Jing-Zhou Hou, MD, PhD, University of Pittsburg, Pennsylvania, discusses his study on how the standard of care for chronic lymphocytic leukemia (CLL) has evolved among community oncologists since 2020 and how clinical and demographic factors impact treatment selection. The study, "Assessing Adoption of Standard of Care and Comparing Clinical and Demographic Differences in First-Line (1L) Treatment (Tx) of Chronic Lymphocytic Leukemia (CLL)," was presented at the 2023 ASH Annual Meeting & Exposition. The transcript of the interview has been lightly edited for clarity.

Transcript:

Jing-Zhou Hou, MD, PhD: Good afternoon, I’m Dr Jing-Zhou Hou from University of Pittsburg in Pennsylvania. I'm a clinical hematologist and clinical investigator, specialized in non-Hodkin Lymphoma, including CLL. And I'd like to share my study on CLL, which was presented at ASH 2023.

Could you please provide an overview of your study and its main findings?

Dr Hou: As we know, CLL treatment has been rapidly evolving and because of the newer type of therapy with the BTK inhibitors and the BCL2 inhibitors. And since March 2016, the first BTK inhibitor was approved, which was ibrutinib, then the second one or second generation, such as the venetoclax, and then acalabrutinib was approved. And in 2019, the venetoclax class, a BCL2 was also approved.

And this therapy, these agents are really active, they are a great agent for CLL in both in the relapse, setting as well as in the frontline setting. The current guidelines recommend both BCL2 inhibitors and BTK inhibitors for frontline treatment of CLL.

We sought to understand how the standard of care has evolved among the community oncologists in the US since 2020. That will be the time that acalabrutinib was approved. And we also have data on zanubrutinib usage as well. And so the objective, as I mentioned, is to try to understand the targeted therapy, such as first generation BTK and the second generation BTK and BCL2 inhibitors. And also, traditional chemotherapy and immunotherapy such as anti-CD-20 antibodies.

And to understand any demographic factors, such as age, race, and gender, may impact the treatment selections. And also understand if other clinical features, such as cardiac comorbidity or performance status, have any impact on the treatment selections. And we're also trying to understand if the testing of TP53 or 17p deletion have any impact on the treatment choices because these are all very relevant clinical questions or important questions for clinical management.

So, the data source from the Integra Connect Precision Q  de-identified a database of over 3 million cancer patients across 500 clinical sites in the US. This data was de-identified by looking at the electronic medical record (EMR) and also the payer's data such as OCM and also the other commercial payers, and we extracted the data based on EMR. And on the right side [of the slide], you can see the inclusion criteria for the CLL patients whose first-line treatment was started between January 1, 2020, through June 30, 2023. That's the time of the data cut off to analyze for the ASH submission for the ASH meeting. Only patients who received the frontline therapy for the CLL was included. And the way we did it is that we had to have patients with at least five or more CLL diagnosed visits. And in that way, we could remove the patient who had not been seen for CLL.

And in this descriptive analysis, we did use some statistical analysis using two-tailed two sample z-test. The patients were able to identify the total number of first-line CLL patients who were treated were 6328 patients.

So, the data already shows—you can see on the left side—in 2020, and the blue bar is the patient receiving the BTK inhibitor. The light blue line is the patient using DCL2 inhibitor. In this case, it will be venetoclax.

The green bar stands for the patient who receives anti-CD20 antibodies. And chemotherapy the top with orange bar shows 12%. You can see over time, the trend in 2021, in 2022, on the far right, in 2023, that over time, the usage of BTK inhibitors in the frontline has not changed dramatically. It remained somewhere between 55% to 58%. However, we do see an increase of BCL2 inhibitor with venetoclax up to 19.8 % or 20 % in 2023. And we also see the slight decrease of chemotherapy to 8.7%.

But in general, it's still quite a bit of patients receiving chemotherapy in 2023, which is a little bit of a surprise for us, knowing that the BDK inhibitors and the BCL inhibitor work so well. And maybe some special circumstances made the patient choose the chemotherapy in the age of targeted therapy.

And then we looked at the difference by different BDK inhibitors. The one and in the black, if you look at the one on the left side, that red zanubrutinib, you know, in 2020 was the dominant BTK inhibitor accounted for almost 70% of the usage and acalabrutinib accounted for 30% and zanubrutinib was up .2%.

But if you look at the trend in 2023, you can see that zanubrutinib is rapidly losing the market share from 70% in 2020 to 19% in 2023. And zanubrutinib takes a big bite of the pie from 2% in 2020 and now to 26% in 2023. The zanubrutinib went up and dropped down 54% in 2023. So, we do see the dynamic, the changing landscape of the BTK inhibitors in patients with CLL.

Specifically, when you see the first-line, you can see this transformation of the usage of BTK inhibitor. The one at the bottom is the zanubrutinib. Really, you can see in 2023, you will see the big jump of the increase of zanubrutinib usage. I've written it on the other slide, it really dropped pretty significantly. In January 2021, actually 2020, we see 80% and a gradual drop, drop, drop, drop. And in June 2023, the drop was about 10% in June 2023. And then acalabrutinib in the blue [which] shows a relatively stable market share.

The driving force of this change is that the data the study published in phase 3 trials were published at end of 2020 and also FDA approval for the frontline therapy of zanubrutinib for CLL and that study did show the comparison of zanubrutinib vs ibrutinib. There is a PFS difference in favor of zanubrutinib over ibrutinib. That's probably the reason why zanubrutinib is picking up more shares; people are switching to zanubrutinib.

Impact of Age

And then we can try to understand the age difference. This is a patient younger than 60. On far the right [slide] is a patient 80 or older. I think for this slide, the big difference in the younger patient, the BCL2 usage is 26%. In the elderly patient it is 11%. But having said that, BTK inhibitors are still the favorite, easy to start, it’s the best way to start continuation therapy or indefinite therapy. In contrast, BCL2 inhibitor is a fixed duration for a year or so based on CLL14 study. So, for a younger patient, probably the patient or maybe the physician are in favor of fixed duration. And in that case, there'll be a venetoclax-based therapy.

And surprisingly, that in the elderly patient, we still see that the patient received quite a bit of single use of aCD20 antibody, like 20% in this group of patient population, maybe because of other factors that make the patient feel better and the physician chose the therapy. But the bottom line is, from this you clearly you see the difference of the usage of BTK inhibitor, BCL2 inhibitor antibodies, and chemotherapy among patients with different ages.

Impact of Gender and Race/Ethnicity

And now we also look to understand any gender difference. There really is no difference in BTK usage between male and female patients using the BTK inhibitor or BCL2 inhibitors. And another thing that’s interesting, we actually looked into the risk, in this case we primarily looked at White American vs Black American or Caucasian vs African American. And there's other studies published before this. There's some probably small difference in certain race population. But in this large database, we didn't see the difference between different races in terms of the treatment selections for either BTK inhibitor among these two different races or the BCL2 inhibitor. Statistically the P value is .48 or almost .5. There is almost no statistical difference from this larger database. And I can see that the number of patients here is relatively significant. So this, I think this is very important as highlights of our study. From this study we didn't see any racial disparity in terms of choosing the best drugs for the patient.

And the other thing we also looked at was usage of second generation BTK inhibitors. In this case, you see that in the Caucasian [population] we see 54%, in the African American [population] we see 48%, but statistically, the P value is .09. There are also no statistical differences between Caucasian and African American populations for the use of second generation BTKIs.

Performance Status

And we also looked at performance status. By using targeted therapy, we do notice that patients who have poor performance status have a less usage of targeted therapy, maybe because they worry about toxicities or side effects from the second for the targeted therapy. So there is a difference between for patients with good performance status vs the patient with the poor performance status.

Impact of Preexisting Conditions

And cardiac factors or cardiac conditions or preexisting cardiac conditions are important factors. You can see a patient with preexisting cardiac conditions seems in favor of the first-generation vs the second generation BTKis. And you see a P-value for both, less than .001. As I just said, there's a difference if a patient has a preexisting cardiac condition that will impact the choice of BTK inhibitor. A patient without cardiac issues or conditions seem to receive more ibrutinib than a patient with cardiac conditions. Hence, the second generation of BTK inhibitor are favored by both [types of] patients under their physicians. And we also tried to look at a different risk groups and for patients with 17p deletion or TP53 mutation, tested or not tested. If you see on the on the left side [of the slide], for patients who receive the BCL2 inhibitor, that if a patient is being tested, the patient will have a higher incidence or higher usage of the targeted therapy.

In contrast, if a patient is not being tested for 17p deletion or TP50 mutation, that patient will be less likely to receive the targeted therapy. The patient in the front line for BTK high-risk versus low-risk, we also see a difference for people with high-risk CLL with 17P deletion or TP50 mutation, there's a high usage of BTK inhibitors.

And in contrast, for the BCL2 inhibitor, we see that patients with high-risk features have less usage of BCL2 inhibitors, and the patient has slightly higher usage of BTK inhibitors in this case.

The study really shows that the combination of BCL2 inhibitors and secondary BTK inhibitors really increased significantly from 32% in 2020 to 65% in 2023. We see the trend will likely continue. And the second generation BTK inhibitor [usage] already increased significantly to 80%. The trend also shows that they will continue to probably increase.

One thing to surprise that even in 2023, we still see that 9% of patients are still receiving chemotherapy—we do not know why. This is one study that probably can further analyze the patients who received the chemotherapy rather than targeted therapy. And we also see that in terms of the use of BTK inhibitor, BCL inhibitor is less common.

Often in female patients, elderly patients, or patients with poor performance status, or patients who had not been tested for a 17p division or TP53 mutations. And this analysis is also needed to increase awareness of clinical guidelines for treating CLL, so that way the patient can get the best therapy with  less side effects, which will probably give people the best outcome.

Looking ahead, what potential impact do you hope your findings will have on the standard of care, and or treatment for patients with chronic lymphocytic leukemia?

Dr Hou: Yes, you know, the study is a descriptive analysis. It's more like a real-time snapshot of the paradigm shift of CLL. This paradigm shift is really driven by clinical trials.

And [among] other studies presented, we decided here is a single agent for the BTKi and the venetoclax-based therapy. However, the field is evolving towards more combination with the fixed duration driven by the MRD activity. So the landscape probably will continue to evolve for better, and we anticipate that the CLL will be better managed. And with a study like this, it also helps to increase the awareness of the underusage of the new therapy, and then probably educate providers as well the public and may be helpful to drive the patient to get a more targeted therapy in the future and to have a better outcome for the patient.