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2014 123: 2905-2906
doi:10.1182/blood-2014-03-562124
Indolent and mantle cell NHL: the future is BRIGHT
Nathan Fowler
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l l l CLINICAL TRIALS & OBSERVATIONS
Comment on Flinn et al, page 2944
Indolent and mantle cell
NHL:
the future is BRIGHT
----------------------------------------------------------------------------------------------------Nathan Fowler1
1
MD ANDERSON CANCER CENTER
In this issue of Blood, Flinn et al report a phase 3 study demonstrating
similar complete response rates with bendamustine and rituximab compared
with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone
(R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone
(R-CVP) in untreated indolent and mantle cell lymphomas.1
T
he treatment landscape for patients with
newly diagnosed indolent non-Hodgkins
lymphoma (NHL) and mantle cell lymphoma
(MCL) is changing rapidly. The identification
of drugable biologic targets and rediscovery
and integration of existing agents into effective
combination regimens have resulted in
significant clinical improvements over the last
several decades. These advances, coupled with
improved supportive care techniques, have led
to a progressive lengthening of the expected
survival of patients with newly diagnosed
indolent lymphoma.2
Bendamustine, a bifunctional alkylator,
was first developed in east Germany 50 years
ago as a potentially more effective and less
toxic nitrogen mustard. Over the ensuing
decades, the drug was explored in several
phase 2 studies in patients with both solid
tumors and hematalogic malignancies,
mainly in Germany. Recent preclinical
studies demonstrated that bendamustine had
a unique mechanism of action capable of
inducing rapid and durable DNA damage,
inhibiting DNA repair, and inducing mitotic
catastrophe.3
Despite promising results, the agent
remained in relative obscurity until recent
larger phase 2 European and North American
trials showed significant activity in relapsed
NHL and chronic lymphocytic leukemia. In
2 single agent phase 2 studies, bendamustine
induced overall responses of 75% to 77% in
patients with rituximab-refractory indolent
NHL.4,5 Combining bendamustine with
rituximab, Robinson et al reported overall and
complete response rates of 92% and 41%,
respectively, in patients with relapsed indolent
NHL and MCL.6 In 2008, bendamustine was
approved in the United States for relapsed
indolent NHL and chronic lymphocytic
leukemia.
Table. Select clinical outcomes and adverse events reported with BR compared with R-CHOP/
R-CVP in untreated patients with indolent and mantle cell lymphoma
Efficacy
BR
R-CHOP/R-CVP
Overall response rate
97%
91%
Complete response
31%
25%
Partial pesponse
65%
66%
Toxicity
BR
R-CHOP
R-CVP
63%
58%
39%
Opportunistic infection
10-12%
7%
9%
Rash
20-24%
12%
16%
Nausea
Neuropathy
9-14%
44%
47%
3-4%
51%
21%
Neutropenia (Gr31)
39-49%
87%
56%
Lymphopenia (Gr31)
61-63%
33%
28%
5-10%
12%
2%
Alopecia
Platelets (Gr31)
Adapted from Tables 2 and 4 in the article by Flinn et al that begins on page 2944.
BLOOD, 8 MAY 2014 x VOLUME 123, NUMBER 19
On the basis of these and earlier studies, the
German Study Group, Indolent Lymphoma
(STiL), launched a phase 3 noninferiority trial
to determine whether 6 cycles of bendamustine
and rituximab (BR) were equivalent to one of
the more common standards for frontline
treatment of indolent NHL: 6 cycles of
R-CHOP. Entry criteria included untreated
advanced stage disease requiring therapy (rapid
progression, disease related symptoms, bulk,
or threatened organ function). The study
enrolled 514 subjects between 2003 and
2008, randomizing patients 1:1 to each
arm. Although the study was designed as a
noninferiority trial, at a median follow-up
of 45 months, the median progression-free
survival was significantly longer in the BR arm
(69.5 vs 31.2 months; P , .0001).7 Treatment
with BR was associated with a higher complete
response rate, and overall response rates were
similar between the 2 groups. Fewer serious
adverse events were reported in the BR arm
compared with R-CHOP (19% vs 29%).
Neutropenia, leukopenia, and serious
infections were also less common following
bendamustine.
Flinn and colleagues present the data of
a follow-up/validation phase 3 clinical trial
comparing bendamustine and rituximab
with R-CHOP or R-CVP in patients with
untreated indolent NHL or MCL. During
screening, investigators preassigned patients
to R-CHOP or R-CVP based on clinical
condition and disease presentation. The
primary objective of the trial was to
demonstrate noninferiority of BR compared
with R-CHOP/R-CVP with regard to
complete response rate. Entry criteria were
similar to the German STiL trial and included
only patients with advanced stage disease and
a requirement to initiate therapy. Patients with
indolent NHL and MCL were randomized to
receive 6 cycles of BR (n 5 224) or R-CHOP/
R-CVP (n 5 223; 2 additional cycles were
allowed at investigator’s discretion). Responses
were assessed by study investigators and
a blinded independent review committee.
In the evaluable population, the reported
complete response rate was similar between
BR and R-CHOP/R-CVP (31% vs 25%,
respectively, P 5 .0225 for noninferiority).1
Complete response rates in the 134 evaluable
patients with MCL were higher in the BR arm
(50% vs 27%, respectively). The toxicity
profiles were unique and differed between
treatment arms (see table). BR was associated
2905
From www.bloodjournal.org by guest on December 4, 2014. For personal use only.
with a higher rate of significant lymphopenia,
whereas R-CHOP/R-CVP was associated with
increased neutropenia. BR was also associated
with a slightly increased risk of opportunistic
infections and nausea but decreased
neuropathy and alopecia compared with
R-CHOP/R-CVP. Follow-up is ongoing, and
progression-free survival/overall survival data
were not reported.
This report by Flinn et al confirms that the
future of therapy for indolent NHL and MCL
is increasingly bright, and bendamustine and
rituximab are effective agents adding to the
armamentarium of resources for patients with
untreated disease. However, the potential
superiority of a given combination will not
be evident without longer follow-up and
a comparison of progression-free survival,
overall survival, and the incidence of long-term
toxicities. Although complete and overall
response rates were similar between
combinations, each regimen was associated
with its own unique toxicity profile.
Furthermore, differences between the German
StiL study and the current report possibly stem
from differences in toxicity reporting and the
use of an independent review committee.
While we wait for the next report, the
management of symptomatic indolent NHL
and most MCLs should remain individualized,
with continued emphasis on trial entry and
management decisions based on close attention
to comorbidities, cost, tolerability, and goals
of therapy.
Conflict-of-interest disclosure: The author declares
no competing financial interests. n
in patients with relapsed indolent B-cell and mantle cell
non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(27):
4473-4479.
7. Rummel MJ, Niederle N, Maschmeyer G, et al; Study
group indolent Lymphomas (StiL). Bendamustine plus
rituximab versus CHOP plus rituximab as first-line
treatment for patients with indolent and mantle-cell
lymphomas: an open-label, multicentre, randomised,
phase 3 non-inferiority trial. Lancet. 2013;381(9873):
1203-1210.
© 2014 by The American Society of Hematology
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on Middeke et al, page 2960
Abnl(17p) in AML: who will
guard
the guardian?
----------------------------------------------------------------------------------------------------Minoo Battiwalla1
1
NATIONAL INSTITUTES OF HEALTH
In this issue of Blood, Middeke and colleagues highlight the poor outcome of the
abnormal (17p) [abnl(17p)] subgroup of cytogenetically adverse-risk acute myeloid
leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT).1
M
etaphase cytogenetics at the diagnosis
of AML is routinely used to establish
favorable, intermediate, and unfavorable
prognostic categories. Unfavorable-risk
cytogenetics is a standard indication for HSCT
in first complete remission (CR1) for subjects
with an available donor. Further dissection
of the impact of individual cytogenetic
abnormalities within the unfavorable-risk
group is ongoing by retrospective analyses of
registry studies. Eventually, it will be possible
to identify patients who would unequivocally
REFERENCES
1. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized
trial of bendamustine-rituximab or R-CHOP/R-CVP in
first-line treatment of indolent NHL or MCL: the
BRIGHT study. Blood 2014;123(19):2944-2952.
2. Rodriguez MA, Walters RS, Burke TW. Indolent B-cell
Non-Hodgkin lymphomas. In: Sixty Years of Survival
Outcomes at The University of Texas MD Anderson Cancer
Center. Springer, New York; 2013:241-250.
3. Leoni LM, Hartley JA. Mechanism of action: the
unique pattern of bendamustine-induced cytotoxicity.
Semin Hematol. 2011;48(Suppl 1):S12-S23.
4. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine
is effective therapy in patients with rituximab-refractory,
indolent B-cell non-Hodgkin lymphoma: results from
a Multicenter Study. Cancer. 2010;116(1):106-114.
5. Friedberg JW, Cohen P, Chen L, et al. Bendamustine
in patients with rituximab-refractory indolent and
transformed non-Hodgkin’s lymphoma: results from
a phase II multicenter, single-agent study. J Clin Oncol.
2008;26(2):204-210.
6. Robinson KS, Williams ME, van der Jagt RH, et al.
Phase II multicenter study of bendamustine plus rituximab
2906
Schema for the physiological role of the p53 network in promoting genetic stability. WT p53 is normally targeted for
proteasomal degradation by mdm2 but accumulates in states of cellular stress or damage. p53 transcriptionally
regulates numerous target genes (including p21) as well as interacts directly with other proteins to either quarantine the
cell for repair or condemn it to die. Professional illustration by Marie Dauenheimer.
BLOOD, 8 MAY 2014 x VOLUME 123, NUMBER 19