Mazyar Shadman, MD, MPH, on Chronic Lymphocytic Leukemia: Update on BTK Inhibitors

At the ASCO meeting, we presented data on Network meta-analysis comparing the efficacy of covalent BTK inhibitors for treatment of relapsed refractory CLL. As the background, there are three covalent BTK inhibitors currently approved for CLL, and we do have some randomized trials comparing some of these drugs. For example, acalabrutinib was compared to ibrutinib in the relapse setting in Elevate RR study, and zanubrutinib was compared to ibrutinib in the Alpine trial. However, we don't have a comparison between the two second-generation covalent BTK inhibitors, zanubrutinib and acalabrutinib. There has been an effort recently to indirectly compare the efficacy of this drug through methods like matching adjusted indirect comparison or MAIC. Here we are using another methodology for this indirect comparison called Network meta-analysis, and this is a technique that gives us the opportunity of comparing multiple interventions and use both direct and indirect comparisons. So here we use three clinical trials after going through the inclusion criteria for different trials, and we used Alpine, which compared zanubrutinib versus ibrutinib. We used Elevate RR, which compared acalabrutinib versus ibrutinib, and we also used Ascend trial which compared acalabrutinib versus chemotherapy. And the findings were summarized and in brief, when we looked at the overall response, zanubrutinib was superior to ibrutinib in terms of overall response, the CR rate was not as statistically significant. Also in terms of the overall response and CR rate comparison between zanubrutinib and ibrutinib while there was a trend in favor of zanubrutinib this was not as statistically significant. We also looked at progression free survival, and we did it by adjusting for COVID-19 and also presented the unadjusted comparison. So in the high risk population defined by each clinical trial, zanubrutinib was found to be superior to both ibrutinib and acalabrutinib and also chemo immunotherapy through this PFS analysis. And that was true whether or not we adjusted for COVID-19 or not. When we limited the analysis to only patients with del(17p), zanubrutinib remained superior to ibrutinib and chemo immunotherapy. And also zanubrutinib in the adjusted analysis, but on the unadjusted analysis there was no statistically difference between zanubrutinib and acalabrutinib. And we also looked at overall survival. And while there was a trend in favor of zanubrutinib, this was not a statistically significant. So overall, this is an important study in providing another piece of data and evidence for both clinicians and investigators to put it next to the other analysis that we have recently done and others have done. I would like to remind ourselves that the gold standard remains to be randomized to have clinical trials, and in the absence of direct comparison, we can use methods like MAIC or MET Network meta-analysis to give us a better understanding of the efficacy.