How I Treat

How I treat CLL patients with ibrutinib

Jennifer R. Brown

Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients.
In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more
widespread in the community, however, its full adverse event profile has emerged and proven more challenging than

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was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the
first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient
starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics
discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.
(Blood. 2018;131(4):379-386)

Introduction
Ibrutinib has demonstrated marked efficacy in chronic lym-
phocytic leukemia (CLL) in clinical trials1-3 and is approved by the
US Food and Drug Administration for the therapy of any CLL
patient in any line of therapy. Its use has rapidly become
standard of care for relapsed CLL patients, as well as for many
frontline high-risk or older patients. In the most recent update
of the RESONATE registration trial, with 4-year follow-up, only
12% of relapsed CLL patients had discontinued for adverse
events (AEs) that included atrial fibrillation (AF), bleeding, and
infection.1,2,4,5 Diarrhea, arthralgia, and skin toxicity can also be
significant, and hypertension emerges over time.6,7 Data from
real-world use of ibrutinib indicate that these toxicities may limit
ibrutinib use, however, with a recent retrospective report
showing that 42% of 621 primarily relapsed patients had dis-
continued the drug, almost half because of toxicity, at a median
of 6 months.8 The most common reasons were AF, infection,
pneumonitis, bleeding, and arthralgia, all well-recognized tox-
icities of ibrutinib. The median progression-free survival (PFS)
was 35 months, significantly less than the 52 months reported for
more heavily pretreated patients on the phase 1b/2 trial.7
that may increase complications. The most important of these are
a bleeding diathesis or cardiac disease.
Bleeding diathesis, the need for full-dose anticoagulation, or
both Ibrutinib is associated with low-grade ecchymoses and
petechiae in about half of patients13 and with major hemorrhage
rates that vary from 1%14 to 9%,15 depending on the clinical
study. Although some hemorrhages are periprocedural, spon-
taneous major bleeding also occurs, likely in several percent of
patients.16 This susceptibility is related to the role of BTK and
TEC kinases in platelet activation downstream of the collagen
receptor glycoprotein VI. Addition of ibrutinib ex vivo to healthy
donor platelets, or therapy in vivo, inhibits collagen-induced
platelet aggregation17-19 and platelet adhesion under high
shear.18,20,21 This in vitro effect correlates with low-grade bleeding
in ibrutinib-treated patients.17-19 Platelet aggregation defects have
also been described in CLL patients at baseline in comparison with
healthy controls, which were then further exacerbated by ibrutinib
therapy.17,19,22 Two studies have independently suggested pre-
treatment screening by either ristocetin-induced platelet aggre-
gation23 or low von Willebrand factor (VWF) activity or factor VIII
levels,19 but neither approach has yet been validated.

In early ibrutinib trials, major hemorrhage including subdural

What do I think about before starting a
patient on ibrutinib?
Comorbidities
Age is a risk factor for AEs with ibrutinib. Studies from Ohio State
University have identified increasing age as the primary pre-
dictor of discontinuation for reasons other than progressive
disease,9,10 with rates of .60% at 6 months in patients over
80 years of age. Recent population-based studies have also
found that worse performance status11 or higher Cumulative
Illness Rating Scale comorbidity score12 was associated with
worse outcomes, increasing the chances of discontinuation or
death11 or reducing PFS.12 In older patients for whom I am con-
sidering ibrutinib, I carefully weigh disease risk with comorbidities
hematoma occurred in the context of warfarin,24 leading to
the exclusion of these patients from ibrutinib clinical trials. The
experience of combining long-term anticoagulation with ibru-
tinib is therefore extremely limited.14 Antiplatelet agents are
more common, reported at 34% in one study,14 but dual anti-
platelet therapy is very rare. Generally, the latter should be
avoided given evidence of increased major bleeding with this
combination, without ibrutinib.25 A recent meta-analysis of
published trial data on ibrutinib and bleeding demonstrates a
2.72 relative risk of any bleeding and a trend toward increased
major bleeding at 1.66 relative risk, despite being underpowered
for this outcome.26 These data likely underestimate the actual risk
of bleeding in an unselected patient population. For example, a

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center-based report of 71 ibrutinib patients with a median age of
73 found that 70% were also receiving an antiplatelet medication,
17% were receiving an anticoagulant, usually apixaban for atrial
fibrillation, and 13% were receiving both.27 Major bleeding oc-
curred in 18% of patients, including 78% receiving both anti-
platelet and anticoagulant therapy.27 No major bleeds occurred in
this study in patients who were not also receiving antiplatelet,
anticoagulant, or a CYP3A4-interacting therapy, underscoring the
need for care in combining these agents.
In practice I avoid ibrutinib in patients with a history of major or
potentially life-threatening hemorrhage owing to an irreversible
cause. Similarly, if a reasonable alternative therapy is available for a
patient requiring long-term anticoagulation or dual antiplatelet
therapy, I favor the alternative CLL therapy. If ibrutinib is uniquely
the best option, then I evaluate the true necessity of the anticoag-
ulation or dual-antiplatelet therapy. I also suggest that all patients
stop vitamin E, fish oils, and nonsteroidal anti-inflammatory drugs,
as in the ibrutinib clinical trials, and if on aspirin, consider stopping
or reducing to the lowest available dose.
Management of surgical procedures Ibrutinib should be held
3-7 days prior to and after any invasive procedures owing to
the risk of periprocedural bleeding.6,27,28 Therefore, if a patient
needs a surgical procedure, I attempt to get it done before
initiating ibrutinib. This is particularly relevant for patients with a
large disease burden or aggressive disease who may experience
disease regrowth if ibrutinib is held early after initiating
therapy.6,27 Once patients have been on ibrutinib for some time
(.6-12 months) and achieved solid disease control, transient
holds for procedures are not as problematic.
Cardiac effects of ibrutinib The best studied cardiac side effect
of ibrutinib is AF, which occurs initially in about 6% of patients,2,3,26
increasing to 10% to 15% over 2 years.29 An analysis from 4
randomized registration trials identified risk factors for AF on
ibrutinib as age .65 and a prior AF history. Hypertension and
hyperlipidemia were significant in univariate but not multivariate
analyses.29 The recently described Shanafelt risk score for AF also
stratified patients in this cohort into risks ranging from 0.4% to
17.9% (older age, male sex, valvular heart disease, and hyper-
tension). In these clinical trial populations, most patients with 1
instance of AF stayed on ibrutinib, although multiple episodes
were more common among ibrutinib-treated patients. This ob-
servation contrasts with a real-world experience in which com-
plications, including congestive heart failure (CHF) and bleeding,
were much more common and in which almost half the patients
discontinued ibrutinib.30 In evaluating patients for risk on ibrutinib,
however, a history of major cardiac disease such as CHF or
unrevascularized coronary artery disease is of greater concern to
me than is AF, which can often be managed. Among the former
patients, I have seen cases of elevated troponin or decom-
pensated heart failure soon after starting ibrutinib. Our group
recently reported rare cases of ventricular arrhythmias and sudden
death associated with ibrutinib, and concern remains that risk of
this serious outcome would be higher with significant cardiac
disease.31 Prior to initiation, even difficult-to-control hypertension
should be managed, because patients very commonly develop
worsened hypertension on ibrutinib.1,6
Other issues Ibrutinib is ,1% renally excreted, and exposure is
not altered with mild-moderate renal impairment (creatinine
380 blood® 25 JANUARY 2018 | VOLUME 131, NUMBER 4
clearance . 25 mL/min). A published case report describes the
successful use of ibrutinib in a hemodialysis patient.32 However,
caution is in order, because ibrutinib has rarely been associated
with causing renal impairment.
In mild, moderate, or severe hepatic impairment, single-dose
ibrutinib pharmacokinetics showed mean increases in exposure
of 4.1, 9.8, and 13.4 times, on the basis of the area under the
curve (AUC), leading to the recommendation of 140 mg daily in
patients with mild-moderate impairment, whereas a single daily
dose was considered too high for severely impaired patients.
Ibrutinib-induced acute liver failure has been reported,33 as has
reactivation of hepatitis B (HBV),34,35 which should be screened
for prior to initiation. Hepatologist referral and therapy for un-
treated chronic active hepatitis B (ie, surface antigen positive) is
needed prior to ibrutinib, whereas patients who are hepatitis B
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surface-antigen negative and HBV DNA negative, but anti–
hepatitis B core positive, can be monitored closely during therapy,
including with HBV DNA testing.36
Drug interactions
Ibrutinib is hepatically metabolized, a major substrate of CYP3A4
and a minor substrate of CYP2D6. Modeling of ibrutinib drug-
drug interactions show that coadministration with a strong
inhibitor such as ketoconazole may increase ibrutinib AUC
exposure by 24-fold, and moderate inhibitors led to a 4.9- to
7.5-times increase. Strong inducers such as rifampin can decrease
AUC by 10-fold. Administration of ibrutinib with strong CYP3A4
inhibitors or inducers is therefore not recommended, though
if a moderate inhibitor is absolutely required, the ibrutinib
dose should be reduced to 140 mg daily.37 Key moderate
CYP3A4 inhibitors include diltiazem, verapamil, amiodarone,
fluconazole, and voriconazole. Consumption of grapefruit and
Seville oranges, as well as some supplements, also alter exposure
of CYP3A4-metabolized drugs such as ibrutinib. A recent
study from the Mayo Clinic found that 64% of 118 CLL patients
treated with ibrutinib were on medications that could increase
toxicity through drug interactions, the majority of which were
antiplatelet medications, but 18% were drug interactions through
CYP3A.38 Thus a careful medication review prior to ibrutinib
prescription is important to avoid AEs such as one reported with
coadministration with the moderate CYP3A4 inhibitor verapamil.39
Infections and prophylaxis (including vaccines)
Infections, in particular pneumonia, are common in the clinical
trials of ibrutinib, with grade 31 pneumonia in 25% and grade
31 infection in 51% of relapsed refractory patients on the phase
1b study.5 The infection rate has been reported to decline by
more than half after 6 months of therapy, although what hap-
pens after many years is unknown.1,6,40 Ibrutinib has been re-
ported to allow for partial reconstitution of normal B cells,40 and
immunoglobulin G (IgG) levels remain stable for the first 6
months of therapy5,40 before declining thereafter.40 IgA levels
increase,5,40 and a greater increase was associated in one study
with a lower rate of infections.40 Preclinical data also suggest that
ibrutinib may help repair the T-cell defects in CLL.41 Multiple
studies have reported that ibrutinib decreases Th2 cytokines
in vivo,41-43 normalizes total T-cell numbers,42 and decreases
T-regulatory cells43 during the first 6 months of therapy.
Despite these observations, as ibrutinib is widely used, it is clear
that susceptibility to infection remains significant. For example,
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cases of invasive aspergillosus, including 3 central nervous system
(CNS) cases,44 and Cryptococcus have been reported.45,46 Seven of
18 patients with primary CNS lymphoma treated on a phase 1b
study of ibrutinib followed by chemotherapy developed invasive
aspergillosus, 2 while on ibrutinib alone and 4 with CNS disease.47
In this study, BTK knockout and wild-type mice were infected with
Aspergillus, and the former had significantly greater mortality,
suggesting that BTK is needed for immune control of Aspergillus.47
Increased vigilance for fungal infection is therefore warranted in
ibrutinib-treated patients, but prophylaxis would be challenging
given the duration of therapy and the CYP3A4 interactions with
azoles.
Other infections are also seen. Our infectious diseases group
has recently reported a 8.1% rate of opportunistic infections
among hematologic malignancy patients receiving first-line
BTK inhibitors.48 In the ibrutinib phase 1b/2 study, 5 patients
experienced varicella-zoster virus (VZV) reactivation despite
antiviral prophylaxis at some point in 85 out of 101 patients6;
subsequent reports confirm this.49 Mild cases of pneumocystis
jiroveci pneumonia (PJP) identified predominantly by poly-
merase chain reaction were reported in 5 patients out of
96 receiving single-agent ibrutinib, at a median of 6 months on
therapy.50 Although PJP was clearly the cause of symptoms and
related to ibrutinib, 3 of the patients did not immediately re-
ceive secondary prophylaxis, and none recurred, leading the
authors to suggest increased vigilance as opposed to universal
prophylaxis.50 Even so, I have continued my practice of using
prophylaxis for both VZV and PJP in any relapsed CLL patient
on any therapy. Given the cases noted above, I now usually do
so in previously untreated patients receiving ibrutinib who are
without contraindication, but many other CLL specialists do
not. More data are needed to clarify the risk prior to a universal
recommendation.
What about vaccinations? One study of influenza vaccination in
19 patients on single-agent ibrutinib found that 26% had se-
roconversion to at least 1 vaccine strain.51 A subsequent study
looking at 13 relapsed CLL patients on ibrutinib for a median of
7.5 months found no responders to influenza vaccine.52 A similar
study of 13-valent pneumococcal conjugate vaccination found
that all 4 untreated patients responded, whereas none of the
4 ibrutinib patients did, suggesting that if it is possible to vac-
cinate prior to starting ibrutinib, this is preferred.53 My practice is
to vaccinate prior to ibrutinib if feasible, but if not, to still provide
vaccinations to patients on ibrutinib, because data are limited,
and any response is helpful.
Autoimmunity
Autoimmune complications in CLL are common. Ibrutinib is
thought to have the potential to control autoimmunity because
of its activity in a rheumatoid arthritis mouse model,54 and
because it decreases differentiation of Th17 T cells42 and
normalizes expanded CD8 T-cell compartments54 in patients.
Multiple case reports demonstrate ibrutinib effectively control-
ling steroid refractory autoimmune hemolytic anemia,55,56 and a
report from the RESONATE trial57 supports safe administration
of ibrutinib with the suggestion of enhanced control of auto-
immunity. Another study reported acute flare of autoimmunity
right after ibrutinib initiation, with longer-term control in patients
maintained on ibrutinib.58 My experience largely recapitulates
this report, namely, occasional flare of autoimmunity after
HOW I TREAT CLL PATIENTS WITH IBRUTINIB
ibrutinib initiation but control over the long term. I therefore treat
the autoimmunity first to optimize control prior to initiation of
ibrutinib and then overlap the autoimmune therapy with ibrutinib
for some time. Similarly, if a patient flares shortly after starting
ibrutinib, I will institute therapy for the autoimmune complication
while continuing ibrutinib and slowly taper the other autoimmune
therapy.
What are my absolute contraindications
to initiating ibrutinib?
This question is challenging, because choice of therapy always
requires balancing the risk of the patient’s CLL with the risk of a
given therapy. Ibrutinib is sufficiently effective that in very high
risk CLL, it may need to be tried regardless of contraindication,
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particularly because it is typically more readily available than
venetoclax or idelalisib. That being said, the following constitute
circumstances under which I would think very carefully before
starting or resuming ibrutinib: (1) ongoing, poorly controlled
bleeding; (2) history of major life-threatening bleeding, espe-
cially if not due to a reversible cause; (3) requirement for high
treatment dose anticoagulation that cannot be stopped even
briefly; (4) older patient (.70-75 years old) with cardiac
comorbidity, including systolic or valvular dysfunction, recurrent
uncontrolled congestive heart failure or AF, symptomatic un-
revascularized coronary artery disease, or history of ventricular ar-
rhythmia without automatic implantable cardioverter-defibrillator;
(5) unexplained syncope concerning for cardiac etiology after
initiation of ibrutinib; (6) ongoing invasive fungal infection re-
quiring therapy; and (7) refractory autoimmune complications
developing soon after ibrutinib initiation, particularly bone
marrow aplasia.
What are the early complications after
starting ibrutinib?
Symptoms: patient 1
Patient 1 was a 90-year-old woman who presented with
CLL/small lymphocytic lymphoma (SLL) in 2001 and received
6 lines of therapy prior to January 2014, when she had a
.25-cm abdominal mass, and was started on ibrutinib 420 mg
daily. She experienced mild diarrhea, increased low-extremity
edema, and arthralgia, which resolved after a few months.
Symptoms after starting ibrutinib include diarrhea, which is
usually self-limited and easily managed with supportive care, as
well as occasional nausea; diffuse body, joint, or muscle aches
that vary from mild to severe; and ecchymoses or petechiae with
minimal trauma (particularly when combined with antiplatelet
drugs). Some patients also report significant fatigue and loss
of concentration or attention on ibrutinib. Taking ibrutinib at
night helps prevent the gastrointestinal side effects. The body
aches or migratory arthralgias that affect 1 joint 1 day and
an entirely different joint the next can be quite troublesome
and are a frequent reason for ibrutinib discontinuation in clinical
practice.59 These aches often abate without major intervention.
Magnesium supplements or tonic water containing quinine can
be helpful. For severe arthralgias, management is anecdotal and
variably effective, with options including a brief methylpred-
nisolone taper, anti-inflammatory drugs (without antiplatelet
blood® 25 JANUARY 2018 | VOLUME 131, NUMBER 4 381
effects), or drug holiday or dose reduction. The latter is the only
real option for fatigue or attention problems.
Is dose reduction or drug holiday a good solution?
The ibrutinib clinical trials recommended holding ibrutinib for
grade 31 toxicities until resolution to grade 1, followed by re-
suming at full dose at least once. The goal was to maintain full
BTK occupancy (considered .95%), which is predicted in only
26% to 51% of patients treated at 140 to 280 mg daily.60 Clinical
outcome data at lower doses are limited. One retrospective
investigation of 197 ibrutinib-treated patients reported similar
objective response rate, PFS, and overall survival in 37 patients
(19%) receiving a reduced median dose of 4.3 mg/kg/d.61 The
UK and Ireland expanded access program also did not report
reduced OS in patients who had dose reductions.11
The literature suggests that drug holds may be more prob-
lematic, with decreased PFS among ibrutinib patients who
missed .8 consecutive doses on the RESONATE registration
trial.62 This subgroup of patients had reduced creatinine clear-
ance and advanced stage disease, however, and may have been
likely to do poorly anyway. Progression was also defined by the
independent review committee solely based on imaging.62 The
expanded access programs show conflicting data on drug holds,
with no effect in the Polish experience but worse outcomes in
the UK-Ireland experience, with greater than 14-day holds.11
Although overall, these data appear reassuring, particularly for
dose reductions, follow-up time remains short, and caution is still
in order because of concern that inadequate BTK occupancy
could potentially drive resistance. Ideally, an assay to mea-
sure BTK occupancy would be available clinically, but this does
not exist. A key question is whether dose reduction helps with
symptoms, and in my personal experience, patients may ex-
perience some improvement but not always a marked differ-
ence. Systematic studies addressing these issues are very limited
and desperately needed. In the meantime, I encourage patients
to stay at full dose for the first few months, because many of
these early side effects resolve, and only after that to consider
dose reduction if the symptoms remain challenging.
What about cytoses and cytopenias? Patient 2
A 67-year-old man with immunoglobulin heavy chain variable
region (IGHV) unmutated, del(11q) deleted CLL with complex
karyotype had a 4-year remission after fludarabine, cyclophos-
phamide, and rituximab in 2011, but by mid-2016 had white
blood cell (WBC) count of 108 000/mL, hemoglobin of 10 g/dL,
and platelet count of 69 000/mL. He started ibrutinib, and his
WBC rose to 250 000/mL before slowly declining. He had a
history of premature ventricular contractions (PVCs), which in-
creased despite metoprolol. An event monitor demonstrated
PVCs, premature atrial contractions, and brief atrial tachycardia,
and he was put on aspirin, which in combination with ibrutinib
and platelets at 60 000/mL, resulted in significant bruising.
An increase in circulating lymphocyte count is common and
peaks at 1 to 2 months, followed by a slow decline, but a subset
of patients never resolve their lymphocytosis fully.63 Data show
that patients with prolonged lymphocytosis have outcomes as
good as those who do not (likely because prolonged lympho-
cytosis is associated with favorable prognostic factors).63 This
382 blood® 25 JANUARY 2018 | VOLUME 131, NUMBER 4
sharp early increase in lymphocyte count should not be mis-
taken for progressive disease in a patient who is symptomatically
improved and whose nodes are decreased. It is also important to
note that the improvement in anemia on ibrutinib can be quite slow,
sometimes requiring 4 to 6 months, although stabilization is usually
seen early. Thus lymph node shrinkage is the simplest early in-
dicator of response. Progression in the first 1 to 2 years on ibrutinib
is often Richter’s transformation, while CLL progressions tend to
occur later.10 A slow, steady increase in lymphocyte count at later
times should raise the possibility of progressive disease. The
identification and management of progressive disease on ibrutinib
has been well covered in a previous “How I Treat” article.64
Also very common after initiation of ibrutinib is a drop in platelet
count, which is typically not problematic, because it is usually of
small magnitude and remains stable prior to slowly improving
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over time. Because of this drop and the antiplatelet effect of
ibrutinib, I am cautious when initiating ibrutinib in a patient with a
platelet count below 30 000/mL (clinical trial cutoff), and I will usually
use a higher platelet transfusion threshold of about 25 000/mL
shortly after initiation. These patients, in particular, should have
all other anticoagulant drugs stopped.
Cardiac complications of ibrutinib
Patient 2 A few months later, patient 2 presented with fa-
tigue and different palpitations and was in AF, which converted
spontaneously. His CHADS2 (congestive heart failure, hyperten-
sion, age $ 75, diabetes, previous stroke/transient ischemic
attack) VASc (vascular, age 65-74, sex) score was 2 (age and hy-
pertension), potentially warranting anticoagulation. He already
had experienced significant bruising, with platelets still in the
60 000s/mL. Cardiology therefore felt that his bleeding risk likely
exceeded his stroke risk but, given the ongoing need for
ibrutinib in a high-risk CLL patient, decided to suppress the
burden of AF with amiodarone. Given the drug interaction, the
ibrutinib dose was reduced to 140 mg daily. With amiodarone,
the patient has not had AF or PVCs and feels well. His CLL
remains in good control, and he continues on low-dose aspirin.
Patient 3 Patient 3 was a 70-year-old man with CLL, with
del(11q) and del(13q) deletions and unmutated IGHV, who was
treated in early 2009 on CALGB 10404 with fludarabine and
rituximab, with complete response. His disease progressed, and
he started ibrutinib in June 2016, complicated by easy bruising.
At a routine preoperative evaluation, he was in AF and started on
metoprolol and apixaban, and ibrutinib was held. He under-
went cardioversion successfully, and ibrutinib was resumed, but
2 weeks later, he was again in AF. He was asymptomatic and
restarted on low-dose apixaban without concurrent antiplatelet
agents. He was counseled about increased risk of bleeding, and
he elected to continue both drugs.
And back to patient 1 Several months after starting ibrutinib,
patient 1 presented with syncope and was found to have severe
bradycardia, for which a pacemaker was placed. She continued
on ibrutinib with the pacemaker.
Patient 1 illustrates that older patients, in particular, can de-
velop a range of cardiac complications not well represented in
the younger trial patients. The most common cardiac com-
plication is AF, though, and I will typically hold ibrutinib at least
briefly while controlling the AF. The long-term management
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decisions are complex, as in the 2 cases, and cardiologists are
helpful with the risk-benefit assessment and decision making.
Systematic data to guide management are lacking, but recent
reviews have proposed management guidelines consonant
with my approach.65,66 Although not studied in these patients,
the CHADS2 VASc score for clotting risk and the HAS-BLED
(Hypertension, Abnormal renal/liver function, Stroke, Bleeding
history or predisposition, Labile INR, Elderly, Drugs/alcohol
concomitantly) score for bleeding risk can provide some guid-
ance when considering anticoagulation. Whether or not to con-
tinue ibrutinib also depends on the patient’s remission status and
the underlying aggressiveness of his or her disease, as well as
patient preference. Ibrutinib might in principle provide some
helpful antiplatelet activity in cardiac disease, but at present this is
completely unknown. For those patients who do continue ibrutinib
and anticoagulation, our group has favored apixaban, given the
cardiology and thromboembolism literature, which suggest that
apixaban may result in fewer bleeding events than warfarin or other
new oral anticoagulants.67-70 That being said, almost no safety data
exist for this combination, and ibrutinib is a P-glycoprotein inhibitor
that may increase the concentration of apixaban, leading us to use
the lower 2.5-mg twice-daily dose in many patients also on
ibrutinib. I typically maintain the ibrutinib dose, because most
patients in the clinical trial series tolerated continuing full dose.29
Bleeding: patient 1
She had near resolution of her bulky abdominal mass on ibrutinib
but developed a pulmonary embolism after a cross-country
plane flight in December 2015 and received anticoagulation
without holding ibrutinib. She also had an infected leg ulcer with
osteomyelitis and experienced clinically significant recurrent
bleeding from this wound until ibrutinib was held. She was
then quite debilitated and stayed off ibrutinib without a problem
for nearly 2 years, at which time she was off anticoagulation
and resumed ibrutinib with good response of her recurrent
abdominal adenopathy.
Despite all precautions, some patients develop clinically sig-
nificant bleeding. My management typically involves holding
ibrutinib and providing platelet transfusions as needed, re-
gardless of platelet count, to overcome the platelet function
defect induced by ibrutinib. Case reports of the benefit of
platelet transfusion have been published, although data are
sparse.71 A recent randomized trial in the context of other
antiplatelet agents suggested that platelet transfusion may ac-
tually increase mortality in CNS bleeding.72 Given the absence of
data with ibrutinib, management should be individualized.65
Holding ibrutinib alone will typically substantially resolve the
antiplatelet effects in 2 to 3 days.17,18 I planned for patient 1 to
complete 6 months of anticoagulation for her pulmonary em-
bolus, and during that time I would not have added ibrutinib
back. Whether or not to continue ibrutinib in a patient with a
bleed is an individualized decision that depends on the bleed
severity, the reversibility of its cause (periprocedural or transient
anticoagulation, for example), the quality of the CLL response,
and the aggressiveness of the underlying CLL. This patient did
well off of ibrutinib and was subsequently able to resume ibrutinib
when her other issues had resolved.
Infection: patient 4
This 75-year-old woman first presented with CLL, complicated
by cold agglutinin disease, in 1992, and despite multiple rounds
HOW I TREAT CLL PATIENTS WITH IBRUTINIB
of therapy, was dependent on weekly transfusions by July 2014,
when she started ibrutinib. She had an excellent response and
became transfusion independent. In December 2016 she pre-
sented with acute bilateral vision loss, right hemiparesis, and
dysarthria after 1 week of sinus symptoms and headache. She
was diagnosed with cavernous sinus thrombosis and suffered
rapid neurologic deterioration. Invasive mucormycosis involving
both cavernous sinuses was confirmed at autopsy.
Infection is one of the most common AEs for patients on ibru-
tinib, especially in the first 6 months of therapy.6 Any patient
presenting with likely pneumonia or systemic infection should
have a complete workup, including evaluation for opportunistic
infections. Typically, if a patient presents acutely with fever and is
hospitalized, I will hold ibrutinib until a diagnosis is established
and the patient is clearly improving. Ibrutinib can cause a drug-
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related pneumonitis responsive to prednisone, reported in a
small series73 and seen occasionally in clinical practice. Lung
biopsies demonstrated organizing pneumonia and interstitial
inflammation or granulomas without organisms.73 Whether
ibrutinib can be resumed in these patients is not clear; 1 patient
in this series resumed ibrutinib and developed recurrent in-
terstitial pneumonitis.73 For most patients with typical bacterial
or viral pneumonia, however, ibrutinib can be resumed once the
patient is improving. An exception may be patients who develop
invasive fungal infections on ibrutinib, who will need to be
comanaged with infectious disease. Ibrutinib has significant drug
interactions with both voriconazole and posaconazole. The al-
ternative agent isavuconazole has less severe drug interactions
but is less proven. In limited anecdotal experience, these pa-
tients often do need to discontinue ibrutinib for an extended
period to enable full control of their infection.44,47 More data on
the natural history of opportunistic infections and long-term
incidence of infections on ibrutinib are desperately needed.
Other issues
Dermatologic changes Rash is a common ibrutinib side effect
in 2% to 27% of patients3,5,24,28 but is often self-limited or easily
managed with topical steroids.74,75 A case series from Stanford
University of 14 patients has been published, in which 2 cate-
gories of rash were identified.74 The first was a nonpalpable
asymptomatic petechial rash, perhaps related to ibrutinib-induced
platelet dysfunction, and the second was a palpable pruritic rash,
which on biopsy showed an inflammatory infiltrate. The latter
sometimes required ibrutinib interruption and corticosteroids to
resolve, but all patients were eventually able to resume ibrutinib.74
More recently, erythema nodosum has been seen in ibrutinib-
treated patients and may require systemic steroids or extended
time off of ibrutinib for resolution.
Finally, brittle nails and hair are common on ibrutinib and in-
crease over time. In a National Institutes of Health report, 67% of
patients reported brittle fingernails at a median of 6 months on
ibrutinib, with about a quarter reporting brittle toenails or hair
changes at a median of 9 months.76 We generally recommend
nail oil to the cuticle bed.
Hypertension Over time, hypertension increases in patients on
ibrutinib and often requires initiation or increase of drug therapy.
The incidence is in the 5% to 14% range1,2 at 1 to 2 years but rises
to 25% to 30% with 5-year follow-up in clinical trials.6,7 This
blood® 25 JANUARY 2018 | VOLUME 131, NUMBER 4 383
incidence may be even higher outside of trials and with longer
follow-up, requiring vigilance on the part of treating physicians.
Conclusion
Ibrutinib is a highly effective therapy for CLL, which at present is
planned to be given indefinitely, yet we still have much to learn
about its side-effect profile over time. Managing toxicities to
keep patients on the drug long enough to achieve a deep re-
sponse is critical to ibrutinib benefit, and at present, little is
known about the potential durability of response after ibrutinib
discontinuation for AEs. For patients who come off of ibrutinib
for AEs, I typically try to delay subsequent therapy as long
as possible while the AEs resolve; sometimes this observa-
tion period can last years. For patients who received ibrutinib
only briefly frontline, I would typically favor trying chemo-
in inducing complete response and minimal residual disease
negativity.78,79 Minimizing toxicity is just one of the benefits of
moving toward time-limited therapy, along with patient pref-
erence, reduced cost, and reduced resistance. Another potential
advance will be the upcoming availability of more specific BTK
inhibitors, including acalabrutinib80 and BGB-3111,81 which may
have fewer side effects, although experience at present remains
limited. Meanwhile, however, we need systematic population-
based studies of the natural history of ibrutinib therapy over time
to optimally inform our patient management.
Acknowledgment
The author thanks Jeffrey Zwicker for the initial idea for this article.

Downloaded from https://ashpublications.org/blood/article-pdf/131/4/379/1465597/blood764712.pdf by guest on 03 February 2020

immunotherapy (CIT) next, although we have almost no data on
its efficacy after ibrutinib. In the relapsed setting, I would likely
use either venetoclax or idelalisib at progression, the former
more likely if the patient had been on ibrutinib for some time or
progressed while taking ibrutinib. I have, however, had good
success with idelalisib, particularly in older patients with sig-
nificant cardiac disease who are pretreated with CIT. Just as we
need a better understanding of ibrutinib side effects over time,
we need more information on the outcomes of these subsequent
therapies, particularly CIT, in patients who received ibrutinib
frontline. Ultimately, the development of combination shorter-
duration regimens that result in deep remissions may allow
treatment breaks that could reduce both short- and long-term
toxicities in those who develop them. These ibrutinib combi-
nations could be based on anti-CD20 antibodies such as obi-
nutuzumab,77 particularly in patients who are frailer, but will
likely involve venetoclax in fit patients because of its efficacy
Authorship
Contribution: J.R.B. developed the concept, drafted the paper. and
approved the final manuscript.
Conflict-of-interest disclosure: J.R.B. has served as a consultant for
Janssen, Pharmacyclics, Astra-Zeneca, Sun, Redx, Sunesis, Loxo, Gilead,
TG Therapeutics, Verastem, and Abbvie and receives research funding
from Sun and Gilead.
Correspondence: Jennifer R. Brown, Department of Medical Oncology,
Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215;
e-mail: jennifer_brown@dfci.harvard.edu.
Footnotes
Submitted 5 August 2017; accepted 5 December 2017. Prepublished
online as Blood First Edition paper, 18 December 2017; DOI 10.1182/
blood-2017-08-764712.

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BROWN