Efficacy and Toxicity of Lenalidomide for Treatment of Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis
Authors: Kotapati Sravanthi , Selene Insija Ilyas , Shafqat Madeeha , Hassan Syeda Fatima , Shah Zunairah , Akbar Arshia , Rehman Owais ur , Syed Tariq Iqtidar Sadiq , Ghani Marium , Abdullah Syed Maaz , Khan Maimoona , Jose Jemin Aby , Anwer Faiz 
Published: November 2019

Background: During last decade, several therapeutic options have emerged for newly diagnosed (ND) or relapsed / refractory (RR) patients with chronic lymphocytic leukemia (CLL). Lenalidomide (Lena) has immunomodulatory, anti-angiogenic and antitumor activity. Lena is showing antitumor activity against CLL with durable responses.The main aim of our analysis is to study the published literature on the efficacy and safety of Lena based regimens in patients with ND and RR CLL.
Methods: We performed the literature search (10/5/2019) using following databases (PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials.gov) identified a total of 4835 articles. Following PRISMA guidelines, we selected twenty articles (Phase I/II/III) with a total of 1309 patients (pts) in which eleven articles (n= 914) were about ND CLL pts and nine articles (n=396) had pts with RR CLL. CMA software v.3 was used for meta-analysis.
Results: Lenalidomide based regimens in previously untreated CLL
Based on the pooled analysis,(table 1)(an overall response rate (ORR) of 59.9% (95% CI: 55.4-64.2) with complete response (CR) of 17.6% (95% CI: 8.9-31.8) is observed in previously untreated CLL and ORR of 57.6% (95% CI: 50.4-64.4) with a CR of 12.9% (95% CI: 7.7-20.8) in RR CLL were calculated. Most common grade (G) ≥3 adverse events (AE's) based on regimen were calculated using pooled analysis in CLL pts and results are given intable2.
Lena in single drug regimen: Three studies (n=445) evaluated the efficacy of Lena as single agent (5mg-25mg). Subgroup pooled analysis showed an ORR of 56.4% (95% CI: 51.6-61) with CR of 7.3% (95% CI: 4.4-11.3). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 72.2% (95% CI: 45.1-89.2), thrombocytopenia (tcp) 29.7% (95% CI: 9.1-64), anemia 0.8% (95% CI: 0.1-11.1), fatigue 3% (95% CI: 1.5-5.8) and infections 5% (95% CI: 1.22-18.7).
Lena in two drug regimen: One study (n=69) evaluated the efficacy of Lenaas double regimen with ofatumumab. Sub-group pooled analysis showed an ORR of 88% (95% CI: 78-93.8) with CR of 16% (95% CI: 9.1-26.6). Best response was seen when Lena was used with Ofatumumab, with reported ORR of 71%. Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 58% (95% CI: 46.1-69), anemia 10% (95% CI: 4.8-19.6), tcp 3% (95% CI: 0.8-11) and fatigue 6% (95% CI: 2.3-14.7).
Lena in three drug regimen: For six studies (n=375), a pooled analysis on Lena as three drug regimen calculated an ORR of 59.2% (95% CI: 45.2-86) with CR of 24.1% (95% CI: 18.5-30.7). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 55% (95% CI: 28.4-79.1), tcp 17.6% (95% CI: 6.1-41.3), anemia 13.9% (95% CI: 4.2-37.5), fatigue 29.1% (95% CI: 0.8-95.6) and infection 10.4% (95% CI: 5.6-18.5).
Lena in four drug combination regimen: One study (n=25) evaluated Lena in quadruple regimen (Lena, rituximab, cyclophosphamide and fludarbine) with ORR of 98.1% (95% CI: 75.6-99.9) with CR 75% (95% CI: 54.8-88.1). Pooled analysis for common AE's were neutropenia of 51.6% (95% CI: 37.7-70), tcp of 1.6% (95% CI: 0.1-27), anemia of 1.6% (95% CI: 0-27) and infections of 3% (95% CI: 0.3-23.5) Lena based regimens in Relapsed or Refractory (RR) CLL
Nine studies ( n=396)(table 1) evaluated the efficacy of Lena in RR CLL and have given promising results in these pts. Three studies (n=209) evaluated the efficacy of Lena as single agent, pooled analysis (95% CI) on Lena as mono measured an ORR of 32.7% (95% CI: 15.1-57)(fig. 1) with CR of 8.8% (95% CI: 3.1-22.8). Similarly subgroup pooled analysis for double regimen which includes four studies (n=139) measured ORR of 63.2% (95% CI: 54.4- 71.3) with CR of 14% (95% CI: 5.7-30.4). Two studies (n=56) evaluated Lena as triple regimen, an ORR of 52.5% (95% CI: 39.5-65.2) with CR of 21% (95% CI: 10.4-37.8) was calculated. Pooled analysis (95% CI) common G ≥3 AE's are neutropenia 69.9% (62.8-76.2), tcp 26.5% (18.4-36.5), anemia 9.4% (6.4-13.5), infections 29.4% (10.7-59) and fatigue 14.6% (6.2-30.6)(table 2)
Conclusion: Lenalidomide is highly efficacious when used for treatment of previously untreated or RR CLL. Regimen efficacy is greater in untreated CLL compared to RR CLL. Four drug Lena based combination regimen showed the best result with an ORR of 98.1% (95%CI: 75.6-99.9). Large prospective studies are required to evaluate efficacy and safety of Lena in newer combination regimens.

Disclosures
Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.