Roundtable Discussion: Risk-Based Prevention of Tumor Lysis Syndrome for Hematologic Malignancies

Hetty Carraway, MD, MBA (Moderator)

Professor of Medicine

Cleveland Clinic Lerner College of Medicine

Case Western Reserve University

Vice Chair of Strategy and Enterprise Development

Taussig Cancer Institute, Cleveland Clinic

Cleveland, OH

CARRAWAY: In general, what TLS risk factors are most significant to you and the patient population you treat, and of which are you most mindful in your current practice?

HADDAD: I look at the underlying disease—particularly hematologic malignancies, occasionally solid tumors like small cell [lung cancer]—the bulk of the disease mainly, advanced stage, indications by high lactate dehydrogenase [LDH], and the baseline uric acid. To me, TLS is always on my mind in situations like this and I take a very proactive approach to prevent it as best I can.

CARRAWAY: Tell me a little bit about your thoughts on the proactive approach and how you are responding to some of the risk factors that you are talking about.

HADDAD: As I prepare patients for treatment, I plan on giving them hydration and rasburicase [Elitek] a day before, on top of allopurinol, particularly if the uric acid is in the range of 6 mg/dL or higher that I feel concerned with a high tumor burden. I see that approach as easy to do as outpatient; it prevents admissions and rapid emergencies after treatment. If the patient is already in the hospital and they’re sick and weak, that’s something, but if they’re not, then I will [give hydration and rasburicase], and typically outpatients do well. We bring the patient in multiple days in a row, check on them, make sure they are hydrated, and give rasburicase according to the common dose, not the package insert dose.¹ And usually we do well on that end to prevent TLS.

MISBAH: I recently had a patient who was in acute renal failure to begin with and in the process of their admission we learned that they had lymphoma, so we had to start therapy while they were still in the unit, and that was challenging in every which way. So we did end up giving that patient rasburicase and allopurinol.

There was some disagreement with the nephrologist with the dose of the allopurinol. We usually use a dose of 300 mg and we went back and forth but finally they accepted our dose. It was bad all over, but after 2 days the patient was OK—they were on continuous dialysis the entire time, even as we started the therapy and continued it afterwards. But we did end up giving rasburicase and allopurinol daily.

NEMUNAITIS: I don’t see much TLS, but when I have, I’ve used the same dose of allopurinol, the 300 mg.² Do you use a different dose, like the nephrologists were recommending?

MISBAH: I usually use 300 mg, but the nephrologist was telling me not to use that dose because the patient was in renal failure.

But they were undergoing or going to be undergoing dialysis and we gave rasburicase. So we ended up giving the 300 mg [of allopurinol]. I’ve always given that dose to prevent and to treat it.

SHULMAN: What I’ve done in that setting, if there is kidney injury, I make sure I load them with the 300 mg/m² dose, and then I’ll go with the package insert recommendations for acute renal failure along with the rasburicase, and then follow the uric acid level. Just make sure to keep [the blood sample] specimen on ice. That’s the tricky part when you have to monitor it twice a day if they’re an inpatient.

CARRAWAY: With regard to the renal dosing of allopurinol, I have done the 300 mg as the loading dose for allopurinol, and then if they’re having renal impairment, there are dose modifications for allopurinol to dose decrease to 100 mg once a day for renal function.²

So based on the contributions thus far, things to be mindful of [include] whether the patient has appropriate renal function and how we can help them out in the context of dialysis, which complicates this, and then issues with regard to bulky disease and how to manage this and anticipate things in the outpatient setting so you can prevent admission into the hospital.

CARRAWAY: With regard to your experience, what clinical manifestations of TLS have been most problematic or challenging in the short term or the long term?

CHOWDHARY: It seems like when we have patients with TLS, they are usually patients who are either admitted or being admitted for some very aggressive basal lymphoma that we’re treating them for, or they received treatment and came in with TLS, though I think the majority of patients we’ve seen have developed the issue while in the inpatient unit.

And I think, in that sense, they use controlled environments where we have the nephrologists on board fairly early so the acute renal failure, the hyperphosphatemia, and the hyperkalemia is being looked at. They are hyperuricemic when we usually have them started on the rasburicase. I know this whole algorithm, and you can go down all these multiple decision trees; even in low-, high-, and medium-risk [groups], there are various decision pieces.

But in general, if the uric acid level is more than 8 mg/dL, I usually have reached for the rasburicase, whether it’s medium or high risk, regardless. If we have the rasburicase on board and we have the nephrologists on board, even though the patient is on IV [intravenous] fluids [and we have] your alkalines, all those interventions helped fairly quickly in controlling the situation and then if they need to be dialyzed during that controlled environment.

I think the vast majority of our experience has been [that] we find very few [of these] patients, though we had a patient with chronic lymphocytic leukemia but [with] an escalating white [blood cell] count. There was a worry about Richter transformation. He went into severe cardiorespiratory decompensation on the PET scan table, was immediately taken to the emergency department, intubated on pressors, and he was in severe tumor lysis.

We [think] he had a cytokine storm from the Richter transformation but also was in tumor lysis. We gave him rasburicase and we were able to control it fairly quickly as we were trying to stabilize him. Those are the situations we’ve seen in general. I haven’t seen a lot of long-term issues once it’s controlled and treated appropriately.

CARRAWAY: That sounds like a very challenging patient, particularly with an onset of the dire need to get help urgently. Some of the things that challenge us are the concurrent renal failure that happens with our patients, and then we have to navigate, along with nephrologists, how to best manage not just dialysis [and] hydration, but [also] the electrolyte disturbances that transpire.

[For] the patients that are urgently not doing well, you want to act quickly…and in that situation it’s hard to even imagine TLS prophylaxis.

CARRAWAY: Do you have challenges with TLS prophylaxis in both the inpatient and the ambulatory settings?

CHOWDHARY: In the setting of prophylaxis—especially in the setting of renal dysfunction—I know that febuxostat [Uloric] has much less interaction with renal dysfunction,^3,4 but I don’t see a lot of that advised or used. I know it’s a bit more expensive than allopurinol.

I was wondering, for TLS prophylaxis, what role does febuxostat have and have you used it? I haven’t used it myself, but I was wondering about that within this discussion.

CARRAWAY: That’s a great question. I have not personally used [febuxostat].

CHOWDHARY: I did want to know if anyone had experience with febuxostat because it is one of those options out there for TLS prophylaxis, especially in adults. I don’t think any study has shown it being any better than allopurinol.

SHULMAN: I certainly have not used it, but I think one of the issues that comes up, especially as an inpatient, is the cost of the rasburicase and how many vials you’re going to use based on the weight and the dose. Usually, the pharmacy only wants to give 1 dose and then they balk if you want to give any more than that because the drug is so expensive. So that’s sometimes one issue, do you do 0.1 mg/kg or 0.2 mg/kg.

CARRAWAY: The [agents] that I have personally used have been allopurinol and rasburicase, and we have specific criteria and algorithms, as you mentioned, whereby we’re allowed to use rasburicase, but certain criteria have to be met within our institutional standard operating procedures.

With regard to the vial size we just talked about with rasburicase, for many institutions there may be different policies. Prior to working at this institution I was elsewhere, and the policies elsewhere were trying to use smaller doses with regard to the vial size. I’ve equally seen a practice where we have to wait for the uric acid to get to a certain level, or the white [blood cell] count to get to a certain level, or the creatinine to meet certain criteria in order to qualify that patient to receive the agents. So I’d be interested if any of you have experience one way or the other. I think you can sometimes advocate for patients, depending on each specific scenario, so I’d be curious to hear how physicians are navigating that, if they’re having issues or questions.

HADDAD: Well we established protocols with an institution and our clinics. We use a small dose, ranging between 3 mg and 6 mg, typically 3 mg and sometimes 4.5 mg. Sometimes 1 dose is all you need. And by the next morning, in the majority of patients you see that uric acid drop significantly to levels just under 2 mg/dL, and sometimes even lower than that. So in the vast majority of cases where we used it, we were able to control it with a single dose, ranging between 3 mg and 6 mg.

CARRAWAY: Are you having any challenges with that algorithm that you could share or wins in that situation that are working well?

HADDAD: The 2 most important factors are the diagnosis within aggressive lymphoma or reasonably bulky disease, and uric acid that’s usually 7 mg/dL or higher. With these 2 factors I can push for 1 dose of rasburicase the majority of the time.

MUTHUSAMY: I have a question regarding the dose. There are studies of patients on a lesser dose than 3 mg—a 1.5-mg single dose has been used—and they’re showing it as being very effective, even 1.5-mg prophylaxis.^5,6 Why 3 mg or 4.5 mg? It could be even cheaper.

CARRAWAY: I think institutions [may], when they’re opening that vial, want to use the entire vial so the drug isn’t going to waste. [That] is my understanding.

CARRAWAY: Does your institution have a standard order set or protocol for TLS? How and when [was it] developed and who was involved? Do you have any trouble testing uric acid after rasburicase is given?

MISBAH: At our institution, the hematologists are the only people who can order [rasburicase]. So if the nephrologist wants it, even if we’re not involved, we do get involved and we have to physically put the order in. So we end up doing a consultation and most times it is appropriate for us to also see the patient, but there are a few times that the nephrologist wants to use it and we have no major involvement with it.

KOKO: I have a few experiences with rasburicase, but most times I tend to start my patients on allopurinol, even up to a week or 2, except in situations where the patient developed TLS. But I do use a lot of allopurinol to prevent TLS before instituting therapy. The few patients I’ve had were patients with Hodgkin lymphoma. In my institution it’s only the oncologists as well that can prescribe rasburicase, so I haven’t had any situation where the nephrologists have requested the rasburicase. But that’s the only situation. They tend to be quite conscious of the cost and I have never had a situation where I use more than 1 dose of rasburicase, and in the majority, the uric acid level goes down significantly the next day.

TANDRA: We have a bone marrow transplant service and high-grade malignancies service. We have a pharmacy department that’s quite on top of things when it comes to rasburicase use. We try to minimize the 3-mg dose. I haven’t seen the 1.5-mg dose, but 3 mg is quite optimally used. We also review the use of rasburicase once every quarter or every 6 months to see if there is anything we can do better, but we use it often.

CARRAWAY: Yes, I’m not surprised. Everybody seems to have a different way of controlling the use of rasburicase. For our institution, we can order it but it won’t be released by the pharmacy unless the people that are controlling the approval of rasburicase approve it. So there are multiple mechanisms and steps in place and I think much of that is class containment and appropriate use of the agent.

MUTHUSAMY: I have never done any G6PD [testing] in any of my patients in outpatient settings. Mainly I have given it for patients with lymphoma, bulky disease, and high LDH, [in] the diffuse large B-cell lymphomas. I never [gave rasburicase] in [patients with G6PD deficiency]. I have only given 1 dose as prophylaxis in those high-risk patients.

SHULMAN: I think there’s an UpToDate [article] that says if you’re concerned about it and you don’t have time to test for G6PD, you can use a small test dose, and I think wait a certain period of time to make sure there’s no hemolysis, and then if they’re OK, administer the rest of the dose. I think I did that with 1 patient, but [G6PD deficiency occurs in] mainly [Black] and Mediterranean populations.

WASELENKO: Dr Carraway, I have a couple questions for you. One is about the immunogenicity of rasburicase with multiple uses. You can have decreased efficacy over time, if you use it in multiple iterations.¹ Is there subsequent risk for hypersensitivity issues with having to use it on a recurrent basis in a patient? And then the other issue, which I’ve certainly never seen with this, is methemoglobinemia; it looks like if it’s combined with certain drugs—one is dapsone [Aczone], which we certainly use in patients with biologic malignancies as well—[that it] potentiates that risk.⁷ So I just wanted to get some of your thoughts about the nuances.

CARRAWAY: [Concerning] the immunogenicity of rasburicase with multiple uses and the decreased efficacy over time, I personally haven’t had any struggles with that with the use of rasburicase. For many of the patients, I think it’s important to make sure that you’re addressing the issues with regard to their TLS in a multitude of things, not just with rasburicase but also the IV hydration and all of the other parameters that are ongoing. I have not personally experienced the decreased efficacy over time, so I don’t know that I have any specific guidance with regard to that question for you.

And then with regard to the hypersensitivity issues and the concurrent drug-drug interactions with dapsone and other agents, I do worry about G6PD deficiency, especially in the context of those drug-drug interactions. And I think it is important to be mindful of those things, in particular for at-risk populations. At our institution, we have a very quick turn-around time for checking for G6PD deficiency. So, if you anticipate that you potentially are going to need to use this drug for patients, if you know what the turnaround time for testing G6PD is, [you should] get that in the queue before you are in trouble and [need] to give that agent if you’re at all concerned about it.

_References

_{1. Elitek. Prescribing information. Sanofi-Aventis US LLC; 2019. Accessed March 28, 2022. https://bit.ly/3uxTgO3}

_{2. Zyloprim. Prescribing information. Casper Pharma; 2018. Accessed March 28, 2022. https://bit.ly/3Dg3QNE}

_{3. Tamura K, Kawai Y, Kiguchi T, et al. Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol. Int J Clin Oncol. 2016;21(5):996-1003. doi:10.1007/s10147-016-0971-3}

_{4. Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12(1):22-34. doi:10.1097/00045391-200501000-00005}

_{5. Philips A, Radhakrishnan V, Ganesan P, et al. Efficacy of single dose rasburicase (1.5 mg) for prophylaxis and management of laboratory tumor lysis syndrome. Indian J Hematol Blood Transfus. 2018;34(4):618-622. doi:10.1007/s12288-018-0938-9}

_{6. Thorat J, Majumdar S, Jain H, et al. A phase II non-randomized study to evaluate the efficacy of single dose rasburicase (1.5mg) in adult acute leukemia and high grade lymphomas with established tumor lysis syndrome. Blood. 2019;134(suppl 1):2914. doi:10.1182/blood-2019-128755}

_{7. Ahmed M, Sanchez T, Norgbe S, Picking CR, Millner PG. Rasburicase-induced methemoglobinemia. Cureus. 2021;13(4):e14406. doi:10.7759/cureus.14406}