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Role of CNS intrathecal prophylaxis in DLBCL
Table 3A. Studies reporting an efficacy analysis of stand-alone intrathecal prophylaxis in front line diffuse large B-cell lymphoma in rituximab era
Reference: author, journal, year
N
Data set: type and years
Post hoc
analysis of RICOVER-60 trial
Study inclusion
60-80 years with untreated ‘aggressive B-cell lymphoma’. 944 (81.6%) DLBCL. 1% PMBCL.
No age limit
defined; untreated
1st line R-chemotherapy
R-CHOP-14: 608 CHOP-14: 609.**
CNS Relapse
Total: 58/22R Isolated: 34/16R Concurrent: 24/6R
% receiving IT prophylaxis
22.4% (273/1222) ≥1 IT MTX. 16.6% (202/1222) 4 IT MTX
Median time to CNS relapse (range/95% CI
Cumulative incidence of CNS relapse (95% CI provided
Site of CNS relapse
11R parenchymal, 2R both; 9R leptomeningeal
Boehme et al., 1217 Blood
200930***
All patients: 8 months (range 1-39)
2-year:
4.1%
(95% CI 2.3-5.9%)R
givenasavailable) wherereported)
Evidence
of IT CNS prophylaxis effectiveness?
Overall
percentage
of CNS events:
IT MTX 2.5% vs. nil
4.4%; whole cohort.
A subgroup analysis of high risk
patients adjusted for IPI
found a significant interaction
between IT MTX exposure and
Rituximab exposure (RR = 6.1),
with the risk of CNS relapse
significantlyreduced if IT MTX
was given in CHOP group but
no difference in R-CHOP group. Effect of rituximab significant
CASP Score
3
Shimazu et al., Int J of Hematol 200931
Villa et al. Ann Oncol 200925***
Tai et al., Ann Hematol 20112
403
Retrospective
single center; 1996-2007
CHOP/
Total: 42/22R
4.7% (18/385)
IT prophylaxis
4% (12) IT prophylaxisR alternating IT MTX and ara-C
18% (59/320)
IT prophylaxisR
21.5 monthsR
6.7 monthsR
All patients:
1-year: 6.5% (95% CI: 6.0-7.14)
3-year: 6.4%R
32
parenchymal; 10 leptomeningeal
regardless of IT MTX.
Overall % of CNS
2
2
CHOP-like: 165 Isolated: 28/14R R-CHOP/ Concurrent: 14/8R
events 1/18 (5.6%)
IT prophylaxis vs. 40/367 (10.9%)fornil.
Use of IT prophylaxis did not appear significantly decrease CNS relapse
in logistic regression UVA (P=0.478) or MVA (P=0.571).
denovoDLBCL R-CHOP-like:338 or transformed
indolent NHL
435 Retrospective, single
center; 1999-2005
CHOP: 126 R-CHOP: 309
Total: 31/19 R Isolated: 18/15R Concurrent: 13/4R (including 4/3R) post- systemic
Total: 30/20R
Isolated: N/R Concurrent: N/R
Overall % of CNS
events: CHOP cohort,
3/8 (37.5%)
IT prophylaxis vs.
9/118 (7.6%) for nil. R-CHOP cohort,
0/12 (0%) IT prophylaxis
vs. 19/297 (6.5%) (7.6%) for nil. Use of IT prophylaxis did not appear to decrease CNS relapse on UVA (P=0.364, R-CHOP cohort) not included in MVA (P>0.1 in UVA)
499 Retrospective,
single center; 2000-2008
No age limit
defined; untreated DLBCL
CHOP: 179
R-CHOP: 320
All patients:
6.7 months (range 1.9-45.2) 2-year: 6.0% (95% CI: 3.8-9.4)R
N/R
Overall % of CNS events 2
(all patients): 9/82 (11.0%) IT prophylaxis vs. 21/417(5.0%) for nil. Use of IT prophylaxis did not appear to decrease CNS relapse on UVA (P=0.032; higher in
those receiving IT prophylaxis, or P=0.98, high risk only). For all patients,
MVA non-significant (P-value not reported), unclear if IT prophylaxis was included in R-CHOP only MVA.
Only factors with P<0.1 in UVA included in MVA. No IPI-adjusted analysis.
≥16 years
with advanced stage or any stage DLBCL or PMBCL with testicular involvement
12R parenchymal; 4R both;
3R leptomeningeal
*two patients received high dose methotrexate. **five CNS involvement at diagnosis excluded. R = in RCHOP subgroup. ***studies added after initial and post-systematic review scoping. NCCN: National Comprehensive Cancer Network; CNS: central nervous system; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; RDA-EPOCH: rituximab plus dose adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin; O-CHOP: obinutuzumab, cyclophosphamide, doxorubicin, vincristine, prednisolone DLBCL: diffuse large B-cell lymphoma; NHL: non-Hodgkin lymphoma; ASCT: autol- ogous stem cell transplantation; HGT: high grade transformation; CLL: chronic lymphocytic leukaemia; FL: follicular lymphoma; GZ: gray zone; CR1: first complete remission; PMBCL: primary mediastinal B-cell lym- phoma; IPI: international prognostic index; IT: intrathecal; MTX: methotrexate; HD: high dose; ara-C: cytarabine; HC: hydrocortisone; HR: hazard ratio; CI: confidence interval; UVA: univariable analysis; MVA: multivari- able; N/R: not reported; IQR: interquartile range; RR: risk ratio; OS: overall survival; PFS: progression-free survival.
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