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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