Hi, my name is Dr Lori Leslie. I am the Director of the Indolent Lymphoma and CLL Research Program at the John Theurer Cancer Center in Hackensack, New Jersey. I am also medical co-director of the oncology program at Mountainside Cancer Center in Montclair, New Jersey.

Today, I will be reviewing the oral presentation based on abstract 372 from the 2020 ASH Annual Meeting entitled "Clinical Outcomes Among Real-World Patients with CLL Initiating First-Line Ibrutinib or Chemoimmunotherapy Stratified by Risk Status."

Entitled "Clinical Outcomes Among Real-World Patients with CLL Initiating First-Line Ibrutinib or Chemoimmunotherapy Stratified By Risk Status -- Results from a US Retrospective Chart Review."

For a little background, it has been repeatedly demonstrated across clinical trials in both treatment-naive and relapse refractory CLL space that certain cytogenetic and molecular features are associated with poorer outcomes in patients with CLL treated with chemoimmunotherapy, versus small molecular inhibitor therapy.

Standard guidelines, including IWCLL 2018, as well as NCCN, highlight that it is considered standard of care to check FISH, p53 mutation status, and IgHV mutation status, with or without standard genetics, prior to starting therapy, and that is strongly recommended and preferred to use targeted therapy for patients with high-risk CLL due to improved outcomes compared to chemoimmunotherapy.

In this study, we reviewed charts from 516 CLL patients from 40 US clinical centers. 58 percent of these sites were community, and the remaining one-third were academic. Those with either 17p deletion on 11q deletion by FISH, mutated p53 status, unmutated IgHV, or complex cytogenetics, which was defined as three or more chromosomal abnormalities from standard karyotype were considered high-risk.

Those that were non high risk had to have a known absence of high-risk features. To be non high risk, you had to have FISH testing, p53 mutation testing, and IgHV mutational status testing without the presence of high-risk feature.

If the patient had incomplete testing without a known high-risk feature present, those charts were excluded. Unfortunately, the number of charts excluded for this reason is not known. Of the total charts reviewed, we identified 270 patients meeting criteria for high-risk CLL.

Of these patients, 175 were treated with ibrutinib and 96 with chemoimmunotherapy. Considering that, in the real world, patient treatment assignment is not random, we then performed inverse probability treatment weighting in the high-risk groups.

This is to balance baseline characteristics, while preserving sample size, and is a well-established and accepted statistical method. Those with high-risk CLL treated with ibrutinib had a longer time to next treatment than those treated with chemoimmunotherapy.

This was used as a surrogate for progression-free survival. The median time to next treatment for ibrutinib in high-risk CLL was not reached, compared to a median of 34 months for those patients treated with chemoimmunotherapy.

The next outcome, we are looking at the percentage of patients that only needed one line of therapy during the study period. There were more patients that only needed one line of therapy in the ibrutinib arm (74.7 percent) compared to those treated with chemoimmunotherapy, for which only 47.2 percent needed one line.

The remainder of patients went onto subsequent therapy during the study period. We also performed intra-treatment comparisons. However, due to the fact that baseline differences may reflect differences associated with risk, we did not perform inverse probability weighting for this group.

For patients treated with ibrutinib, the median time to next treatment and percentage of patients requiring only one line of therapy was not statistically different in the high-risk versus non-high-risk group. The median time to next treatment was not reached in either group, and the percentage requiring only one line of therapy was 82 percent in the high-risk group, versus 92 percent in the non-high-risk group.

For patients treated with chemoimmunotherapy, the time to next treatment was shorter in patients with high-risk CLL. Time to next treatment was 39 months for high risk, versus 42 months for non high risk, in patients treated with chemoimmunotherapy.

Additionally, patients with high-risk CLL treated with CIT were less likely to need only one line of therapy during the study period. 46 percent of patients with high-risk CLL, versus 70 percent with non-high-risk CLL only needed one line of therapy.

In summary, to our knowledge, this is the largest real-world study to-date of patients with high-risk CLL who received chemoimmunotherapy versus ibrutinib in the frontline setting.

The results of this real-world study are important, because they replicate multiple prior clinical trial results of chemoimmunotherapy versus targeted therapy in high-risk CLL and support standard practice guidelines, highlighting the importance of checking for high-risk features, including FISH for 17p and 11q, p53 mutation status testing, and IgHV mutation status for all patients, particularly, prior to considering treatment with chemoimmunotherapy.

Outside of extenuating circumstances, based on these and other results, due to inferior outcomes demonstrated repeatedly in clinical trials and in real-world studies, patients with high-risk CLL should not be treated with chemoimmunotherapy.

This study also raises many further questions that we hope to answer in the future. What adverse events are experienced during ibrutinib versus chemoimmunotherapy? What is the cost of care? That is another very important consideration that is being studied for patients with CIT versus targeted therapy.

In non-high-risk patients, unfortunately, the ECHO assessment was used to determine patient similarity and feasibility of unbiased comparative effective and researched showed that the two groups were not similar enough to compare.

Therefore, weighting in this scenario was not deemed to be appropriate. Therefore, this study cannot address the question of whether patients with high-risk CLL have different outcomes if treated with frontline CIT versus ibrutinib.

Additionally, the number of patients excluded for known absence of high-risk features on full risk stratification testing is unknown, and the rate of testing with FISH, IgHV, and p53 mutation testing in community practices remains uncertain and likely variable.

Hopefully, this study highlights the important standard of care practice of checking all patients for high-risk features to assist in treatment selection, intensiveness and monitoring, and to predict the likely outcomes of first-line therapy.