TRAINING and EDUCATION
How I Treat In Brief
Jennifer A. Woyach, MD, associate professor at the Ohio State University Comprehensive Cancer Center, wrote
about her strategy for the management of patients with chronic lymphocytic leukemia whose disease is refractory
to ibrutinib. Below, we summarize her approach.
This material was repurposed from “How I manage ibrutinib-refractory chronic lymphocytic leukemia,” published
in Blood on January 17, 2017.
Managing Ibrutinib-Refractory
Chronic Lymphocytic Leukemia
The introduction of the oral Bruton tyrosine
kinase (BTK) inhibitor ibrutinib for the treat-
ment of patients with chronic lymphocytic
leukemia (CLL) dramatically changed the
management of this disease. In clinical trials,
ibrutinib improved both progression-free
survival (PFS) and overall survival for patients
with relapsed and treatment-naive CLL, includ-
ing those with high-risk disease, compared
with prior standard of care.
While the remarkable data make it tempt-
ing to think that patients could be treated with
ibrutinib for the rest of their natural lives,
relapse does indeed occur, and ibrutinib-
refractoriness is becoming an increasingly
common clinical problem.
Defining Relapse on Ibrutinib
Relapse on ibrutinib occurs in two forms:
• progressive CLL, which typically occurs
after at least 1 year of therapy and increases
in frequency with time on therapy
• histologic transformation, or Richter
transformation, which generally occurs
within the first 2 years of treatment, more
frequently with large cell lymphoma or
prolymphocytic leukemia
Because most patients who are on continuous
ibrutinib therapy will not attain a complete
response and many will have circulating leuke-
mia cells for long periods of time, determining
which patients are indeed relapsing can be a
challenge.
Case #1: Ruling out Ibrutinib
Resistance
A 53-year-old man with relapsed CLL started
ibrutinib seven months ago and had a partial
response with lymphocytosis (PRL), along
with a steadily decreasing absolute lymphocyte
count (ALC; last recorded value was 20,000/μL
1 month prior). He was feeling well until about
four days ago, when he began to have a low-
grade fever, myalgia, cough, and new cervical
adenopathy. On exam, he has bilateral cervical
nodes 2×2 cm and no other adenopathy. His
white blood cell count (WBC) is 36×10 9 /L,
with an ALC of 30/μL.
Comments: This patient’s scenario is common
for an upper respiratory infection leading
to cervical adenopathy and increased WBC.
Infections are frequently accompanied by
a rise in lymphocyte count, especially in
patients with residual lymphocytosis on
ASHClinicalNews.org
ibrutinib. The PRL status is a newer designa-
tion in which patients may meet criteria for
a partial response (PR) by node resolution
and blood count improvement long before
lymphocytosis resolves; however, it has not
been shown to result in an inferior remission
duration compared with patients who achieve
a standard PR.
For this patient, ibrutinib should be con-
tinued but, because constitutional symptoms
can occasionally herald the development of
Richter transformation in these patients, I
would have the patient return if symptoms
persist longer than one week
and consider rechecking blood
counts in one month.
Patients must show progression
on repeated evaluations to avoid
abandoning an effective therapy.
If a relapse is confirmed, ibruti-
nib should not be discontinued
until a new treatment plan is in
place.
Case #2: Identifying
Ibrutinib Relapse
A 50-year-old woman with CLL
has been receiving ibrutinib
for three years as her third-line
therapy and has been feeling well.
On routine exam, she has no
palpable lymphadenopathy, but
ALC has increased from 3,000/μL
to 6,000/μL. Two months later, her
ALC has further risen to 8,000/μL,
and, although she remains asymptomatic, she
has a new 1.5 cm lymph node in her neck.
Comments: This patient is relapsing on
ibrutinib with an increasing WBC count
and the presence of new palpable adeno-
pathy. It is important to closely monitor
patients who show any signs of disease
progression, so that relapse can be caught
early. The tempo of relapse tends to escalate
when ibrutinib is discontinued, so ibrutinib
should be continued until the next therapy
is started. If a wash-out period is necessary
Fast Facts
✓ ✓ Ibrutinib-refractoriness is determined by progression on repeated
evaluations so that an effective therapy is not abandoned.
✓ ✓ There are two forms of ibrutinib relapse: progressive CLL and histologic
transformation.
✓ ✓ Ibrutinib should not be discontinued in a relapsing patient without a
new treatment plan in place.
✓ ✓ Karyotypic complexity at baseline and the development of BTK and
PLCG2 mutations can help clinicians identify which patients will relapse
on ibrutinib.
✓ ✓ Short-term disease management options include venetoclax or
idelalisib plus rituximab in certain patients.
✓ ✓ Long-term disease control can include transplant for eligible patients
or enrollment in a clinical trial of CAR T-cell therapies or a checkpoint
inhibitor for transplant-ineligible patients.
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