TRAINING and EDUCATION
How I Treat In Brief
before a next-line clinical trial, the patient will need
to be watched closely for disease escalation during the
off-ibrutinib period.
Approach to Treating a Patient Diagnosed With
Ibrutinib-Refractory CLL
FIGURE
Case #3: CLL Progression Without Ibrutinib
Resistance
A 75-year-old man with relapsed CLL who has been
taking ibrutinib for two years has achieved a PR, with re-
sidual small abdominal nodes and low-level bone marrow
involvement, but normal peripheral counts. Seven days
before a planned procedure, he discontinues ibrutinib.
On the morning of the procedure, he notes he has experi-
enced three days of night sweats and fatigue and he has a
WBC of 2×10 9 /L, hemoglobin of 9.4 g/dL, and platelets of
110×10 9 /L – similar to symptoms he had prior to initiat-
ing ibrutinib. He has previously stopped ibrutinib for
three months with no symptoms.
Comments: The patient has developed signs of disease
progression while holding the drug, but not ibrutinib
resistance. The drug should be reinstated as soon as
possible, and a quick response can be expected. Drug
discontinuations need to occur for as short a period as
possible with occasional steroid use for palliation until
ibrutinib is restarted.
Predicting Disease Progression on
Ibrutinib
Although symptomatic disease progression upon ibru-
tinib withdrawal appears to be most common earlier
in therapy and in patients with higher levels of residual
disease, it cannot routinely be predicted. The most
significant independent predictor for ibrutinib relapse
appears to be baseline karyotypic complexity on stimu-
lated karyotype, but other risk factors will likely emerge
as clinical trial data mature, including a patient’s number
of prior treatments and del17p status.
Relapse while on ibrutinib primarily occurs through
the acquisition of mutations in BTK (the most common is
BTK C481S) or its immediate downstream target, PLCG2.
These mutations have been detected using high-sensitivity
assays in 85 to 90 percent of patients at disease relapse.
Clonal evolution is a hallmark of ibrutinib resistance,
with researchers noting a recurrent deletion in 8p in
patients at the time of relapse.
At our center, we have begun to screen all patients
with CLL every three months for BTK and PLCG2
mutations. The detection of these mutations reliably
predicts patients whose disease will go on to relapse. In
the context of a clinical trial, we will offer the addition
of a novel agent to ibrutinib to patients who develop an
ibrutinib-resistance mutation to try to prolong remission
duration. Whether this strategy does indeed prolong re-
mission duration remains to be seen; if effective, it would
certainly be preferable to prevent relapse than to treat
uncontrolled CLL.
Treatment Options for Ibrutinib-
Refractory CLL
My approach to treating a patient with ibrutinib-
refractory CLL is summarized in the FIGURE . When I
see patients in clinic who are relapsing on ibrutinib, we
discuss short-term disease management and long-term
disease control. In the short-term, I prefer enrolling a
patient in a clinical trial whenever possible.
I always repeat FISH and cytogenetic testing at
the time of relapse. The most promising treatment
option for ibrutinib-resistant patients is venetoclax, a
BCL2 inhibitor, which was approved by the U.S. Food
and Drug Administration (FDA) in June 2018 for all
patients with previously treated CLL, regardless of
50
ASH Clinical News
Ibrutinib-refractory
diagnosis
• Perform FISH/stimu-
lated cytogenetics
• Assess for mutations
in BTK or PLCG2 as
available
Enrollment in
clinical trial or
venetoclax off-
study in selected
patients
No
remission
Remission
For transplant
eligible patients,
refer for
transplant and
start typing
potential related
donors
del17p status – expanding on its initial approval for only
patients who harbored a del17p mutation.
Upregulation of PI3K commonly is seen in patients
with ibrutinib-resistant lymphoma, suggesting that
idelalisib-based therapy may be successful in the ibrutinib-
refractory population. For patients without del17p-mutated
CLL, treatment with the PI3K inhibitor idelalisib plus rit-
uximab is a reasonable consideration although, given the
limited PFS reported with PI3K inhibitors in this setting,
I view idelalisib as a bridge to a long-term strategy. So far,
a real-world experience of patients treated with idelalisib
upon ibrutinib resistance showed a 28-percent response
rate with a median PFS of eight months.
While the remarkable
data about ibrutinib in
CLL make it tempting
to think that patients
could be treated
indefinitely, relapse
does indeed occur.
Duvelisib, another PI3K inhibitor, was approved by
the FDA in September 2018 for the treatment of patients
with relapsed or refractory CLL, although patients in the
pivotal trial were not stratified based on BTK mutational
status.
I do not consider chemoimmunotherapy or single-
agent CD20 antibodies to be a reasonable intervention,
as anecdotal reports have not indicated efficacy and there
are no formal data about this approach.
For long-term disease control, hematopoietic cell
transplantation with reduced-intensity conditioning is an
option for eligible patients, including those with Richter
transformation. For those who are transplant-ineligible,
I would consider a clinical trial evaluating a chimeric
antigen receptor (CAR) T-cell therapy.
Patients who relapse with Richter transformation
Enrollment in
clinical trial
Remission
Reduced-intensity alloHCT
for transplant candidates.
Consider clinical trial of CAR T
cells for select patients.
present a treatment challenge, as there are limited trial
data in this population and outcomes are dismal. For the
few patients without complex karyotype or who have
clonally unrelated Richter transformation, I use chemo-
immunotherapy. I typically choose R-EPOCH (rituximab,
etoposide, prednisone, vincristine, cyclophosphamide,
doxorubicin), based on data showing particularly good
outcomes. Other chemoimmunotherapy regimens can be
considered as well. For all other patients, I recommend a
clinical trial of an investigational agent, if available, and
all eligible patients with Richter transformation following
ibrutinib should be considered for transplant.
Future Directions
Patients with acquired resistance to ibrutinib have poor
survival outcomes, underscoring the need for new,
effective therapies for this high-risk patient popula-
tion. Several agents for the treatment of CLL are under
investigation.
Entospletinib, a spleen tyrosine kinase (Syk) inhibi-
tor, is being studied in patients with CLL who were
previously treated with a BTK inhibitor. This approach
is supported by preclinical data suggesting that the
inhibition of Syk can overcome PLCG2 mutations and
thus could also be beneficial in the presence of upstream
mutations. The preliminary response rate is 28 percent
after 16 weeks of treatment.
Because the mutations that have been associated with
relapse do not substantially alter the B-cell receptor (BCR)
pathway, alternative targeting of the BCR pathway at or
downstream of sites of mutation also may be an effective
strategy to treat relapsed patients. Reversible BTK inhibi-
tors have shown preclinical efficacy, and, for patients with
PLCG2 mutations or BTK mutations, downstream targets
such as PKCβ may be clinically relevant.
Agents that target BTK in a manner distinct from
ibrutinib (including HSP90 inhibitors, HDAC inhibitors,
and XPO1 inhibitors) also have the potential to be benefi-
cial in ibrutinib-refractory patients.
As more research is performed to determine which
patients are at risk for relapse on ibrutinib, it will be
important to identify high-risk patients a priori and
consider them for combination therapies, hematopoietic
cell transplantation, or other long-term intervention.
The identification of biomarkers of impending relapse
also may allow for salvage therapies or combination
strategies before the accelerated disease progression
associated with relapse. ●
November 2018