The Magnitude of Improvement in Progression-Free Survival with Targeted Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia Based on Genetic Risk: A Systematic Review and Meta-Analysis
Authors: Molica Stefano , Giannarelli Diana , Mirabelli Rosana , Levato Luciano , Shanafelt Tait D. 
Published: October 2019

Abstract
Background Currently, only genetic testing, del(17p) or TP53, determines choices of therapy in chronic lymphocytic leukemia (CLL) whereas mutational status of IGHV and 11q deletion are not recognized as reliable parameters for treatment selection (with exception for fludarabine, cyclophosphamide and rituximab [FCR] in mutated IGHV).
To increase understanding of the predictive value of prognostic parameters in the novel therapy era, we conducted a systematic review and meta-analysis assessing the magnitude of improvement in progression-free survival (PFS) with B-cell receptor (BCR) or BCL2 pathway inhibitors based on the presence or absence of 17p deletion/TP53 mutations, 11q deletion and IGHV mutational status in relapsed refractory (R/R) CLL patients.
Methods Randomized trials comparing BCR or BCL2 inhibitors to other treatment regimens were considered eligible for this analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was utilized as a reporting guideline. The search strategy yielded 1184 records for screening with 97 full-text articles assessed for eligibility. Finally, seven randomized trials were included in the quantitative meta-analysis, all of which compared BCR or BCL2 inhibitors to a different comparator.
Results Meta-analysis of seven randomized trials comprising 2415 patients with R/R CLL revealed that treatment with BCR or BCL2 pathway inhibitors improved OS compared with the combined comparator treatments [Hazard ratio (HR) 0.555;95% confidence interval (CI): 0.452-0.680;P=0.000]. Of note, the I2 statistic for heterogeneity (i.e.,8.8% [P=0.36] ) and Q values (i.e., 6.583) indicated a high level of homogeneity of results across studies. Similar results were obtained with PFS (HR, 0.196; 95% CI: 0.144-0.268; P=0.000) although significant statistical heterogeneity existed across the studies (I2 = 78.6%, P<0.00001;Q=28.08).
Next, we evaluated the magnitude of improvement in PFS obtained with BCR or BCL2 pathway inhibitors in R/R CLL patients with high-risk genetic features (Fig 1). The risk of progression was lower for 17p deleted patients (n= 450) treated with BCR or BCL2 inhibitors in comparison to combined comparator treatments (HR, 0.206; 95% CI, 0.108-0.392; P = .000; I2 = 76%; P=0.001;Q=20.853). The same applied with the analysis of TP53 which included five studies enrolling 582 R/R CLL patients with mutated TP53 (HR, 0.231 (95% CI:0.1370.390;P=0.000;I2=75.8%,P=0.0002;Q=16.513).
Data for PFS by 11q deletion status, restricted to 4 studies (3 of ibrutinib and one of venetoclax) including 433 patients , revealed a significantly higher risk of progression for 11q deleted patients treated with comparator treatments [HR,0.081; 95% CI: 0.054-0.121; I2= 0.0% (P=0.56), Q =2.06]. Finally, data for PFS by IGHV mutational status that relied on 6 studies including 1580 IGHV unmutated patients favoured treatment with BCR or BCL2 inhibitors ( HR, 0.172; 95% CI, 0.109-0.272; P=0.000; I2= 84.8%, P<0.0001; Q= 32.98).
An additional pooled meta-analysis restricted to patients with low risk genetic features revealed that the benefit observed with BCR or BCL2 inhibitors in patients with high-risk genetic features may extend to former (data not shown). Of note, the interaction analysis comparing the magnitude of PFS improvement in patients with and without high risk genetic features, respectively, showed that the benefit was independent of mutational status of IGHV (HR,1.39; 95% CI,0.77-2.40;P=0.26), mutational status of TP53 (HR,1.06; 95% CI,0.56-2.00;P=0.43) and 17p deletion (HR,1.10;95% CI,1.10;95%CI, 0.52-2.35;P=0.40). Interestingly, R/R CLL patients who carried 11q deletion treated with BCR or BCL2 inhibitor fared significantly better in terms of the improvement of PFS than patients without 11q deletion (HR,0.39; 95% CI,0.25-0.62;P<0.0001) indicating the particular value of novel therapies in patients with this genetic defect.
Conclusions The important information provided by present meta-analysis is that the improvement over traditional treatments observed with BCR or BCL2 pathway inhibitors is common to all patients with R/R CLL, including those patients with unfavorable and favourable prognostic parameters. BCR signal transduction and BCL2 inhibitors have broad utility and overcome many but not all of the traditional poor risk molecular features in CLL.
Figure 1. Figure 1.

Disclosures
Molica: Gilead: Other: Advisory board; AbbVie: Other: Advisory board; Roche: Other: Advisory board; Jansen: Other: Advisory board. Levato:Novartis: Other: Advisory board. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding; Pharmacyclics: Research Funding.