Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Morschhauser, Franck; Fowler, Nathan; Feugier, Pierre; Bouabdallah, Réda; Tilly, Hervé; Palomba, M. Lia; Fruchart, Christophe; Libby, Edward N.; Casasnovas, René-Olivier; Flinn, Ian W.; Haı̈oun, Corinne; Maisonneuve, Hervé; Ysebaert, Loïc; Bartlett, Nancy L.; Bouabdallah, Kamal; Brice, Pauline; Ribrag, Vincent; Daguindau, Nicolas; Gouill, Steven Le; Pica, Gian Matteo; García-Sancho, Alejandro Martín; López‐Guillermo, Armando; Larouche, Jean-François; Ando, Kiyoshi; Silva, Maria Gomes da; André, Marc; Zachée, Pierre; Sehn, Laurie H.; Tobinai, Kensei; Cartron, Guillaume; Liu, David; Wang, Jianming; Xerri, Luc; Salles, Gilles

doi:10.1056/nejmoa1805104

Cited by 273 publications

(212 citation statements)

References 27 publications

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“…Fourteen of the 53 studies did not report any data on severe adverse events, 22 had no data on serious events, and two had no data on deaths. Such under-reporting of harms is common in oncology trials 56. However, when trials mention an acceptable, tolerable, or favourable toxicity profile in the experimental treatment arm, it seems wrong not to report the supporting data.…”

Section: Description Of Harmsmentioning

confidence: 99%

“…For example, a recently published trial of rituximab plus lenalidomide versus rituximab plus chemotherapy reported in its abstract conclusion that “the safety profile differed in the two groups.”5 Although this statement is not very informative, it is at least an objective description and readers can look at the adverse effect profiles and frequencies for themselves. Another trial abstract concluded: “The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.”12…”

Section: Better Reportingmentioning

confidence: 99%

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Reporting harms more transparently in trials of cancer drugs

Gyawali

Shimokata

Honda

et al. 2018

BMJ

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Section: Description Of Harmsmentioning

confidence: 99%

Section: Better Reportingmentioning

confidence: 99%

Reporting harms more transparently in trials of cancer drugs

Gyawali

Shimokata

Honda

et al. 2018

BMJ

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“…ORR/CR 97·1/36·3% and 94·5/43·6% in the R‐CVP and R‐CHOP arm respectively, was lower than in similar studies. In the FOLL05 study, ORR/CR rates in the R‐CVP and R‐CHOP arms were 88%/67% and 93%/73% respectively (Federico et al , ) and in the RELEVANCE study, ORR/CR (confirmed/ unconfirmed) rates for the R‐lenalidomide and R‐chemotherapy arms were 61/48% and 65/53% respectively (Morschhauser et al , ). We used revised response criteria as per Cheson et al () where the CRu category was abandoned and counted as PR unless the FDG‐PET scan was negative.…”

Section: Discussionmentioning

confidence: 99%

First‐line R‐CVP versus R‐CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4

et al. 2019

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Summary R‐CVP (cyclophosphamide, vincristine, prednisone) and R‐CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone + rituximab) are immunochemotherapy regimens frequently used for remission induction of indolent non‐Hodgkin lymphomas (iNHLs). Rituximab maintenance (RM) significantly improves progression‐free survival (PFS) in patients with complete/partial remission (CR/PR). Here we report the final results of a randomized study comparing R‐CVP to R‐CHOP both followed by RM. Untreated patients in need of systemic therapy with symptomatic and progressive iNHLs including follicular (FL) and marginal zone lymphoma (MZL), mucosa‐associated lymphoid tissue (MALT), small lymphocytic (SLL), and lymphoplasmacytic (LPL) lymphoma were eligible. Patients were randomized to receive R‐CVP or R‐CHOP for eight cycles or until complete response (CR). All patients with CR/PR (partial response) received RM 375 mg/m2 q 2 months for 12 cycles. Primary endpoint was event‐free survival (EFS). Two‐hundred and fifty patients [FL 42%, MZL/MALT 38%, LPL/ Waldenström Macroglobulinaemia (WM) 11%, SLL 9%] were enrolled and randomized (R‐CHOP: 127, R‐CVP: 123). Median age was 56 years (21–85), 44% were male, 90% were in stage III–IV, 43% of FL patients had a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥3, and 33·4% of all patients had an IPI score ≥3. At the end of induction treatment, the CR/PR rate was 43·6/50·9% and 36·3/60·8% in the R‐CHOP and R‐CVP groups (P = 0·218) respectively. After a median follow‐up of 67, 66, and 70 months, five‐year EFS was 61% vs. 56% (not significant), progression‐free survival (PFS) was 71% vs. 69% (not significant) and overall survival (OS) was 84% vs. 89% in the R‐CHOP vs. the R‐CVP arm respectively. Grade III/IV adverse events (65 vs. 22) occurred in 40 (33·1%) and 18 (15·3%) patients, P = 0·001; neutropenia in 16 (11·6%) and 4 (3·4%) patients, P = 0·017; infection in 14 (10·7%) and 3 (2·5%) patients,; P = 0·011; and a second neoplasm in three versus seven patients., in the R‐CHOP and the R‐CVP groups respectively. This multicentre randomized study with >five‐year follow‐up shows similar outcome in patients with indolent lymphoma in need of systemic therapy treated with R‐CVP or R‐CHOP immunochemotherapy and rituximab maintenance in both arms. The minor toxicity of the R‐CVP regimen makes it a reasonable choice for induction treatment, leaving other active agents like doxorubicin or bendamustin for second‐line therapy.

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“…As part of correlative biomarker studies associated with the RELEVANCE trial (Morschhauser et al , ), changes in T and NK cells in the peripheral blood of 193 FL patients receiving treatment with either R 2 ( n = 101) or R‐CHOP ( n = 92) were examined. Blood samples were collected at screening and at the end of induction therapy (week 24).…”

Section: Resultsmentioning

confidence: 99%

“…In the clinic, R 2 has demonstrated synergy in FL in both front‐line and relapsed/refractory settings in phase 2 trials (Fowler et al , ; Tuscano et al , ; Leonard et al , ; Martin et al , ). Results of the recently reported phase 3 RELEVANCE trial, evaluating R 2 versus R‐chemotherapy in previously untreated advanced FL patients, demonstrated similar efficacy in the two treatment arms, but found a greater frequency of grade 3/4 neutropenia was associated with R‐chemotherapy (Morschhauser et al , ). R 2 immunotherapy has also shown activity in marginal zone lymphoma (MZL), where the combination achieved an overall response rate (ORR) of up to 89% in phase 2 studies (Fowler et al , ; Sacchi et al , ) and is currently being evaluated in the phase 3 MAGNIFY study (Andorsky et al , ).…”

mentioning

confidence: 92%

Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma

Chiu¹,

Trisal²,

Bjorklund³

et al. 2019

Br J Haematol

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Summary Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma ( FL ) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R 2 ) has shown clinical synergy in front‐line and relapsed/refractory FL . Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer ( NK ) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R 2 treatment increased circulating T‐ and NK ‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R 2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.

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Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Cited by 273 publications

References 27 publications

Reporting harms more transparently in trials of cancer drugs

Reporting harms more transparently in trials of cancer drugs

First‐line R‐CVP versus R‐CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4

Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma

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