Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice

Gribben JG, Bosch F, Cymbalista F, Geisle CH, Ghia P, Hillmen P, Moreno C, Stilgenbauer S. Br J Haematol. 2018 (Epub ahead of print).

Ibrutinib is licensed for the management of treatment-naïve and relapsed/refractory CLL. However, data suggests that in clinical practice the administration of ibrutinib remains suboptimal. These European consensus guidelines by Gribben et al., seek to change that by offering practical recommendations to optimise outcomes with ibrutinib through appropriate dosing, monitoring and management of adverse events.

Ibritunib therapy has high efficacy and a favourable toxicity profile in the treatment of chronic lymphocytic leukaemia (CLL). However, recent data suggest that it is not always administered optimally in clinical practice.

An expert panel of European haematologists convened in November 2016 to identify practical issues in the management of ibrutinib-treated CLL patients and to generate best practice guidelines. The key outcomes of this meeting are outlined in this digest.

 

Suitability for ibrutinib therapy

Evidence: CLL primarily affects older people with pre-existing medical conditions and co-medication.

Recommendations:

  1. All patients should be given a CV assessment [e.g. family history, existing hypertension, heart rate, electrocardiogram (ECG) and other risk factors for CV diseases] before initiating ibrutinib.
  2. Patients should subsequently be monitored regularly by pulse and auscultation, particularly within the first 6 months. Routine laboratory testing, including full blood counts and general biochemistry, should also be completed.
  3. Patients with night sweats, elevated lactate dehydrogenase (LDH), or increasing lymphadenopathy at single sites should be evaluated for Richter’s Transformation using a positron emission tomography (PET-CT) scan.

 

Initiation of therapy

Evidence: CLL primarily affects older people with pre-existing medical conditions and co-medication.

Recommendations: The ibrutinib dose should not be withheld or reduced without a clinically robust reason, such as concomitant medications. If dose adjustments are required, these should be in accordance to the ibrutinib summary of product characteristics, as shown in Figure 1.

A flow chart showing the recommended dose reduction scheme for c l l

Figure 1. Recommended dose reduction scheme for CLL. QD, once-daily.

Drug-drug interactions - CYP450 inhibitors and inducers

Evidence: Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 in the liver, which increases the potential risk of drug–drug interactions (DDIs) (de Zwart et al., 2016).

Recommendations:

  1. Concomitant use of ibrutinib with CYP34A inducers or inhibitors should be avoided wherever possible. Other options that do not interact with CYP450 should be explored if concomitant use is being considered. If co-administration absolutely necessary, the dose of ibrutinib should be reduced to 140 mg once daily (one capsule) and patients monitored closely.
  2. Ibrutinib withdrawal is not recommended, as this can be detrimental to patient outcomes (Barr et al., 2017).
  3. Concurrent, or subsequently introduced medication should be continuously and carefully monitored, particularly for elderly patients where polypharmacy may be a challenge.

 

Lymphocytosis

Evidence: BCR-inhibitor use is associated with lymphocytosis; however, this is usually transient, does not predict patient relapse, affect PFS, and is not associated with clinical adverse events (Honigberg et al., 2010; Herman et al., 2014; Woyach et al., 2014; Byrd et al., 2015; Hallek, 2015). Prolonged lymphocytosis may be associated with better patient outcomes (Woyach et al., 2014).

Recommendations:

  1. The use of bulking agents is not justified.
  2. Patients with very high lymphocyte counts do not require any particular precautions, however, allopurinol can be considered at treatment initiation in these patients.
  3. While leucostasis is rare, this should be managed appropriately.

 

Patient compliance 

Evidence: Patient compliance often decreases as patients become less symptomatic.

Recommendations: Patients should receive continuous support during therapy and should be made aware of the risks and benefits of treatment before starting therapy. The mode of action of their medication should be explained to patients in lay terms. The results of the RESONATE-2 and HELIOS studies may be helpful for patients to understand the impact of compliance on outcomes (Barr et al., 2016; Fraser et al., 2016).

RESONATE-2 Frequency of complete responses increased from 7% to 18% during 2 years of follow-up

HELIOS After bendamustine + rituximab, the continuous administration of ibrutinib alone improved the rate of minimal residual disease negativity, from 0.7% at the end of 6 cycles of chemotherapy to 26% at 3-year follow-up.

Management of adverse events

Shatzel et al., 2017 recently published guidelines on risk reduction strategies and management of ibrutinib-associated bleeding, atrial fibrillation and concomitant use of anti-thrombotic agents. These risk reduction and management strategies are endorsed by these current guidelines (Shatzel et al., 2017).

Major bleeding

Evidence: Major haemorrhage has been reported in patients treated with ibrutinib (Byrd et al., 2013, 2014, 2015; Burger et al., 2015); however, there is currently no evidence to suggest a correlation between major haemorrhage and low-grade bleeding events.

Recommendations: Physicians should remain aware of the potential for major bleeding events and should evaluate the risk in each individual patient.
In the event of a major bleed, if this is ibrutinib-related, this treatment should be stopped while investigations are performed. Anticoagulant and antiplatelet therapy should be reviewed and stopped if necessary.
If the bleeding is non-CNS, platelet therapy should be initiated, even if patients are not thrombocytopenic.
CNS-related bleeds should be assessed on a patient-by-patient basis; however, platelet therapy is not recommended (Shatzel et al., 2017).
If the patient is undergoing surgery, ibrutinib should be withheld for 3–7 days pre- and post-surgery, according to the bleeding risk, to allow time for reversal of antiplatelet effects. If the patient is undergoing emergency surgery, a platelet transfusion (to receive 50% of fresh platelets) should be given, taking into account the timing of the last dose and half-life of ibrutinib (Levade et al., 2014; Shatzel et al., 2017).
Concomitant medications should also be reviewed based on the risk of bleeding.
Ibrutinib can be reinstated if it is safe to do so, however, alternative treatment options should be discussed in the meantime. If the patient is not able to continue with ibrutinib, other options should be explored.

Minor bleeding and haematuria

Evidence: Ibrutinib has been associated with an increased risk of any grade bleeding since the completion of early phase clinical trials (Byrd et al., 2013; Wang et al., 2017). Most were low grade (1–2), occurred early, and did not require dose interruption or modification, and improved and often disappeared over time.
Ibrutinib has also been associated with haematuria in early clinical experience (Wang et al., 2017).

Recommendations: Symptoms should be investigated in patients with a known history of bruising.
Minor bleeding events (e.g. bruising, history of minor bleeding) is not reason enough to interrupt or reduce the dose of ibrutinib.
Patients with haematuria should be checked for other underlying causes, and a urology consultation should be considered if haematuria is persistent.
There is no evidence to support initiating ibrutinib at a lower dose for a patient with a history of minor bleeding.

Atrial fibrillation

Evidence: Atrial fibrillation is common in elderly patients, including those who develop CLL. However, ibrutinib is also associated with increased incidence of AF (Byrd et al., 2014; Burger et al., 2015; Chanan-Khan et al., 2017; Dreyling et al., 2017).

Recommendations: As AF is common in elderly CLL patients (Shanafelt et al., 2017), prior history of AF and the potential for developing AF should not deter physicians from considering ibrutinib for their patients.
Physicians should always consider the possibility of AF in patients who develop CV/respiratory symptoms while taking ibrutinib and have an ECG performed. If a patient does develop grade ≥3 AF, ibrutinib should be temporarily withheld and AF managed with the advice of a cardiologist or according to the institution’s internal procedures.
Patients should be referred to cardiologists for rate and rhythm control; cardiologists should be made aware of the potential for drug–drug interactions if using drugs that may interfere with the CYP3A4 pathway, such as amiodarone.
A cardiologist should also be engaged when starting anticoagulant therapy; physicians should ensure that they adhere with the European Society of Cardiology (ESC) guidelines for management of AF (Kirchof et al., 2016).
Patients who develop AF should have ibrutinib either maintained or withheld and restarted as soon as the cardiac situation is normalised or under control, depending on the severity of AF.
For those patients who have had treatment withheld, the risk: benefit ratio should be evaluated for each patient when ibrutinib is introduced by considering the level of disease control that the patient had prior to the AF event.
Not all patients will require anticoagulant therapy.

Concomitant anticoagulation and antiplatelet therapy

Evidence: Anticoagulants and antiplatelet therapies are commonly used in patients with CLL, as many of these are elderly patients with an already increased risk for CV complications (Jones et al., 2017). However, both classes of drugs are associated with increased risk of bleeding, as is ibrutinib itself (Makris et al., 2013).

Recommendations: Patients receiving ibrutinib and concomitant anticoagulants/antiplatelets should always be closely monitored for the risk of bleeding.
If anticoagulants and/or antiplatelets are clearly indicated, physicians should carefully evaluate their approach to therapy.
Physicians should understand the rationale for patients who have previously started an anticoagulant or antiplatelet beforehand and consider if the medication is still required.

Antiplatelets

Evidence: Many CLL patients receive antiplatelet therapy before starting ibrutinib. Patients receiving dual antiplatelet therapy (DAPT), e.g. aspirin and clopidogrel, tend to bleed excessively once ibrutinib is initiated due to multiple antiplatelet activity.

Recommendations: Patients taking aspirin should be closely monitored. If there are signs of excessive bleeding or bruising, consider stopping treatment.
For patients taking ibrutinib and DAPT, consideration should be given to stopping one of the antiplatelet treatments, particularly if there are limited effective antineoplastic agents available.
Alternatively, ibrutinib treatment could be withheld if short-term DAPT is required. If long-term DAPT is indicated, alternative options should be explored.
Patients should be consistently cautioned against using NSAIDs, fish oils and vitamin E.

Anticoagulants

Evidence: There are no formal restrictions on the concomitant use of anticoagulants with ibrutinib, however, the use of vitamin K antagonists (VKA) was excluded from early clinical trials with ibrutinib (Byrd et al., 2013, Burger et al., 2015, Wang et al., 2017), and few data exist to confirm the clinical experience. Non-VKAs, including novel oral anticoagulants (NOACs) have been investigated in clinical trials.

Recommendations: NOACs are the most appropriate method of anticoagulant.
Patients taking a vitamin K antagonist (VKA) alongside ibrutinib should have careful International Normalised Ratio (INR) monitoring.
When considering treatment options for CV diseases, physicians should follow the ESC guidelines without modification and work closely with a cardiologist.
Patients who develop AF while on ibrutinib should be treated with anticoagulants/antiplatelets based on their risk scores for cardioembolic stroke:

If CHA2DS2VASc = 0, no anticoagulants/antiplatelets are required
If CHA2DS2VASc = 1, a NOAC should be considered
If CHA2DS2VASc ≥2, a NOAC is preferable to VKA

Concomitant antiplatelets should be discontinued (Kirchhof et al., 2016).
Patients should be maintained on ibrutinib where possible, using the dose modification scheme within the ibrutinib summary of product characteristics. However, physicians should plan potential alternative treatment strategies in case a patient’s AF cannot be fully controlled and they need to discontinue ibrutinib.
Patients receiving concomitant anticoagulation should be closely followed, particularly during the early phase of treatment.
When selecting an anticoagulant, consideration should be given to the potential for DDIs.

To read more about non-vitamin K oral anticoagulants, please visit the Oral Anticoagulation Reversal Knowledge Centre.

Hypertension

Evidence: Many CLL patients often have a history of hypertension (Gillespie & Hurovitz, 2013; Thompson et al., 2016).

Recommendations: If a patient experiences hypertension or worsening hypertension with ibrutinib therapy, it is important to treat this and determine the cause. Ibrutinib dose should be maintained and the hypertension should be vigorously treated to minimise the risk of further complications, such as AF.
The European Society of Hypertension (ESH) and ESC guidelines should be followed to optimise antihypertensive agents (Mancia et al., 2014).

Infection

Evidence: Infections are common during CLL treatment due to both disease- and drug-related factors and contribute to high levels of infection and morbidity (Morrison, 2009).
In patients treated with ibrutinib, infections occur early after initiation and decrease with time (Byrd et al., 2013; Burger et al., 2015; Moreno et al., 2017). Ibrutinib treatment is associated with improved immune function (Sun et al., 2015).

Recommendations: Prophylactic treatment is not recommended, particularly for first-line treatment. Instead this should be considered on a case-by-case basis depending on factors such as prior therapy, immune status, splenectomy and prior infections.
Before starting ibrutinib therapy, patients should be encouraged to have relevant vaccinations.
Once ibrutinib treatment has started, patients should be monitored for fever, neutropaenia, and infections as part of their routine checks.
All treatment-emergent infections should be carefully assessed for cause, treated vigorously and the use of growth factors considered.
For low-grade infections, ibrutinib should be continued, and dose-adjustments considered while anti-infectives are administered, only if there is a potential for drug–drug interactions.
For patients with more severe infections (grade ≥3), ibrutinib should be paused and steps taken to determine the cause of any unexplained fever or infection. Once the infection has been resolved, ibrutinib should be restarted at the appropriate dose.

Arthralgia and myalgia

Evidence: Arthralgia and myalgia have been reported in the RESONATE and RESONATE-2 trials with ibrutinib (Byrd et al., 2014; Burger et al., 2015). However, pooled safety analysis from these studies demonstrated that arthralgia is largely mild, short-lived and manageable with concomitant medications (Courte et al., 2016).

Recommendations: Patients experiencing arthralgia/myalgia should be treated with low-dose analgesics in the first instance with dose-escalation if required.
Low-dose opioids or antiepileptics should be considered; however, the use of NSAIDs should be carefully considered due to the risk of increased bleeding. Care should be taken to select an NSAID with the lowest levels of platelet inhibition after confirming the need for pharmacological intervention.
In severe cases, ibrutinib dose reduction or discontinuation should be considered with advice from a rheumatologist and/or pain clinic.Care should be taken to investigate the potential for underlying conditions that may resemble arthralgia/myalgia, which could be resolved in other ways.

Diarrhoea

Evidence: Diarrhoea is commonly observed in patients treated with ibrutinib (Byrd et al., 2014; Burger et al., 2015). This is generally mild, self-limiting and resolves without additional therapy or dose modification.

Recommendations: Patients should maintain hydration levels, report any worsening of diarrhoea, particularly in the later stages of treatment.
Other potential causes of diarrhoea, such as cancer or infection should be ruled out.

Rash

Evidence: Rash has been reported in 8% of patients in the RESONATE study, and grade ≥3 rash reported in 3% of patients in RESONATE-2 (Byrd et al., 2014; Burger et al., 2015).

Recommendations: In patients with rash, steps should be taken to investigate whether the cause is concomitant medications, infection or associated with ibrutinib treatment.
Not all cases of confirmed ibrutinib-associated rash will require treatment (especially if the rash is haemorrhagic).
If treatment is required, topical steroids and antihistamines should be given regardless of severity as they are beneficial in treating pruritus.
Ibrutinib should not be withheld, as often the rash can be treated successfully.
In cases of severe rash, or if signs of intolerance appear, such as face or lip swelling and lip tingling, physicians should consider withholding ibrutinib and the patient should be examined.
Once the rash resolves, ibrutinib should be reintroduced at the appropriate dose; if it returns then ibrutinib should be stopped and initiated at a lower dose.
If the rash is severe and continues after dose modification, an alternative therapy should be considered.
Patients with persistent rash that does not resolve should have a skin biopsy taken for assessment.

Fatigue

Evidence: Severe fatigue has been reported in a minority of patients in clinical trials (2% with grade 3–4 fatigue in RESONATE and 1% of patients with grade ≥3 in RESONATE-2) (Byrd et al., 2014; Burger et al., 2015).

Recommendations: If a patient experiences severe fatigue on ibrutinib, other possible causes should be ruled out.
Fatigue is likely to be a symptom of the disease rather than being specifically associated with ibrutinib therapy; therefore, correct dosing and maintenance of ibrutinib is essential. Once the disease is under control, the symptoms of fatigue may subside.

Autoimmune cytopenias

Evidence: Ibrutinib has been associated with a low rate of treatment-emergent autoimmune cytopenias (AIC) (Rogers et al., 2016; Vitale et al., 2016). AIC flares can occur infrequently during the first few weeks of ibrutinib therapy and may require additional treatment (Vitale et al., 2016).

Recommendations: AIC can be managed while continuing with ibrutinib therapy. Treatment of underlying CLL is critical for the long-term control of AIC.

Progression on ibrutinib treatment

Evidence: Most patients will show signs of improvement soon after initiating treatment with ibrutinib, however, some patients will become refractory to ibrutinib and show signs of progressive disease (e.g. increasing white cell count) (Woyach, 2017).

Recommendations: Monitoring for early signs of progression is essential (Woyach et al., 2014; Ahn et al., 2017).
Progression should be confirmed by ruling out a temporary increase in absolute lymphocyte count or nodal enlargement due to dose interruption or infection.
Patients with signs of progression should be investigated for the potential presence of Richter’s Transformation (RT).
Patients who have progressed and developed RT should be treated in the same way as those with typical RT according to their institutional practice.
Relapsed patients should continue with ibrutinib until they are ready for their next treatment option, as discontinuation has been associated with rapid disease progression (Maddocks et al., 2015; Woyach, 2017).

Summary

Ibritinub has become an important treatment choice for patients with CLL and is now included in both the European Society for Medical Oncology and National Comprehensive Cancer Network Guidelines (O’Brien et al., 2014; Eichhorst et al., 2016; Weirda et al., 2017).

Ibrutinib constitutes a meaningful advancement in the treatment of CLL, and these recommendations are intended to help healthcare professionals maximise the clinical benefits of treatment.

Patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy. For more challenging AEs, patients can often be maintained with minimal disruption to treatment through careful management. The correct dose of ibrutinib should be used, alongside increased awareness, vigilance, mitigation and management of AEs to maximise outcomes for CLL patients treated with ibrutinib.

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