Lymphomasaffecting the CNS

Michele Ghielmini

Oncology Institute of Southern SwitzerlandOspedale San Giovanni - 6500 Bellinzona, Switzerland

Prognosis of extranodal lymphomasin 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 relatedmortality of 30%).

• More common in elderly pts treated withHD-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 clearanceGood BBB penetration at HD

Schedule Infusion durationInfusion timingDose

3 hoursevery 2wks = 3wks≥ 3 g/m2

CNS avalability ≥ 1 g/m2 tumoricidal levels in the brain≥ 3 g/m2 tumoricidal levels in the CSF24-hr inf. NO tumoricidal levels in CSF

Tolerability 8 g/m23.5 g/m2

45% dose reduct.good compromise

Ferreri AJM. Blood 2011

Alkylating Agents

BCNU, CCNU, Ifosfamide, Temozolomide, Thiotepa

- are largely used to treat aggressive lymphomas

- are able to cross BBB

- increase antimetabolites cytotoxicity

- hit quiescent (G0 phase) cells

- increase overall toxicity

0.9 mg/Kg = 33 – 35 mg/m 2

Strong JM, et al. Cancer Res 1986

Thiotepa

New DrugsRegimen N ORR m OR

durationG3-4 neutro G3-4 thrombo

RituximabBatchelor T, et al. Neurology 2011

12 5 (42%) 8 0% 0%

RituximabRaizer JJ, et al. Pro ASCO 2000

3 2 N/A

TemozolomideReni M, et al. Br J Cancer 2007

36 11 (31%) 7+ 6% 3%

Temozolomide (Upfront - old)Kurzwelly D, et al. JNO 2010

17 9 (53%) 21+ 12% 12%

Temozolomide + RituximabEnting RH, et al. Neurology 2004

15 8 (53%) 14 20% 27%

Temozolomide + RituximabWong ET, et al. Cancer 2004

7 7 6

TopotecanVoloschin A, et al. JNO 2008

15 6 (40%) 3 30% 5%

TopotecanFischer L, et al. Ann Oncol 2006

27 9 (33%) 9 26% 11%

PemetrexedAltman JK, et al. ASCO 2008

8 4 (50%) 5+ 63% 50%

Therapeutic Strategies for PCNSL

Reni M, et al. Ann Oncol 1997

Overall survival

History: the MSKCC schemeYear 2000: «The next step»

Cases: n=5723<60y34>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/m 2 , 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/m 2 , d1araC 2 g/m 2 x 2/d, d2-3(x 4 c., every 3 weeks)

Followed by WBRT

IELSG #20: Survival Curvesn = 80

Median f-up: 30 months

0

20

40

60

80

100

0 12 24 36 48 60 72

months

Pro

babi

lity

OS

Median f-up: 46 months

MTX

MTX-araC

24 ± 8%

45 ± 8%

p= 0.05

Ferreri AJM, et al. The Lancet 2009

Rituximab against PCNSL5-7 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/m 2 d 1 (max. 6x) (+ IFO 1.5 g/m 2 d 3-5)

CR

WBI WBI at relapse WBI AraC 3 g/m2 x 2/dd 1-2 (max. 4x)

RandomWBI 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/m 2 d.1 Thiotepa 5 mg/Kg x 2/d; d.2-3

+ APBSCT

4 c. MTX 3.5 g/m 2 d.1araC 2 g/m 2 x 2/d, d. 2-3every 3 weeks

4 c. rituximab 375 mg/m 2 d-5 & 0MTX 3.5 g/m 2 d.1araC 2 g/m 2 x 2/d, d. 2-3every 3 weeks

4 c. rituximab 375 mg/m 2 d-5 & 0MTX 3.5 g/m 2 d.1araC 2 g/m 2 x 2/d, d. 2-3Thiotepa 30 mg/m 2 d.4every 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 trialRitux d -5 and 0 of each cycle

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)

• 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 1998Zinzani et al. Leuk Lymphoma 1999Herrlinger 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 2005Boehme V et al Ann Oncol 2007 Laskin JJ et al. Leuk Lymphoma 2005Zucca E et al. J Clin Oncol 2003 Savage K et al JCO 2009

Months

Pro

port

ion

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 forthe IPI)

Relative risk

p-value 95% CI

Kidney and/or adrenal gland

2.8 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