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PAPER SPOTLIGHT
Ibrutinib and Palbociclib: A New
Combination for Mantle Cell Lymphoma?
The combination of ibrutinib and
the CDK-4/6 inhibitor palbociclib
could be safely administered to
patients with previously treated
mantle cell lymphoma (MCL),
according to results from a phase
I trial published in Blood.
This regimen also was associ-
ated with a response rate that
was similar to that reported in
historical studies of single-agent
ibrutinib, the authors, led by
Peter Martin, MD, of Weill Cornell
Medicine in New York, wrote.
“Bruton tyrosine kinase (BTK)
inhibition will likely be the main-
stay of therapy for several years to
come in patients with previously
treated disease,” Dr. Martin told
ASH Clinical News, explaining the
rationale for the trial. “The chal-
lenge is that BTK inhibitors don’t
work for everybody, or forever, with
most patients developing resis-
tance within 10 to 14 months.”
Earlier research demonstrated
that palbociclib induced prolonged
cell cycle arrest in MCL tumor cells;
based on these observations, the
investigators evaluated whether
treatment with palbociclib could
overcome ibrutinib resistance in a
cohort of 27 patients with previ-
ously treated MCL.
Patients were eligible if
they had MCL and no previous
treatment with BTK or CDK4/6
inhibitors. Their median age was
65 years (range = 42-81 years),
and the median number of prior
therapies was one (range = 1-5).
Participants received once-daily
ibrutinib plus palbociclib in one of
the five following schedules:
• level 1: ibrutinib 280 mg and
palbociclib 75 mg (n=3)
• level 2: ibrutinib 420 mg and
palbociclib 75 mg (n=3)
• level 3: ibrutinib 420 mg and
palbociclib 100 mg (n=6)
• level 4: ibrutinib 560 mg and
palbociclib 100 mg (n=10)
• level 5: ibrutinib 560 mg and
palbociclib 125 mg (n=5)
In each group, palbociclib was
administered for 21 days of each
28-day cycle.
The median number of treat-
ment cycles administered was 15
(range = 1-51), and nine patients
are still receiving treatment as of
study publication. The reasons for
study withdrawal included:
• disease progression (n=9)
• allogeneic hematopoietic cell
transplantation (n=4)
• cytopenia (n=2)
• elevated liver enzymes (n=1)
• patient refused further
treatment (n=1)
• death unrelated to study
treatment or MCL (n=1)
Level 4 (ibrutinib 560 mg and
palbociclib 100 mg) was identified
as the maximum tolerated dose of
the study drugs, after researchers
observed a dose-limiting toxicity
of grade 3 rash in two patients
enrolled in level 5. One additional
dose-limiting toxicity, grade 4 neu-
tropenia lasting longer than seven
days, occurred at dose level 3.
Cytopenias were the most com-
mon grade 3-4 adverse events
(AEs) observed in the entire
study cohort (neutropenia, 41%;
thrombocytopenia, 30%; anemia,
15%), followed by hypertension
and febrile neutropenia.
The authors also identified sev-
eral other “AEs of interest,” includ-
ing one each of the following: grade
1 reactivation of viral hepatitis,
grade 2 C. difficile infection, grade
3 varicella zoster viral encephalitis,
grade 3 influenza A infection, and
grade 3 atrial fibrillation.
Four patients across all dose
levels required treatment inter-
ruptions, and eight required dose
reductions, which the research-
ers noted were “mostly due to
cytopenias.”
Two-thirds (18) of the patients
(67%) had a partial response or
better to treatment. This included
10 patients who experienced a
complete response (37%).
Over a median follow-up of
25.6 months (range not report-
ed), the rate of progression-free
survival (PFS) and overall survival
at two years were 59.4 percent
and 60.6 percent, respectively.
The investigators found no
association between PFS and
disease severity (per Mantle Cell
International Prognostic Index
score; p=0.222), Ki67 prolifera-
tion (p=0.359), or response to
last therapy (p=0.262). Eleven
patient deaths occurred during
the study, most of which were
related to MCL (n=9).
The overall response rate was
similar to that reported in the
phase II pivotal trial of single-
agent ibrutinib, the authors
noted, adding, “Although BTK
inhibitor–based combinations
appear promising, the degree to
which they improve upon single-
agent ibrutinib is unclear.”
Limitations of this early-phase
study include its small patient co-
hort, the lack of randomization, and
the lack of a comparator control.
An ongoing phase II study is
evaluating the ibrutinib-palbociclib
combination at the maximum
tolerated dose identified in this
trial. This phase II trial incorporates
genetic profiling and functional
assays of gene and protein expres-
sion “to have a better understand-
ing of tumor- and patient-specific
factors to better tailor treatment
to individual patients.”
The authors report relationships
with Janssen and Pharmacyclics,
the manufacturers of ibrutinib.
REFERENCE
Martin P, Bartlett NL, Blum KA, et al. A phase I trial of
ibrutinib plus palbociclib in previously treated mantle cell
lymphoma. Blood. 2019 January 28. [Epub ahead of print]
PERSPECTIVES
Ibrutinib is one of two BTK inhibitors approved by the U.S. Food and Drug Administra-
tion and has become a standard treatment option for patients with relapsed/refractory
MCL, given its excellent single-agent activity and favorable toxicity profile. However, not
all patients with relapsed/refractory MCL derive significant clinical benefit, as approxi-
mately one-third of patients do not achieve a response to the drug, and most patients
experience disease progression within 10 to 18 months.
Combination strategies are being evaluated, including combinations with veneto-
clax, lenalidomide, and other targeted agents. As reported in this article, the combi-
nation of palbociclib, a CDK-4/6 inhibitor, with ibrutinib is appealing given previous
observations. MCL is a lymphoid cancer characterized by dysregulation of the cell cycle,
which can be inhibited by palbociclib’s ability to induce cell-cycle arrest.
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ASH Clinical News
While the molecular basis of ibrutinib resistance is unclear in MCL, palbociclib has
been shown to sensitize ibrutinib-resistant cell lines to ibrutinib. This phase I trial
demonstrated the safety of this combination and determined the recommended
phase II dose, but it remains unclear if the activity of this novel combination will be
superior to ibrutinib. A phase II study by the Alliance for Clinical Trials in Oncology is
under way to help answer this question.
The biologic rationale behind this novel doublet is compelling and hopefully clinicians
will have a new and active regimen in the near term.
John Kuruvilla, MD, FRCPC
Cancer Clinical Research Unit, Princess Margaret Cancer Centre
Toronto, ON
March 2019