Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations

Figures & data

Table 1. Panel recommendations before introducing ibrutinib.

Patient evaluation and precautions before initiating ibrutinib – Extensive review of patient clinical history and thorough clinical examination. – Particular focus on cardiac history and risk of bleeding; consider patients with a history of atrial fibrillation for alternative therapies. – History of heart failure, hypertension, thrombocytopenia and other cardiovascular events should prompt caution when introducing ibrutinib. – Age by itself is not a limiting factor for ibrutinib treatment. Weighing the risks and benefits of ibrutinib in very old or frail patients presenting multiple comorbid conditions is mandatory. – Previous autoimmune conditions should be adequately managed before introducing ibrutinib. Infections and prophylaxis. – A comprehensive serology testing is important (including but not limited to: HIV, HSV-1, EBV, CMV, and HBV/HCV). – Active HBV infection (HBV-DNA positive and HBsAg positive) is not a contraindication for ibrutinib. Antivirals (entecavir or tenofovir) should be started one week before initiating ibrutinib. HBV-DNA testing should be performed every 3 months in the 1st year of treatment. – Screening for latent tuberculosis should be considered based on the region’s epidemiological profile. CLL treatment should be delayed for at least one month in patients testing positive for TB and isoniazid should be offered for a period of 9 months. – Annual Influenza vaccination, programmed pneumococcal vaccination and pre-treatment hepatitis B vaccination are recommended. – We recommend the following anti-infectious prophylaxis, particularly in previously treated patients: Acyclovir to prevent herpetic/varicella zoster reactivation; Cotrimoxazole to prevent recurrent pneumocystis or in treatment-experienced patients. – Antiparasitic treatment such as ivermectin – 200 mcg/kg/day orally, for 2 days – or alternatively albendazol – 400 mg bid for 7 days – should be provided to prevent strongyloides hyperinfection, if epidemiological evaluations suggest this risk. – Hypogammaglobulinemia should be identified, and replacement considered, in patients with severe or recurrent infections when antimicrobial treatment is not effective, when there is an existing specific antibody deficiency, or when serum IgG levels are< 4 g/L. Drug–drug interactions – Concomitant medications and potential for DDI must be evaluated. – Patient should be educated regarding potential DDIs and ibrutinib-induced adverse events. – Patients on dual antiplatelet therapy and patients with ventricular arrhythmias should not receive ibrutinib. – Refer to the ibrutinib Summary of Product Characteristics (SPC) for dosing recommendations with concomitant medications [8].

Table 2. Proportion of patients with selected AEs of clinical interest with ibrutinib, obtained from pivotal clinical trials and real-world evidence studies (CTCAE ≥ 3).

								Proportion of patients with selected grade ≥ 3 AEs of clinical interest with ibrutinib (%), except when stated otherwise
Study	Indication^a	Setting^b	Median follow-up (months)	Study type^c	Study arm^d	# of patients included	Median age	Diarrhea	Arthralgia	Fatigue	Rash	Infection	Bleeding	Hypertension	Atrial fibrillation
CLL12 [84]	CLL	1L	31	Ph III	I	182	64	1.1	–	–	–	–	3.2	1.6	6.5
ECOG-E1912 [85]	CLL	1L	33.6	Ph III	I + R	354	56.7	4.3	4.8	2.0	3.1	9.4	1.1	18.8	3.2
ALLIANCE [47]	CLL	1L	38	Ph III	I	182	71	–	–	–	–	20	2	29	9
PCYC1102/1103 [44]	CLL	1L/RR	87	Ph Ib/II	I	31/101	71/64	7	–	6	–	39	–	28	9
iLLUMINATE [86]	CLL	1L	31.3	Ph III	I + Obi	113	70	3	1	0	2	11	–	4	5
RESONATE-2 [64]	CLL	1L	60	Ph III	I	136	73	4	–	–	–	12	6	8	5
RESONATE [63]	CLL	RR	65.3	Ph III	I	195	67	7	–	–	–	45	10	9	6
Ahn, I.E. et al. [87]	CLL	1L/RR	57	Ph II	I	53/33	66	3.5	–	–	2.3	9.3	0	–	5.8
Abrisqueta et al. [88] *RWE	CLL	1L/RR	19.2	–	I	84/121	71/70	–	1.1	–	–	12.2	3.4	–	1.9
Winqvist et al. [58] *RWE	CLL	RR	30	–	I	95	69	1	4	–	–	51	1	2	1
Wang et al. [89]	MCL	RR	26.7	Ph II	I	111	68	5	–	–	–	28	6	–	6
RAY [90]	MCL	RR	38.7	Ph III	I	139	67	3.6	–	5		2.2	9	–	5
iNNOVATE [91]	WM	1L/RR	47	Ph III	I + R	75	70	–	–	–	–	–	9	13	12
Treon et al. [92]	WM	RR	59	Ph II	I	63	63	0	0	–	0	6.3	0	0	1.6

^a Indication – CLL: Chronic lymphocytic leukemia, MCL: Mantle cell lymphoma, WM: Waldenström’s macroglobulinemia.

^b Setting – 1L: first-line treatment, RR: relapsed/refractory.

^c Study Type – Ph: Phase.

^d Study Arm – I: ibrutinib, I + R: Ibrutinib–Rituximab, I + Obi: Ibrutinib plus Obinutuzumab.

* RWE – Real-world evidence.

Table 3. Panel recommendations for monitoring and managing patients on ibrutinib.

General considerations – Monthly hematology consultations are recommended in the first 6 months, and every 3 months thereafter. – Regular Complete Blood Count, renal and function tests, medical examination and review of concomitant medication in the first 6 months. – Patients should regularly self-monitor their blood pressure.

Drug–drug interactions – Amiodarone should be avoided, and calcium-channel blockers should only be used if beta-blockers are unsuccessful, due to known DDI. – The azole antifungals voriconazole and posaconazole should be avoided or ibrutinib should be temporarily interrupted (up to 7 days)/dose reduced to 140 mg/day, with careful vigilance. – Non-VKA direct oral anticoagulants (DOAC) should be used as an alternative to warfarin or other vitamin K antagonists (VKAs). – Ibrutinib treatment regimen should be carefully adjusted when CYP3A4 inhibitors, CYP3A4 inducers, or antiplatelet medication are used, either by dose reductions or by selecting alternative comedications.

Management of infections during ibrutinib treatment – Previously treated patients with prior infections should be closely monitored for the development of opportunistic and other infections. – Grade ≥ 3 infections prompt treatment interruption until resolution to grade ≤ 1. – Patients who experience severe infections (grade ≥3) while on ibrutinib can benefit from consultation with an infectious disease specialist. – Fungal infections should be carefully monitored, especially during the first 6-months of treatment with ibrutinib, namely on patients with known risk factors (corticosteroid-treated, with comorbidities and previously treated). – Ibrutinib should be withheld for a short period until the infection is stabilized or resolved.

Management of cardiovascular events during ibrutinib treatment – Patients experiencing hypertension or AF should be closely monitored but not necessarily discontinue ibrutinib. – Ibrutinib interruption is recommended in patients experiencing AF (grade ≥ 3). – Beta-blockers are recommended for managing hypertension and AF. – Apixaban is a recommended anticoagulant with a favorable safety profile. – In patients with strict indication for antiaggregation, the decision should always involve the cardiologist. Aspirin indication should be assessed, with triflusal as a viable option.

Management of other common adverse events during treatment with ibrutinib – Low-dose analgesics (avoiding NSAIDs) and a more active lifestyle are the preferred options for arthralgias. – Loperamide is recommended for treating proved non-infectious diarrhea. – If life-threatening bleeding (grade ≥ 3) occurs, antiplatelet drugs should be stopped and ibrutinib withheld until event resolution. Platelet transfusions may be needed. – Patients with cardiovascular risk factors (e.g. diabetes, dyslipidemia) or fatigue (if persistent and with no known etiology) should be referred to a cardiologist.

Figure 1. Proposed algorithm for managing AF in patients treated with ibrutinib.

Figure 2. Proposed algorithm for evaluating hemorrhagic risk and for managing bleeding events.

Table 4. Panel Recommendations from pharmacist perspective.

– Pharmacists play a vital role in patient education for both AEs and DDI, working to increase adherence and empowering patients for a more active role in treatment. – Medication and adherence monitoring should be done on a monthly basis regardless of patient profile. – Patients experiencing toxicities while on ibrutinib should interrupt/discontinue this treatment as follows [8]: First grade ≥3 event – ibrutinib treatment (full-dose) should be resumed after event resolution to baseline or grade 1; Second grade ≥3 event –ibrutinib treatment should be resumed with reduced dose (dose initially recommended minus 140 mg); Third grade ≥3 event – ibrutinib treatment should be resumed with reduced dose (dose initially recommended minus 280 mg); Fourth grade ≥3 event – ibrutinib should be discontinued. – Dietary cautions: fish and flaxseed oils (can increase risk of bleeding), grapefruit, pomegranate, St. John's wort or bitter orange (can modify ibrutinib concentrations).

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