Written in Blood
cohorts of lenalidomide and ibrutinib. No
dose-limiting toxicities were observed, so the
MTD of ibrutinib was set at 560 mg (dose
level 2).
Patients underwent positron emission
tomography and computed tomography
(CT) scans at enrollment and again at weeks
10, 24, and 52, after which patients underwent CT scans every four months for two
years, followed by every six months until
progression for 10 years. Bone marrow biopsies were also performed at enrollment and
again in patients who achieved complete
remission (CR) and had marrow involvement at baseline.
TABLE 3.
Dose Level Cohorts
Dose Level
Lenalidomide
Ibrutinib
Level 0 (n=3)
15 mg
420 mg
Level 1 (n=3)
15 mg
560 mg
Level 2 (n=16)
20 mg
560 mg
The most common grade 3 and 4 hematologic adverse event (AE) was neutropenia
(18%), while the most common grade 3 nonhematologic AEs were rash (36%), diarrhea
(5%), febrile neutropenia (5%), atrial flutter
(5%), and arthralgia (5%). Almost all patients
(n=18/22) developed a rash, with grade 1 or 2
rash occurring in 46 percent of patients, and
grade 3 occurring in 36 percent. Two patients
withdrew from the study due to persistent
rashes that occurred after cycle one.
Half of the patients (50%; n=11) from all
dose levels required dose reduction due to
AEs, including rash (n=7; 36%), neutropenia
(n=3; 14%), and thrombocytopenia (n=1;
5%). Six patients discontinued treatment due
to AEs, including grade 3 rash (n=2; 9%),
grade 3 atrial flutter (n=1; 5%), grade 3 diarrhea (n=1; 5%), hypertension (n=1; 5%), and
depression (n=1; 5%).
In addition, five patients reported new
malignancies.
Focusing on efficacy, the overall response
rate was 95%, with 36% of patients achieving
a complete response. The median time to first
response was 2.3 months (range = 1.9-11.1
months), and the median time to best response
was 5.5 months (range = 1.9-25.1 months).
See TABLE 4 for dose responses. After a median
follow-up of 19.2 months (range = 2.3-27.1
months), the 12-month progression-free
survival was 80 percent (95% CI 57-92). None
of the eight patients who discontinued therapy
early experienced FL progression.
The authors noted that responses were
independent of FLIPI score and bulky disease,
TABLE 4.
“further supporting the consideration of biologic regimens for the treatment of FL,” they
wrote.
The study is limited by its small patient
cohort, short median follow-up, and lack of
repeat bone marrow biopsies in some patients
to confirm CR.
However, given the toxicity profile, the
investigators did not recommend further
studies of the ibrutinib, lenalidomide, and
rituximab combination. “An improvement
in clinical benefit with the additional third
agent was not apparent,” the authors concluded. “While further investigation of the
triplet seems unwarranted in this setting, the
rituximab–lenalidomide combination remains
a promising option. Ibrutinib may have a place
in the relapsed setting as a single agent or in
combination with another biologic.”
REFERENCE
Ujjani CS, Jung SH, Pitcher B, et al. Phase I trial of rituximab, lenalidomide, and
ibrutinib in previously untreated follicular lymphoma: Alliance A051103. Blood.
2016 October 3. [Epub ahead of print]
Response Rates According to Dose Level (DL)
All patients
(n=22)
DL 0
(n=3)
DL 1
(n=3)
DL 2
(n=16)
Overall response rate
95%
100%
100%
94%
Complete response
36%
33%
33%
38%
Partial response
59%
67%
67%
56%
Stable disease
5%
0%
0%
6%
Response
Lenalidomide Plus Cyclophosphamide and
Prednisone: A Safe, Effective Option for
Lenalidomide-Refractory Multiple Myeloma
and corresponding author of the study, told
ASH Clinical News. “We think that REP is a
good treatment option when patients have
lenalidomide-refractory MM or doublerefractory MM (disease refractory to both
lenalidomide and bortezomib).”
Inger S. Nijhof, MD, also of the VU
University Medical Center, and authors
conducted this prospective, investigator-
generally well tolerated,” Niels W.C.J. van de
Patients with multiple myeloma (MM) who
Donk, MD, PhD, from VU University Mediare refractory to lenalidomide and bortezocal Center in Amsterdam, the Netherlands,
mib have limited treatment options and poor
outcomes, with a median
event-free survival of five
TABLE 5. Responses Treated at the Maximum-Tolerated Dose
months and an overall surLenalidomidePatients with highPatients treated with REP, directly folvival (OS) of nine months.
All patients
and bortezomibrisk cytogenetic
lowing the development of lenalidomideResults of a phase I/II study
(lenalidomiderefractory
abnormalities*
refractory disease (25 mg or equivalent in
evaluating lenalidomide
refractory; n=66) patients (n=42)
(n=24)
case of renal insufficiency; n=46)
plus cyclophosphamide and
Stringent complete
1.5%
0%
0%
0%
prednisone (REP) suggest
response (CR)
that this combination could
CR
3%
2.4%
0%
0%
be a safe, effective treatment
Very good partial
18.2%
21.4%
20.8%
15.2%
approach for patients with
response (VGPR)
lenalidomide-refractory
Partial response (PR)
44%
36.1%
45.9%
50%
MM.
Minimal response (MR)
16.6%
21.1%
16.6%
17.4%
“Double-refractory
Stable
disease
7.6%
9.5%
4.2%
10.9%
patients have a very poor
Progressive disease
9.1%
9.5%
12.5%
6.5%
outcome, but REP induces
a high response rate and a
≥VGPR
22.7%
23.8%
20.8%
15.2%
relatively long progression≥PR
66.7%
59.9%
66.7%
65.2%
free survival (PFS) in these
≥MR
83.3%
81%
83.3%
82.6%
patients. Furthermore, the
REP = lenalidomide plus continuous low-dose cyclophosphamide and prednisone
combination is fully orally
*
High-risk disease was defined by the presence of t(4;14), t(14;16), del(17p), and/or amp1(1q) as determined by fluorescence in situ
[administered] and was
hybridization on purified multiple myeloma cells before start of REP treatment.
40
ASH Clinical News
November 2016