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Important considerations before Initiation
of Ibrutinib Treatment
Nahla A M Hamed*
Professor of Hematology, Faculty of Medicine, Alexandria University, Egypt
Submission: July 15, 2019; Published: September 03, 2019
*Corresponding Address: Nahla A M Hamed, Professor of Hematology, Faculty of Medicine, Alexandria University, Egypt
How to cite this article:Ibrutinib is very well-tolerated in general. However, there are several adverse effects that warrant consideration prior to its initiation . Canc Therapy & Oncol Int J. 2019; 15(1): 555902.
Ibrutinib is a Bruton’s tyrosine kinase inhibitor which interferes with signaling through the B-cell receptor pathway. Ibrutinib is metabolized via cytochrome P450 enzyme 3A. Potential drug interactions need to be considered with its use. Ibrutinib is generally well tolerated. Diarrhea and skin rashes are relatively common, often transient, and can resolve with no specific management. Bleeding, atrial fibrillation, arthritis and arthralgia, fatigue, cytopenias, and infections are more serious but less common drug specific complications.
Ibrutinib is very well-tolerated in general. However, there are several adverse effects that warrant consideration prior to its initiation . The most common side effects of ibrutinib are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I–II). However atrial fibrillation and bleeding are important and may be grade III or higher and require strict monitoring .
Pneumonia, upper respiratory tract infections, sinusitis and urinary tract infections are the most commonly reported infections in pivotal CLL trials . Infections were more frequent during the first 6 months and in relapsed/refractory CLL . It is assumed that the infection rate will decrease with time and when ibrutinib is started earlier in CLL disease course therapy . Patients with a ≥50% increase in serum IgA levels had a lower rate of infection . Immune deficiency, such as hypogammaglobulinemia, contributes to the relatively high rates of infection and morbidity in CLL patients . Ibrutinib treatment resulted in a partial reconstitution of the humoral immunity  and the normal B-cell subpopulations, rendering a lower rate of infection in CLL patients. Serum immunoglobulin G levels still decrease during treatment . Effects of ibrutinib on dysregulation of the normal T and natural killer cell compartment still require an extensive investigation .
a. Routine check at every clinic visit for fever, neutropenia and infections .
b. Infections prophylaxis was not recommended especially in the first line setting. Factors such as prior therapy, immune status, splenectomy and prior infections should be determined .
c. For low-grade infections, continue ibrutinib therapy . Adjust the dose of clarithromycin, ketoconazole or voriconazole (moderate/strong CYP3A4 inhibitors) if used .
d. Coadministration of 140 mg ibrutinib with voriconazole demonstrated an acceptable safety profile, and the adverse event profile was consistent with the ibrutinib safety profile at therapeutic doses .
e. Sulfamethoxazole and trimethoprim combination
may be appropriate for patients previously received
f. Vigorous treatment of emergent infections including
the opportunistic infections, such as Pneumocystis (jirovecii)
pneumonia. The use of growth factors should be considered
CLL patients are at increased risk for major bleeding
because of the disease itself, comorbid conditions, concomitant
medications or clinically significant thrombocytopenia .
Bleeding events of any grade  have been reported in ibrutinibtreated
patients  with a 2.93-fold increase compared to the
control arms. Lower grade (<3) bleeding (mainly ecchymosis
and petechiae during the first 6 months) was reported in 28% of
50 patients not on simultaneous AP or AC therapy. None of the
studied patients had major bleeding. Collagen-induced platelet
aggregation was inhibited, whereas ADP induced platelet
aggregation improved on ibrutinib therapy . BTK and TEC are
expressed in platelets and act downstream in glycoprotein (GP)
VI signaling involved in collagen-mediated platelet aggregation.
BTK is thought to play a more dominant role than TEC .
Platelet therapy should be initiated if the site of bleeding
is non-CNS, even in non-thrombocytopenic patients. Platelet
transfusions are not advised in the event of CNS bleeding. In
emergency surgery, a platelet transfusion (to receive 50% fresh
platelets) is appropriate, taking into consideration the timing of
the last dose and the half-life of ibrutinib . Precautions should
be taken on concomitant use of anticoagulants and antiplatelet
agents, along with adherence to perioperative ibrutinibwithholding
The only significant cardiac adverse events (AEs) reported
is grade 1–2 hypertension (observed in 18–29% of clinical trial
patients) and atrial fibrillation (grade 3 or higher toxicity in 4%
of patients on ibrutinib as compared to 1% on temsirolimus
in phase III study) . The increased risk of atrial fibrillation
associated with ibrutinib may be related to on-target toxicity to
the PI3K–Akt pathway in cardiomyocytes . Most AF events
typically occurred within the first 6 months after initiation of
ibrutinib therapy and continued at a low rate over time .
Physicians should always consider the possibility of AF in patients
who develop CV/respiratory symptoms while taking ibrutinib
and have to perform an ECG . The choice of anticoagulants in
cases ibrutinib related AF is not clear enough .
Ibrutinib is often associated with asymptomatic
lymphocytosis (70%) upon treatment initiation. Lymphocytosis
is inherent to its mechanism of action, as ibrutinib disrupts
integrin-mediated adhesion and homing of malignant B cells
to the lymphoid microenvironment . Lymphocytosis usually
peaks after one month of therapy, and subsequently slowly
declines. The median time to resolution of lymphocytosis on
ibrutinib therapy is 19 weeks, but prolonged lymphocytosis up
to 124 weeks has been seen in patients with ongoing treatment
responses. The rate of decline of lymphocytosis is usually
slower in patients with mutated IGHV and 13q14 deletion (less
aggressive disease) and faster in patients with unmutated IGHV
. It does not require any specific management even when
persistent for months .
i. Pharmacologic interactions between ibrutinib and
P-glycoprotein substrates (digoxin and dabigatran), CYP3A4-
inhibitors and inducers including anti-arrythmic drugs
(verapamil and amiodarone) and direct oral anticoagulants
(apixaban, rivaroxaban), antimicrobials (azoles, macrolides,
or rifampicin,  clarithromycin, ketoconazole or
voriconazole)  and antiepileptic drugs (carbamazepine)
ii. Options for patients requiring short period (≤7 days)
of moderate or strong CYP3A inhibitors, include i. withhold
ibrutinib therapy and change to an alternative drug with a
lesser degree of CYP3A inhibition, or ii. reduce the dose of
ibrutinib to 140 mg daily .
iii. Concomitant use of either AC or AP treatment with
ibrutinib does not increase the risk of major bleeding .
Care should be exercised when initiating ibrutinib therapy
in patients on anticoagulants and are at increased risk for
experiencing major hemorrhagic events at baseline .
iv. Ibrutinib should be avoided in patients requiring dual
or triple anti-coagulant and anti-platelet therapy .
v. Switch to low molecular weight heparin or direct oral
anticoagulants if patient is receiving vitamin K antagonists.
Concurrent use of warfarin is not recommended in cases
with major hemorrhage .
a. Attention for co-incidental use of nonsteroidal antiinflammatory
drugs and herbal supplements with CYP3A4
inhibitors or inducers .
b. Avoid grapefruit/juice, pomegranate/ juice, and Seville
oranges with ibrutinib to prevent potentially significant
Ibrutinib should be held for hematologic toxicity (grade
3 neutropenia with infection/fever or any grade 4) or non hematologic toxicity (any grade 3) . For grade ≥3 infections,
ibrutinib treatment should be paused and determine the cause
of any unexplained fever or infection (e.g. CT scans). Ibrutinib
should be reintroduced at the appropriate dose following
infection resolution . After improvement to grade 1 toxicity
or baseline, the drug should be resumed at the starting dose.
Of note, for each recurrence of toxicity, the daily dose should
be reduced by 140 mg (one capsule), and if toxicity persists
after the doses have been reduced two times, therapy should
be discontinued . Ibrutinib must be stopped also 3–7 days,
dictated by the risk level for bleeding, before  and postinvasive
procedures, to allow time for the reversal of antiplatelet
Ibrutinib has toxicity profiles that are different from those of
immunochemotherapy. Bleeding and atrial fibrillation especially
can pose complex treatment dilemmas. This is especially
important in the light of continuous use of B-cell receptor
inhibitors and should be taken into consideration when making
individual treatment decisions.