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.
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.
OncLive: What was the rationale for this study?
: 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.
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—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—and it’s been very well defined in venetoclax what thresholds of disease burden puts people in the low-, intermediate-, or high-risk categories—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.
What is the take-home message from your findings?
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.