Clinical Insights on TLS Prophylaxis With Venetoclax in CLL

In an interview with Targeted Oncology^TM, Mark Geyer, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center, director of the Acute Myeloid Leukemia Program and the Adolescent and Young Adult Leukemia Program, and Yannis K. Valtis, MD, second-year fellow in medical oncology at Memorial Sloan Kettering Cancer Center, discussed their real-world findings on the incidence, prevention, and management of tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) treated with venetoclax (Venclexta).

According to findings from a single-institution, retrospective cohort study, laboratory TLS was observed, though clinical TLS was not. Baseline hyperuricemia and impaired renal function were more common among those who developed lab TLS compared with those who did not.

Geyer and Valtis noted that prophylactic measures, including use of intravenous (IV) hydration, may have contributed to low rates of observed TLS in the outpatient setting.

Their insights highlight the effectiveness of comprehensive prophylactic measures and provide valuable guidance for healthcare professionals managing CLL.

Read part 1: HERE

Targeted Oncology: The study also mentioned the prophylactic measures used. How effective were those strategies in preventing TLS?

Valtis: This is a cohort that received rather comprehensive prophylaxis for TLS. A lot of this is driven by the guidelines that are published by [National Comprehensive Cancer Network] and also included in the venetoclax prescribing information, but some of it is individual practice or individual center variation. We were interested in prescribing the prophylactic maneuver. This cohort overall received rather strong prophylaxis. The overwhelming majority had an agent aimed at preventing the rise of uric acid, 71% of patients received intravenous hydration, so many of these patients were being escalated into the outpatient setting, but we would still bring them in and give them intravenous hydration on the days that they were increasing the dose of venetoclax to help flush out any products of lysis.

Then, 13% received IV diuretics. About 10% received prophylactic rasburicase [Elitek], which actively lowers the uric acid, about 18% received phosphate binders, and about 10% received ion-exchange resins which managed potassium. The overwhelming majority got allopurinol, and most of the patients got IV hydration. The numbers I gave were for the first escalation. In subsequent escalations, some of these numbers dropped because as [patients] are doing well and their labs are completely normal, [patients] usually decide they would not need to be brought in for intravenous hydration anymore.

Geyer: One thing that is important to remember is that one of the most important strategies that is used for prevention of TLS in this cohort is doing this escalation in a stepwise fashion over the course of weeks, and that a lot of these other measures are somewhat adjunctive. We strongly encourage oral rehydration in all of our patients. In fact, there are some patients where, both by grabbing information and informed by real-world data, aggressive oral hydration in addition to other therapies may be sufficient without as aggressive IV hydration. However, increasing the dose over the course of 5 weeks helps to attenuate some of the risk of TLS that is inherent here. As Dr. Valtis mentioned, informed by the prescribing information and informed by the available clinical trial data and real-world data, these patients did have fairly aggressive TLS prophylaxis in terms of hydration receipt of a xanthine oxidase inhibitor and in some of the patients of the highest risk, receipt of recombinant urate oxidase.

Were there any specific decision-making processes for hospitalizing patients prophylactically vs managing them in the outpatient setting?

Valtis: Some of the decision making is not known to us because this was a range of physicians that treated these patients. For some of them, it is obvious why they were hospitalized vs not. For others, it was a decision that was made and maybe TLS was not fully documented in the chart. The [patients[ who have high TLS risk, essentially, almost all of them were hospitalized for their escalations as per the guidelines in the prescribing information, and so that is consistent with what would have been done everywhere. What was interesting is that there were a number of patients that had low TLS risk that were hospitalized prophylactically and the vast majority of them did not end up developing TLS. It does bring into question this concept for [patients] who are at low risk for TLS, it is possible that some of these hospitalizations can be avoided in the future now that we have such robust methodologies for preventing TLS in the outpatient setting.

Hopefully our paper will, once it is fully published, contribute to that idea that low-risk patients can be safely escalated in the outpatient setting and maybe some of these prophylactic hospitalizations can be avoided. Now, probably not all of them can be avoided, there will always be situations where, for example, the patient being escalated in the outpatient setting still needs to come in for labs, both the day of escalation and oftentimes the following day, and IV hydration, and there will be some patients for whom that is logistically impossible or there is some other kind of medical reason that makes it so that this cannot happen. There probably will always be a number of [patients] that need to be hospitalized for venetoclax escalation, but our hope is that in the future, some of these low-risk patients can go into the outpatient setting.

Geyer: I also will comment that if you take a look through the data and you look at what the incidence is of tumor lysis syndrome in patients who were hospitalized vs not hospitalized, on first glance you might say, wait a minute, the risk of TLS was higher in the patients who were in the hospital. That is because the patient population who was impatient for all or most of their dose escalations largely reflects those who have higher TLS risk, as assessed by the treating physician as well as assessed by the TLS risk score that we have. There may be reasons beyond TLS risk related to patient performance status and related to caregiver support that can also inform decision making and whether or not to admit a patient. We are hoping that these data will help reassure physicians that patients who are logistically able to come to the clinic for 2 days in a row for laboratory studies, for hydration, if appropriate, and for assessments, can avoid these inpatient hospitalizations and the costs associated with them.

What insights does this study provide regarding the safety and efficacy of venetoclax in the first-line setting?

Valtis: Overall, part of our ongoing hypothesis was that we were going to see some amount of TLS, but that amount of TLS was going to be low, and none of the patients that developed TLS were going to be at significant risk. That is exactly what we found. There was a low risk of laboratory TLS, 0 clinical TLS, and of the ones that did develop TLS, most of them could be safely managed in the outpatient setting. Only 1 person needed to be admitted because they developed TLS. A few others developed it in the inpatient setting, so they were admitted anyway. But a couple of others that were outpatient were successfully managed in the outpatient setting. Overall, this provides a picture where TLS is a rare event. Nobody had significant complications, and many were successfully managed in the outpatient setting. It further provides confidence in the safety of this regimen. The second insight is that it is possible that there are a number of low and intermediate-risk patients that are being hospitalized currently, who maybe could be escalated safely in the outpatient setting. Hopefully, in the future, we can try to reduce the number of hospitalizations for this cohort of patients.

Geyer: I agree. One of the areas of interest that we have at [Memorial Sloan Kettering Cancer Center] in the CLL program, as well as a number of other institutions, is trying to reduce the risk of TLS at the time that patients are starting venetoclax. That can be accomplished by instituting debulking therapy with drugs like obinutuzumab [Gazyva], certainly prior to beginning venetoclax, and can potentially be attenuated by having a comprehensive program in place for prevention of TLS with hydration with xanthine oxidase inhibitors, if appropriate with recombinant your oxidase like like rasburicase, etc. I think that these data provide an important foundation that, even in a real-world setting, does appear to be feasible. Hopefully, we can reduce impatient resource utilization and reduce the incidence of laboratory TLS even more through efforts aimed at reducing disease burden prior to starting venetoclax, as well as having the right individualized strategies in place for our patients who are starting venetoclax.

What advice would you give to other healthcare professionals based on the results and experiences from the study?

Valtis: This is a treatment that can be useful for a lot of patients. For younger patients that want to have that treatment-free remission, venetoclax usually in combination with a CD20 antibody can be an appropriate, even first-line, choice, because we are going to teach them how to be successfully used in the first line. For [patients] that have already tried other lines that have not worked or have stopped working, adequate space regimens can be a good option for [patients with] CLL. If physicians or practitioners are concerned about the risk of TLS and choose not to pursue this treatment because of the risk of TLS, we hope that our data kind of provides some peace of mind that it can be done safely.

Geyer: In CLL, we have a few tools that are effective for treatment, including venetoclax and Bruton tyrosine kinase [BTK] inhibitors. While BTK inhibitors do have the advantage in the sense where they can get a continuous therapy once or twice a day and come in for labs once a week for say for a few weeks, and then continue their drug that sometimes is more attractive to community practitioners then needing to go through the escalation of venetoclax. However, I am hoping that these data will illustrate for our colleagues, especially in the community, that venetoclax dose-escalation can be done safely in the outpatient setting. Yes, it does involve some more attention in those first 5 weeks in terms of having 2 days in a row, potentially, of evaluations for laboratory studies and for hydration, and for making sure that that patient is not experiencing evidence of TLS. But this can result in a low incidence of TLS, and certainly an exceptionally low incidence of TLS needing hospitalization.

Ultimately, as Dr. Valtis mentioned that payoff can be at the back end, and these patients are able to have a treatment-free remission, especially in the frontline setting in many cases after just as little as 1 year of therapy. For patients who are interested in being able to come off treatment for a period of time, venetoclax is an important treatment option to consider. Hopefully, these data will allow our colleagues in the community to feel comfortable discussing all of the treatment options with patients who are starting therapy for CLL or are starting a new line of therapy for CLL.

Disclosure: This study was investigator-initiated and received grant support from Sanofi to facilitate data collection and enable completion of this research.

REFERENCE:

Valtis Y, Nemirovsky D, Derkach A, et al. Real world incidence, prevention, and management of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax in the inpatient and outpatient settings. J Clin Oncol. 2024, 42(16): 7045. doi:10.1200/JCO.2024.42.16_suppl.7045