Real-World Findings on TLS Prevention and Management With Venetoclax in CLL
Mark Geyer, MD, and Yannis K. Valtis, MD, delved into the background and findings from a study looking at clinical and laboratory tumor lysis syndrome in patients with CLL who were treated with venetoclax in the inpatient and outpatient settings.
Mark Geyer, MD
A study found a low incidence of laboratory tumor lysis syndrome (TLS) and no clinical TLS in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), underscoring the safety of venetoclax (Venetoclax) when managed properly.
A total of 136 patients aged 18 years and older with a diagnosis of CLL/SLL were enrolled in the single-institution, retrospective cohort study. These patients were given commercial venetoclax in any line of treatment at Memorial Sloan Kettering Cancer Center between January 1, 2016, and December 31, 2020. Among the patients, the trial included 616 venetoclax escalations.
The median age of those enrolled was 70 years, 86% of patients were White, and 11% had high TLS risk at baseline. Venetoclax was part of the first line of treatment for 48 patients (35%). Forty-seven (35%) patients received venetoclax monotherapy, 74 (54%) patients were escalated exclusively outpatient, 35 (26%) had at least 1 prophylactic hospitalization, and 27 (20%) patients were escalated exclusively inpatient.
Findings showed that of all the patients included in this cohort, 8 (5.9%) developed lab TLS and no patients developed clinical TLS. A total of 11 TLS events were seen, and 2 patients developed TLS in more than 1 escalation. For those who escalated exclusively inpatient, the TLS incidence was 15%, while it was 5.7% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively outpatient. Moreover, patients who developed TLS were more likely to have a higher risk for TLS at baseline.
These findings show the promise of venetoclax for those concerned about TLS risks, particularly when they are used in combination with CD20 antibodies, for achieving treatment-free remission in this patient population.
In an interview with Targeted OncologyTM, 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 this research on the real-world incidence, prevention, and management of TLS in patients with CLL who were treated with venetoclax in the inpatient and outpatient settings.
Yannis K. Valtis, MD
Targeted Oncology: Can you provide some background on this research?
Valtis: This is a project that has to do with the use of venetoclax in patients with chronic lymphocytic leukemia. Chronic lymphocytic leukemia is one of the more common leukemias; it affects a lot of [patients]. One of the ways we treat it is with venetoclax either alone or, more commonly, in combination with other medications. It is 1 of the treatments that tends to work well for [patients]. One of the advantages of venetoclax-based treatment is that it can be time-limited, which means that the patient can take it for about a year and then have an interval where the patient does not need to be treated. That is something that several patients, especially younger patients, tend to value, this ability to stay off treatment for hopefully several years for this disease that otherwise sometimes necessitates a kind of continuous lifelong treatment.
One of the issues with venetoclax-based treatments is that venetoclax does have the risk of causing tumor lysis syndrome, which is a medical syndrome where the tumor cells are dying quickly, and they release different substances into the bloodstream that can be dangerous to the patient if not managed appropriately. What we set out to do is to look at a cohort of patients that were treated at [Memorial Sloan Kettering Cancer Center], outside of clinical trials, to see what is happening in the real world, not just in the highly monitored setting of clinical trials, and tried to figure out, of everyone who received venetoclax for CLL, how many [patients] ended up developing tumor lysis syndrome among those [patients], and among those [patients], how did they do? Did anyone need to get hospitalized? Did anyone need to get a high level of care? That was kind of the motivation for the project.
Geyer: What I will add is that tumor lysis syndrome can lead to a number of complications, including renal failure, volume overload, cardiac arrhythmias, and seizures. TLS is something that we commonly see in treatment of what are chemosensitive diseases. Generally, acute leukemias. Rarely can it be seen in solid tumors that are rapidly growing. CLL is classically considered a slow growing leukemia. Historically, the risk of tumor lysis syndrome in patients treated for CLL was relatively low. However, during the initial development of venetoclax, which helps to restore natural cell death or apoptosis, it was observed that in the early phase studies, some patients were experiencing TLS. This has led to the adoption of a schedule in which the dose of venetoclax is increased or escalated slowly, over the course of 5 weeks, so that we have a little bit of tumor breakdown, essentially at the outset, and that we are not introducing further doses until we have had some debulking of the disease in order to reduce the risk of someone experiencing this TLS complication early on. This is important for the reasons that Yannis has outlined in the treatment of our patients with CLL, where venetoclax can be a great tool for delivering time-limited therapy. It is effective at delivering complete remissions.
What were the methods and design of this study? Who was included?
Valtis: It was a retrospective study and we looked at everyone who received venetoclax for CLL during the study period, early 2016 to the end of 2020, so it was a 4-year period. We included [what] ended up being 136 patients, and then we went into their medical records and extracted the relevant information. We extracted information about their disease, how they were treated, whether the venetoclax was given alone or in combination with other medications, and we also looked at all the laboratories to determine whether they developed TLS. There is something called the modified Cairo Bishop Criteria that [is used] to define the emergence of tumor lysis syndrome.
Blood smear of chronic lymphocytic leukemia (CLL), analyze by microscope: © jarun011 - stock.adobe.com
TLS is kind of classified into 2 categories: laboratory TLS and clinical TLS. Laboratory TLS means that you have some lab abnormalities, usually an elevation of your uric acid and your phosphorus, maybe an elevation of potassium, or a little bit of a lowering of the calcium, but it has not started causing any damage in the body or in the other organs. It has not caused any renal damage, it has not caused any cardiac arrhythmia, certainly no neurologic issues. Then clinical TLS is where you start seeing consequences in the end organs. Most commonly, you see elevations in the creatinine and damage in the renal function. We went through all the labs and clinical notes to figure out how many [patients] developed laboratory and/or clinical TLS.
Geyer: We took a deep dive into the charts of these patients in order to assess all of the different elements that might have gone into their risk of tumor lysis syndrome, including all the different prophylactic strategies, what the baseline disease burden was, what other medications may have been used in addition to venetoclax for treatment of their CLL, and looking at what happened with that patient in terms of events occurring in the outpatient setting, or in the hospital. One of the strengths of this is the ability to have done such a deep dive into the charts of these patients in a real-world setting to identify the incidence and risk factors for development of tumor lysis syndrome.
What were the primary results regarding the incidence of laboratory TLS vs clinical TLS?
Valtis: Reassuringly, we found that the incidence was low. Eight patients, which represented about 6% of the total sample, developed laboratory TLS, and nobody developed clinical TLS. That was an encouraging finding in that, even though TLS did occur, it was rare. Consistent with prior reports, it was relatively rare. Reassuringly, nobody had clinical TLS. Nobody needed haemodialysis, nobody had any damage [to] their kidneys, any life-threatening arrhythmias, or anything like that. That was reassuring to us. After we ascertained that the event rate was quite low and that only a few patients developed TLS, we tried to figure out if there is any way that we can predict who is at risk for developing TLS? Then, we also delved into this question that Dr. Geyer pointed out of the inpatient vs outpatient.
In terms of who is at risk for developing TLS, in the venetoclax prescribing information that is published through its approval mechanism, there is a TLS risk score system that basically says, [we] should look at how big the patient's lymph nodes are either by physical exam or by an image like a CT scan and should look at their circulating absolute lymphocyte count. Based on those 2 variables, [one] can assign [patients] into high, medium, or low TLS risk. Essentially, the guidelines say that if someone has a high TLS risk, then they should be admitted into the hospital for the initial venetoclax escalation to make sure that if TLS occurs, it can be managed.If they have low TLS, that can be done as an outpatient.
What we found in our data set is that TLS risk score did predict who is at risk for developing TLS. [Patients] were much more likely to develop TLS if they were going in with a high TLS risk score than if it were going in with a low or an intermediate risk score. In fact, when we look at some other variables, things like age and whether the patient was treated with other medications, and what their renal function was, we did not find any other variables that had any more predictive power than the TLS risk score in determining who is going to get TLS.
Geyer: TLS risk based on their prescribing information was the only variable in a multivariable analysis that held up as independently predictive of tumor lysis syndrome. When we looked at univariable analysis, we did see that, for example, creatinine clearance and age did have marginal associations with incidence of tumor lysis syndrome. This tended to wash out essentially in the multivariable analysis, and patients who had a lower creatinine clearance who had higher age, had impatient dose escalation, tended to be those patients who had a higher TLS risk score. The influence of some of those variables could be accounted for by using the TLS risk score in the prescribing information. That was the only independent risk factor.
What were the key demographic characteristics of the patients included in the study? How might that have influenced the results?
Valtis: I think that this is a population that is relatively representative of [patients] with CLL. The median age was 70. It was 86% White or Caucasian ancestry and 8.1% Black or African-American ancestry. They had a reasonable distribution of their performance status by ECOG. Most of them were going in with a good performance, the renal function was overall, quite good. Three quarters of the patients maintained good renal function or clearance above 60 for the entirety of their venetoclax escalation; about a quarter of the [patients]had some dips into creatinine.
The other piece that I think was interesting, and maybe a little bit of a unique strength of this paper, is that a lot of [patients] receive venetoclax in combination with other medications. There have been prior reports of the risk of TLS in venetoclax-based regimens, but a lot of the [patients] in those studies were given venetoclax as monotherapy whereas here, about half of the patients received obinutuzumab [Gazyva] before venetoclax, which results in some debulking of the disease and hopefully also helps contribute to the low TLS risk that was observed. About half received obinutuzumab, 12% received rituximab [Rituxan], and about 3% received ibrutinib [Imbruvica] around the same time, so 1 of the strengths of the study was that it includes a number of [patients] that received prior debulking.
Geyer: As Dr. Valtis mentioned, CLL is a disease of older adults. The median age of CLL diagnosis in the US is around 70. That is essentially identical to what we had in this cohort, so it does appear to be representative, and CLL is also more common against patients with male sex, and around 65% of the patients in our cohort fit that demographic as well. As has been noted when venetoclax was first introduced, it was used most commonly by itself as monotherapy. Increasingly, venetoclax is being used in combination with other agents. The cohort reflects the use of additional agents with venetoclax in this setting and helps to provide some further insight into how this plays into development of tumor lysis syndrome.
Disclosure: This study was investigator-initiated and received grant support from Sanofi to facilitate data collection and enable completion of this research.
