P637: FRONTLINE THERAPY CLL WITHOUT 17P DEL/P53 ABERRATIONS: SYSTEMATIC REVIEW AND BAYESIAN NETWORK META-ANALYSIS

Abstract

Background: Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia, with a median age at diagnosis of 72 years. IgVh unmutated CLL without 17p del/p53 aberrations (UN-only CLL) still carry a poorer prognosis as compared to IgVh mutated (MU-only) cases. Although many treatment options are currently available for the front-line therapy, the best choice and treatment sequencing stratified on efficacy and tolerability for UN/MU-only CLL remains to be defined. Aims: We performed a systematic review and Bayesian network meta-analysis to define best frontline therapy and treatment sequence for UN/MU-only CLL. Methods: Analysis of the literature was performed through the main databases. Due to different therapeutic approaches to front-line therapy of CLL, we chose to conduct a Bayesian Network Meta-Analysis (NMA), allowing to rank (from best to worst) multiple treatments in a single analysis. We generated a rank for Progression Free Survival (PFS), Overall Response Rate (ORR), Minimal Residual Disease (MRD), assessed by flow cytometry on peripheral blood, and tolerability. PFS was evaluated in unselected population for IgVh, and in UN/MU-only CLL patients. Results: Fifteen clinical trials, with a total of 7958 patients, have been included, while 16 different treatments were considered to build four different network meta-analyses to identify the best treatment in PFS, ORR, MRD, and tolerability: Acalabrutinib (ACA); ACA + Obinutuzumab (ACA-O); Alemtuzumab; Bendamustine + Rituximab; Chlorambucil; Chlorambucil + O; Chlorambucil + Ofatumumab; Chlorambucil + Rituximab; Fludarabine + Cyclophosphamide + Rituximab; Fludarabine + Cyclophosphamide; Ibrutinib (IBR); IBR + O; IBR + Rituximab; Lenalidomide, Venetoclax + IBR (VEN-IBR), Venetoclax + Obinutuzumab + Ibrutinib (VEN-O-IBR), Venetoclax + O (VEN-O). ACA-O scored the best in PFS in an unselected population (SUCRA 100%, probable the best 99.9%), UN- and MU- only CLL patients. Our analysis showed that VEN-O ranked the first for ORR (SUCRA value 100%, probably the best 100%). VEN-O ranked the first also for MRD (SUCRA 90.4%, probably best 36.2%) versus the second VEN-O-IBR (SUCRA 84.0%, probably best 35.9); in the direct comparison, the difference between VEN-O and VEN-O-IBR is not statistically significant (Odds Ratio 1.44, CrI 0.00,563.57). Finally, ACA monotherapy is the most tolerable therapy (SUCRA value 100%, probably the best 100%), whereas IBR-O turned to be the most toxic treatment (SUCRA value 0%, probably the best 1%). Interestingly, IBR monotherapy ranked the 9th in the network, whereas all combination regimens including Obinutuzumab carried a high risk of toxicity. Image:Summary/Conclusion: To our knowledge, this is the first network meta-analysis that compares at the same time PFS, tolerability, ORR, and MRD. Our PFS analysis showed that ACA-O was the best treatment in both MU/UN-only patients. Furthermore, ACA turned out to be the most tolerated regimen, whereas the BTKis-O based regimens significantly carried a high toxicity profile as compared to BTKis alone, counterbalancing the advantage of O-addition in terms of ORRs, where O-based regimens achieved the higher rank, when combined either with VEN or BTKis. ACA-O was the best treatment for PFS, although with a worse toxicity profile as compared to ACA monotherapy. VEN-O scores as the best in ORR and MRD. The combination ACA-O has the highest probability to be the best treatment for prolonging the PFS in untreated, UN/MU-only CLL patients. ACA monotherapy is a valuable alternative considering both the safety and efficacy profile.