Efficacy and Safety of Lenalidomide Based Regimens in Diffuse Large B Cell Lymphoma: A Systematic Review and Meta-Analysis of Clinical Trials
Authors: Aiman Wajeeha , Ali Muhammad Ashar , Ali Rimsha , Fatima Farwah N. , Mirza Nayab , Javaid Anum , Anwar Muhammad Yasir , Bajwa Shammas Farooq , Gul Rohail , Ahmad Asrar , Anwer Faiz 
Published: November 2020

Background:
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the US. Lenalidomide (Len), an immunomodulator, is used in the treatment of multiple hematological malignancies. This systematic review and meta-analysis aimed to assess the efficacy and safety of Lenalidomide based regimens in Newly Diagnosed (ND) and Relapsed/Refractory (R/R) DLBCL.
Methods :
A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, "Lenalidomide" OR "Revlimid" AND "diffuse large B cell lymphoma" from the inception of literature till 06/20/2020. We screened 1640 articles and included 2 randomized clinical trials (N=72) and 21 single-arm clinical trials (N=860) in this meta-analysis. We excluded case reports, case series, preclinical trials, review articles, meta-analysis, observational studies, and clinical trials not providing any information about the lenalidomide efficacy or safety in DLBCL. We used the R programming language (version 4.0.2) to conduct a meta-analysis.
Results :
In 23 studies (N=932), Len based regimens were used in patients with age 19-92 years (range) Table 1. In 5 trials on R/R patients (N=252), Len was used as a maintenance therapy. Cumulative overall response rate (ORR) and cumulative complete response (CR) were 0.27 (95% CI 0.21; 0.33, I2=0%) (Fig1) and 0.10 (95% CI 0.07; 0.16, 8%) (Fig2), respectively. In one phase III trial, the ORR and CR were significantly improved in the Len arm vs investigator's choice drug. In 4 trials on R/R patients (N=207), Len with monoclonal antibodies (MoAb) was used. Cumulative ORR and CR were 0.40 (95% CI 0.28; 0.54, I2=71%) and 0.28 (95% CI 0.17; 0.42, I2=72%), respectively. In a trial on R/R patients (N=33), Len with Gemcitabine, Rituximab, and Oxaliplatin was used. Cumulative ORR and CR were 0.61 (95% CI 0.43; 0.76, I2=0%) and 0.39 (95% CI 0.24; 0.57, I2=0%), respectively. In a trial on R/R patients (N=15), Len with RICE was used with ORR and CR of 0.73 (95% CI 0.47; 0.90, I2=0%) and 0.60 (95% CI 0.35; 0.81, I2=0%), respectively. In a trial on R/R patients(N=55), Len with Everolimus was used. ORR and CR were 0.27 (95% CI 0.17; 0.40, I2=0%) and 0.07 (95% CI 0.03; 0.18, I2=0%), respectively. In a trial on R/R patients (N=19), Len with R-ESHAP was used. ORR and CR were 0.79 (95% CI 0.55; 0.92, I2=0%) and 0.47 (95% CI 0.27; 0.69, I2=0%), respectively. In a phase III trial on R/R patients (N=21), Len with Gemcitabine and Rituximab was used vs. placebo The ORR and CR were significantly improved in the Len arm vs placebo.
In 4 trials on ND patients (N=158), Len with R-CHOP was used and the cumulative ORR and CR were 0.94 (95% CI 0.88; 0.97, I2=12%) and 0.81 (0.75; 0.87, I2=0%), respectively. In a trial on ND patients (N=15), Len with R-EPOCH was used with ORR and CR of 0.93 (95% CI 0.65; 0.99, I2=0%) and 0.87 (95% CI 0.59; 0.97, I2=0%), respectively.
In 2 trials (N=103), Len with Ibrutinib and Rituximab was used. In R/R patients (N=45), cumulative ORR and CR were 0.38 (95% CI 0.25; 0.53, I2=0%) and 0.24 (95% CI 0.14; 0.39, I2=0%), respectively. In ND patients (N=58) has ORR and CR 0.86 (95% CI 0.75; 0.93, I2=0%), respectively. In 2 trials with a combination of ND and R/R patients (N=54), Len with Rituximab and Bendamustine was used. Cumulative ORR and CR were 0.63 (95% CI 0.49; 0.75, I2=0%) and 0.39 (95% CI 0.27; 0.52, I2=0%), respectively.
The most common serious treatment-related adverse events (TRAE) were infection, thromboembolism, fatigue, sepsis, respiratory, neurological, cardiac (arrhythmias), gastrointestinal, rash, seizures, and hematological side effects (Table 1).
Conclusion :
Based on early phase trials, Len based regimens are well tolerated and effective in the treatment of both ND and R/R DLBCL patients. Combinations of lenalidomide with Tafasitamab and R-ESHAP have shown the highest response in R/R patients and combination with R-CHOP has shown the best response in ND patients. In randomized trials, lenalidomide has shown significant improvement in the survival of DLBCL patients as compared to placebo or physician's choice drug. Additional double-blind multicenter randomized clinical trials are needed to compare the efficacy and safety of lenalidomide based regimens in DLBCL patients.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.