Venetoclax (Venclyxto▼): updated recommendations on tumour lysis syndrome (TLS)

Fatal cases of tumour lysis syndrome (TLS) have been reported, some occurring in patients with chronic lymphocytic leukaemia receiving the lowest venetoclax dose used in the dose-titration schedule. For all patients, it is important to strictly adhere to the dose-titration schedule and to the measures to minimise the risk of TLS as outlined in the updated Summary of Product Characteristics (SmPC).

From:
Medicines and Healthcare products Regulatory Agency
Published
10 December 2021
Therapeutic area:
Cancer, Haematology

Advice for healthcare professionals:

  • tumour lysis syndrome (TLS) is a known risk of venetoclax; fatal cases have been reported, with some occurring in patients with chronic lymphocytic leukaemia receiving a single dose of venetoclax 20 milligrams (the lowest dose used in the dose-titration phase) and in patients with low-to-medium TLS risk
  • for all patients prescribed venetoclax, perform TLS risk assessment and adhere to guidance on appropriate prophylactic measures (including hydration and anti-hyperuricaemics), laboratory monitoring (including blood chemistries), dose titration, and drug interactions
  • refer to appropriate sections of the SmPC for the full specific advice on prevention and management of TLS during treatment with venetoclax for each indication (chronic lymphocytic leukaemia and for acute myeloid leukaemia)
  • advise patients about TLS and measures to reduce the risk, discuss the symptoms of TLS, and provide the Patient Information Leaflet and the patient card (for patients with chronic lymphocytic leukaemia)
  • report any suspected adverse drug reactions associated with black triangle medicines to the Yellow Card scheme

Advice for healthcare professionals to provide to patients:

  • venetoclax treatment is associated with tumour lysis syndrome (TLS), a complication that occurs when the cancer cells are destroyed too quickly and release unusual levels of some body salts (such as uric acid and potassium) into the blood
  • the risk for TLS occurs in the first days or weeks of treatment with venetoclax, as your dose is increased
  • follow your doctor’s instructions on drinking plenty of water, having frequent blood tests, and taking medicines to prevent the build-up of uric acid
  • if you are taking venetoclax for chronic lymphocytic leukaemia, your doctor will give you the patient card; carry this card with you at all times and share it with healthcare professionals involved in your care
  • TLS can be very serious if untreated; if you develop any of the TLS symptoms listed in the Patient information Leaflet, stop taking your tablets and talk to a healthcare professional immediately
  • always read the Patient Information Leaflet that accompanies your medicines and talk to your healthcare professionals if you are concerned

Risk of tumour lysis syndrome with venetoclax

Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor authorised in the UK for the treatment of chronic lymphocytic leukaemia and more recently for acute myeloid leukaemia (see section below for full indications).

Tumour lysis syndrome (TLS) is a known important risk with venetoclax treatment. Cases have been reported in clinical trials and in clinical use (post-marketing), including in the UK (see Frequency information).

TLS has been associated with severe consequences including renal failure requiring dialysis and death. Risk minimisation measures should be followed to reduce the risk of TLS. If TLS is suspected, urgent medical attention is required.

The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function) and tumour burden, and splenomegaly (in chronic lymphocytic leukaemia).

Information about the risk of TLS has been present in the SmPC and Patient Information Leaflet for venetoclax since authorisation, but precautions were previously focused on risk factors such as level of tumour burden.

Characteristics of TLS

The administration of venetoclax can cause rapid reduction in tumour burden. Thus, the risk for TLS is present at treatment initiation and during the dose-titration phase.

TLS may lead to blood chemistry changes (hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia), which can sometimes progress to clinically toxic effects, including renal insufficiency, cardiac arrhythmias, seizures, and death (so-called clinical TLS).

Changes in electrolytes consistent with TLS requiring prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax and also at each dose increase. Blood chemistries should be monitored and abnormalities managed promptly.

Patients should stop taking their tablets and seek medical attention immediately if they have any of the signs and symptoms of TLS listed in the Patient Information Leaflet.

Review of TLS risk with venetoclax

Fatal cases of TLS have been reported in the post-marketing setting in patients with chronic lymphocytic leukaemia treated with venetoclax. Some of these events have occurred in patients receiving a single dose of venetoclax 20 milligrams (the lowest dose used at initiation and during the dose-titration phase) and in patients with low-to-medium TLS risk.

Following a European safety data assessment, including these fatal cases, the SmPC warnings were updated to include that fatal events of TLS have been reported after a single 20mg dose. Information in the Special warnings and precautions section of the SmPC has been revised to emphasise that all patients should be assessed for the risk of TLS, and that treatment with venetoclax requires adequate risk assessment that considers comorbidities (particularly reduced renal function) and other risk factors such as splenomegaly (in chronic lymphocytic leukaemia).

All patients should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. New tables have been added in the posology section of the SmPC to clarify TLS risk minimisation based on the level of tumour burden and display recommended dose modifications for toxicities.

A letter to prescribers was sent in June 2021 to communicate the new advice. Since then, a patient card has also been sent to healthcare professionals to provide to each patient with chronic lymphocytic leukaemia undergoing venetoclax treatment. These patients should be advised to carry the card with them at all times and provide the card to any healthcare professional they see for information.

Cases of TLS associated with venetoclax treatment for acute myeloid leukaemia have been reported. The SmPC provides specific advice to prevent and reduce the risk of TLS during treatment with venetoclax in patients with acute myeloid leukaemia.

Frequency of TLS during venetoclax treatment

In the SmPC the frequency of TLS in patients with chronic lymphocytic leukaemia treated with venetoclax is listed as common (may affect up to 1 in 10 people), both at any grade and for grade 3 or higher reactions. This is based on clinical trial data. Similarly, the frequency of TLS in patients with acute myeloid leukaemia treated with venetoclax is listed as common, with grade 3 or higher reactions listed as uncommon (may affect up to 1 in 100 people).

Since authorisation and up to 6 October 2021, we have received 28 Yellow Card reports where TLS was reported as a suspected adverse drug reaction (ADR) in association with venetoclax treatment. Where indication was reported, 12 reports were associated with use of venetoclax in chronic lymphocytic leukaemia and 6 with use in acute myeloid leukaemia.[footnote 1] Of the 28 reports, there were 7 deaths. We are aware of a report of TLS and fatal cardiac arrest in a patient with chronic lymphocytic leukaemia in which the reporter noted that the venetoclax drug dose-titration was not performed.

Details of the full authorisation for venetoclax

Venetoclax is currently authorised in the UK:

  • in combination with obinutuzumab, for adults with previously untreated chronic lymphocytic leukaemia
  • in combination with rituximab, for adults with chronic lymphocytic leukaemia who have received at least one prior therapy
  • as monotherapy, for the treatment of chronic lymphocytic leukaemia
    • in the presence of 17p deletion or TP53 mutation in adults who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
    • in the absence of 17p deletion or TP53 mutation in adults who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
  • in combination with a hypomethylating agent, for adults with newly diagnosed acute myeloid leukaemia who are ineligible for intensive chemotherapy

Report on a Yellow Card

Venetoclax ▼ is under additional monitoring and any suspected adverse drug reactions (ADRs) should be reported to the MHRA via the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 15, issue 5: December 2021: 2.

  1. In interpreting these data, caution should be exercised as the data may not be complete, and the reporting rates and the information provided within the reports can be influenced by many factors. Reporters are asked to submit Yellow Card reports even if they only have a suspicion that the medicine may have caused the adverse drug reaction. ↩

Updates to this page

Published 10 December 2021
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