Optimizing Use of Prognostic Markers for the Treatment of CLL

Richard R. Furman, MD

Richard R. Furman, MD

The number of prognostic markers in chronic lymphocytic leukemia (CLL) is almost unlimited, said Richard R. Furman, MD, but a challenge exists with identifying the approximately 20% of patients who will progress on the standard of care, and deciding on different treatments for these patients.

It is most important to identify patients who will not have long-term progression-free survival with a Bruton’s tyrosine kinase (BTK) inhibitor or similar therapy, individuals who will progress in general, and those who are at risk for developing Richter’s transformation.

Clinical studies like the GENIUNE trial (NCT02301156) have shown how focusing on the high-risk cytogenetic features in patients with CLL when treating them can produce positive results. The phase III study randomized patients to ublituximab (TG-1101) plus ibrutinib (Imbruvica) versus ibrutinib alone to evaluate the safety and efficacy of the BTK/monoclonal antibody combination.1

The long-term results of the GENUINE trialshowed an improvement in progression-free survival.¹In the results presented at the American Society of Clinical Oncology Annual Meeting 2017, there was an overall response rate (ORR) of 78% in the combination arm and 45% with ibrutinib alone. With ublituximab plus ibrutinib, there was a 19% incidence of minimal residual disease negativity and a 7% complete response rate. In the ibrutinib monotherapy arm, 2% of patients showed minimal residual disease negativity and there were no complete responses. Additionally, the combination arm had a 1.97-month median time to response and the ibrutinib arm had a 3.8-month median time to response.²

Adverse events occurred in the combination arm and the monotherapy and respectively, the most common were diarrhea (42% vs 40%), fatigue (27% vs 33%), insomnia (24% vs 10%), nausea (22% vs 21%), and headache (20% vs 28%). Fifty-four percent of patients also experienced infusion reactions, 5% of which were grade 3 or higher. The combination was considered well tolerated and showed no new safety signals.²

Furman noted that toxicity is the determining factor when deciding which therapy to give patients while there are so many available options. Additionally, he recommends that oncologists single out high-risk patients and try alternate therapies.

“It's important to identify patients who are high risk and treat them differently. The high risk are those withTP53dysfunction and either a deletion 17p or a mutation,” Furman stated.

In an interview with Targeted Oncology at the 2019 Chemotherapy Foundation Symposium, Furman, the Morton Coleman, MD, Distinguished Professor of Medicine, Weill Cornell Medicine, reviewed his presentation on prognostic markers and their importance in the treatment of patients with CLL.

TARGETED ONCOLOGY: Can you provide an overview of your presentation at CFS?

Furman: I think it's very important to appreciate that in 2019, approximately 80% of patients with CLL will be able to enjoy a long-term disease control with our available agents. The important question is, can we can identify the 20% of patients who aren't going to be able to enjoy a long-term progression-free survival and do something different to hopefully impact their outcomes?

Patients do progress on upfront therapy, like BTK inhibitor therapy, which is the paradigm, especially since we now have 8-year data on its follow up. We have to identify those people who progress so that we can actually prevent them from progressing and possibly avoid having to go to second-line agents. We also want to avoid dealing with issues like running out of options, but, more importantly, to address those patients who are at risk for developing Richter’s transformation. Those patients progress at a median of 1.8 years. In many cases, this is before they start therapy. Even those who progress on BTK inhibitor therapy, have likely had the initial event happen before they started therapy. That's primarily related to data that comes out showing that patients who have progression on ibrutinib if they progressed within 1 to 2 years of initiation of therapy, they most likely have a Richter's transformation. Whereas, those who progress beyond year 2 will more than likely just have a CLL progression.

In looking at the prognostic markers in 2019, the most important are those that predict for the ability to have a mutation in theBTKgene, like C481S, that leads to resistance to BTK inhibitor therapy with the covalent inhibitors, or the risk of Richter's. These translate into prognostic markers such as 17p deletion,TP53dysfunction, complex karyotype,MEKabnormalities. It also translates toNOTCH1mutations and certain stereotyped [IGHV] genes like 4-39 that indicate a risk of developing Richter's transformation.

TARGETED ONCOLOGY: What broad role do molecular markers play in CLL? How are we learning from them to predict high-risk CLL?

Furman: We have almost an unlimited number of prognostic markers in CLL and all of these have been established in terms of predicting time to treatment. But, if you have excellent treatments, what's the value of knowing the time to treatment? That's where we are in 2019.

The important markers that we have going forward are those that are going to predict for patients who are not responding long term on our treatments. Those will ones that predict for progression on BTK inhibitor therapy—like complex karyotype, 17p deletion—and those that will predict for the development of Richter's transformation—NOTCH1mutation, 17p deletion, etc. Those are the prognostic markers that I believe matter most in 2019.

TARGETED ONCOLOGY:What does the treatment landscape look like for high-risk CLL? Are there any novel therapies being investigated?

Furman: Assuming that BTK inhibitor therapy is the standard of care, the next line of therapy is often going to be BCL-2 inhibitor therapy. What we have found is that combining the 2 is extremely powerful and effective. It will likely help avoid the development of resistance to BTK inhibitor therapies and achieve deep and hopefully long-lasting responses.

We have data from the CAPTIVATE study that's currently maturing, looking at ibrutinib plus venetoclax (Venclexta). We have studies looking acalabrutinib (Calquence) plus venetoclax, with or without obinutuzumab (Gazyva). We also have 2 multi-institutional, national cooperative group studies (Alliance and ECOG), looking at combinations of ibrutinib/obinutuzumab with or without venetoclax in all patients.

TARGETED ONCOLOGY: Can you discuss the ublituximab/ibrutinib combination in the GENUINE trail?

Furman: Ublituximab is a new antibody that targets CD20 and has a similar efficacy receptor characteristic of obinutuzumab. It's expected to be much more efficacious in interacting in the FC receptors of effector cells. We see the antibody is well tolerated and I suspect its efficacy overall is going to be similar to that of obinutuzumab. Combining it will ibrutinib is likely going to generate rapid depletion of the tumor clone. Whether or not that results in deeper remissions or longer-lasting remission is yet to be seen.

The regimen is well tolerated and is being used as a backbone to combine with other B-cell receptors and BCL-2 antagonists as well.

TARGETED ONCOLOGY: What factors go into the decision making of which patients get which treatment?

Furman: At this point, it's based on which patients I think will have an issue with toxicity. BTK inhibitor therapy is my first-choice therapy and the decision to not use BTK inhibitor therapy is primarily going to be based upon those patients who because of anticoagulation or cardiac risk factors have a high likelihood of developing toxicity. Those are patients who I then move onto BCL-2 inhibitor therapy. I look to use that to get a rapid depletion and a deep depletion of disease and to hopefully get long-lasting responses.

TARGETED ONCOLOGY: What challenges still remain in this field?

Furman: Identifying the 20% of patients who are going to develop resistance to ibrutinib or another BTK inhibitors or develop Richter's transformation and trying to identify a means to intervene and prevent those events from happening is the most important goal right now.

A couple of different ideas include combination therapies, which would achieve more rapid depletion and one that would avoid resistance. It might be an effective option for those patients who develop resistance to BTK inhibitor therapies most commonly mediated by a mutation in C481S. Using a combination therapy of ibrutinib and venetoclax or a BCL receptor and a BCL-2 inhibitor, in general, will allow us to control the tumor clone rapidly to prevent the mutation from developing.

We have data now suggesting that the mutation is pre-existing. Therefore, by treating with just 2 agents, we're likely going to overcome the resistance that's associated with the C481S mutation. Concerning the Richter's, it's difficult to deal with because once you develop a Richter’s transformation, it's a very different situation for the patient. There, a potential option may be early intervention, considering that the median time to develop Richter's is 1.8 years and that 48% of patients develop a Richter's transformation prior to initiating therapy.

TARGETED ONCOLOGY: What is most important for community oncologists to know about treating this patient population?

Furman: It's important to identify patients who are high-risk and treat them differently. The high-risk are those withTP53dysfunction and either a deletion 17p or a mutation. Interesting data were presented, showing how variant allele frequencies are getting as low as .2%. If people have mono allelicTP53dysfunction, meaning one allele is either deleted or mutated, they can have good outcomes on ibrutinib. It's just those patients who have bi-allelic dysfunction who run into trouble. Hopefully, we will one day be able to make that determination.

I believe that everyone should be tested forNOTCHmutations by next-generation sequencing as well as looking for the [IGHV] gene to know whether or not you have a stereotyped B-cell receptor that might predict for the development of a Richter's transformation, namely the 4-39.

References

1. TG Therapeutics Announces Final Long-Term Results from the Phase 3 GENUINE Study Demonstrated that Ublituximab in Combination with Ibrutinib Improved Progression-Free Survival in Patients with High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia as Compared to Ibrutinib Monotherapy [press release]. New York: TG Therapeutics; October 24, 2019. https://bit.ly/31QroEM. Accessed October 25, 2019.
2. Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study.J Clin Oncol. 2017;35(suppl; abstr 7504).