Very Few Interventions after Tumor Lysis Monitoring in Patients with Chronic Lymphocytic Leukemia Who Are Started on Venetoclax in the Real-World Setting- Suggests Less Intensive Monitoring Maybe Safe for Low-Risk Patients
Authors: Matuszfisher Ashley , Bose Rupali , Boselli Danielle , Magee Gray , Chen Tommy , Hu Bei , Moyo Tamara K. , Soni Amy , Park Steven I. , Copelan Edward A. , Avalos Belinda , Symanowski James T , Raghavan Derek , Jacobs Ryan , Ghosh Nilanjan 
Published: November 2021

Abstract
Background: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in adults. Venetoclax, an orally administered B-cell lymphoma 2 (BCL2) inhibitor, is a FDA approved therapy offering durable responses. Due to risk of tumor lysis syndrome (TLS) upon venetoclax initiation, a strict dose escalation schedule with frequent laboratory monitoring is recommended in the package insert (PI). Real world data reflecting adherence to this schedule and frequency of interventions resulting from intense monitoring are not described.
Methods: Retrospective review of the Levine Cancer Institute database identified 73 consecutive patients with CLL who were initiated on venetoclax between July 2017 and March 2021. This included those initiated at the central academic site and regional academic-hybrid community sites. In the first two weeks of venetoclax, ramp up dosing and TLS labs (creatinine, potassium, calcium, phosphorous and uric acid) were evaluated for compliance consistent with the PI. Compliance required labs to be performed pre-dose, and at 6-8 hours and 24 hours after the initial 20 mg and 50 mg doses on weeks 1 and 2. The consequent interventions within these first 2 weeks, based on TLS labs, were then recorded. Patients who strictly adhered to all these laboratory checks at the various timepoints were considered compliant. Those who missed even a single lab or time point were considered non-compliant. Tumor lysis was measured by standard criteria using the Cairo-Bishop definition. The following Interventions were recorded: rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, ICU admissions, unplanned administration of IV fluids, the use of calcium supplementation, phosphate binders, treatment for hyperkalemia, dose reduction or holding of venetoclax. Baseline patient, disease, and treatment characteristics were summarized and described; rates of compliance were compared between tumor burden categories using Fisher's Exact test.
Results : Baseline characteristics of the 73 identified patients were: 64% male, 79% white and 19% black, median age at venetoclax initiation was 67 (44 - 84). There were 49% of patients in the low tumor burden category, 44% in the medium tumor burden category and 6% in the high tumor burden category. Compliance with TLS labs during the first 2 weeks was 66% overall (n=48), with compliance between the tumor burden categories being 75% in high, 66% in medium and 67% in low (P&gt;0.99). Interventions occurred in 6 (8%) of the patients, with all interventions occurring in the medium or high tumor burden group. These interventions included administration of IV fluids (n=2), calcium supplementation (n=1), phosphate binders (n=2) and holding of venetoclax (n=1). None of these 6 patients requiring an intervention had clinical or laboratory TLS. None of the 73 patients required rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, or ICU admissions during this 2 week ramp up period. Of the 6 patients requiring interventions, 4 patients had TLS labs performed by the PI versus 2 patients who did not. Clinical and laboratory TLS in the PI-compliant group was recorded. None of these patients had clinical TLS and 1 patient met the criteria for laboratory criteria TLS based on a 25% change from baseline in phosphorus and uric acid, however, labs remained in normal range. There were no deaths during the venetoclax ramp up.
Conclusion: Compliance with the strict TLS lab monitoring during venetoclax initiation is not universal, likely due to real world patient and institutional barriers. The intervention rates during the first 2 weeks were low, with no patients in the low tumor burden category requiring an intervention. These results suggest that a less strict laboratory monitoring schedule may be safe in patients with low tumor burden CLL. If the safety is confirmed prospectively, it would make the venetoclax initiation less cumbersome and result in increased access to venetoclax for patients with low burden CLL.

Disclosures
Hu: Kite: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Cellectar: Membership on an entity's Board of Directors or advisory committees. Moyo: Seattle Genetics: Consultancy. Park: Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; G1 Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding. Copelan: Amgen: Consultancy. Avalos: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMJ Best Practice: Patents & Royalties: Royalties from a co-authored article on evaluation of neutropenia. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Jacobs: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; Verastem: Consultancy; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Genentech: Consultancy; Jannsen: Speakers Bureau. Ghosh: Genmab: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding.