A review of the incidence of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax and debulking strategies

Abstract We reviewed the literature (January 2010–June 2021) on the effectiveness of debulking strategies before venetoclax initiation in patients with chronic lymphocytic leukemia to reduce tumor burden, downgrade tumor lysis syndrome (TLS) risk, and avoid hospitalization. Low TLS incidence and reduced TLS risk based on tumor burden were reported following debulking in clinical trials. Real‐world observational studies reporting debulking regimens recorded no TLS events, and those without debulking strategies had greater TLS incidence. Debulking prior to venetoclax considerably reduces TLS incidence. Further clinical trials and real‐world studies may provide additional evidence on effectiveness of debulking in reducing TLS incidence and hospitalization need.

TA B L E 1 Summary of tumor lysis syndrome (TLS) prophylaxis and monitoring measures [48] Prophylaxis measures

Hydration
Patients should be instructed to drink plenty of water daily (1.5-2.0 L is recommended), starting 2 days before and throughout the dose-titration phase, especially at each subsequent dose increase, to enable adequate hydration. Intravenous fluids should be administered for patients deemed at high risk of TLS or for those who cannot maintain an adequate level of oral hydration Anti-hyperuricemic agents Administered 2-3 days prior to venetoclax initiation in patients with high uric acid levels or at risk of TLS. May be continued through the titration phase Laboratory assessments Pre-dose: Blood chemistries should be assessed for all patients prior to the initial dose, to evaluate kidney function and correct pre-existing abnormalities. Blood chemistries should be re-assessed prior to each subsequent dose increase during the titration phase.
Post-dose: For patients at risk of TLS, blood chemistries should be monitored 6-8 and 24 h after the first dose of venetoclax. Electrolyte abnormalities should be corrected promptly. Evaluation of the 24-h blood chemistry results should occur before administration of the next dose of venetoclax. The same monitoring schedule should be followed at the start of the 50 mg dose and at subsequent dose increases for patients who continue to be at risk following reassessment Hospitalization Based on physician assessment. Some patients, for example, those at high risk of TLS, may require hospitalization on the day of the first dose of venetoclax for more intensive prophylaxis and monitoring during the first 24 h. Hospitalization should be considered for subsequent dose increases based on a reassessment of risk  50 20 20 10 into the systemic circulation) during treatment initiation. Patients treated with venetoclax should be stratified by TLS risk and receive prophylactic measures, per the label guidance, as well as monitoring throughout treatment so that occurrences of TLS are identified early and can be managed (Table 1) [10,11]. Information on the diagnosis and classification of TLS is provided in Supplementary Table S1 Tables   S2 and S3). Further, "debulking" (to reduce as much of the volume/bulk of cancer cells as possible) with chemotherapy, immunochemotherapy, or targeted therapy treatment cycles prior to initiating venetoclax can potentially reduce tumor burden and, consequently, the need for hospitalization (by downgrading high-risk tumor burden to medium-or low-risk or medium-risk with creatinine clearance [CrCl] < 80 mg/dl to low-risk for TLS; Supplementary Table S2). Thus, debulking has helped to combat the severity and reduce the incidence of TLS [12][13][14][15][16][17].
Despite these mitigating measures, there is still a risk of TLS, which may potentially increase in incidence as venetoclax becomes more widely used in real-world settings [18].
The aim of the current review was to investigate the impact of debulking strategies prior to venetoclax initiation, especially their efficacy in reducing tumor burden and the need for hospitalization.

Search strategy
A comprehensive literature search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was undertaken from November 2020 to June 2021. The search used the free-text terms "venetoclax," "chronic lymphocytic leukemia," "tumor lysis syndrome" and "debulking," along with their other derivatives (ABT-199, GDC-0199, RG-7601) and abbreviations (CLL, TLS).

Debulking strategies utilized and reported rates of TLS in clinical trials
In clinical trials, tumor debulking was most commonly achieved using obinutuzumab, ibrutinib, or bendamustine; however, other treatments were investigated, including umbralisib and ublituximab (U2), duvelisib, and acalabrutinib (Table 2). Notably, the timing of debulking varied significantly between clinical trials, occurring within the same cycle as venetoclax initiation in some studies and starting up to three cycles prior to venetoclax in others. No TLS-related deaths were observed, and only low numbers of TLS events (very few of which were clinical) were reported following debulking regimens in clinical trials of venetoclax (Table 3).

Effect of debulking on TLS risk reported in clinical trials
Several clinical trials have indicated a reduction in TLS risk following debulking, compared with baseline risk, highlighting the effectiveness of including a debulking regimen prior to initiation of venetoclax ( 28% of patients were high risk, and 60% were medium risk prior to debulking; following debulking, only 1% of patients were high risk, and 15% were medium risk [49]. In the Phase 3b M16-788/CLL-076 trial, medium and high TLS risk (73% and 26% of patients, respectively) at baseline were mainly driven by increased ≥25 × 10 9 cells/L in 85% of patients) [24]. The median decrease in lymph node size was 0.5 cm for obinutuzumab monotherapy [24]. After two cycles of debulking therapy, low TLS risk was achieved in 56/61 (92%) patients treated with Obinutuzumab [24]. This reduction in TLS risk may facilitate outpatient venetoclax initiation and thus reduce the need for hospitalization.

Bendamustine monotherapy
Debulking with two cycles of bendamustine (for patients with an ≥25

Real-world data on the use of debulking strategies and TLS risk with venetoclax
Although the evidence for the impact of debulking is of lower quality from real-world studies, compared with data from clinical trials, there is some indication that previous therapy can affect TLS risk in some patients within these more heterogeneous populations. These retrospective descriptive papers are summarized here to further characterize how other investigators have evaluated this strategy.
No cases of clinical or laboratory TLS have been reported in realworld studies that included debulking regimens, such as the retrospective Moffitt Cancer Center study (where patients at intermediate/high risk of developing TLS could receive debulking) [52]. Risk stratification for patients with R/R CLL at the Moffitt Cancer Center enabled 15/20 (75%) patients who were considered to be at medium or high risk of developing TLS to receive debulking therapy with rituximab, ofatumumab, or obinutuzumab prior to initiation of venetoclax [52]. Following debulking, TLS risk status was reduced to low risk in 12 patients based on reduction in ALC.
Real-world studies in the R/R setting that did not report the use of a debulking strategy appeared to be associated with a greater incidence of TLS, compared with real-world studies that used debulking, although direct comparisons across studies are not possible due to differences in study methodology. Two TLS events were reported for the UK CLL Forum (one case of clinical TLS defined by the Howard criteria, one separate case of biochemical TLS, and one case of isolated hyperphosphatemia) [53], while six patients (13%) developed laboratory TLS (three of whom also developed clinical TLS) in the Mayo clinic study [54]. Clinical TLS occurred in 2.7% of patients (n = 8), and laboratory TLS occurred in 5.7% of patients (n = 17) in the international collaboration of the CLL Collaborative Study of Real-World Evidence (CORE) and UK CLL Forum [55]. Similarly, TLS occurred in 9.7% of patients (nine clinical events) in a retrospective cohort study of R/R CLL patients treated with venetoclax across 24 US and 42 UK academic and community centers in partnership with the UK CLL Forum and the CLL CORE [56]. It is likely that these similarities in outcomes are due to overlapping patient populations, as these different real-world cohort studies (with the exception of the Mayo clinic study) all use centers from the UK CLL Forum and CORE [53,55,56].

Authors' perspectives
So far, as can be seen from the results described above, we conclude that it is the effectiveness of the debulking strategy rather than any specific treatment strategy that is important with regard to reduc-

ETHICS STATEMENT
No experiments were performed on humans or animals, only previously published data were included.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study. All information discussed within the literature review is derived from articles and abstracts published between January 2010 and June 2021. As such, the data are all included within the manuscript and referenced accordingly.