Kayexalate, furosemide, and insulin with dextrose were used as needed for rising potassium. Phosphate binders were routinely used upfront. If uric acid was >8 mg/dL after venetoclax dose, rasburicase was administered. If the uric acid level was >8 mg/dL despite IV fluids and allopurinol, a dose of rasburicase was considered before venetoclax. Maintenance fluids (eg, dextrose 5%/sodium chloride 0.45%) at a rate of 150 mL per hour were administered at least 12 hours before first venetoclax dose. There were no standard criteria employed for when to increase the dose, but attempts were made by practitioners to escalate every 1 to 2 days if TLS did not occur.Īllopurinol was initiated at least 1 day before venetoclax. Laboratory parameters were evaluated every 4 to 8 hours. Venetoclax dose was increased in stepwise fashion from 20 to 400 mg in a rapid manner, based on patient tolerability and TLS, with close in-hospital monitoring. We have adopted this approach at our institution for select patients in whom there is a rapid need to achieve the target dose of venetoclax, and we performed this retrospective cohort study to report our experience.Īll patients undergoing venetoclax RDE from May 2016 to December 2018 were retrospectively reviewed under an institutional review board–approved protocol and in accordance with the Declaration of Helsinki. 5 This limitation of venetoclax in this CLL patient population can potentially be overcome with more rapid dose escalation (RDE) of venetoclax.
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In the same phase 2 trial of venetoclax in this population, 11% of patients who discontinued for progressive disease did so within the first 5 weeks.
6 However, the kinetics of relapse after BCRi's can frequently outpace attainment of an effective venetoclax dose. To mitigate this, a 5-week dose ramp-up to the target dose of 400 mg with close monitoring and prophylaxis demonstrated reduced incidence of TLS, from 18% to 1.7%. The most substantial risk with venetoclax is TLS with treatment initiation. These patients also had a significant tumor lysis syndrome (TLS) risk (26 patients with high TLS risk and 31 with medium TLS risk per venetoclax prescribing information). 5 This study was performed in a high-risk patient population that was heavily pretreated, with a median of 4 prior therapies (range, 1-15 therapies). 1 - 4 The BCL-2 inhibitor venetoclax demonstrated an overall response rate of 65% and median progression-free survival (PFS) of 24 months in patients relapsing after ibrutinib in a phase 2 trial and is currently the most effective standard therapy in this patient population. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.ĭespite sustained disease control observed with B-cell receptor pathway inhibitors (BCRi's), particularly Bruton tyrosine kinase inhibitors (BTKis), patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with these agents often have rapidly progressive symptomatic disease. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. 02), after controlling for venetoclax dose level.
Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre–venetoclax dose to 24 hours post–venetoclax dose of 10 × 10 3/μL was associated with an increased risk of TLS (hazard ratio, 1.32 P =. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. TLS was seen in more patients with a higher initial tumor burden. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. This limitation can potentially be overcome with rapid dose escalation (RDE). Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis) however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose.
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