Supplemental Table 1: Conventional therapy * = sentinel articles
Aggressive therapy
*
*
Publication
Intervention
Population
assessed
Type of
study
Dosing and schedule
Outcomes
assessed
Results
Comments
Delarue, et al,
Blood prepublished
online June 20,
2012
CHOP and DHAP plus R
f/b autologous SCT
Stage III-IV MCL
Phase II
3 cycles CHOP every 21 d, R 375mg/m2 with
third cycle, f/b 3 cycles R-DHAP every 21 d,
responders received PBSCT harvest,
radiochemotherapy with TBI and HD
cytarabine and melphalan f/b autologous
SCT
EFS, 5 y OS
60 patients, ORR 95% 5y, median EFS 83.9m, prob of 5y
EFS 64%, median DFS 78m, PFS 84m, median OS not
reached, OS 75%. 49 patients underwent SCT. Of patients
who underwent SCT, 96% had CR
Cytarabine-based therapy has high RR.
Improved EFS vs other studies without R,
excluded patients with high mitotic count,
11 secondary malignancies likely due to
MCL rather than therapy
Hermine, et al, ASH
annual meeting
abstracts 2010
116: #110
CHOP vs CHOP and
DHAP plus R f/b HD
ara-c myeloablative
chemo and autologous
SCT
Previously
untreated stage
II-IV MCL up to
65 yoa
Phase III
Standard R-CHOP x6 f/b myeloablative
radiochemotherapy and ASCT (arm A) vs
alternating CHOP x3 and DHAP x3 + R f/b
high dose ARA-C myeloablation and ASCT
(arm B)
CR, DR, TTF,
3y OS
497 patients, CR/Cru 41% arm A vs 60% arm B (p=0.0003),
OR after transplant 97% in both arms, TTF 49m arm A vs
NR arm B (p=0.0384), RD after ASCT 51m arm A vs NR arm
(p=0.077), 3y OS 79% arm A vs 80% arm B
DHAP led to improved CR, DR, TTF,
equivalent OS. Authors recommend ara-c
induction f/b ASCT as new SOC in patients
<65 yoa, increased grade 3/4 hematologic
toxicity in arm B not clinically relevant
LaCasce, et al ASH
annual meeting
abstracts 2009
114: #403
R-CHOP f/b HD
therapy and ASCT vs RhyperCVAD vs RCHOP
alone
Previously
untreated MCL
Phase III
3y PFS, OS
156 patients, no difference in PFS between R-hyper-CVAD
and R-CHOP f/b ASCT. R-CHOP alone had poorer PFS than
both other arms (p=0.001). no differences in OS. Median
PFS 3 years
Authors recommend focusing on novel
agents for future trials
Romaguera et al,
Br J Haematol 2010
15:200-208;
Romatuera et al,
JCO 2005 23(28)
7013-7023
R-hyperCVAD
(rituximab,
cyclophosphamide,
vincristine,
doxorubicin,
dexamethasone),
alternating with R-MA
(HD methotrexate and
cytarabine)
Previously
untreated MCL
Phase II
Cycles 1, 3, 5, 7 rituximab 375mg/m2,
cyclophosphamide 300mg/m2 IV q12h x6 d24, doxorubicin 16.6mg/m2 IVCI 72h d 5-7,
vincristine 1.4mg/m2 IV d5 and 12,
dexamethasone 40mg d 2-5 and d12-15,
cycles 2, 4, 6, 8 rituximab 375mg/m2 d1,
methotrexate 200mg/m2 IV d2,
methotrexate800mg/m2 IVCI 22h d2,
cytarabine 3000 mg/m2 q12h x4 d3-4
Median OS,
TTF
10 year f/u. 97 patients, 87% CR, median OS not reached,
median TTF 4.6y,
Beta2 microglobulin, IPI, MIPI were
predictive of OS, Ki-67 was not predictive.
Significantly worse OS and TTF if age >65,
increase hematologic toxicity with age
Lenz, et al, JCO
2005 23(9), 19841992
CHOP vs R-CHOP,
randomized to
myeloablative chemo
f/b autologous SCT vs
IFN maintenance
Previously
untreated MCL
Phase III
Standard CHOP every 21 d +/- rituximab
375mg/m2 on day 0
ORR, CR,
TTF
122 patients, ORR 94% R-CHOP vs 75% CHOP (p=0.0054),
CRR 34% vs 7% (p=0.00024), TTF 21m vs 14m (p=0.0131),
no difference between auto SCT and IFN maintenance
groups
Defines R-CHOP as superior to CHOP in
MCL
Dreyling et al,
Blood 2005 107(7):
2677
Myeloablative
radiochemotherapy
f/b auto SCT in first
remisison
Previously
untreated MCL
Phase III
CHOP fb either IFN-alpha or myeloablative
radiochemotherapy and auto SCT
PFS, 3y OS
122 patients, ASCT arm had longer PFS 39m vs 17m
(p=0.0108). 3y OS 83% ASCT vs 77% IFN (p=0.18)
Shea, et al, Biol
Blood Marrow
Transplant, 2011
17(9):1395-1403
Reduced intensity
allogeneic SCT
Advanced
indolent B cell
malignancies
Phase II
Cyclosphosphamide 1g/m2/d d1-3,
fludarabine 25mg/m2/d x5, allogeneic SCT
EFS, OS
44 patients, 4 with MCL. 6m TRM 2.4%, 3y TRM 9%. 3y
EFS and OS in MCL and indolent B cell patients were 55%
and 64%,
Grade II-IV aGVHD 29%, extensive chronic
GVHD 18%
Elderly/nontransplan
t eligible
Robinson, et al,
JCO 2008
26(27):4473-4479
Bendamustine + R
R/R indolent Bcell and MCL NHL
Phase II
Rituximab 375mg/m2 d1, bendamustine
90mg/m2 d2, 3 of 28d cycle for 4-6 cycles
with R one week before cycle 1 and 1m after
last cycle
ORR, DR,
PFS
12 patients with MCL ORR 92%, median DR 19m
36% grade 3 or 4 neutropenia, 9% grade 3
or 4 thrombocytopenia, good ORR even in
patients with prior R exposure
*
Rummel et al,
ASCO annual
meeting abstract
2012: #3; Rummel
et al, ASH annual
abstract 2009, 114:
#405
Bendamustine + R vs
R-CHOP
Upfront indolent
and MCL
Phase III
Rituximab 375mg/m2 d1 plus either
bendamustine 90mg/m2 days 1, 2 every 28
days or standard CHOP every 21d, max 6
cycles
PFS, OS
514 patients, B-R improved PFS vs R-CHOP, median 69.5m
vs 31.2m (p<0.001), no difference in OS between two
groups
Less toxicity in B-R than R-CHOP,
equivalent secondary malignancies in two
groups
Forstpointner, et
al, Blood 2006 108:
4003-4008
FCM +/-R +/maintenance rituximab
R/R Follicular and
MCL
Phase III
R maintenance 375mg/m2 weekly for 4
weeks, two courses of R at 3 and 9 months
after completion of R-FCM
DR
26m f/u, 319 patients, 56 with MCL. In MCL group no
improvement in DR, but increase percentage with
prolonged remission
Consider in patients with good response to
R with induction
Kluin-Nelemans
ASH annual
meeting abstracts
2011 118: #439
R-CHOP vs R-FC f/b
maintenance R vs IFNalpha
Elderly MCL, not
transplant
eligible
Phase III
Standard R-CHOP x8 cycles vs R-FC
(rituximab 375mg/m2 d1, fludarabine
30mg/m2, cyclophosphamide 250mg/m2 IV
both day 1-3) x6 cycles, responders received
maintenance R one dose q2m vs IFN-alpha
until progression
PRR, OS, DR
560 patients, median age 70y, ORR lower with R-FC 78%
vs 87% (p=0.0508), median OS inferior with R-FC (40vs
64m p=0.0072). increased DR with MR vs IFN (4y 57% vs
26%, p=0.0109), significant OS advantage in R-CHOP with
MR vs IFN (4y OS 87% vs 57%, p=0.0061)
Worse outcomes with worse toxicity in RFC vs R-CHOP. Authors recommend RCHOP with R maintenance as new SOC in
elderly
Kahl et al, Ann
Oncol 2006,
17:1418-1423
Maintenance R
following modified
hyperCVAD
Mostly stage IV,
previously
untreated MCL
Phase II
Rituximab 375mg/m2 d1 (except cycle 1),
cyclophosphamide 300mg/m2 q12 d1-3,
doxorubicin 25mg/m2/d d1-2, vincristine
2mg IV d3, dexamethasone 40mg po d 1-4,
every 28d for 4-6 cycles. Responders
received rituximab 375mg/m2 weekly x4
every 6m for 2 years
OR
22 patients, OR 77%, CR 64%, median PFS 37m, median
OS not reached
Study authors eliminated second dose of
vincristine/dexamethasone due to
toxicity/deaths
*
Kluin-Nelemans, et
al, NEJM 2012
R-FC or R-CHOP, with
either R maintenance
or IFN-alpha
MCL age >/=60,
ineligible for high
dose therapy
Phase III
R-FC every 28 days up to 6 cycles, or R-CHOP
every 21 days up to 8 cycles,
532 in intention-to-treat analysis. Similar CR for R-FC and
R-CHOP (40% vs 34%), increased PD with R-FC (14% vs
5%). OS better with RCHOP (62% 4yr OS vs 47% p=0.005),
316 received maintenance R, RRR of progression or death
of 45% (p=0.01), maintenance R improved OS in R-CHOP
group (4yr OS 87% vs 63% with IFN-alpha p=0.005)
Equivalent grade 3-4 hematologic toxicity.
In elderly, R-CHOP f/b maintenance R is
effective.
*
Chang et al, Br J
Haematol 2011
155(2): 190-197;
Kahl et al, ASH
annual abstract
2009 114: #1661
Modified R-hyperCVAD
with bortezomib with
maintenance rituximab
Previously
untreated MCL
Phase II
VcR-CVAD (bortezomib, rituimab,
cyclophosphamide, vincristine, doxorubicin,
dexamethasone) every 21d for 6 cycles, if PR,
consolidation R 375mg/m2 x4 weekly doses
and maintenance R, 375mg/m2 every 12
weeks x20 doses
OR, CR, 3y
PFS and OS
30 patients, 77% with CR, median f/u 42m, 3y PFS 63%, 3y
OS 86%
E1405 cooperative group trial is ongoing
with same regimen
Martin, et al, JCO
2009 27(8):120913
Watch and wait
MCL
Retrosp
ective
analysis
n/a
Survival
97 patients, 31 in observation arm, median TTFT 12m,
median survival not reached in obs arm vs 64m in
treatment arm (p=0.004), obs patients had better PS,
lower standard IPI
Forstpointner, et
al, Blood, 2004
R-FCM (rituximab,
fludarabine,
R/R follicular and
mantle cell
Phase III
Fludarabine 25mg/m2 on d 1-3,
cyclophosphamide 200mg/m2 d1-3,
CR, OS
147 patients, 52 with MCL. Median obs time 18m, ORR
58% in MCL with R-FCM vs 46% with FCM, median PFS 8m
*
Relapsed/refractory
104(10):3064
cyclophosphamide,
mitoxantrone)
lymphoma in
patients who had
received CHOP
Cohen, et al,
Leukemia and
Lymphoma, 2001
42(5) 1015-1022
Cyclophosfamide/fluda
rabine
Inwards, et al,
Cancer 2008
113(1):108-116
Cladribine +/- R
Newly diagnosed
or R/R MCL,
older patients
Rummel et al, Ann
Oncol 1999
10:115-117
2-CDA alone
Newly diagnosed
or R/R MCL
Herold J, et al
Cancer Res Clin
Oncol 2006
132:105-112
Bendamustine,
vincristine and
prednisone vs
cyclophosphamide,
vincristine and
prednisone
Adavanced
indolent NHL and
MCL
mitoxantrone 8mg/m2 d1 of 28d cycle for 4
cycles with or without rituximab 375mg/m2
on d0
Two
phase II
studies,
coalesc
ed data
2-CDA 5mg/m2 IV d1-5 every 28d,
for R-FCM vs 4m FCM, median OS not reached for R-FCM,
was 11m for FCM
RR, PFS, 2y
OS
51 received 2-CDA alone: ORR 81%, median PFS 13.5m, 2y
OS 81%. 29 received 2-CDA +R: ORR 66%, median DR not
achieved, median f/u 21.5m
Well-tolerated, may increase difficulty of
SCT harvest
ORR 58%
Phase III
Vincristine 2mg d1, prednisone 100mg/m2
d1-5 with either bendamustine 60mg/m2 d15 or cyclophosphamide 400mg/m2 d1-5 in
21d cycles x8
TTP, PFS, 5y
OS
5y OS 61% BOP vs 46% COP, in responders 74% vs 56%
(p=0.05)
BOP = improved 5 y survival, can be used in
younger population, similar toxicity profile
with BOP and COP