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Rituximab Plus Lenalidomide Noninferior to
Chemotherapy in Treatment-Naïve Follicular Lymphoma
Treatment with the chemotherapy-free
combination of rituximab and the immuno-
modulatory agent lenalidomide (R2)
was noninferior to the combination of
rituximab and chemotherapy (R-chemo)
in patients with previously untreated
follicular lymphoma (FL), according to
results from a phase III trial published in
The New England Journal of Medicine.
Lead study author Franck Morsch-
hauser, MD, PhD, of the University of Lille
in France, told ASH Clinical News that these
results represent a landmark in this disease
setting. “There are multiple considerations
for patients when comparing the results for
first-line R2 with R-chemo plus rituximab
maintenance for both,” he said. While
each regimen was associated with different
safety profiles, “R2 provides an alternative
treatment option with a safety profile favor-
ing patients who are unable to tolerate or
unwilling to receive chemotherapy.”
The randomized, phase III RELEVANCE
(Rituximab Lenalidomide versus Any Chemo-
therapy) trial enrolled 1,030 patients with
histologically confirmed, CD20-positive
FL (grade 1 to 3a) who had not received
any prior systemic lymphoma treatment.
Participants were randomized 1:1 to
one of two treatment arms:
• R2: lenalidomide 20 mg/day plus
rituximab 375 mg/m² (n=513)
• R-chemo (control arm): rituximab
plus investigator choice of R-CHOP,
R-bendamustine, or R-CVP (n=517)
In the R2 arm, the lenalidomide dose was
lowered to 10 mg/day if patients achieved
a complete response (CR) following six
treatment cycles; patients who had a
partial response (PR) after six cycles
received lenalidomide 20 mg/day for
three or six additional treatment cycles
or until a confirmed or unconfirmed CR
(CRu) was achieved. Participants in each
arm received maintenance therapy with
rituximab 375 mg/m 2 every eight weeks
for 12 cycles.
Baseline characteristics were similar
between the R2 and R-chemo arms, with
a similar incidence of bulky disease (42%
and 38%), high-risk FL International
Prognostic Index score (49% and 48%),
and B symptoms (27% and 26%).
At a median follow-up of 37.9 months
(range not reported), there was no signifi-
cant difference between the two treatment
ASHClinicalNews.org
groups for either of the co-primary end-
points (assessed by independent review
committee):
• CR/CRu at 120 weeks: 48% (n=247)
for R2 vs. 53% (n=274) for R-chemo
(p=0.13)
• 3-year progression-free survival
(PFS): 77% vs. 78% (hazard ratio
[HR] = 1.10; 95% CI 0.85-1.43;
p=0.48)
The investigator-assessed rates were
similar:
• CR/CRu at 120 weeks: 55% (n=283)
vs. 58% (n=299; p=0.38)
• 3-year PFS: 77% vs. 78% (HR=0.94;
95% CI 0.73-1.22; p=0.63)
At the three-year interim analysis, rates
of overall survival also were the same
between the two groups: 94 percent for
R2 vs. 94 percent for R-chemo (HR=1.16;
95% CI 0.72-1.86; p value not reported).
The safety analysis included 507
patients in the R2 group and 503 in the R-
chemo group, most of whom experienced
at least one adverse event (AE; 99.8% and
99.0%, respectively). As Dr. Morschhauser
noted, the safety profiles differed between
the R2 and R-chemo groups: R2-treated
patients experienced lower rates of grade
3/4 neutropenia (32% vs. 50%), grade 3/4
febrile neutropenia (2% vs. 7%), grade 3/4
leukopenia (2% vs. 6%), and upper respi-
ratory tract infections (9% vs. 11%), while
R-chemo–treated patients had a higher
incidence of grade 3/4 cutaneous reactions
(7% vs. 1%; p values not reported).
The investigators noted that the dif-
ferences between lenalidomide-induced
neutropenia and chemotherapy-induced
neutropenia may be partly due to the bio-
logic differences of the regimens’ mecha-
nisms of action.
The authors added that “a higher
percentage of the patients in the [R2]
group than in the [R-chemo] group had
AEs that led to dose reduction (36% vs.
14%), dose interruption (59% vs. 35%),
or early discontinuation of trial treatment
(11% vs. 3%; p values not reported).” In
the R2 group, neutropenia was the most
common reason for dose reduction (20%)
and interruption (32%); neutropenia led to
discontinuation in 1 percent of patients.
The study’s findings are limited by
the follow-up time for time-to-event
endpoints; the authors noted that “longer
follow-up with more mature survival data
will be needed to assess long-term out-
comes.” The study was also unblinded.
further characterize potential biomark-
ers and the immune-based mechanisms
of action of R2 in patients, as well as
potential differences between arms for
other exploratory endpoints (e.g., mini-
mal residual disease status).”
“R2 provides an alternative
treatment option [for] patients who
are unable to tolerate or unwilling
to receive chemotherapy.”
—FRANCK MORSCHHAUSER, MD, PhD
“The RELEVANCE study is continu-
ing to collect progression and survival
data, as more mature data will be needed
to fully characterize the benefit-to-risk
profile of R2 versus R-chemo in this
setting,” Dr. Morschhauser noted. “Ad-
ditional analyses will be conducted to
The authors report financial relation-
ships with Celgene and LYSARC, which
supported the study.
REFERENCE
Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus
lenalidomide in advanced untreated follicular lymphoma. N Engl J Med.
2018;379:934-47.
Post-Transplant Gene
Mutations Predict Risk
for MDS Progression
Sequencing bone marrow samples early
after patients with myelodysplastic syn-
dromes (MDS) have undergone alloge-
neic hematopoietic cell transplantation
(AHCT) could help identify patients who
are at an increased risk of disease pro-
gression, according to findings published
in The New England Journal of Medicine.
In the exploratory study, led by Eric
Duncavage, MD, from the Washington
University School of Medicine in St.
Louis, patients who harbored at least
one persistent disease-associated muta-
tion 30 days after AHCT had higher
rates of progressive disease and lower
rates of progression-free survival (PFS)
at one year.
“Knowing this information may
provide an opportunity for earlier inter-
vention to delay or prevent progression
and also may identify patients who can
be recommended for more aggressive
monitoring,” coauthor Meagan Jacoby,
MD, PhD, also from the Washington
University School of Medicine, told ASH
Clinical News.
The study included 90 patients with a
history of MDS (including secondary or
therapy-related MDS) who underwent
AHCT at Washington University in St.
Louis between 2002 and 2015. Four pa-
tients were excluded because they did not
meet technical requirements for analysis,
leaving 86 patients in the primary analysis.
ASH Clinical News
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