Role of Ibrutinib Based Regimen in Chronic Lymphocytic Leukemia
Authors: Sardar Muhammad , Malik Saad Ullah , Khan Ali Younas , Sohail Chaudhry Saad , Ahmad Malik Qistas , Amin Saher Nasir , Chakraborty Rajshekar , McBride Ali , Azharuddin Muhammad , Sharon David , Lee Patrick , Faridi Warda , Anwer Faiz 
Published: October 2019

Abstract
Background: Treatment of Chronic lymphocytic leukemia (CLL) depends on stage of disease, age, functional status, comorbidities and presence of cytogenetic abnormalities such as (del17p mutation). Ibrutinib was initially approved in CLL given its better response in del17p patients as compared to the standard chemo immunotherapy. Since initial approval, Ibrutinib has also been evaluated in del17p negative CLL patients. Aim of our study is to discuss the efficacy of ibrutinib based regimen in CLL.
Methods: Seven databases (Pub Med/Medline, Elsevier/Embase, Elsevier/Scopus, Wiley/Cochrane Library, and Thomas Reuters/Web of Science, EBSCO/CINAHL, and ClinicalTrials.gov.) were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI32765. Inclusion criteria included prospective clinical trials using Ibrutinib in CLL patients with outcome data available. We excluded systematic reviews, met analysis, case reports and case series. Aim of our review was to evaluate overall response rate (ORR), complete response rate (CR), progression free survival (PFS) and overall survival (OS).
Results:
Treatment naïve (TN)patientIn the extended 5-year median follow up of a phase 1/2b trial (n=31), the ORR with single agent Ibr was 87% (CR-29%). The 5-year PFS and OS was 92%. In phase 3 trial by Burger et al (2015), ORR with Ibr was 92% (CR18%) in 136 patients. 2-year PFS and OS was 89% and 95% respectively. Del17p patients were excluded. Recent phase 2 trial by Jain et al (2017), combination of ibr with fludarabine (flu), cyclophosphamide (cyclo) and obinutuzumab (G) achieved ORR of 100% (CR 46%) in 32 del17p negative patients. In the phase 2 trial by Davids et al (2017) in 49 patients (< 65 years) the ORR was 100% (CR 63%). Phase 1b/2 trial by Migouel, ORR was 96% (CR 52%) with a combination regimen of Ibr + G + venetoclax.
Relapsed/refractory (R/R) patient :In a phase 3 trial by Byrd et al (2014), in 195 patients (median age: 67; del17p: 32%; median prior therapies: 3) the ORR was 63%(CR-O). Median follow up was 9.4 months with 6-month PFS of 88% and 12 months OS of 90%. Phase 2 trial by Burger et al (2014), the ORR was 95% (CR 8%) in 40 patients (median age:63%; del17p:50%; median prior therapies:2). The 18-month PFS and OS was 78% and 84% respectively. In the phase 3 trial by Chanan et al (2016), in 289 (median age 64) del17p negative patients with 2 median prior therapies treated with combination of Ibr + bendamustine + R, the ORR was 83% (CR 10%). The 18-month PFS was 79%. In the phase 3 trial by Sharman et al (2017), in the Ibr + ublituximab arm (n=64) the ORR was 78% (CR 7%) which was higher than in Ibr arm (n= 62) i.e 45% (CR 0). Median age was 67 and each arm received 3 median prior therapies. Del17p was positive in 64% and 66% respectively.
Del17p patients: In the phase 2 trial of by Susan et al (2017), in 145 del17p positive patients (median age: 64) treated with Ibr, the ORR was 64% (CR 0). The median prior number of therapies was 2. Patients were followed for a median of 11.5 months and the 2-year PFS and OS was 63% and 75% respectively. Farooqui et al (2014) evaluated Ibr in del17p patients. In 35 TN patients the ORR was 97% (CR -0) with a 2 year PFS and OS of 82% and 84% respectively. In 16 R/R patients, ORR was 80% (CR 0) and the 2 year PFS and OS were 82% and 74% respectively. Median age was 62
Conclusion: Ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. Ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of Ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients.

Disclosures
No relevant conflicts of interest to declare.