Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single‐agent ibrutinib in patients with chronic lymphocytic leukaemia

Wierda, William G.; Byrd, John C.; O’Brien, Susan; Coutre, Steven; Barr, Paul M.; Furman, Richard R.; Kipps, Thomas J.; Burger, Jan A.; Stevens, Don A.; Sharman, Jeff P.; Flinn, Ian W.; Zhou, Cathy; Ninomoto, Joi; James, Danelle F.; Tam, Constantine S.

doi:10.1111/bjh.15791

Cited by 11 publications

(8 citation statements)

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“…Tumor debulking with three cycles of ibrutinib 27 (reductions in lymph node diameter and absolute lymphocyte count) (Data Supplement) led to substantial reduction in TLS risk category. Together, 36 of 40 patients (90%) with high TLS risk at baseline shifted to medium or low TLS risk categories after ibrutinib lead-in and 4 of 164 (2%) remained at high TLS risk (Fig 3 ); no patients with medium or low TLS risk shifted to high-risk category.…”

Section: Resultsmentioning

confidence: 99%

“…TLS risk category reduction was primarily attributable to rapid reductions in lymph node bulk with single-agent ibrutinib as predicted by earlier studies. 27 , 29 Consequently, the frequency with which hospitalization was indicated for TLS monitoring decreased by more than half (from 47% to 18%) after ibrutinib lead-in. Moreover, rasburicase use for TLS prophylaxis (6%) was lower than that reported with single-agent venetoclax (27%-45%).…”

Section: Discussionmentioning

confidence: 99%

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Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Wierda

Allan

Siddiqi

et al. 2021

JCO

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162

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PURPOSE CAPTIVATE ( NCT02910583 ), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Wierda

Allan

Siddiqi

et al. 2021

JCO

Self Cite

162

146

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“…As venetoclax is highly effective at inducing apoptosis, treatment is associated with an increased risk of tumor lysis syndrome (TLS) [ 9 , 10 ], with label-recommended in-hospital monitoring for TLS development after venetoclax initiation [ 6 ]. One strategy to mitigate the risk of developing TLS post-venetoclax initiation is to employ a lead-in with a tumor-debulking agent, such as an anti-CD20 antibody or single-agent ibrutinib [ 11 , 12 ]. However, given the aggressive nature of MCL, concurrent initiation of ibrutinib and venetoclax may alleviate a potential risk for disease progression (PD) during lead-in.…”

Section: Introductionmentioning

confidence: 99%

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study

et al. 2021

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Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174.

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“…For this reason, dose ramp-up was explored for venetoclax. Post-hoc analysis of three major trials on ibrutinib therapy has concluded that the use of ibrutinib may reduce the risk of TLS in CLL 8 . None of 45 discontinuations recorded in four sequential trials of ibrutinib with 308 participants were related to TLS 9 .…”

Section: Discussionmentioning

confidence: 99%

A Rare Side Effect of Ibrutinib: Tumor Lysis Syndrome

Öztürk¹,

Özünal²

2021

MMJ

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Chronic lymphocytic leukemia (CLL) is a progressive disease with an indolent course, and tumor lysis syndrome (TLS) is rarely seen in CLL. Ibrutinib is a novel bruton kinase (BTK) inhibitor increasingly used in CLL treatment. Ibrutinib has significant side effects such as atrial fibrillation, bleeding, diarrhea, and infections. However, TLS is reported rarely with ibrutinib treatment. This report focuses on a 69-year-old female patient diagnosed with relapsed CLL who developed grade 4 TLS after ibrutinib monotherapy. The patient developed TLS on the third day of ibrutinib treatment necessitating discontinuation of the treatment and initiation of hemodialysis and supportive care. Ibrutinib treatment was re-initiated at a daily dose of 140 mg therapy after an interval of seven days, and then any additional side effect was not seen. Tumor lysis syndrome secondary to ibrutinib has been reported in an increasing number of cases. There is currently no information on managing adverse effects of TLS attributed to ibrutinib. Consequently, ibrutinib treatment of this patient was not terminated, and restarted after a short interval. It must not be forgotten that TLS secondary to ibrutinib treatment may be rarely seen, and can be life-threatening. Treatment with ibrutinib should be initiated in consideration of this side effect, and the development of complication of TLS may not necessitate discontinuation of ibrutinib treatment.

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Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single‐agent ibrutinib in patients with chronic lymphocytic leukaemia

Cited by 11 publications

References 9 publications

Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study

A Rare Side Effect of Ibrutinib: Tumor Lysis Syndrome

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