Management of Venetoclax Dose Escalation in patients with Chronic Lymphocytic Leukaemia (CLL)

• Background
• Dose Escalation
• Tumour Lysis Syndrome (TLS)
• Risk Assessment
• Initiation of Venetoclax
• Treatment of TLS

Background

BCL-2 (B-Cell Lymphoma 2) is a member of the family of proteins that regulate the process of programmed cell death (apoptosis). This family consists of both anti-apoptotic proteins (including BCL-2) which promote cell survival and pro-apoptotic proteins which promote cell death. The dynamic balance between the pro- and anti-apoptotic proteins determines whether a cell will live or die (as shown in Figure 1). Over-expression of anti-apoptotic proteins such as BCL-2 can block cell death by sequestering and preventing the activation of pro-apoptotic proteins and caspases that carry out this process. This can lead to survival of cancer cells.

Venetoclax is a BCL-2 inhibitor which binds selectively to BCL-2, freeing pro-apoptotic proteins, which then go on to activate caspases and initiate cell death (as shown in Figure 2).

Venetoclax is licensed and funded to be used:

• in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL (Ven-O) (NICE TA 663) (2)
•  in combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy (NICE TA 561) (3)
• as monotherapy for the treatment of CLL:
  • in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
  • in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor (NICE TA 487) (4)

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Dose Escalation

Venetoclax can cause a rapid reduction in tumour burden, and thus poses a significant risk of TLS. For this reason, the dose is escalated weekly over an initial 5 week dose titration phase (see table 1). This 5-week schedule is designed to gradually debulk and therefore decrease the risk of TLS.

Table 1: Venetoclax dose titration schedule (5)

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Tumour Lysis Syndrome (TLS)

TLS is a recognised risk in haematological malignancies. It is a metabolic syndrome caused by the breakdown of malignant cells, the catabolism of which leads to an excess of uric acid. In TLS, the normal homeostatic mechanisms for the removal of cellular content following cell death are overwhelmed. TLS is characterised by:

• Hyperuricaemia (increased plasma uric acid)
• Hyperphosphataemia (increased phosphate)
• Hyperkalaemia (increased potassium)
• Hypocalcaemia (reduced plasma calcium)

The consequences are potentially severe and include acute kidney injury, cardiac arrhythmias, seizures and even death.

The risk of TLS in CLL patients is a continuum based on multiple factors, including comorbidities. Patients with high tumour burden are at greater risk of TLS when initiating venetoclax including those with:

• any lymph node with a diameter ≥5 cm or
• high absolute lymphocyte count [ALC ≥25 x 10⁹/l]

Reduced renal function (creatinine clearance [CrCl] <80 ml/min) further increases the risk.

It is important to be aware that deaths have been reported within 24 hours of taking venetoclax when dose escalation has been too rapid or TLS precautions have not been taken. Figure 3 demonstrates that risk mitigation measures have successfully reduced the risk of clinical TLS. However, it does demonstrate that despite risk mitigation, there will still be patients who develop biochemical TLS. It is crucially important to recognise and manage biochemical TLS early to prevent it developing into clinical TLS. Changes in electrolytes consistent with TLS can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose increase.

Figure 3: Representation of the incidence of TLS before and after risk mitigation measures (dose titration, TLS prophylaxis) were implemented (1)

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Risk Assessment

Prior to initiating venetoclax, the following investigations must be undertaken:

• tumour burden assessment, including radiological evaluation (e.g. CT scan) for all patients.
• blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) should be assessed and pre-existing abnormalities corrected where appropriate.
• renal function should be calculated using either Cockcroft and Gault or Wright formula (eGFR should not be used). Inform a Consultant if CrCl < 30ml/min.
• baseline Hepatitis B, C and HIV serology

Figure 4: Risk Assessment of CLL patients requiring treatment with venetoclax

Patients should be assessed according to their category of highest risk.

For example, if a patient had a lymphocyte count of 15 x 10⁹/L (Low) and only small sub-centimetre nodes (Low), but had a CrCl of 40ml/min (High), they would be HIGH RISK.

HIGH Risk patients (especially those with a CrCl 30-50ml/min) must be managed as an in-patient for dose escalations.

• Risk assessment must be undertaken each week prior to dose escalation. This can be based on clinical criteria (palpable lymph nodes and lymphocyte count) rather than radiological assessments each week. A patient’s risk category can be de-escalated to medium or low risk if tumour burden reduces and/or renal function improves. This is a Consultant only decision.
• Medium / Low Risk patients can be managed in an outpatient setting (see guidance below)

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Initiation of Venetoclax

Practical steps to take PRIOR to initiation of Venetoclax:

• Complete Blueteq form (take care as multiple forms for different combinations / lines of therapy)
• Prepare appropriate prescription and give to Pharmacy team in advance for validation
• Ensure a clear dose escalation plan is available in a clinic letter or on PPM+
• Inform Clinical Nurse Specialist of plan to commence venetoclax (they will kindly ensure correct bookings are made for inpatient bed / blood tests / J80 / J87 as appropriate)
• Ensure patient is taking a uric acid lowering agent for at least 3 days prior to starting venetoclax:
  • Allopurinol 300mg OD is the preferred choice
  • Febuxostat 120mg OD may be used as an alternative if allopurinol allergy
• Patients should be encouraged to drink 2-2.5 litres / day for at least 3 days prior to starting venetoclax
• Ensure a comprehensive drug history is taken to check for CYP3A4 interactions. The Pharmacy team are happy to help with this.
• Advise patients to avoid grapefruit, Seville oranges and star fruit whilst taking venetoclax.
• All patients should be prescribed PJP prophylaxis (co-trimoxazole 480mg OD is first choice unless allergy) and anti-viral prophylaxis (aciclovir 400mg BD is first choice).
• Anti-fungal prophylaxis is not routinely required. All azoles interact with venetoclax. Please check with Pharmacy if any anti-fungal prophylaxis/ treatment is required.

In-Patient Setting for HIGH RISK patients

Day -1: 

Elective admission to the ward:

• Baseline bloods including FBC, U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate within 24 hours prior to dosing.
• Check Chemocare prescription has been confirmed and printed and with Pharmacist for validation
• Regular and supportive medications and fluids prescribed on eMEDS
• Start Glucose 4%/Sodium Chloride 0.18% 1 litre over 8 hours at a rate of 125 mls/hr. Do NOT add any potassium to the prescribed fluid.
• If CrCl < 50ml/min, large tumour bulk or high ALC, prescribe rasburicase 3mg IV STAT dose (in 50ml sodium chloride 0.9% over 30 minutes) on eMEDS. This is to be given 30 minutes prior to venetoclax dosing on Day 0.

Day 1:

• Give rasburicase if prescribed (omit allopurinol (or febuxostat)). If rasburicase not required, ensure allopurinol or febuxostat given.
• Give venetoclax early morning (6am) and ensure time recorded.
• TLS risk is highest 6-8 hours after the dose of venetoclax. Ensure blood tests (U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate) are requested and taken 6-8 hours post dose. If rasburicase has been given, there is no need to check uric acid.
• IMPORTANT: The blood results should be checked in real time. At each time point, there should be a nominated person (Consultant/Registrar) to review the results. Please follow the guidance in figure 5 if there is any concern regarding TLS.

Day 2:

• TLS bloods including FBC, U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate should be performed in the early morning (approximately 24 hours post Day 0 dosing). 
• IMPORTANT: Day 1 venetoclax should not be administered until the 24 hour safety blood results have been reviewed. At each time point, there should be a nominated person (Consultant/Registrar) to review the results. Please follow the guidance in figure 5 if there is any concern regarding TLS. 
• If blood results are satisfactory, the patient can be dosed and then discharged home. eDAN can be done in advance if any medications required (patients should have own regular medications and venetoclax and supportive medications will have been supplied from Chemocare prescription). 
• Book patient with the bed manager for next week’s admission (unless week 5). 

Figure 5: TLS monitoring for In-Patients

Out-Patient Setting for MEDIUM and LOW RISK patients
Day -1: 

• Baseline bloods including FBC, U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate
• Review in CLPD clinic (Monday AM) with blood results
• Confirm and print Chemocare prescription and give to Pharmacist for validation
• Ensure patient already taking allopurinol / febuxostat and has increased oral fluid intake
• Advise patient to take venetoclax the next morning at 6am (and record time taken)

Day 1:

• Patient to take venetoclax early morning (6am) and record time.
• TLS risk is highest 6-8 hours after the dose of venetoclax. Patient to attend J87 around 1pm for urgent blood tests (U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate) and Doctor review.
• IMPORTANT: The blood results should be checked in real time. At each time point, there should be a nominated person (Consultant/Registrar) to review the results. Please follow the guidance in figure 6 if there is any concern regarding TLS.
• If TLS is suspected, patient should be admitted and TLS guidelines followed
• If no evidence of TLS, the patient should be discharged home and advised to attend at 9am the following morning for bloods. They must bring their venetoclax with them but MUST NOT take until advised to do so by clinician.

Day 2:

• Patient to attend J87 at 9am and TLS bloods including FBC, U&E, LFTs, LDH, uric acid, magnesium, calcium, phosphate should be performed and sent urgently. The patient can wait in the hospital for the results or can go home and await a phone call re dosing.
• IMPORTANT: Day 1 venetoclax should not be administered until the 24 hour safety blood results have been reviewed. At each time point, there should be a nominated person (Consultant/Registrar) to review the results. Please follow the guidance in figure 6 if there is any concern regarding TLS.
• If blood results are satisfactory, the patient can be advised to take their dose. Venetoclax and supportive medications will have been supplied from Chemocare prescription on day -1.
• Ensure patient is booked into clinic for following week (unless week 5). 

Figure 6: TLS monitoring for Out-Patients

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Treatment of TLS

• Inform the responsible Consultant

• Aggressive hydration:
  Glucose 4%/Sodium Chloride 0.18% (1 litre over 6-8 hours) is recommended fluid of choice. The rate of infusion should be individualised. Do not add potassium to the fluids. It is very important to maintain fluid balance chart.

• Treat hyperkalemia as per local guidance
  Please refer to link

• Treat hypocalcaemia as per local guidance.
  Please refer to: link

• Full dose rasburicase.
  The dose is 0.2mg/kg/day in 50ml sodium chloride 0.9% over 30 minutes. Please review daily and it can be administered for a maximum of 7 days. Please stop allopurinol or febuxostat whilst on rasburicase. Please refer to link

• Involve nephrology team early
  Patient may need renal replacement therapy

• Intense renal function and electrolyte monitoring
  The monitoring should be performed 2-4 hourly. Depending on the response to TLS combatting measures, the frequency of monitoring can be de-escalated.

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