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Role of CNS intrathecal prophylaxis in DLBCL
Table 3C. 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
Cai et al Chin j Cancer 201634
N
511
Data set: type and years
Retrospective, single center; 2003-2012
Study inclusion
≥18 years with newly diagnosed DLBCL
1st line R-chemotherapy
CHOP: 135 R-CHOP: 376
≥1 cycle R-CHOP R-CHOP-like or (100%)
R-CHOP-14 or 21 (100%)
≥2 cycles R-DA-EPOCH. No ASCT
CNS Relapse
Total: 25/14R Isolated: N/R
% receiving IT prophylaxis
11.8%R
Median time
to CNS
relapse
(range/95% CI
given as
available)
6.5 months R
15 months
175 (17.8%)
overall: *163 IT (95% CI: 1.0-15.1)
(44/373 Concurrent:N/R (3unknown)):
Cumulative
incidence
of CNS
relapse
(95% CI provided
where reported)
3-year: 4.9%. 3-year: 2.7%R
5-year:
8.4% (95% CI: 5.6-12.4%)
6.5 year: 1.9%
Not reported;
Site of CNS relapse
Not reported
Evidence CASP of IT Score CNS
prophylaxis effectiveness?
3-year risk in IT 2 prophylaxis vs. nil:
6.5%vs.1.8%(P=0.083)R. IT prophylaxis not associated with CNS relapse on MVA (P-value not reported).
Kanemasa et al. 413 Ann Hematol
201628
Retrospective, No age limit
single center; defined;
Total: 27
Isolated: 16 Concurrent: 11
Total: 21 Isolated: 11 Concurrent: 10
Total: 13
Isolated: 13 Concurrent: 0
Total: 61 Isolated: 47 Concurrent: 14
Total: 38
Isolated: N/R Concurrent: N/R
IT MTX and ara-C for each cycle of R-CHOP
15.0% ≥1 IT MTX +/-ara-C prophylaxis
9 parenchymal;
2 both;
16 on UVA (HR 0.85, range
leptomeningeal (0.29–2.45) P=0.76). No IPI-adjusted analysis
or MVA performed.
17 parenchymal; Adjusting for CNS-IPI, 2
IT prophylaxis no 2
protective effect
2004-2015
Post hoc
untreated de novo DLBCL
Gleeson et al. Ann Oncol 201727
Malecek et al. Am J Hematol 201726
984
223
≥18 years with untreated bulky stage I or stage II–IV DLBCL
8.1 months
analysis of R-CHOP-14 vs. 21 trial; 2005-2008
MTX (16.6%);
11 unknown;
1 IT ara-C and MTX
4 leptomeningeal
4 parenchymal;
no demonstrated benefit (HR=1.12; 95% CI, 0.40-3.14; p=0.83)
In all patients; 2
Retrospective, ≥18 years,
38.6% (86/223)
(IT MTX 83; IT ara-C 2; ITMTXand ara-C 1)
10.9% IT prophylaxis. 11.8%R.
8 HDMTX or ara-C overall.
9.9%
(140/1418) IT prophylaxis (either MTX, ara-C or both)
10 months
(range 2.1–27.0)
8.4 months (IQR 5.9–12.2)
8.5 months
(range 0.9-43.5)
multi-center; 2004-2014
(CLL or FL), GZ NHL, PMBCL.
5.8% rate of CNS
relapse in both ITprophylaxis
and no prophylaxis
groups (P>0.99). Subgroup (n=139) non-HIV DLBCL: 7 (5%) CNS relapse; no difference in risk for prophylaxis vs. nil (P=0.699), no factors significant in MVA (assuming this included IT prophylaxis).
untreated
de novo DLBCL ortransformed consolidation
overall rate: 5.8% 1 both;
5 leptomeningeal;
(100%)
R-CHOP
or RCHOP-like: 663 CHOP-like: 1371
≥18 years, untreated
de novo DLBCL; IPI ≥2 or IPI 1 if ≤60 years or IPI 0 if bulk
3unknown
23 parenchymal;
Wudhikarn et al.2034 Ann Hematol
201735
≥15 years with untreated DLBCL; ≥1 cycle of CHOP-like
2-year: 2.7%
IT prophylaxis no 2 protective effect on
UVA (HR 3.5, range 1.98–6.06, P<0.001) higher in those receiving IT prophylaxis).
This remained the case in MVA (P<0.001, no effect size given).
2-year CNS relapse 3
Retrospective, nationwide multi-center; 2006-2013
(95% CI 2.0-3.5%) 7 both; 25
2-year: 2.8%
leptomeningeal; unknown; 6
Klanova et al. Blood 201924***
1418
Post hoc
O-CHOP: 706
R-CHOP: 712
27
parenchymal;
3 both;
6 leptomeningeal; 1 intraocular; unknown; 1
analysis
of GOYA trial
rate no different between IT vs. no
IT prophylaxis: overall
(2.8% vs. 2.6%)
and according to CNS-IPI. No formal MVA including IT prophylaxis performed.
*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, pred- nisolone, vincristine, cyclophosphamide, doxorubicin; O-CHOP: obinutuzumab, cyclophosphamide, doxorubicin, vincristine, prednisolone DLBCL: diffuse large B-cell lymphoma; NHL: non-Hodgkin lym- phoma;ASCT:autologous 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 lymphoma; IPI: international prognostic index; IT: intrathecal; MTX: methotrexate; HD: high dose; ara-C: cytarabine; HC: hydrocortisone; HR: hazard ratio; CI: confidence interval; UVA: uni- variable analysis; MVA: multivariable; N/R: not reported; IQR: interquartile range; RR: risk ratio; OS: overall survival; PFS: progression-free survival.
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