We were very interested by the article by Nowakowski et al.1 describing the combination of lenalidomide and R-CHOP in patients with aggressive lymphoma. Our group conducted a similar phase 1b study of this combination in a patient population with predominantly indolent B-cell lymphoma.
The primary objective of the study was to determine the recommended dose of lenalinomide administered for 14 days in association with standard 21-day R-CHOP (R2-CHOP). Dose of lenalidomide was assessed during the first two cycles. Secondary objectives were to assess the safety and efficacy of R2-CHOP for a maximum of six cycles.
Patients from 18 to 70 years of age had documented B-cell CD20-positive lymphoma: mantle cell lymphoma, marginal zone lymphoma, lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma or histological transformation from low grade to high grade lymphoma. Lenalidomide (5, 10, 15, 20 or 25 mg once daily) was escalated in serial patient cohorts using a standard 3+3 design. Each cycle of R2-CHOP comprised the dose of lenalidomide from day 1 to day 14 in combination with 375 mg/m2 of rituximab, 50 mg/m2 of doxorubicin, 750 mg/m2 of cyclophosphamide and 1.4 mg/m2 of vincristine (up to a maximal dose of 2 mg, in 50–100 ml normal saline in 10–20 min i.v. infusion after cyclophosphamide) on day 1 and 60 mg/m2 of prednisone on days 1 through 5. Pegfilgrastim was given at day 4 of each cycle at a dose of 6 mg.2 Aspirin prophylaxis (100 mg daily) was mandatory during the study period. A prophylaxis of Pneumocystic jirovecii pneumonia was recommended during the study and until 3 months after last cycle administration.
Dose escalation was determined by the number of dose limiting toxicities (DLTs) observed during the administration of the two first cycles of R2-CHOP. DLTs were defined as any grade 3–4 non-hematological toxicity, grade 3 neutropenia or thombocytopenia lasting more than 7 days, or grade 4 neutropenia or thombocytopenia lasting more than 3 days. Once maximal tolerated dose was reached, the cohort was expanded to a total of 12 patients. There was no individual dose adjustment of lenalidomide. If a patient experienced a DLT, lenalidomide treatment was definitively stopped and the patient continued on treatment with R-CHOP. There was no dose adjustment of R-CHOP in case of hematological toxicity or failure to recover neutrophil count of 1.5 × 109/l or platelet count <100 × 109/l at day 21, but the next cycle could be postponed for a maximum of 7 additional days (day 28). If grade 1 neurological toxicity was related to vincristine, the dose was reduced to 1 mg. If the neurological toxicity increased despite of dose reduction, vincristine was stopped.
All patients provided written informed consent. The study was approved by the Comité de Protection des Personnes Sud-Est II, Lyon, France and by the regulatory authorities. Clinical Trials.gov identifier NCT00901615.
Twenty-eight patients were enrolled in the study from January 2009 to June 2010. One patient did not receive any treatment and was excluded from analysis. Patient characteristics are summarized in Table 1. Although the inclusion criteria limited the age to 70 years, a patient aged 77 years was included. The majority of patients had follicular lymphoma and the majority had disseminated disease.
No DLTs occurred at lenalidomide dose of 5, 10 and 15 mg. One neutropenic grade 4 episode lasting more than 3 days occurred at the 20 mg level. One of six patients at the 25 mg level experienced a transient grade 3 hepatic toxicity in the course of the first cycle. As there was no intent to increase the lenalidomide dose above 25 mg, this dose was considered the recommended dose and the 25 mg cohort was expanded.
Safety and tolerability
Lenalidomide was discontinued in six patients, three because of hematological toxicity (after two cycles in two patients and after four cycles in one patient), two for thrombosis (after three and four cycles, respectively) and one for hepatic toxicity at the first cycle. R2-CHOP was discontinued after the fifth cycle in one patient whose disease progressed. Lenalidomide was interrupted during 1–9 days in the course of six of the 143 cycles administered in five patients, mostly because of neutropenia. Six patients had cycle delays; five resulting from hematological toxicity and one resulting from bronchitis associated to chronic respiratory insufficiency.
Adverse events are shown in Table 2. Grade 3 and 4 neutropenia occurred in 19% and 41% of patients, respectively. Two neutropenic patients experienced a grade 3 febrile episode. Grade 3 and 4 thrombocytopenia occurred in 26% and 4% of patients, respectively. One patient had propionibacterium acnes septicemia outside of a neutropenic phase. Two thrombosis episodes occurred despite aspirin prophylaxis. One patient, the one who was 77 years old, had a pulmonary embolism and recovered rapidly with anticoagulation therapy and one patient had a deep venous thrombosis related to the central catheter. Seven patients had a mild rash attributed to lenalidomide. We did not observe grade 3–4 neuropathy but nine patients experienced grade 1 and four patients had grade 2 sensory neuropathy. Two patients had vincristine discontinuation at cycle 4 and 6, respectively.
Response to treatment
Response according to lenalidomide dose is given in Supplemental Table 1. The overall response rate was 96%, with 74% of patients achieving a complete remission (CR/CRu). Only one patient with disseminated follicular lymphoma had histological transformation with meningeal involvement after the fifth cycle.
Results of this 1b trial of the combination of R-CHOP and lenalidomide confirm the results from Nowakowski et al.1 The toxicity profile was similar in the two studies resulting in infrequent discontinuation of lenalidomide and only few delays related to slow hematological recovery. Although primary prophylaxis with pegfiltrastim was used in both studies, the potentially lower incidence of grade 4 neutropenia in our study could be due to the administration of this drug on day 4 of the cycle.2 With this policy, the rate of febrile neutropenia episodes after R2-CHOP did not appear to be more frequent than after R-CHOP.3 Mild sensory neuropathy symptoms were observed in half of our patients leading to discontinuation of vincristine for the last cycles of the treatment in two patients. Similarly to Nowakowski et al.,1 we observed a thrombosis episode in two patients who were receiving aspirin prophylaxis. Lenalidomide was discontinued in both patients and symptoms resolved with anticoagulation. We agree that ongoing phase 2 trials will help better assessing the risk of thrombosis in patients treated with R2-CHOP.
A 14-day treatment with lenalidomide during each 21-day cycle, in our study, as compared with 10 days in the study from Nowakowski et al.,1 results in longer exposure to lenalidomide and does not appear to increase the toxicity of the combination. Overall, both studies conclude that a daily dose of lenalidomide 25 mg appears to be safe in combination with R-CHOP and worth studying in phase 2.
There is a strong rationale to study the combination of lenalidomide and R-CHOP in follicular lymphoma. Although the mechanism of action of lenalidomide appears complex, several of its activities exhibit a potential interest in the treatment of B-cell lymphomas.4 Lenalidomide has been shown to repair the defective immunological synapse between T cells and follicular lymphoma cells in vitro.5 Results of an early phase II study in patients with refractory/relapsed indolent lymphoma have shown an overall response rate of 27% in the subgroup of patients with follicular lymphoma.6 Furthermore, several studies have shown that lenalidomide has the potential to enhance natural killer cell activity, monocyte-mediated antibody-dependent cellular cytotocity and aptoptosis effect of rituximab on lymphoma B-cell lines.7, 8 Recent clinical results demonstrate a remarkable efficacy of the combination of lenalidomide and rituximab in the frontline treatment of follicular lymphoma, which confirms this synergy.9
Long-term follow-up of patients with follicular lymphoma has shown that quality of CR could be correlated to an improved survival.10 It is then conceivable that the combination of lenalidomide with R-CHOP, currently the most effective treatment for follicular lymphoma,11, 12 will increase the efficacy of immunochemotherapy. Our group is currently conducting a phase 2 trial to test this hypothesis in patients with high tumor burden follicular lymphoma.
Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia 2011; 25: 1877–1881.
Zwick C, Hartmann F, Zeynalova S, Poschel V, Nickenig C, Reiser M et al. Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia. Ann Oncol 2011; 22: 1872–1877.
Pettengell R, Johnson HE, Lugtenburg PJ, Silvestre AS, Duhrsen U, Rossi FG et al. Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma. Support Care Cancer 2012; 20: 647–652.
Chanan-Khan AA, Cheson BD . Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008; 26: 1544–1552.
Ramsay AG, Clear AJ, Kelly G, Fatah R, Matthews J, Macdougall F et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood 2009; 114: 4713–4720.
Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol 2009; 27: 5404–5409.
Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008; 14: 4650–4657.
Zhang L, Qian Z, Cai Z, Sun L, Wang H, Bartlett JB et al. Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol 2009; 84: 553–559.
Fowler N, Hagemeister FB, McLaughlin P, Kwak L, Romaguera J, Fanale M et al. Lenalidomide plus rituximab a highly effective and well-tolerated biologic therapy in untreated indolent B-cell non-hodgkin lymphoma. Ann Oncol. 2011; 22 (Supp 4): iv129.
Bachy E, Brice P, Delarue R, Brousse N, Haioun C, Le Gouill S et al. Long-term follow-up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival--A study from the groupe d’etude des lymphomes de l’adulte. J Clin Oncol 2010; 28: 822–829.
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–3732.
Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42–51.
This trial was supported by a grant from the French Ministry of Health (PHRC 2009 13-03). Celgene Corporation financially supported the trial and provided the study drug. We thank the staff of the GELA-Recherche Clinique, and especially Yvain Robreau, for the management of the trial.
Dr Tilly, Dr Morschhauser, Dr Salles, Dr Haioun and Dr Coiffier received grant support from Celgene. Dr Tilly, Dr Morschhauser, Dr Salles, Dr Haioun and Dr Coiffier received payment for lectures from Celgene. Dr Tilly, Dr Morschhauser, Dr Salles and Dr Coiffier have served on advisory boards of Celgene. Dr Casasnovas, Dr Feugier, Dr Molina, Dr Jardin and Dr Terriou declare no conflict of interest.
Supplementary Information accompanies the paper on the Leukemia website
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Tilly, H., Morschhauser, F., Salles, G. et al. Phase 1b study of lenalidomide in combination with rituximab-CHOP (R2-CHOP) in patients with B-cell lymphoma. Leukemia 27, 252–255 (2013). https://doi.org/10.1038/leu.2012.172
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