Silvia MappaUnit of Lymphoid Malignancies
Department of Onco-HematologySan Raffaele H Scientific Institute, Milan, Italy
Convegno regionale SIE-Delegazione Marche“Appunti sui linfomi extranodali”
Ascoli Piceno, 8 Ottobre 2011
PRIMARY CNS LYMPHOMAS
PCNSL is an aggressive lymphoma arising exclusively inthe CNS (brain parenchyma, spinal cord, eyes, cranialnerves and/or meninges)
PCNSL
It represents 4% of intracranial neoplasms and 4-6% ofall extranodal lymphomas
Progressively increasing incidence in immunocompetentpatients
Even if it exhibits one of the worst prognoses amongNHL, it is a curable brain tumor
The esecution of randomized prospective trials isdifficult due to the rarity of this tumour and the poorperformance status of patients
Molecular and biological knowledge is incomplete
Particular microenviroment and sanctuary sites stronglyaffects treatment efficacy
PCNSL: open issues
Active treatments are known to be associated withdisabling neurotoxicity
Literature is mostly constituted by retrospectivestudies or single-arm prospective trials
Presenting symptomsFocal deficits (70%)
Neuropsychiatric sym. (43%)High intracranial pressure (33%)
Seizures (14%)Headache, ocular symptoms,
confusion, lethargy
PCNSL suspicion
Stereotactic biopsy
Diffuse large B-cell lymphoma
StagingPhysical examinationRoutine blood studies
Whole-brain MRIContrast total body CT scanOphtalmologic examination
CSF examinationBone marrow biopsy
Testicular ultrasonography18FDG-PET (investigational)
Sites of presentationBrain emisphere (38%)
Thalamus/basal ganglia (16%)Corpus callosum (14%)
Periventricular region (12%)Cerebellum (9%), eyes (5-20%)
Meninges (16%) spinal cord (1%)Cranial and spinal nerves (< 1%)
Neuroimaging (MRI)Lesions are hypointense in T1
isointense to hypointense in T2reduced ADC,
variable surrounding edema,strong enhancement
Baseline evaluationNeurologic examination
Biochemical serum profileNeuropsychiatric testsRenal funcionality tests
Hepatic functionality testsCardiac functionality tests
HIV, Hepatitis B and C virus
Prognostic factorsAge (< 60 years vs > 60
years)Performance status (0-1 vs > 2)
LDH (normal vs elevated)CSF protein (normal vs
elevated)Deep regions (no vs yes)
Histopathological features
Figure 3
CD3
CD20
VL
VL
VL
use only.For personal at FONDAZIONE CENTRO S RAFFAELE on May 30, 2011. bloodjournal.hematologylibrary.orgFrom
90-95% DLBCL
Neoplastic B lymphocytes growforming perivascular cuffings
Figure 3
CD3
CD20 VL
VL
VL
use only.For personal at FONDAZIONE CENTRO S RAFFAELE on May 30, 2011. bloodjournal.hematologylibrary.orgFrom
Costant expression of pan-B-cellmarkersRarely positive for CD10 (<10%)Negative for EBVHigh proliferating index
Variable 0 1
Age ≤ 60 ys. > 60 ys.ECOG-PS 0 - 1 2 - 4LDH normal elevatedCSF protein normal elevatedDeep lesions no yes 0
20
40
60
80
100
0 12 24 36months
Prob
abili
ty O
S
0 - 1
2 - 3
4 - 5
p= 0.00001
IELSG Prognostic Score
Ferreri AJM, et al. J Clin Oncol 2003a
p < 0,00001
0 24 48 72 96months
0
20
40
60
80
100%
sur
viva
l
Chemo-radiotherapyChemotherapy alone
Radiotherapy aloneSurgery alone
Untreated
Reni M, et al. Ann Oncol 1997
Therapeutic Strategy
Therapeutic Dilemma
The dilemma posed by PCNSL treatment is the choice between strategiesdesigned to intensify therapy to improve cure rate and treatment de-
escalation strategies to avoid neurotoxicityFerreri AJM. Blood 2011
Efficacy Neurotoxicity
ChemotherapyIts efficacy is limited by several factors including thebiology and microenvironment of this malignancy,which is protected by the BBB
III) drugs with poor BBB penetration that cannot beadministered at high doses due to dose-limiting toxicity(i.e., anthracyclines, vinca-alkaloids) are inefficient
I) most regimens include drugs able to cross the BBB at conventional doses (i.e., steroids, some alkylating agents)
II) cytostatics with low to moderate ability to cross the BBBcan be safely administered at high doses to improve CNSbioavailability (i.e., MTX, Ara-C)
CHOP regimen
Mead GM, et al. Cancer 2000
WBRT 40 + 14 Gy; n=15
WBRT + CHOP; n=38
Pharmacokinetics Triphasic plasmatic clearanceGood BBB penetration at HD
Schedule Infusion duration 3 hoursInfusion timing every 2 wks = 3 wksDose ≥ 3 g/m2
HD-MTX
CNS availability ≥ 1 g/m2 tumoricidal levels in the brain≥ 3 g/m2 tumoricidal levels in the CSF24-hr inf. tumoricidal levels in the CSF
Tolerability 8 g/m2 45% dose reductions3.5 g/m2 good compromise
Ferreri AJM. Blood 2011
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 , d1araC 2 g/m2 x 2/d, d2-3(x 4 c., every 3 weeks)
IELSG #20: Activity & Tolerability
Ferreri AJM, et al. The Lancet 2009
IELSG #20: Survival CurvesMedian f-up: 30 months
Ferreri AJM, et al. The Lancet 2009
Median f-up: 46 months
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72
months
Pro
ba
bil
ity
OS
MTXMTX-araC
24 ± 8%
45 ± 8%
p= 0.05
Clinical relevance of ara-C dose
0
20
40
60
80
100
0 12 24 36 48 60 72
months
Prob
abili
tyty
IELSG #20 arm B
MAT
Ferreri AJM, et al., The Oncologist 2011
Median follow-up: 26 monthsMTX 3.5 g/m2 , d1Ara-C 1 g/m2 x 2/d, d2-3Thiotepa 30 mg/m2, d4
MTX MTX +araC
MAT
N° pts 40 39 20
CR 7 (18%) 18 (46%) 4 (20%)
PR 10 (25%) 9 (23%) 3 (15%)
SD 1 ( 3%) 2 ( 5%) 0 ( 0%)
PD 21 (53%) 7 (18%) 12 (60%)
TD 1 ( 3%) 3 ( 8%) 1 ( 5%)
ORR 17 (43%) 27 (69%) 7 (35%)
New DrugsRegimen N ORR m OR
durationG3-4
neutroG3-4
thrombo
RituximabNABTT
10 3 (30%) N/A
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 + 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%
Alkylating AgentsBCNU, CCNU, Ifosfamide, Thiotepa- are largely used to treat aggressive lymphomas- are able to cross BBB - increase antimetabolites cytotoxicity- hit quiescent (G0 phase) cells
0.9 mg/Kg = 33 – 35 mg/m2
Strong JM, et al. Cancer Res 1986
Thiotepa
Rituximab - the cons
The potential efficacy of intravenous R in PCNSL seems tobe limited as MAbs are high molecular weight proteinswhich may be unable to pass the BBB
Harjunpaa, et al., L&L 2001; Ruhstaller et al., Ann Oncol 2000; Raizer, et al., ASCO 2000
As the majority of PCNSL are CD20 pos B-cell neoplasms,treatment with Rituximab might be reasonable
The CSF concentration of R after systemic admnistrationis 0.1 % of the serum level Rubenstein Blood 2003
Promising effects of rituximab were reported, both assalvage monotherapy and combined with HD-MTX
Batchelor T et al, Neurology 2011; Shah G et al, JCO 2007; Fritsch K et al, Ann Onc 2010
Although the low evidence supporting the role of rituximab for the treatment of PCNSL, its inclusion in chemotherapy regimens in prospective trials should be encouraged
Rituximab may achieve therapeutic concentrations in regions of a brain tumor manifesting contrast enhancement secondary to BBB disruption
Rituximab – the pro
Radiotherapy
PCNSL is a radiosensitive tumor
WBRT is rarely curative in PCNSL patients since responseis usually short-lived, with median survivals ranging from 10 to 18 mo Nelson DF et al, JNO 1999
As exclusive treatment radiotherapy plays a palliative rolein pts with CSF dissemination, but it is a curative strategy inindolent lymphomas (marginal zone, small lymphocytic, lymphoplasmacytic most arising in the meninges)
Consolidation after HD-MTX-based chemotherapy is thebest role for RT in PCNSL
Radiation Field
Radiation Doses
++
RESPONSE
COMPLETE REMISSION
30-36 Gy
PARTIAL RESPONSE
36-40 Gy10 Gy
PROGRESSIVE DISEASE
40-45 Gy10 Gy
Neurotoxicity
25-35% cumulative incidence at 5 years and 30% related mortality Abrey LE et al, JCO 1998
Long term impairment in the areas of attention, executive function, memory and psychomotor speed
Unknown pathogenesis, but demyelination, necrosis andmicrocavitary changes have been described
Usually assessed in small series and rarely in prospective trials
Reducing RT-related Neurotoxicity
To replace RT with other strategies
To avoid consolidation RT (only CRs)
To improve radiation parameters
Consolidation RT withdrawal?
Abrey LE et al, JCO 2000
52 ptsMTX 3.5 gr/mq (5)Procarbazine 100 mg/mqVincristine 1.4 mg/mq
30 pts WBRT 45 Gy
22 older pts: no WBRT
10/12 pts older than 60 who received WBRT developed neurotoxicity, compared with 1/22 who received chemotherapyalone
10/22 older pts who deferred WBRT experienced relapse, most of whom died of progressive disease
Older pts had similar median survival with or without WBRT: 32 vs 33 mo
Consolidation RT withdrawal?
Rubenstein J, et al. ASH 2010
CALGB 50202 trial
MTX (8)RituximabTMZ x 8 c.
46 pts CR araC (8)96-hr VP16
- CRR (induction)= 63%- Median f-up of 3.3 years, 21 experienced PD and 15 died- TRM (sepsis) 2%. No evidence for neurotoxicity- 3-year PFS was 50% and 3-year OS was 67%- EFS was similar in pts older and younger than 60 (p<0.56)
Improving radiation parametersRetrospective analysis of 33 PCNSL pts CR after HD MTX-chemo referred toconsolidation RT; median follow-up: 50 months
30 - 36 Gy
40 - 45 Gy
WB dose
36 - 44 Gy
45 - 54 Gy
Tumor Bed dose
FFS
Ferreri AJM, et al. IJROBP 2011
WBRT doses > 40 Gy are not associated with a better FFS andOS; while neurological deterioration evaluated with MMSEis more common > 40 Gy
Shah GD et al, JCO 2007
Rituximab 500 mg/mq d1 MTX 3.5 gr/mq d2 Vincristine 1.4 mg/mq d2 Procarbazine 100 mg/mq d1-7
N mAGE mKPS ORR (CR+PR) mPFS 2yOS 2yPFS
30 57 70 93% (21+4) 40 m 67% 57%
Low dose consolidation WBRT
Low-dose Consolidation WBRT
R-MPV followed by dose-reduced WBRT and Ara-C wasnot associated with asignificant cognitive decline upto 2 years post treatment
Correa DD, et al. JNO 2009
For the 19 patients whoreceived reduced-doseWBRT the estimated 2-year OS is 89% and PFS is57%
High-Dose Chemo + ASCT
Rationale Higher doses to cross the BBBHigher doses to achieve therapeutic concentrationsin “sanctuaries”Higher doses to overcome drug resistance
Concerns Higher risk of neurotoxicity in irradiated ptsFeasible only in fit and young patients
Facts Encouraging results both as upfront & salvagetreatmentExcellent neurotolerability when RT is avoidedHigh activity in pts with residual disease afterinduction
Why High-Dose Chemo + ASCT?
1) Soussain, JCO 2001; 2) Soussain, JCO 2008; 3) Brevet, EJH 2005; 4) Colombat, BMT 2006; 5) Abrey, JCO 2003;6) Montemurro, Ann Oncol 2007; 7) Cheng, BMT 2003; 8) Illerhaus, JCO 2006; 9) Illerhaus, Hematologica 2008
1)2)
3)4)
5)
6)
7)
8)
9)
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
+ APBSCTwww.ielsg.org
4 c. MTX 3.5 g/m2 d.1araC 2 g/m2 x 2/d, d. 2-3every 3 weeks
4 c. rituximab 375 mg/m2 d-5 & 0MTX 3.5 g/m2 d.1araC 2 g/m2 x 2/d, d. 2-3every 3 weeks
4 c. rituximab 375 mg/m2 d-5 & 0MTX 3.5 g/m2 d.1araC 2 g/m2 x 2/d, d. 2-3Thiotepa 30 mg/m2 d.4every 3 weeks
Response assessment
CR - PR - SD PD – tox SC harvest
WBRT 40 Gy± boost 9 Gy
Endpoint: CRR: 45% (P0) vs. 65% (P1)α: 0.05 - β: 0.20 - 42 pts/armStrata: IELSG score
Endpoint: 2-yr PFS65% (P0) vs. 85% (P1)α: 0.05 - β: 0.20 - 31 pts/arm
§[CR vs. PR/SD]
Strata: OR§ & 1ry chemo
Take home message….
AcknowlegmentOnco-Hematology UnitDr. Andrés JM FerreriDr.ssa Silvia Govi
Dr. Marco FoppoliDr. Giovanni DonadoniDr.ssa Angela Zanoni
Prof. Federico Caligaris Cappio
Neuroradiology UnitDr. Paolo VezzulliDr. Letterio PolitiDr.ssa Nicoletta AnzaloneDr. Andrea FaliniProf. Giuseppe Scotti
Hematology and BMT UnitDr.ssa Marta Bruno VentreDr. Fabio Ciceri
Neurosurgery UnitDr. Alberto Franzin Dr. Piero Picozzi
Pathology UnitDr. Maurilio PonzoniDr.ssa Maria Rosa TerreniProf. Claudio Doglioni
Radiotherapy UnitDr.ssa Anna ChiaraDr. Angelo BolognesiDr.ssa Nadia Di Muzio
Neurology UnitDr.ssa Monica FalautanoDr. Giulio TruciProf. Giancarlo Comi
Oncology UnitDr. Michele Reni
BACKGROUND
Intrathecal chemotherapy CSF acts as reservoir for PCNSL tumor cells, increasing risk
of failure
IT chemo efficacy has not been prospectively confirmed andmost trials do not use
IT is associated with additional risk of infectivecomplications, neurotoxicity and chemical meningitis
HD-MTX (≥ 3 g/m2) can clear the CSF of neoplastic cells
No benefit from adding IT to HD-MTX Khan R, JNO 2002
Ferreri AJM, et al. Neurology 2002Ferreri AJM, et al. JCO 2003Pels H, et al. JCO 2003
Weigel R, et al. Clin Neurol Neurosurg 2004Batchelor T, et al. Clin Cancer Res 2003
Smith JR, et al. Ophthalmology 2002
Intraventricular chemotherapy
Combination of MTX/Ara-C based chemotherapy with intraventricular MTX, Ara-C and steroids in 65 PCNSL ptsresulted in a mEFS of 21 m with 57% of young patients aliveat a mFU of 100 mo
Pels H et al, JCO 2003
Admninistration of the same chemotherapy regimen withoutintraventricular treatment in 18 pts produced a similar response rate with half of responders relapsing within the first year
Pels H et al, JNO 2009
Temozolomide in PCNSL
It is feasible and active in association with rituximabEnting RH, et al. Neurology 2004; Wong ET, et al. Cancer 2004
Salvage TMZ has been associated with CRR= 31% and amedian CR duration of 7+ m. in 36 pts with r/r PCNSL
Reni M, et al. BJC 2007
TMZ + HD-MTX combination is feasible and active (CRR:45%) even in 23 elderly patients
Omuro A, et al. JNO 2007
Upfront TMZ has been associated with an CRR of 47% in17 elderly patients (62-90 ys) and a median OS of 21 m.
Kurzwelly D, et al. JNO 2010
refractory PS prior prior <3 priorN° mAge relapsed 0-1 PFS RT cht lines36 60 22/78% 28% 19 86% 83%
TEMOZOLOMIDE
ORR (CR+PR) mPFS mOS 1yOS G3-4N PLT other31% (9+2) 2.8 m 3.9 m 31% 6% 3% 3%
Reni BJC 2007 (prospective phase II trial)
150 mg/m2 x 5 days every 4 w up to 6 cycles after SD
Alkylating agents
Kurzwelly JNO 2010
TEMOZOLOMIDE UPFRONT
MONOTHERAPY IN THE ELDERLY
N mAge PS ORR (CR+PR) mPFS17 75 nr 53% (47+6%) 5 m mOS 1yOS mNcycles G3-4hematoxicity21 m 29% 3 12%
*Retrospective series
100-200 mg/m2 x 5 days every 4 w up to max 8 cycles
UPFRONT TEMOZOLOMIDE + HD MTX
Omuro JNO 2007
InductionMTX 3 gr/mq g 1-10-20 + TMZ 100 mg/mq gg 1-5MaintenanceMTX 3 gr/mq g 1+ TMZ 100 mg/mq gg 1-5 q28 up to 5
N° mAge mKPS ORR (CR+PR) mEFS mDoR23 68 60% 55% (55+0%) 8 m 21 m
mOS 2yOS G3-4 hematoxicity35 m 38% 43%
refractory prior prior <3 priorN° mAge relapsed KPS PFS RT cht lines15 69 7/93% 70% 9 m 13% 100%
TEMOZOLOMIDE+RITUXIMAB
ORR (CR+PR) m PFS m OS 1yOS G3-4N PLT other53% (6+2) 2.2 m 14 m 58% 7% 27% 7%
Enting Neurology (retrospettivo)
Rituximab 750 mg/mq day 1,8,15,22 up to 2 cycles
Temozolomide 100-150-200 mg/mq days 1-7 and 15-21
Maintenance TMZ days 1-5 q28
TEMOZOLOMIDE + RITUXIMAB
Results: ORR: 100% (3 CR+1PR) mPFS and mOS: 6 mo
Wong Cancer 2004
Rituximab 375 mg/mq d 1 every 28 d up tu 4 cycles
Temozolomide 150-200 mg/mq d 1-5 every 28 d up to 12 cycles
4 PCNSL, 3 relapsed and 1 newly diagnosed; m age: 59 y
All relapsed after HD MTX
1 pts: persistent myelosuppression for 3 months after
1° cycle
TOPOTECAN
N mAge refractory PS prior prior <3 prior relapsed 0-1 PFS RT cht lines27* 51 13/14 60% 6 m 48% 78%15 56 ? ? ? 7% 100%* 2 systemic recurrence
ORR (CR+PR) mPFS mOS 1yOS G3-4N PLT3 other33% (5+4) 2 m 8.4 m 39% 26% 15% 11%40% (3+3) 2 m 32.7 m 67% 73% 20% nr
1.5 mg/m2/d days 1-5 q21 up to 6 - 10 cycles
Fisher Ann Oncol ’06, Voloshin JNO ‘08 (prospective trials)
Topoisomerase I inhibitors
RITUXIMAB MONOTHERAPY
Batchelor, Neorology 2011 (pilot study)
N mAGE mKPS ORR (CR+PR) mPFS mOS
12 64 85% 36% (3+1) 57 d 20.9 m
375 mg/mq iv every week up to 8 ws
RITUXIMAB-HD MTX elderly patients > 65 y
Fritsc K, Ann Oncol 2011 (single arm monocentric pilot trial)
Rituximab 375 mg/mq iv d -6, 1, 15, 29 up to 3 cyclesMethotrexate 3 gr/mq iv d 2, 16, 30 Procarbazine 60 mg/mq po d 2-11Lomustine 110 mg/mq po d 2
N mAGE mKPS ORR (CR+PR) mPFS mOS
28 75 60% 82% (18+5) 16 m 17.5 m
3yPFS 3yOS TRM G3-4WBC G3-4PLT 31% 31% 7% 92% 39%
INTRAVENTRICULAR RITUXIMAB
Pels H, JNO 2002 (case report): • 375 mg/mq iv d1 and 8• Intraventricular: 10 mg d16, 40 mg d17, 25 mg d24, 25 mg d25 Clearing of all lymphoma cells in the CSF lasting for more than 4 weeks, slight improvement of clinical symptoms, no change in size of tumour mass. Evaluation of Ab levels in CSF one week after systemic administration revealed minimal concentrations of rituximab. A 3-fold higher Ab level was measured 2 weeks after the end ofintraventricular therapy. Reversible side effects G3 (nausea, chills and hypotension) wereobserved after 40 mg intraventricular administration.
Rubenstein J, JCO 2007 (phase I, sequential dose escalation in 10 pts)Recurrent primary or secondary CNS NHL
• 3: 10 mg• 5: 25 mg (MTD) twice/week up to 5 ws (Ommaya reservoir)• 2: 50 mg
Results: 4 CR 6 cytologic response (the longest 9 mo) 2 intraocular resolution (1 lasting over 6 months)
INTRAVENTRICULAR RITUXIMAB
Consolidation RT withdrawal?
Thiel E, et al. Lancet Oncol 2011
G-PCNSL-SG-1 trial
551 pts with newly diagnosed PCNSL were enrolled from 75 Germancentres and treated between 2000 and 2009
G-PCNSL-SG-1 trial: results
G-PCNSL-SG-1 trial: Statistics
Thiel E, et al. Lancet Oncol 2010
SALVAGE THERAPY: R-IE2 cycles of
Rituximab 375 mg/m2 d 0Ifosfamide 2 g/m2/d d 1-3Etoposide 250 mg/m2 d 1
(every 21 days)
PBSC collection + MRICNS
(if PD off study)
Other 2 cycles of R – IE
BCNU 400 mg/m2 d -6Thiotepa 5 mg/kg d -5 -4
ASCT d 0
WBRT +/- boost (if ASCT not possible)
SALVAGE THERAPY: R-IERESULTS
Planned coursesDelivered coursesOngoing treatment
88 56 (64%)
1
Interrupted treatments: lymphoma progression toxicity patient’s refusal
16 12 3 1
G4 hematologic toxicity: neutropenia thrombocytopenia anemiaG4 non-hematologic toxicityToxic death
11 (50%) 5 (23%) 3 (13%) 1 ( 4%) 1 ( 4%)
ORR (95%CI)* CR PR median CR duration
41% (21%-61%)72
15+ months
Successful PBSC collection
Consolidation ASCT WBRT
8 / 8
31
Alive**Causes of death: lymphoma infection neurological impairment (NED)
8
11 1 2
PATIENTS (n=22)
Median ageRangeM/F ratio
6039 – 71
1.4RefractoryRelapsed
13 9
Previous lines of treatment:onetwo or three
Previous WBRT
16 6
12ECOG PS ≤ 3 all
HIV negative all
0
20
40
60
80
100
0 12 24 36 48
months
probability
PFS
SAR
Median follow-up: 15 months
2-yr PFS: 31% ± 11%
2-yr OS: 25% ± 12%
