Lymphomas
affecting the CNS
Michele Ghielmini
Oncology Institute of Southern Switzerland
Ospedale San Giovanni - 6500 Bellinzona, Switzerland
Conflicts of interest
Astra Zeneca
Roche
Cellgene
Mundipharma
Janssen
Gilead
Bayer
Abbvie
Prognosis of extranodal lymphomas
in the IELSG series
The clinical peculiarities
of CNS lymphomas
• Radiotherapy to CNS is particularly toxic
• CNS is a drug sanctuary
Neurotoxicity
• As disabling as lymphoma itself (dementia,
ataxia, incontinence in 40% and related
mortality of 30%).
• More common in elderly pts treated with
HD-MTX + WBRT.
Chemotherapy and CNS
BBB: Blood-Brain Barrier
BBB
penetration
Doses CNS
availability
Examples
Good conventional good steroids,
alkylating ag.
Low to
moderate
high good MTX, araC
Poor conventional
(-limiting tox)
low anthracyclines,
vinca-alkaloids
HD-MTX
Pharmacokinetics Triphasic plasmatic clearance
Good BBB penetration at HD
Schedule Infusion duration
Infusion timing
Dose
3 hours
every 2wks = 3wks
≥ 3 g/m2
CNS avalability ≥ 1 g/m2 tumoricidal levels in the brain
≥ 3 g/m2 tumoricidal levels in the CSF
24-hr inf. NO tumoricidal levels in CSF
Tolerability 8 g/m2
3.5 g/m2
45% dose reduct.
good compromise
Ferreri AJM. Blood 2011
Therapeutic Strategies
for PCNSL
Reni M, et al. Ann Oncol 1997
Overall survival
History: the MSKCC scheme
Year 2000: «The next step»
Cases: n=57
23<60y
34>60y
Schedule:
MTX 3.5g/m2 qd 2wks x 5
+ VCR and procarbazine
+ it MTX
+ RT 45 Gy (only if age<60)
+ HD-AraC x 2
10 years follow-up
Gavrilovic at al, JCO 2006
MTX 3.5 g/m2 , d1
(x 4 c., every 3 weeks)
Histological or cytological diagnosis of NHLDisease exclusively localized in the CNS
At least one measurable lesionAge 18 - 75 ys - ECOG-PS 3
MTX 3.5 g/m2 , d1
araC 2 g/m2 x 2/d, d2-3(x 4 c., every 3 weeks)
Followed by WBRT
IELSG #20: Survival Curves
n = 80
Median f-up: 30 months
0
20
40
60
80
100
0 12 24 36 48 60 72
months
Pro
bab
ilit
y O
S
Median f-up: 46 months
MTX
MTX-araC
24 ± 8%
45 ± 8%
p= 0.05
Ferreri AJM, et al. The Lancet 2009
Rituximab against PCNSL
5-7 c. of rituximab 500 mg/m2 + MPV regimen OR-tailored WBRT araC 3 g/m2 x 2
Hystorical comparison
N° Age PS G3-4 tox ORR CRR 2-yr PFS 2-yr OS
MPV 52 65 70 59%-20% 90% 56% 66% 72%
R-MPV 30 57 70 50%-28% 93% 78% 57% 67%
Shah GD, et al. JCO 2007
The role of RT: PCNSL-G1 trial
MTX 4 g/m2 d 1 (max. 6x) (+ IFO 1.5 g/m2 d 3-5)
CR
WBI WBI at relapse WBI AraC 3 g/m2 x 2/d
d 1-2 (max. 4x)
Random
WBI or no WBI
437 pts
Thiel et al, lancet Oncol. 2010
No CR
G-PCNSL-SG-1 trial: results
Thiel et al, lancet Oncol. 2010
PCNSL [≤ 65 ys. + PS 0-3] or [65-70 ys. + PS ≤2]
®
®
WBRT 36 Gy
± boost 9 Gy
BCNU 400 mg/m2 d.1
Thiotepa 5 mg/Kg x 2/d; d.2-3
+ APBSCT
4 c. MTX 3.5 g/m2 d.1
araC 2 g/m2 x 2/d, d. 2-3
every 3 weeks
4 c. rituximab 375 mg/m2 d-5 & 0
MTX 3.5 g/m2 d.1
araC 2 g/m2 x 2/d, d. 2-3
every 3 weeks
4 c. rituximab 375 mg/m2 d-5 & 0
MTX 3.5 g/m2 d.1
araC 2 g/m2 x 2/d, d. 2-3
Thiotepa 30 mg/m2 d.4
every 3 weeks
Response assessment
CR – PR - SD PD – tox
SC harvest
WBRT 40 Gy
± boost 9 Gy
Randomised study of HD MTX/AraC
+/- Thiotepa +/- Rituximab
PFS OS
A vs. B= 0,01
A vs. C= 0,00005
B vs. C= 0,13
A vs. B= 0,01
A vs. C= 0,0005
B vs. C= 0,24
Ferreri et al, Abstract ICML Lugano, 2015
IELSG 32 trial
Ritux d -5 and 0 of each cycle
Consolidation: OS
ITT PP
Ferreri et al, ASH 2016, Abstract 731
Randomised phase II ANOCEF-
GOELAMS (2 x 38 pts)
Houillier, Soussain et al, ASH 2016, Abstract 782
PFS
Houillier, Soussain et al, ASH 2016, Abstract 782
OS
Houillier, Soussain et al, ASH 2016, Abstract 782
Conclusions PCNSL
• Main component of treatment is HD-MTX
• Give 3.5 g/m2 every 2-3 weeks for 4-8 times
• If possible, add HD-araC (2g/m2 x4), rituximab and thiotepa
• Consolidation with RT is still standard if age<60
• Consider temozolomide instead of AraC in elderly
• Consider HDCT instead of RT in younger
Frequency of lymphomatous
meningitis in NHL subtypes
van Besien et al. Blood 1998
Zinzani et al. Leuk Lymphoma 1999
Herrlinger et al. Semin Oncol 2009
Ferreri et al. Hemato Oncol 2009
• indolent lymphomas <3%
• DLBCL & PTCL ~5%
• lymphoblastic and Burkitt’s ~30%
Risk Factors : sites
• Particular organs • testis (breast, ovary, skin, soft tissue, bone marrow ?)
• Localisations in the anatomical regions near to the base of the skull or spinal canal• oral cavity, tongue, salivary glands, orbita, paranasal sinuses
• retroperitoneal mass > 10 cm
Feugier P et al. Ann Oncol 2004 Avilés A e al. Oncology 2005
Boehme V et al Ann Oncol 2007 Laskin JJ et al. Leuk Lymphoma 2005
Zucca E et al. J Clin Oncol 2003 Savage K et al JCO 2009
Months
Pro
po
rtio
n
0 10 20 30 40 50 60 70 80 90 1000.00
0.05
0.10
0.15
0.20
0.25
0.30
Kidney/adrenal not involved
(n=2074)
Kidney/adrenal involved
(n=90)
p<0.001
Impact of kidney/adrenal involvement on CNS
relapse treated with R- CHO(E)P (n=2164)
Factor (adjusting for
the IPI)Relative
riskp-value 95% CI
Kidney and/or adrenal
gland2.8 0.006 (1.3; 5.8)
DLBCL – Risk of CNS relapse
Risk of CNS relapse according to the CNS International Prognostic Index. BCCA, British Columbia Cancer Agency; DSHNHL, German High-Grade Non- HodgkinLymphoma Study Group.
/
Schmitz N, JCO 2016
DLBCL – which kind of prophylaxis?
• Before 2008 : no CNS prophylaxis
• After 2007 CNS prophylaxis was indicated in DLBCL pts with high CNS recurrence risk, defined by:– Involvement of testis, spine, skull, paranasal sinuses, orbit,
nasopharynx, kidney/adrenal and/or breast
– Simultaneous presence of advanced stage and high LDH
• CNS prophylaxis consisted of 3-4 courses of methotrexate 3 g/m2 with or without four doses of IT liposomal cytarabine
Ferreri A, BJH 2014
DLBCL – which kind of prophylaxis?
* Pts managed with IT only due to concomitant renal insufficiency
Ferreri A, BJH 2014
• CNS relapse : 12% without prophylaxis
2.5% with prophylaxis (P=.08)
DLBCL – which kind of prophylaxis?
Cheah CY, BJC 2014
• Retrospective multicenter study
• 217 DLBCL high risk for CNS involvement
Double hit lymphoma
Oki Y, BJH 2014
• 129 cases of DHL
• the cumulative incidence of CNS involvement was 13% at 3 years
• incidence of CNS involvement was lower in patients receiving prophylactic intrathecal che-motherapy (5% at 3 years) than in those who did not (15% at 3 years, P = 0017)
Dual expresser lymphoma
Savage K, Blood 2016
• Dual expresser MYC+ BCL2+ DLBCL defines a group at high risk of CNS relapse
• Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies
Conclusions CNS prophylaxis
• CNS prophylaxis for DLBCL is controversial
• Usually CNS relapse is associated with systemic relapse
• Modern (+R) and aggressive first line regimens might reduce
the risk for CNS relapse
• If prophylaxis is to be done, HD-MTX may be preferred