Tumor lysis syndrome (TLS) is a known risk with venetoclax (VEN) initiation during treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Risk stratification prior to initiation is based on tumor burden (TB) (absolute lymphocyte count, lymph node [LN] size) and renal function. While acalabrutinib (acala) is known to reduce disease burden, the impact of acala lead-in on TLS risk during subsequent VEN initiation remains poorly characterized. Here, we report on the use of acala debulking prior to VEN initiation and its effect on TB reduction, TLS risk stratification, lab monitoring, interventions, and observed TLS events.

This is a retrospective cohort observational study of a single-center investigator-initiated clinical trial NCT04169737. Pts with CLL/SLL ≥18 years of age with a 2018 iwCLL indication for treatment were debulked with acala 100mg twice daily for 2 cycles and had TLS risk assessment prior to the standard 5-week VEN initiation. All pts with low TB regardless of renal function and those with medium TB with a CrCl>80 ml/min after debulking were included. All pts received TLS prophylaxis with uric acid lowering therapy and at least 2 liters of oral hydration per day. The primary outcome was incidence of the composite endpoint including lab or clinical TLS (defined by Howard Criteria) or hyperkalemia (potassium>6 mmol/L) during VEN initiation. Secondary outcomes include the individual components of the primary outcome and incidence of TB reduction after acala lead-in.

A total of 68 pts received acala debulking prior to VEN initiation (42 treatment naive [TN] and 26 relapsed/refractory [RR]). Of those, 52 pts had low TB regardless of renal function or medium TB with a CrCl>80 ml/min after debulking and were included in this analysis; 32 TN and 20 RR with a median of 1 prior line of therapy. Most pts had medium TB after acala lead-in at C3D1, with 24 (75%) TN pts and 14 (70%) RR pts. A quarter of pts (13) lowered their TB after debulking. In TN pts, 10 pts reduced TB (5 high to medium, 1 high to low, 4 medium to low). In RR pts, 3 lowered TB (1 high to medium, 2 medium to low), and 4 pts increased TB due to redistribution lymphocytosis (4 low to medium).

No pt experienced lab or clinical TLS or hyperkalemia>6 mmol/L. There were no appreciable differences in incidence of lab abnormalities between TN and RR pts, however numbers are small. Only one TN pt with medium TB had elevated creatinine>0.3 mg/dL above baseline during week 1, despite prophylactic IV fluid prior to VEN. 24-hour post-dose labs returned to baseline with increased oral hydration. Elevated potassium (4.5-6 mmol/L) was observed in 11 pts during week 1 (TN=6, RR=5) and 14 pts in week 2 (TN=9, RR=5) at the 6-8 hour post-dose lab. At weeks 3, 4, and 5, elevated potassium was seen in 14 (TN=11, RR=3), 12 (TN=6, RR=6), and 7 (TN=4, RR=3) pts at pre-dose lab assessment, respectively. At any point during VEN initiation, 78% of elevated potassium levels occurred in pts with medium TB. Hyperphosphatemia>4.5 mg/dL was the second most common abnormality observed (4%). One TN pt with medium TB had uric acid>8 mg/dL during week 5 at pre-dose labs. The pt continued with VEN escalation, received 1L IV fluid, and uric acid normalized 24 hours later. No pts experienced hypocalcemia. Treatment of lab abnormalities was determined by provider discretion, and most commonly occurred week 1.

Most pts began VEN initiation in the outpatient setting, however, pts could be initiated inpatient per provider discretion. During week 1, 9 pts were initiated inpatient (1 low TB and 8 medium TB). During week 2, 7 pts were initiated inpatient (all medium TB). During week 3, 4, and 5 no pts were initiated inpatient. Prophylactic IV fluid (most commonly a 1L bolus) was given to 45 (87%) pts during week 1 (36 of 38 pts with medium TB) and 38 (73%) pts during week 2 (34 of 38 of pts with medium TB). Only 11 (21%), 4 (8%), and 4 (8%) pts received IV fluid in weeks 3, 4, and 5, respectively.

In pts with low or medium TB with CrCl>80 ml/min after debulking with acala, none experienced lab or clinical TLS during VEN initiation. Elevations in potassium and phosphorous were observed; however, these were mild. Many pts received VEN escalation in the outpatient setting, with the majority of pts with medium TB receiving additional IV fluid prophylactically. Acala lead-in debulks pts and reduces TB prior to VEN initiation, leading to reduced risk of TLS.

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2025
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