Regimen Shows Potential for Reducing TLS Risk in CLL

Kerry A. Rogers, MD

Kerry A. Rogers, MD

A brief course of treatment with obinutuzumab (Gazyva) and ibrutinib (Imbruvica) prior to venetoclax (Venclexta) significantly reduced tumor burden and the risk for tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL), according to results presented at the 2018 ASCO Annual Meeting.

In an analysis from a phase Ib/II study, patients were assigned to escalating doses of obinutuzumab first, then ibrutinib, and finally venetoclax. All patients (N = 61) who completed 3 cycles of therapy were included in these results. Twenty-five patients were treatment-naïve and 36 had relapsed/refractory disease.

Investigators separated patients into low- (n = 8), intermediate- (n = 33), and high-risk (n = 20) groups by absolute lymphocyte count (ALC) and recorded lymph node sum of the product of longest diameters. They then assessed the change in TLS risk from cycle 1 to cycle 3.

ALC declined from cycle 1 to cycle 3 (P <.001). The median change was -56.5 k/µL (range, -430.8 k/µL to 3.9 k/µL). Thirteen (65%) patients went from high- to intermediate-risk for TLS and 24 (73%) went from intermediate- to low-risk. At the start of venetoclax treatment, 32 (52%) patients were considered low risk.

OncLive: What was the rationale for this study?

In an interview with OncLive, lead author Kerry Rogers, MD, assistant professor at The Ohio State University Comprehensive Cancer Center, discussed the feasibility of this regimen and what research still needs to be done with these agents in this patient population.Rogers: This was an unplanned analysis in a prospective clinical trial. The trial was started a few years ago. The goal was to study 3 of the most effective drugs we had in CLL at the time, and they are still 3 of the most effective drugs that we have. They are all chemotherapy-free agents and have complementary mechanisms and nonoverlapping toxicity.

When the study was designed, the agents were started sequentially, 1 for each cycle in month-long cycles. Venetoclax has this risk of TLS that increases when disease burden is high. It’s a rational order to start these agents in a study that was designed to study the administration of all 3 in a time-related fashion.

Once we got the patients on treatment, after the 2-month period, where you’re starting the agents, we decided to look at how quickly disease reduced. A major limitation of expanding the use of venetoclax to nonacademic centers or smaller hospitals is this risk of TLS.

What is the take-home message from your findings?

We’re very well equipped to deal with it at our institution—the prescribing information is very clear on how to assess this risk and mitigate it, so it’s not common to see TLS in practice&mdash;but I see patients who are unable to get [venetoclax] closer to home because of this risk for TLS. Not all hospitals are equipped to deal with it. Since we designed this study to decrease disease burden maximally before starting venetoclax&mdash;and it’s been very well defined in venetoclax what thresholds of disease burden puts people in the low-, intermediate-, or high-risk categories&mdash;we thought this was a great opportunity to discuss how well this strategy worked, and how many people we could bring down from a high- to intermediate-risk and from an intermediate- to low- category.This is more of a lead-in or sequencing of agents to start to question our clinical trial, but what we’re looking at is how quickly disease reduces. It’s not a surprise that this [regimen] reduces CLL burden. These are FDA-approved agents, but how quickly can that happen? Everyone who is planning large studies in CLL likes to argue the long-term strategy, but what we can immediately learn from this is that this is a very effective, short-term strategy for reducing the amount of CLL.

Just 1 month of obinutuzumab, which was dosed as per the US prescribing [information] so it was more dose-dense over the first month of treatment, reduces the lymphocyte count dramatically. There was no one with an ALC over the threshold of 25, which puts patients in the medium-risk group.

When ibrutinib is started, generally you see a treatment-related lymphocytosis; the lymphocyte count goes up. We saw a statistically significant increase in lymphocyte count, but it was nowhere near the levels we saw prior to receiving obinutuzumab.

What someone in general practice can take away from this right away is, if it is important to put a patient in a lower-risk category, to reduce tumor burden prior to starting venetoclax is a plan. This is especially true in a practice environment where it might be less preferable to treat a high-risk patient, or the patient is unwilling or unable to be hospitalized.

Did you perform repeat CT scans?

Was lymphocytosis a problem for patients treated with ibrutinib?

Are there still unanswered questions surrounding this regimen?

You could use one of these strategies to give obinutuzumab alone. You would have to be very careful to make sure you repeat CT scans to ensure that lymph node bulk had decreased, but it could be used to downgrade tumor lysis risk so that venetoclax could be started safely in settings that avoid hospital stays.We did not reassess patients with cross-sectional imaging, CT scans, before starting venetoclax unless they requested that to downgrade risk, and we only had 2 who made that request. If we had put that in the study, more people would have reduced to a medium- or low-risk category. The reductions we have in this abstract were all based on lymphocyte count, so people who were in a category because of lymph node bulk stayed in that category. That’s important to realize, especially for anyone who is considering undertaking this approach for a unique situation for their patient, but repeat cross-sectional imaging would be important there.There was not much treatment-related lymphocytosis with ibrutinib compared with what we would have expected. We very rarely encountered people who started ibrutinib and ended up with a lymphocyte count so high that it was problematic and caused potential leukostasis, which of course goes away when you stop ibrutinib. But if that’s the regimen you need people to be on, that’s very difficult. This also suggests that a very short course of obinutuzumab would be a potential way to attenuate that in select patients.This study is fairly crude, but we’ve not yet had everybody reach the primary endpoint. There was a phase Ib portion, which included 12 patients where the dose of venetoclax was explored. We did reach the target dose level of 400 mg in this combination. The other 2 are dosed at the dose on the US label [10 mg, 50 mg, or 100 mg].

The big unanswered question is, once everybody finishes treatment, “What will the rate of minimal residual disease (MRD)-negative complete remission (CR) be?” So, what the final responses will be for the study.

[Another] big unanswered question is, “What will the progression-free survival be after this regimen?” This is a time-limited therapy, which is extremely attractive to both patients and providers, and to people looking at the cost of healthcare for many reasons. Time-limited strategies have been a standard in CLL in the past, especially in the chemoimmunotherapy experience. Many people don’t like taking pills indefinitely and the cost of it is substantial.

Also, there are long-term toxicities and possibility for resistance. Therefore, I’m very excited about this time-limited strategy, but we don’t yet know how long remissions or responses last. That’s going to be a huge question that needs to be answered after patients complete treatment on this study.

What can be done to better educate hematologists and oncologists working outside of large academic centers about managing TLS?

There are also a lot of other very exciting studies with combinations of these novel agents that avoid chemotherapy. None of them are mature enough to say what the progression-free survival is. We’ve recently seen some follow-up data in the fludarabine /cyclophosphamide/rituximab experience that there’s a select group of patients who have an extremely durable MRD-negative CR where at 10 years, disease has not returned. I don’t know that you can say that achieving a MRD-negative CR after a chemotherapy¬—free targeted agent regimen will be as durable, or whether that will mean the same thing for those patients. To me, that is one of the biggest questions.I’m sure most hematologists and oncologists in practice are familiar with TLS and have dealt with it before. Some of the practice environments aren’t geared for a quick turnaround time from the lab. A lot of the inpatient nurses and the double providers that they work with might not see this very often. Physicians that I’ve spoken to, who are in a more community-based practice, have come up with ways to deal with dose escalation of venetoclax because they know how important this agent is for their population. Being very careful, looking at the full prescribing [information], having a plan ahead of time…[and] talking to someone with more experience is always a good idea.

For those who are in an environment where it’s not easy to get TLS handled, especially for those who don’t have access to dialysis or nephrology consultation, if the worst happens and someone does get TLS, it might be advisable to try some of these strategies to reduce the risk for TLS prior to starting venetoclax. [This should be done] even if that’s what is intended to be started as a longer-term treatment. That should be potentially studied more carefully with something like obinutuzumab.

We are going to need more data before we can have standard recommendations, but when treating an individual patient, these are things that can be taken into account.

Rogers KA, Huang Y, Rupper AS, et al. Change in tumor lysis syndrome risk after lead-in treatment in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax for chronic lymphocytic leukemia. J Clin Oncol. 2018;36 (suppl; abstr 7528).