Comparative Safety Analysis of Currently Approved Anti-CD20 Monoclonal Antibodies for First Line Treatment of Chronic Lymphocytic Leukemia (CLL)
Authors: Mwamburi Mkaya , Bal Vasudha , Cascella Teresa , Shah Anshul , Nanavaty Merena , Gala Smeet 
Published: October 2019

Abstract
Introduction:
Treatment of CLL has advanced tremendously in the past decade with significant extension of life expectancy in patients diagnosed with the disease. Three anti-CD20 monoclonal antibody (mAB) combinations approved for previously untreated chronic lymphocytic leukemia (CLL) patients are obinutuzumab-chlorambucil (OBI-CHL), ofatumumab-chlorambucil (OFA-CHL), and rituximab-chlorambucil (RTX-CHL), have comparable efficacy but varying safety profiles in pivotal trials. Grade 3-4 adverse events (AEs), including infusion-related reactions (IRRs), neutropenia, thrombocytopenia, anemia, and infections differ by each mAB. Grade 3-4 AEs, defined as requiring hospitalization or life-threatening, result in reductions in patient quality of life (QoL) and bear cost implications. We sought to compare the safety of the IV-administered anti-CD20 mABs in the first-line treatment of CLL and to evaluate the respective QoL and economic implications of these AEs.
Methods:
A systematic literature review was conducted in PubMed, Embase, and Cochrane library for the time period of 2010-2016 and in conference proceedings of ASH, the American Society of Clinical Oncology (ASCO), and the European Hematology Association (EHA) for 2014-2016. Search was limited to clinical trials conducted on humans and published in English language. The IRRs were compared directly as CHL is administered orally. A Bayesian network meta-analyses (NMA) was conducted with data from phase 3 trials using SAS® (v9.3) to compare grade 3-4 neutropenia, thrombocytopenia, anemia, and infections associated with the three anti-CD20 mABs. A pooled analysis of data from phase 2 trials and cohort studies was conducted using MedCalc® version 16.2.1. Analyses were also conducted to estimate the potential impact of the AEs of respective anti-CD20 mABs on QoL and cost of care based on the NMA results and previously published estimates of utilities associated with CR (0.780), PR (0.790), SD/PD (0.760); disutilities associated with IRR (-0.11), neutropenia (-0.09), thrombocytopenia (-0.05), anemia (-0.09), and infections (-0.20); and costs associated with episodes of IRR ($4,482), neutropenia ($5,406), thrombocytopenia ($12,621), anemia ($8,894), and infections ($7,163) in CLL.
Results:
Of the 86 studies screened, 10 studies were included. Direct comparison showed that the rate of IRRs in OBI-CHL, OFA-CHL, and RTX-CHL were 21%, 10%, and 4%, respectively. Risks for neutropenia were lower for OFA-CHL compared to OBI-CHL (OR = 0.74; 95% CI: 0.12-4.59) and similar to RTX-CHL (1.08; 0.20-5.82); for thrombocytopenia were lower for OFA-CHL compared to OBI-CHL (0.16; 0.02-1.33) and to RTX-CHL (0.49; 0.06-4.15); for anemia were lower for OFA-CHL compared to OBI-CHL (0.80; 0.21-3.06) and similar to RTX-CHL (1.08; 0.24-4.64); and for infections OFA-CHL, OBI-CHL (1.00; 0.15-6.74) and RTX-CHL (0.86; 0.15-4.43) were similar. The pooled analyses of AEs observed in phase 2 / cohort studies revealed similar trends when assessed. The mean pre-progression QoL utilities associated with OBI-CHL, OFA-CHL, and RTX-CHL weighted by rates of AEs, utilities associated with respective response rates to treatments, and disutilities of the respective AEs were 0.772, 0.761, and 0.748 respectively. The total cost of treating AEs per 1,000 patients on OFA-CHL, OBI-CHL and RTX-CHL were $3.9M, $8.0M and $4.2M, respectively.
Conclusion:
The safety profile was most desirable for OFA-CHL, followed by RTX-CHL and OBI-CHL. Though RTX-CHL had the lowest rate of grade 3-4 IRR, OFA-CHL had the better grade 3-4 hematologic safety profile compared to OBI-CHL and RTX-CHL. As efficacy of CLL treatments has improved substantially, safety of treatments is increasingly important particularly on the impact of QoL. In addition, in the cost-conscious payer environment, selecting drugs with a better safety profile and lower cost implications is vital. Our findings demonstrate that better safety profile is associated with less impact on QoL and lower costs. We found that for every 1,000 patients covered by a payer, safety alone can save an excess of $4M based on regimen choice. Fewer incidences of AEs also results in better adherence and reduction in treatment interruption or discontinuation. Safety with the QoL and cost implications should be taken into consideration to maximize the overall benefits of the treatment to CLL patients.

Disclosures
Mwamburi: Novartis Pharmaceuticals: Consultancy. Bal:Novartis Pharmaceuticals: Employment. Cascella:Novartis Oncology: Employment. Shah:Novartis Pharmaceuticals: Consultancy. Nanavaty:Novartis Pharmaceuticals: Consultancy. Gala:Novartis Pharmaceuticals: Consultancy.