg/m 2IV on D1, D8, and D15
    • Dexamethasone 40mg orally on D1, D8, D15, D22, and D28
    • Treatment continued for 2 cycles beyond best response for a max. of 12 cycles
    • Median number of cycles = 6 (range, 1–12 cycles)
  • Response
    • Median follow-up = 23.4 months (range, 1.8–50.9 months)
    • ORR for all pts = 87.9% (29/33 pts); CR = 30.3% (10/33 pts: WM 1/15, FL 6/8, MZL 3/7); PR = 57.6% (19/33 pts)
    • mDoR for all pts = 38.7 months (range, 26.8–not reached; 95% CI, 26.9–not reached)
    • mPFS for all pts = 39.7 months; mOS for all pts = not reached
    • WM pts: ORR = 80%; CR = 1 pt; PR = 11 pts (73.3%)
    • WM pts: mPFS = 38.3 months; mOS = not reached
  • Toxicity
    • Delays in treatment in 13 pts (mostly because of cytopenias) and dose reductions in 18 pts (due to neutropenia)
    • Anemia in 28/33 pts; 82% were grade 1–2
    • Grade 1–2 thrombocytopenia in 19 pts; 10.7% were ≥grade 3
    • Neutropenia ≥grade 3 in 50% of pts; 1 event of febrile neutropenia (3%)
    • Thrombotic events in 5 pts (15%); 4 during treatment (pulmonary emboli n=3; upper extremity deep vein thrombosis n=1); 1 during observation (pulmonary emboli)
    • Secondary primary malignancies = 4 (1 melanoma, 1 non-melanoma, 1 myelodysplasia, and 1 breast cancer)

Currently, 30 patients remain alive and 3 have died, all due to lymphoma. The number of patients remaining progression free is 21 (64%) whereas 12 patients (36%) have progressed.

The authors stated that “LR-CD is a rationally designed, tolerable, and effective treatment strategy for untreated indolent NHL with durable responses.” They also added that this regimen is convenient, by being mostly oral. The authors noted that its size, as well as the few numbers of FL and MZL patients limited their study, however the large numbers of WM patients were a strength. WM patients were able to complete the LR-CD regimen, despite hematologic toxicity, implying this treatment approach is active and tolerable in patients whose management is often complicated by anemia at presentation.  

The authors concluded that larger trials are required to accurately compare lenalidomide-based regimens with traditional immunochemotherapy, and their results add to the growing pool of evidence that lenalidomide combinations can be active and tolerable in patients with indolent B-cell NHL.


Patients with indolent NHL have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR-CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375mg/m2 day 1, oral lenalidomide 20mg days 1-21, cyclophosphamide 250mg/m2 days 1, 8, 15, and dexamethasone 40mg days 1, 8, 15, 22, of a 28-day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty-three patients were treated. Median age was 68 (43-83 years). 39% had stage IV disease. Histologic subtypes included: 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL)(1 splenic, 2 extranodal, 4 nodal), 15 Waldenström's macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low-grade B-cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow up was 23.4 months (range 1.8-50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median PFS was 39.7 months, while median OS has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low-grade B cell NHL. This article is protected by copyright. All rights reserved.

  1. Rosenthal A. et al.A phase 2 study of lenalidomide, rituximab, cyclophosphamide and dexamethasone (LR-CD) for untreated low grade Non-Hodgkin Lymphoma requiring therapy. American Journal of Hematology. 2017 Feb 23. DOI: 10.1002/ajh.24693.[Epub ahead of print].