Combined Immunochemotherapy with Rituximab Improves Overall Survival in Patients with Follicular and Mantle Cell Lymphoma: Updated Meta-Analysis Results.

Abstract Background Rituximab (R) has shown impressive response and prolonged progression free survival (PFS) in patients with indolent lymphoma when combined with CHOP. Randomized phase III trials adding rituximab to a variety of different regimen confirmed this benefit in both previously treated and untreated patients with advanced indolent lymphoma. Furthermore these trials indicating a trend towards improved overall survival (OS) for a combined immunochemotherapy with R. Here we report updated results of a comprehensive systematic review in this group of patients comparing R and chemotherapy with chemotherapy alone with respect to OS, disease control, overall response (OR) and toxicity. Methods Only randomized controlled trials (RCT) comparing R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma and mantle cell lymphoma (MCL) were included. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1990–2005). We included full-text and abstract publications. Number needed to treat (NNT) were calculated to facilitate interpretation. Results We included seven eligible RCTs involving a total of 1943 patients with follicular lymphoma (FL), MCL and other indolent lymphoma. Studies were published as full text (5), and in abstract form (2). OS was statistically significant improved in the R-chemo group when compared to chemotherapy alone (HR; hazard ratio: 0,65; 95% CI 0,54 – 0,78). OR (RR; relative risk: 1.21; 95% CI 1.16–1.27) and disease control (HR: 0.62; 95% CI 0.55–0.71) were also significantly superior after R-chemo. The RR for developing fever and leukocytopenia was significantly higher with R-chemo, but not associated with an increased risk of infection. Conclusion The systematic review demonstrated improved OS, OR and disease control for patients with indolent lymphoma and in the subgroups of follicular and mantle cell lymphoma when treated with R-chemo compared to chemotherapy alone.

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Does Combined Immunochemotherapy with the Monoclonal Antibody Rituximab Improve Overall Survival in the Treatment of Patients with Indolent Non-Hodgkin Lymphoma? Preliminary Results of a Comprehensive Meta-Analysis.

Blood ◽

10.1182/blood.v106.11.351.351 ◽

2005 ◽

Vol 106 (11) ◽

pp. 351-351 ◽

Cited By ~ 7

Author(s):

Holger Schulz ◽

Nicole Skoetz ◽

Julia Bohlius ◽

Sven Trelle ◽

Thilo Kober ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Full Text ◽

Cell Lymphoma ◽

Meta Analysis ◽

Cochrane Library ◽

Newly Diagnosed ◽

Indolent Lymphoma ◽

Survival Chance ◽

Mantle Cell

Abstract Background: The monoclonal anti-CD20 antibody Rituximab (R) has been shown to induce high response rates and to improve progression free survival when added to combined chemotherapy in newly diagnosed and relapsed indolent lymphoma. It remains unclear if R combined with chemotherapy may also have an impact on overall survival (OS). Objectives: To determine the effectivness of a combination chemotherapy plus R versus chemotherapy alone with respect to overall survival. Methods: Randomized controlled trials (RCT) comparing chemotherapy plus R vs chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma and mantle cell lymphoma. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1990–2005). We included full-text and abstract publications. Data extraction and quality assessment were done in duplicate. Data were pooled under a fixed-effects model. Number needed to treat were calculated to facilitate interpretation. Main results: We identified six eligible RCTs involving patients with follicular and mantle cell lymphoma. Treatment regimen combined with R were CHOP (2x), CNOP, CVP, FCM and MCP. A total of 5 trials with 994 randomized untreated pts were included in the survival analysis. The included studies were described by the authors as randomized. In all studies, the method for allocation concealment could not be determined. Three studies were published as full text, and two were abstract publications. Overall survival was statistically significantly improved in the R-chemotherapy group compared to chemotherapy alone (HR 0.61; 95%-CI: 0.47–0.80). There was no statistical heterogeneity between the trials compared. Assuming a survival chance of 85% after 18 months for patients with low grade NHL we estimated that it would be necessary to treat 17 (95%-CI: 13–33) patients with R in addition to chemotherapy to prevent one death. For patients with mantle cell lymphoma and a survival chance of 60% after 18 months the corresponding estimate is 6 (95%-CI: 5–13). Conclusion: This preliminary meta-analysis demonstrated evidence for improved overall survival among patients with indolent lymphoma and mantle cell lymphoma treated with a combination of rituximab plus chemotherapy compared to chemotherapy alone.

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Efficacy of Chemotherapeutic Regimens for Mantle Cell Lymphoma: A Systematic Review of Phase III Trials

Blood ◽

10.1182/blood-2020-141181 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Ali Jaan ◽

Muhammad Tayyeb ◽

Farhan Khalid ◽

Muhammad Khawar Sana ◽

Zahoor Ahmed ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Interferon Alfa ◽

Phase Iii ◽

Cell Transplant ◽

Mantle Cell ◽

Combination Regimens

Background: The mainstay treatment for mantle cell lymphoma (MCL) is chemotherapy ± immunotherapy. The standard chemotherapeutic regimens have limited efficacy in MCL when used alone. In this systematic review, we have assessed the efficacy and safety of various combination regimens for the treatment of MCL evaluated in phase III clinical trials. Methods: We performed a comprehensive systematic literature search on PubMed, Embase, clinicaltrials.gov, and Web of Science databases with the date of inception to May 2020. We used MeSH (Medical Subject Headings) terms for "mantle cell lymphoma", "treatment outcome" along with their keywords, and combined their results. Our search generated a total of 3572 articles. After excluding case reports, case series, observational studies, review articles, meta-analysis, phase I/II clinical trials, and pre-clinical studies, we included five phase III randomized clinical trials (RCTs) reporting the efficacy of combination regimens for MCL treatment. Results Data from five phase III RCTs was pooled with total N=1683 (newly diagnosed (ND), n=1242, relapsed/refractory (RR), n=441). 1610 patients were evaluable. Kluin-Nelemans et al. 2020 (n=560) studied induction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) vs R-FC (rituximab, fludarabine, and cyclophosphamide) for ND-MCL with follow-up on maintenance with rituximab (R) -vs interferon alfa. At a median follow up of 7.6 years (y), median overall survival (mOS) was 6.4 vs 3.9 y (p=0.0054) in R-CHOP vs R-FC group, respectively. The median progression-free survival (mPFS) and mOS in the R-CHOP cohort on R maintenance were significantly better when compared to those on interferon alfa maintenance (mPFS, 5.4 y vs 1.9 y, p<0.001) (mOS, 9.8 y vs 7.1 y, p=0.0026). Robak et al. (2015) (n=487) assessed bortezomib in ND-MCL by substituting it for vincristine in the standard R-CHOP therapy. A cohort of MCL ineligible for stem cell transplant (SCT) was randomly assigned to either R-CHOP or VR-CAP (bortezomib replacing vincristine). At a median follow-up of 40 months (mo), mPFS was 24.7 mo vs 14.4 mo in VR-CAP vs R-CHOP (HR 0.63, p<0.001), respectively. Similar, relative improvements were reported in complete response (CR) (53% vs 42%, p=0.007) and 4-year OS was (64% [95% CI 56-71] vs 54% [95% CI 45-62]). Jin et al. (2018) (n=121) assessed R-CHOP vs VR-CAP in ND-MCL patients ineligible for SCT. After a median follow-up of 42.4 mo, mPFS for VR-CAP was better than R-CHOP (28.6 mo vs 13.9 mo, HR=0.7, p=0.157). The overall response rate (ORR) was almost similar in VR-CAP (97%) and R-CHOP (98%). The 4-year OS was 62% vs 61% in VR-CAP vs R-CHOP, respectively. Flinn et al. (2014) (n=74) studied the efficacy of bendamustine in combination with rituximab (BR) vs R-CHOP or R-CVP (R-CHOP minus doxorubicin) as induction regimens in ND-MCL. 36 patients received BR and 38 patients received R-CHOP/R-CVP. ORR was 94% vs 85% with BR vs R-CHOP/R-CVP, respectively. Hess et al. (2009) (n=162) evaluated temsirolimus in RR-MCL. The study population was randomized to either 175/75mg temsirolimus (arm A), 175/25mg temsirolimus (arm B), and the investigator's choice of chemotherapy (arm C). The mPFS was significantly better in arm A compared to arm C (4.8 mo vs 1.9 mo, HR 0.44 [97.5% CI 0.25-0.7], p=0.0009). Arm B had slight improvement but insignificant. Similarly, mOS was 12.8 mo in arm A (HR 0.8 [95% CI 0.5-1.28], p=0.35), and 8.8 in arm B (HR 0.96 [95% CI 0.60-1.54], p=0.87), when compared to 9.5 mo in arm C. Drelying et al. (2016) (n=280), studied temsirolimus in comparison with ibrutinib, RR-MCL with mPFS of 14.6 mo (95% CI 10.4-not estimable) vs 6.2 mo (95% CI 4.2-7.9), respectively. Toxicities were typically manageable. VR-CAP was associated with a higher incidence of toxicity (100%) vs R-CHOP (94%) majority of which was hematological. Thrombocytopenia was particularly more prominent with temsirolimus. Granulocytopenia was persistent in 30-40% in the R-FC cohort after 5 y. Conclusion: The chemo-immunotherapy combination is favorable compared to chemotherapy alone for the treatment of MCL. R-CHOP induction followed by rituximab maintenance in MCL shows favorable long-term safety and efficacy profile. Bortezomib substituting for vincristine in R-CHOP improves the efficacy outcomes. Ibrutinib-based regimens are superior to temsirolimus-based regimens. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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The Addition of Rituximab to Fludarabine and Cyclophosphamide (FC) Improves Overall Survival in Newly Diagnosed Mantle Cell Lymphoma (MCL): Results of the Randomised UK National Cancer Research Institute (NCRI) Trial

Blood ◽

10.1182/blood.v118.21.440.440 ◽

2011 ◽

Vol 118 (21) ◽

pp. 440-440 ◽

Cited By ~ 6

Author(s):

Simon Rule ◽

Paul Smith ◽

Peter W Johnson ◽

Simon Bolam ◽

George A Follows ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase Iii ◽

Newly Diagnosed ◽

End Of Treatment ◽

Mantle Cell ◽

Experienced Grade ◽

Grade Iii

Abstract Abstract 440 Background: Rituximab is widely used in combination with chemotherapy for treating B cell lympho-proliferative disorders. In MCL, two randomised trials explored the addition of Rituximab to standard initial therapy. Neither demonstrated a significant improvement in either PFS or OS. In 2002 the NCRN initiated a phase II randomised trial of FC chemotherapy with or without Rituximab to evaluate response rates. In 2006 this was extended to a phase III study with overall survival as the primary end point. Trial: Newly diagnosed patients with MCL requiring therapy received up to 8 cycles of oral FC (Fludarabine 40mg/m2 and Cyclophosphamide 250mg/m2 both daily × 3) given every 4 weeks with a randomisation to the addition of Rituximab 375mg/m2 on day 1. There was no age limit to the study, no risk stratification and no consolidation of responses with transplantation or maintenance therapy. Results: 370 patients were randomised. Median age was 66 years (range 36 – 88) with 76% male patients. The arms were well balanced by Mantle Cell International Prognostic Index (MIPI); 77% in the FCR arm and 71% in the FC arm were in the intermediate or high risk groups. 78% and 72% respectively received 4 or more cycles of FCR/FC. At the end of treatment the ORR was 90.6% in the FCR arm and 79.8% in the FC arm (p = 0.01) with CR + CRu rates of 64.7% and 46.9% (p = 0.002) respectively. 5.8% of patients in the FCR arm and 11.9% in the FC arm had PD at the end of treatment. Patients in the FCR arm had longer progression free and overall survival with HRs of 0.56 (95% CI: 0.43–0.73, p < 0.001) and 0.72 (95% CI: 0.54–0.97, p = 0.03) respectively. At a median follow up of 38.8 months the median PFS is 30.6 months in the FCR arm and 16.1 months in the FC arm. The median OS is 45.7 months for FCR and 37 months for FC. The major toxicities were haematological. Significantly more patients in the FCR arm experienced grade 3 or 4 Leucopoenia and Thrombocytopenia however the numbers of grade 4 were not significantly different. Combined grade III/IV toxicity showed 23.3% thrombocytopenia, 45.8% leucopoenia, 12.9% anaemia and 51.4% neutropenia. 11.8% of patients had significant infections. Renal toxicity was modest. 1 patient experienced grade III but there was no grade IV toxicity. Lymphoma was the commonest cause of death, but 29% of patients in the FCR arm and 24% in the FC arm died of other causes, of which almost half were infection related. An additional 11 patients died of a second malignancy, 4 of whom had AML. 14% of patients in the FCR arm and 10% in the FC arm died without evidence of disease progression. Conclusion: The addition of Rituximab to FC chemotherapy leads to a significant improvement in both PFS and OS with an acceptable level of additional toxicity. A significant number of patients treated with FC based chemotherapy die whilst in remission of non lymphoma related causes. Disclosures: Rule: Roche: Consultancy, Research Funding. Off Label Use: Rituximab in mantle cell lymphoma. Follows:Roche: Consultancy, Honoraria. Hillmen:Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKine: Honoraria, Speakers Bureau; Genzyme: Research Funding; MundiPharma: Honoraria, Speakers Bureau. Walewski:Janssen-Cilag: ; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria.

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Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.11.2819 ◽

1995 ◽

Vol 13 (11) ◽

pp. 2819-2826 ◽

Cited By ~ 111

Author(s):

I Teodorovic ◽

S Pittaluga ◽

J C Kluin-Nelemans ◽

J H Meerwaldt ◽

A Hagenbeek ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Response Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Phase Iii ◽

European Organization ◽

Free Survival ◽

Mantle Cell ◽

Duration Of Response

PURPOSE Before recognizing mantle-cell lymphoma (MCL) as a distinct entity, these patients were grouped into low-grade (LG) or intermediate-/high-grade categories (IGHG) according to the Working Formulation and received various therapies. This was a unique opportunity to evaluate characteristics, behavior, response to treatment, and outcome of patients with MCL from two phase III trials conducted by the European Organization for the Research and Treatment of Cancer (EORTC): EORTC 20855 IGHG and EORTC 20856 LG. PATIENTS AND METHODS After histologic review, 64 diagnosed MCL patients (29 IGHG and 35 LG) were compared with other patients in their respective trials. In the IGHG group, patients received cyclophosphamide, doxorubicin, teniposide (VM26), prednisone, vincristine, and bleomycin (CHVmP-VB) or modified doxorubicin, cyclophosphamide, etoposide (VP 16), mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE-MOPP). In the LG group, after receiving cyclophosphamide, vincristine, and prednisone (CVP) induction, patients were randomized between maintenance treatment with interferon alfa-2a (IFN) or no further treatment. RESULTS MCL patients compared with IGHG subtypes showed a similar overall survival and response rate, but shorter duration of response and progression-free survival. Comparing with LG patients, their response rate, duration of response, and progression-free survival showed no difference, while their overall survival was nearly twice shorter. MCL patients treated with CHVmP-VB had the longest survival. No treatment showed any significant improvement in terms of progression-free survival. CONCLUSION These data confirm that MCL represents a clinicopathologic entity. In terms of survival, it behaves like IGHG subtypes, while in terms of progression-free survival, it behaves like LG lymphoma. It is still not clear which first-line treatment offers patients with MCL the best chance to obtain both a complete response (CR) and a long-term survival.

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