Meta-Analysis of the Efficacy and Adverse Reactions of Ibrutinib in the Treatment of Refractory/Relapsed Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that disproportionately affects the elderly. After first-line therapy failure, relapsed/refractory MCL assumes a more aggressive and universally fatal course. Currently, several classes of chemo/biologic therapies are approved in the second line. However, these agents and their combinations have not been compared head-to-head. We conducted this proportional meta-analysis to evaluate their relative impact on selected clinical outcomes. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of relapsed/refractory MCL; trials that explored the efficacy of first-line approved antineoplastic agents and their combinations that comprised: BTK-inhibitors (Ibrutininb (IB), Acalabrutinib, Zanubrutinib), Bortezomib (Velcade, VEL), Venetoclax (VEN), Lenalidomide (LEN), and Bendamustine+Rituximab (B-R); and studies reporting types of responses and duration of response. Proportional meta-analysis was conducted using random-effects model. The respective 95% confidence intervals were calculated, and funnel plots were constructed. Results: Thirteen studies comprising a total of 1,264 participants were included. The pooled overall response rates, ORR (95%CI), of the regimens were: 74% (66,81) BTK-inhibitors, 39% (25,53) VEL, 34% (24,46) LEN, 85% (78,92) B-R, 75% (58,92) VEN-IB, and 88% (79,97) IB-R. The pooled complete responses, CR (95%CI), of the regimens were: 33% (20,47) BTK-inhibitors, 9% (5,13) VEL, 6% (4,9) LEN, 45% (36,54) B-R, 42% (22,63) VEN-IB, and 44% (30,58) IB-R. There were no significant differences in ORR and CR between BTK-inhibitors, B-R, VEN-IB, and IB-R. ORR of VEL and LEN also did not significantly differ. However, ORR and CR of the former group were significantly higher than those of the latter. The pooled partial responses, PR (95%CI), of the regimens were: 41% (32,50) BTK-inhibitors, 28% (20,38) VEL, 28% (15,43) LEN, 41% (35,47) B-R, 34% (15,53) VEN-IB, and 44% (30,58) IB-R. There were no significant differences between PR of the regimens. The weighted duration of responses in months, DOR (95%CI), of the regimens were: 20 BTK-inhibitors, 9 VEL, 16 LEN, and 20 B-R. Conclusions: This proportional meta-analysis is the first to compare the current regimens in first-line relapsed/refractory MCL. It indicates that BTK-inhibitors monotherapy, IB combinations with R or VEN, and B-R provide equivalent ORR and CR rates that are significantly better than VEL and LEN with notably longer duration of response. It also raises questions about whether there is an additional ORR and CR benefits when adding VEN or R to IB in this clinical setting. Disclosures No relevant conflicts of interest to declare.

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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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Inconsistency associated with SOX11 immunohistochemistry in mantle cell lymphoma: a meta-analysis

Journal of Hematopathology ◽

10.1007/s12308-019-00361-z ◽

2019 ◽

Vol 12 (3) ◽

pp. 109-119 ◽

Cited By ~ 1

Author(s):

Woojoo Lee ◽

Eun Shin ◽

Bo Hyung Kim ◽

Hyunchul Kim

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Meta Analysis ◽

Mantle Cell

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Myeloablative or Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Mantle Cell Lymphoma? a Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood.v126.23.2097.2097 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2097-2097

Author(s):

Mohamed A. Kharfan-Dabaja ◽

Tea Reljic ◽

Jessica El-Asmar ◽

Taiga Nishihori ◽

Ernesto Ayala ◽

...

Keyword(s):

Systematic Review ◽

Mantle Cell Lymphoma ◽

Hematopoietic Cell Transplantation ◽

Cell Lymphoma ◽

Meta Analysis ◽

Chronic Gvhd ◽

Pooled Analysis ◽

Reduced Intensity Conditioning ◽

Mantle Cell ◽

Reduced Intensity

Abstract Background: Despite availability of novel agents to treat mantle cell lymphoma (MCL), the disease remains incurable with standard therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) is generally offered in the setting of relapsed or refractory disease. Reduced intensity conditioning (RIC) allo-HCT has expanded availability of the procedure for patients deemed ineligible to receive a myeloablative (MAC) regimen in the past due to advanced age or associated comorbidities. We performed a systematic review and meta-analysis to assess the totality of evidence pertaining to efficacy of allo-HCT (RIC or MAC) in MCL. Materials and methods: A comprehensive search of MEDLINE/PUBMED from inception until July 04, 2015 was undertaken. Data were collected on treatment benefits (event-free (EFS), progression-free (PFS) and overall survival (OS) and harms (non-relapse mortality (NRM) and graft-versus host disease (GVHD)). Results: Fifty-nine manuscripts were identified of which 16 met inclusion criteria (710 patients). For RIC regimens, pooled analysis of 9 studies (n=507) showed an EFS/PFS rate of 47% (95%CI=32-61%) and an OS rate of 53% (95%CI=39-67%). NRM rate for RIC regimens from a pooled analysis of 9 studies (n=507) was 24% (95%CI=16-33%). Incidences of acute (grade 2-4) and chronic GVHD (all grades) following a RIC regimen were 31% (95%CI=20-45%, pooled from 6 studies (n=299)) and 42% (95%CI=30-54%, pooled from 7 studies (n=369)), respectively. For MAC regimens, pooled analysis of 4 studies (n=124) showed an EFS/PFS rate of 34% (95%CI=21-50%). The OS rate was 40% (95%CI=28-52%) from a pooled analysis of 5 studies (n=138). NRM rate for MAC regimens was 37% (95%CI=23-51%) based on a pooled analysis of 4 studies (n=119); only 1 study reported incidence of acute (grade 2-4) and chronic GVHD (all grades) of 36% (95%CI=23-50%) and 35% (95%CI=22-48%), respectively. When analysis was restricted to the late/salvage setting, we analyzed aforementioned outcomes regardless of regimen intensity (RIC+MAC) as well as specifically to RIC or MAC. When RIC and MAC regimens were combined, the pooled analysis of 12 studies (n=578) showed an EFS/PFS rate of 34% (95%=23-46%) and OS rate of 43% (95%CI=32-53%). The NRM rate was 30% (95%CI=20-41%, pooled analysis of 11 studies (n=563)). For RIC regimens in the late/salvage setting, the pooled analysis of 7 studies (n=436) showed an EFS/PFS rate of 40% (95%CI=26-56%) and OS rate of 48% (95%CI=33-62%). For MAC regimens in the late/salvage setting, the pooled analysis of 3 studies (n=105) showed an EFS/PFS rate of 35% (95%CI=17-55%) and OS rate of 38% (95%CI=22-56%). The observed heterogeneity was statistically significant among RIC studies for outcome of OS (p < 0.0001) but not for MAC (p= 0.1315). Conclusion: These results demonstrate that allo-HCT is an effective strategy for treatment of MCL even in the late/salvage setting. On the basis of a relatively lower NRM and a slightly better EFS/PFS and OS, RIC regimens may be the preferred choice when an allo-HCT is being considered for MCL. However, a prospective comparative study in this setting is necessary to generate more conclusive evidence. Disclosures No relevant conflicts of interest to declare.

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Immunochemotherapy With Rituximab and Overall Survival in Patients With Indolent or Mantle Cell Lymphoma: A Systematic Review and Meta-analysis

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djk152 ◽

2007 ◽

Vol 99 (9) ◽

pp. 706-714 ◽

Cited By ~ 260

Author(s):

H. Schulz ◽

J. F. Bohlius ◽

S. Trelle ◽

N. Skoetz ◽

M. Reiser ◽

...

Keyword(s):

Systematic Review ◽

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Meta Analysis ◽

Mantle Cell

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Rituximab maintenance therapy for mantle cell lymphoma: A systematic review and meta-analysis

American Journal of Hematology ◽

10.1002/ajh.25226 ◽

2018 ◽

Vol 93 (10) ◽

pp. 1220-1226 ◽

Cited By ~ 1

Author(s):

Talal Hilal ◽

Zhen Wang ◽

Diana Almader-Douglas ◽

Allison Rosenthal ◽

Craig B. Reeder ◽

...

Keyword(s):

Systematic Review ◽

Maintenance Therapy ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Meta Analysis ◽

Rituximab Maintenance ◽

Mantle Cell

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Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis

Blood Advances ◽

10.1182/bloodadvances.2019001350 ◽

2020 ◽

Vol 4 (13) ◽

pp. 2927-2938 ◽

Cited By ~ 2

Author(s):

Holly A. Hill ◽

Xinyue Qi ◽

Preetesh Jain ◽

Krystle Nomie ◽

Yucai Wang ◽

...

Keyword(s):

Systematic Review ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Meta Analysis ◽

Patient Level Data ◽

Targeted Next Generation Sequencing ◽

Patient Level ◽

Mutational Status ◽

Level Data ◽

Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. We then conducted a meta-analysis using a Bayesian multiregression model to analyze patient-level data in 2127 MCL patients, including prevalence of mutations. In tumor or bone marrow samples taken at diagnosis or baseline, ATM was the most frequently mutated gene (43.5%) followed by TP53 (26.8%), CDKN2A (23.9%), and CCND1 (20.2%). Aberrations were also detected in IGH (38.4%) and MYC (20.8%), primarily through cytogenetic methods. Other common baseline mutations were NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%). Our data also show a change in mutational status from baseline samples to samples at disease progression and present mutations of interest in MCL that should be considered for future analysis. The genes with the highest mutational frequency difference (>5%) are TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1. These findings provide a summary of the mutational landscape of MCL. The genes with the highest change in mutation frequency should be included in targeted next-generation sequencing panels for future studies. These findings also highlight the need for analysis of serial samples in MCL. Patient-level data of prevalent mutations in MCL provide additional evidence emphasizing molecular variability in advancing precision medicine initiatives in MCL.

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