Comparing outcomes of first-line ibrutinib vs chemoimmunotherapy in high-risk CLL

Dr Lori Leslie - John Theurer Cancer Center, Hackensack, USA

It has been demonstrated repeatedly across clinical trials in the treatment naïve and the relapsed/refractory CLL space that patients with high risk cytogenetic and molecular features do poorly with chemoimmunotherapy compared to targeted therapy. So in the standard guidelines with iwCLL and NCCN it is considered standard of care to check all patients for FISH, immunoglobulin heavy chain, p53 mutation status with or without standard cytogenetics prior to deciding frontline therapy.

We performed a study looking at 516 CLL patient charts from 40 different US centres, including about two-thirds that were community practice and a third that were academic practices. Patients that had either 17p, 11q- by FISH, a mutated p53 status or an unmutated immunoglobulin heavy chain as well as complex cytogenetics were considered high risk. Patients that had a known absence of those features were considered standard risk or non-high risk. Of the total 516 patients we looked at, 271 patients were deemed to have high risk CLL; 175 were treated with ibrutinib and 96 were treated with chemoimmunotherapy.

The point of this study is to compare outcomes in those two groups of patients with high risk CLL. Considering also in the real world that patient assignment is not random, we performed inverse probability treatment weighting in the high risk group and this is to balance baseline characteristics while preserving and balancing sample size.

We used time to next treatment as a surrogate endpoint for progression free survival and found those with high risk CLL treated with ibrutinib had longer time to next treatment compared to those treated with chemoimmunotherapy with a median time to next treatment not reached for the ibrutinib arm and a median time of 34 months for the chemoimmunotherapy arm.

We also looked at outcomes by determining the number of patients that only needed one line of therapy during the study period. So this number was higher with ibrutinib with 74.7% of patients only needing one line of therapy during the treatment during the study period and lower with chemoimmunotherapy. So 47% of patients only needed one line of therapy and the remainder went on to their second line of therapy during the study period.

We also performed intra-treatment comparisons, however, due to the fact that baseline differences may reflect inherent differences associated with risk, weighting was not performed. We found in the ibrutinib group, whether high risk or not, time to next treatment was similar as was the percentage of patients needing only one line of therapy during the treatment period. For example, that number was around 91% for patients with non-high risk CLL treated with ibrutinib and 81% for patients with high risk CLL treated with ibrutinib but this was not statistically different.

In the CIT group we found that patients with high risk CLL had a significantly shorter time to next treatment compared to those that had non-high risk CLL. Those with high risk CLL there was a significantly lower proportion of patients that only required one line of therapy, 46% overall, compared to 70% in the non-high risk group.

So, in summary, this study is important because it replicates what we’ve seen repeatedly across clinical trials in that patients with high risk CLL do not do as well with chemoimmunotherapy and that targeted therapy should be the standard of care. This is reflected in the iwCLL guidelines, NCCN guidelines and it is standard of care to check every patient with CLL for high risk features by FISH, looking for 17p or 11q, p53 mutation status as a separate test and as well as the immunoglobulin gene rearrangement status.

What could be the clinical implications of this study?

Due to an [?] assessment showing that in the non-high risk CLL patients the population of those treated with CIT and ibrutinib were not similar enough to compare, that remains an area of interest that further research is needed to determine what we should be doing for patients with non-high risk CLL in the frontline setting. Do some patients benefit from time-limited chemoimmunotherapy or should all patients be treated with targeted therapy? Or is there some other factor we should be considering to make that decision?

Another main point that this study highlights, this was actually highlighted in a different ASH presentation presented by Dr Anthony Mato, showing that the percentage of patients in the community that get testing for high risk CLL prior to upfront or relapsed/refractory treatment remains quite low. Less than a third of patients have FISH testing and only about 11% of patients have p53 mutation status testing. So hopefully this abstract serves to highlight the importance of testing all patients for high risk features because it has both prognostic and predictive value for patients with CLL.