Primary CNS Lymphoma - bhs.be · Primary CNS Lymphoma Andrés J. M. Ferreri Unit of Lymphoid...
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Primary CNS Lymphoma
Andrés J. M. Ferreri
Unit of Lymphoid MalignanciesDepartment of Onco-Hematology
San Raffaele Scientific Institute, Milano, Italy
Management difficulties
- High proportion of elderly pts
- Poor PS at presentation
- Biopsy not performed
- Palliative treatment
- Therapeutic consensus is lacking
- A few centers with adequate expertise
- Many pts can not be referred to other centers
• Several patients receive steroids for months before biopsy:
– Confounding effect on neuroimaging
– Delayed and unsuitable biopsy (52% inter-observer variability)
– Diabetes and other metabolic disorders
– Immunodepression (severe infections)
– Half of cases of early PD are related to interruptions due to toxicity
• CNS tissues exposed to lymphoma infiltration by months:
– Tissue damage results in poor PS and disabling symptoms
– Loss of autonomy and poor treatment tolerability
– CR and cure do not result in neurological and PS improvement
– Therapeutic interruptions due to poor, irreversible conditions
– Negative effects on trials accrual
Early Diagnosis is the Best Therapy
Ferreri AJM. EHA meeting 2016
PCNSL suspicion
Current strategy= low diagnosis sensitivity
• Neuroimaging: T1, T2, flair, DWI, enhancement, spectroscopy
• Site: corpus callosum , basal ganglia, periventricular areas, …
• Response to steroids
Neuroimaging
PCNSL GBM
Response to Corticosteroids
•Multiple sclerosis•Acute disseminated encephalomyelitis•Cerebral infarction•Neurosarcoidosis •Germinoma •Renal cell carcinoma metastases•Prolactinoma•Hemangioma
Response to steroidsLymphoma
Response to Steroids
Bp: Glioblastoma multiformeBp: no tumor
Early Reliable Suspicion
Reliable molecular and biological parameters that can be easily incorporated in routine practice.
Some chemokines (CXCL13) can be used as diagnostic & prognostic tools.
IL-10 concentration in the CSF is a useful diagnostic and prognostic biomarker.
Some miRNA (21, 19b, 92a) are expressed in the CSF of PCNSL patients, with a diagnosis sensitivy and specificity >95%
Recurrent mutations of CD79B (83%) and MYD88 (76%) in tissue samples.
MYD88mutations can be detected in the vitreous and plasma (CSF?).
The combined use of ADC, CSF CXCL13, and IL-10 results in increased diagnostic performance in CNSL.
Rubenstein J, et al. Blood 2013; Fisher L, et al. CCR 2009; Nguyen-Them L, et al. EJH 2016; Baraniskin A, et al. Blood 2011; Bonzheim I, et al. Blood 2015;
Fontanilles et al. ASH 2015; Nakamura T, et al. Neuropathol Appl Neurobiol 2016; Mabray MC, et al. AJNR 2016
Modern Approach
Updated from Ferreri AJM, ASCO 2012
INDUCTION CONSOLIDATION
HD-MTX poly
WBRT
Others
Age & PS
Comorbidity
Prognostic score
Histotype (DLBCL)
Therapeutic Dilemma
Ferreri AJM, Blood 2011
the dilemma posed by PCNSL treatment is the choice between strategies designed to intensify therapy to improve cure rate and treatment de-escalation strategies to avoid neurotoxicity.
Efficacy Neurot oxicity
Chemotherapy
Its efficacy is limited by several factors including the biology and microenvironment of this malignancy, which is “protected” by the BBB.
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
CHOP regimen
Mead GM, et al. Cancer 2000
WBRT 40 + 14 Gy; n=15
WBRT + CHOP; n=38
Pharmacokinetics Triphasic plasmatic clearance
Good BBB penetration at HD
Schedule Infusion duration 3 hours
Infusion timing every 2 wks = 3 wks
Dose 3 g/m2
HD-MTX
CNS availability 1 g/m2 tumoricidal levels in the brain
3 g/m2 tumoricidal levels in the CSF
24-hr inf. tumoricidal levels in the CSF
Tolerability 8 g/m2 45% dose reductions
3.5 g/m2 good compromise
Ferreri AJM. Blood 2011
MTX + Alkylator + Rituximab
INDUCTION CONSOLIDATION N° ORR 2-year PFS
Rituximab
Methotrexate
Procarbazine
Vincristine1
low-dose WBRT 52 79% 57%
Rituximab
Methotrexate
Procarbazine
Vincristine2
TBC - ASCT 33
(≤ 65 ys)
94% 79%
Rituximab
Methotrexate
Temozolomide3
Non-myeloablative
HD-cytarabine
HD-etoposide
44 77% 59%
Rituximab
Methotrexate
Temozolomide4
Hyperfract WBRT
+ TMZ maintenance
53
(<60 yo: 62%)
57% 64%
1Morris PG, et al. JCO 2013; 2Omuro A, et al. Blood 2015; 3Rubenstein JL, et al. JCO 2013; 4Glass J, et al. JCO 2016
The IELSG #32 trial
Ferreri AJM, et al. 13-ICML, Lugano 2015
WBRT 40 Gy
± boost 9 Gy
CR – PR - SD PD – tox
SC harvest
®WBRT 36 Gy
± boost 9 Gy
BCNU 400 mg/m2 d.1
Thiotepa 5 mg/Kg x 2/d; d.2-3
+ APBSCT
PCNSL [≤ 65 ys. + PS 0-3] or [65-70 ys. + PS ≤2]
®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
Arms Activity
Ferreri AJM, et al. Lancet Haematol 2016
0.74
0.0007
0.02
0.69
0.00001
0.05
Activity: Arm and IELSG risk
Logit CR OR
IELSG risk score 0,13 0,09
Arm 0,0004 0,000004
PFS and OS
median follow-up: 30 months (12-66)
Ferreri AJM, et al. Lancet Haematol 2016
Chemotherapy: Elderly Patients
HD-MTX improved outcome in selected pts (biased results).
The age upper limit to define elderly pts remains uncertain.
Ferreri AJM. Blood 2011
Elderly Pts: PHRC 2006 Trial
Omuro A, et al. Lancet Haematol 2015
Arm A M-PVA
Arm B M-TMZ
3 cycles/ 28 d
MTX 3,5 g/m2 d1
Vincristine 1,4 mg/m2 D1
Procarbazine 100 mg/m2/d D1-
7
D7D1 D14 D21 D28
Vincristine 1,4 mg/m2 D1
Methylprednisolone
60 mg/d D1-5
Cytarabine 3 g/m2/d1-2After 3rd Cycle
MTX 3,5 g/m2 d1
TMZ 150 mg/m2/d D1-5 If no tox= TMZ 150 mg/m2/d D15-19 , cycle 2 & 3
D7D1 D14 D21 D28
Methylprednisolone
60 mg/d D1-5
MTX 3,5 g/m2 d1 MTX 3,5 g/m2 d1
3 cycles/28 d
AGE ≥ 60 YEARS
PHRC 2006 Trial
Omuro A, et al. Lancet Haematol 2015
MPV-A
(n= 47)
M-TMZ
(n= 48)
p
CR
PR
SD
PD
62%
20%
2%
16%
45%
26%
7%
22%
0.11
ORR 82% 71% 0.23
AGE ≥ 60 YEARS
Elderly pts: PRIMAIN Trial (n= 108)
Kindly provided by G. Illerhaus and B. Kasenda
TABLE 1: Best response from 4 MRI examinations as per protocol. 108 patients.
Best response Values
CR 46 (42.6%)
PR 34 (31.5%)
PD 12 (11.1%)
SD 1 (0.9%)
Missing 15 (13.9%)
AGE ≥ 65 YEARS
Sanctuaries CSF and eyes (intrathecal and intravitreal chemo).
IT/IV chemo efficacy has not been prospectively confirmed. Most trials do not include IT/IV drug delivery.
IT is associated with additional risk of infective complications, neurotoxicity and chemical meningitis.
HD-MTX ( 3 g/m2) treats adequately meninges.
IVi: is active, but toxic (visual acuity deterioration in 27%).
Impact on OS???Ferreri AJM, et al. Neurology 2002Ferreri AJM, et al. J Clin Oncol 2003Pels H, et al. J Clin Oncol 2003
Weigel R, et al. Clin Neurol Neurosurg 2004Batchelor T, et al. Clin Cancer Res 2003
Smith JR, et al. Ophthalmology 2002
High-dose Ifosfamide
Mappa, HemOnc 2013; Arellano-Rodrigo, EJH 2003; Choquet, Lugano 2013 Abs #3664; Motomura, L&L 2011; Choi, IJH 2013
R-IE (n= 22) VIA (n= 16) ICE (n= 17) ICED (n=25) De-VIC
Line Salvage Salvage Salvage Salvage First
ITX (g/m2/d)x[days] 2 x [3] 1 x [5] 5 x [1] 1.5 x [5] 1,5 x [3]
Other drugs R, VP16 araC; VP16 CBDCA; VP16 CBDCA; VP16 CBDCA; VP16
Previous chemo MA CHOD, MA MA M -
Pre-irradiated pts 55% 100% NR 27% -
Median age 60 (39-72) 54 (31-69) 62 (28-84) 58 (20-73) 61 (19-79)
Refractory (mPFS) 50% (8 mo) 6% (19 mo) 24% (12 mo) 36% (12 mo) 0
Dose reduction 0% NR 24% NR NR
NF (TRM) 14% (5%) 50% (0%) 53% (6%) NR (8%) 10% (0%)
ASCT 20% 0% 35% 52% NA
CRR 27% 37% 76% (ASCT) 48% 62% (2c.)
mPFS 4.0 mo 4.5 mo 2.6 mo 11 mo 37 mo
mOS 6.0 mo 6.0 7.3 mo 27 mo 48 mo
Salvage Single-Agent in Trials
Regimen N ORR m TTP G3-4 N G3-4 T TD
RituximabBatchelor T, et al. Neurology 2011
12 42% 8 0% 0% 0%
TemozolomideReni M, et al. Br J Cancer 2007
36 31% 7+ 6% 3% 0%
TopotecanVoloschin A, et al. JNO 2008
15 40% 3 73% 20% 0%
TopotecanFischer L, et al. Ann Oncol 2006
27 33% 9 25% 11% 13%
PemetrexedRaizer JJ, et al. Cancer 2012
11 55% 6 63% 50% 13%
TemsirolimusKorfel A, et al. JCO 2016
37 54% 2 20% 22% 14%
Chia-Ching W, et al. BJH 2014
Ponzoni M, et al. Ann Oncol 2014
• 13 PCNSL; 7 SCNSL
• Ibrutinib 560 mg and 840 mg was well tolerated.
• No DLT
• Meaningful concentrations in the CSF.
• ORR= 75%
• Median PFS= 5 months.
• Ongoing MTX-IBT-R trial
Ibrutinib at ASH 2016
Grommes C, et al. ASH 2016
• 8 c. LENA 20-25 mg + ritux => 12 c LENA 10 mg
• 50 pts with rrPCNSL
• ORR= 67% (36% after induction) EARLY
• 24% of pts received 1 course
• 50% of pts received 2 courses
• 36% completed induction
• 1-yr PFS: 20%
• Dose reduction in 42%
• Prior vs. LENA median PFS= 4 vs. 8 months
Lenalidomide at ASH 2016
Ghesquieres H, et al. ASH 2016
Reactive Perivascular T-cell Infiltrate
CD20
CD3
NEG (n= 34)
POS (n= 16)
Reactive Perivascular T-cell Infiltrate
Ferreri AJM. Frye-Halloran Conference, Boston 2004
SALVAGE THERAPY: NIVOLUMAB
CA209-647: Multicenter open-label, two-cohort, single-arm phase IIPATIENT POPULATION: Rel/Ref PCNSL and Rel/Ref PTLEnd Points: Safety and Efficacy of NivolumabStatus: 58 c./14 countries; 3 Italian centers. 1 pt enrolled. OSR will be open 9/11/16
FOUR ANECDOTAL CASES OF CR
Modern Approach
Updated from Ferreri AJM, ASCO 2012
INDUCTION CONSOLIDATION
HD-MTX poly
WBRT
Others
Age & PS
Comorbidity
Prognostic score
Histotype (DLBCL)
Response
Quality response
Induction
Observation
WBRT
HDC/ASCT
Non-myeloablative
Maintenance
Radiation Field and Doses
+
+
RESPONSE
COMPLETE REMISSION
30-36 Gy
PARTIAL RESPONSE
36-40 Gy
10 Gy
PROGRESSIVE DISEASE
40-45 Gy
10 Gy
30 Gy
36
Neurotoxicity
Correa D, et al. Neuro-Oncol 2009
Poor QoL and
>50% were not working due to illness
Reducing Neurotoxicity Risk
Ferreri AJM, et al. Blood 2011
To avoid consolidation RT (only CRs).
To improve radiation parameters.
To replace RT with other strategies.
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 German Centers and treated between 2000 and 2009
G-PCNSL-SG-1 trial: results
Low-dose WBRT
Morris PG, et al. JCO 2013; Correa DD, et al. JNO 2009; Kim BH, et al. Cancer Res Treat. 2014
Consolidative HDC/ASCT
MTX± others
ThiotepaBus, CTX
60 72 1421
Alimohamed N, et al. L&L 2012
56 (34-69)PS>1: 70%
24 100
MTXaraC, TTP
ThiotepaBCNU + RT
140 81 330
Kasenda B, et al. Ann Oncol 2012
54 (27-64)70 (30-100)
37 77
MTXaraC
BEAM 28 20 028
Abrey L, et al. JCO 2003
53 (25-71)70 (30-100)
18 50
MVpBP+itx/araC
BEAM + RT 34 60 425
Colombat P, et al. BMT 2006
51 (21-60)PS3-4: 32%
44 68
MTXaraC, TTP
ThiotepaBCNU ± RT
72 77 013
Kasenda B, et al. Ann Oncol 2012
54 (38-67)90 (30-100)
54 85
MTXaraC
Bus, CTXVP16 ± RT
25 30 011
Yoon DH, et al. BMT 2011
52 (33-65)PS1: 91%
73 100
MTX ThiotepaBusulfan
13 15 45 1323
Montemurro M, et al. Ann Oncol 2007
55 (18-70)70 (30-100)
70
TRM(%)
Induction Conditioning F-up(mo)
2-yr EFS(%)
N° Age m(r)PS m(r)
CRR(%)
ASCT(%)
Activity of HDC/ASCT
Kindly provided by G. Illerhaus, Stuttgart, Germany
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
after2nd MTX
after4th MTX
after1st AraC/TT
after2nd AraC/TT
afterHD (d30)
offStudy
n.d.
PD
SD
PR
CR
(central neuroradiological review)
ASCT vs. Alternatives
Ferreri AJM & Illerhaus G. Blood 2016
IELSG32: WBRT vs. ASCT
PRECIS: WBRT vs. ASCT
IELSG43 (MATRix): ASCT vs. NMC
ALLIANCE: ASCT vs. NMC
The IELSG #32 trial
Ferreri AJM, et al. 13-ICML, Lugano 2015
WBRT 40 Gy
± boost 9 Gy
CR – PR - SD PD – tox
SC harvest
®WBRT 36 Gy
± boost 9 Gy
BCNU 400 mg/m2 d.1
Thiotepa 5 mg/Kg x 2/d; d.2-3
+ APBSCT
PCNSL [≤ 65 ys. + PS 0-3] or [65-70 ys. + PS ≤2]
®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
TOXICITY (PP)
Grade 1-2 3 4 5 1-2 3 4 5
Neutropenia 3 ( 5%) 1 (2%) 3 (5%) 0 (0%) 2 ( 3%) 0 ( 0%) 41 (71%) 0 (0%)
Thrombocytopenia 0 ( 0%) 1 (2%) 1 (2%) 0 (0%) 0 ( 0%) 3 ( 5%) 42 (72%) 0 (0%)
Anaemia 7 (13%) 2 (4%) 0 (0%) 0 (0%) 21 (36%) 17 (29%) 2 ( 3%) 0 (0%)
FN/infections 0 ( 0%) 1 (2%) 0 (0%) 0 (0%) 1 ( 2%) 12 (21%) 3 ( 5%) 2 (3%)
Hepatotoxicity 3 ( 5%) 1 (2%) 0 (0%) 0 (0%) 15 (26%) 3 ( 5%) 1 ( 2%) 0 (0%)
Nephrotoxicity 2 ( 4%) 0 (0%) 0 (0%) 0 (0%) 6 (10%) 0 ( 0%) 0 ( 0%) 0 (0%)
Cardiotoxicity 0 ( 0%) 0 (0%) 0 (0%) 0 (0%) 5 ( 9%) 1 ( 2%) 0 ( 0%) 0 (0%)
Coagulopathy/DVT 2 ( 4%) 0 (0%) 3 (5%) 0 (0%) 6 (10%) 1 ( 2%) 0 ( 0%) 0 (0%)
Gastrointestinal 8 (15%) 0 (0%) 0 (0%) 0 (0%) 24 (41%) 11 (19%) 0 ( 0%) 0 (0%)
Mucositis 2 ( 4%) 0 (0%) 0 (0%) 0 (0%) 15 (26%) 12 (21%) 3 ( 5%) 0 (0%)
Erythema 7 (13%) 0 (0%) 0 (0%) 0 (0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 (0%)
Acute neurotoxicity 7 (13%) 3 (5%) 0 (0%) 0 (0%) 4 ( 7%) 0 ( 0%) 0 ( 0%) 0 (0%)
WBRT (n= 55) ASCT (n= 58)
NEUROTOXICITY 57 patients (30 WBRT and 27 ASCT) were assessable for effects of treatments
on cognitive functions and QoL.
Pre-morbid IQ estimation by NART test showed a mean value ± standard error
of 100 ± 7 for WBRT patients and 105 ± 8 for ASCT patients (p= 0.40).
Neuropsychological tests performed immediately after treatment conclusion
showed a fast improvement in the majority of assessed cognitive functions and
QoL, which was more evident for memory and language in arm E.
A significant impairment of some attention/executive functions among patients
treated with WBRT was recorded, while results of tests addressing language
and memory were stable after this therapy.
Patients treated with ASCT exhibited improved functions at most of the
performed test, and improved QoL figures.
ACTIVITY
Afterinduction
32 CR (54%)
Arm D
(WBRT)CR (95%)
Afterinduction
31 CR (53%)
Arm E
(ASCT)CR (93%)
EVENTS: 45 ARM D (%) ARM E (%)
Relapse 16 (27%) 18 (31%)
PD during consolidation 2 ( 3%) 2 ( 3%)
Toxic death 0 ( 0%) 2 ( 3%)
Death off-therapy (NED) 2 ( 3%) 3 ( 5%)
EVENTSMEDIAN FOLLOW-UP: 40 MONTHS (24-76)
EFFICACY: OS
102 (47%) pts are alive:
- 44 (75%) in arm D
- 37 (63%) in arm E
- 21 pts excluded from R2.
Causes of death Arm D Arm E Non R2
lymphoma 11 15 62
treatment toxicity 0 2 13
toxicity during salvage therapy 1 1 0
neurocognitive decline while NED 0 1 1
late infective complications 3 1 2
car accident 0 0 1
acute erythroid leukaemia 0 1 0
sudden death (> 1 year) 0 1 0
unknown 0 0 1
ITT
PP
Schorb E, et al. BMC Cancer 2016
Non-Myeloablative Chemo
Rubenstein J, et al. JCO 2013
Alliance/CALGB 50202 trial
MTX (8)RituximabTMZ x 8 c.
44 pts(age: 12-76)
CR (66%)araC (8)96-hr VP16
No neurotox
Median f-up: 4.9 ys
21 failures 17 deaths
TRM (sepsis) 2%
Nordic Trial: TMZ maintenance
Pulczynski EJ, et al. Haematologica 2015
All PCNSL pts ≥ 70 years old
Trial registration
Eligible for therapy (PS ≤3 – Not eligible for ASCT)
Elegible for HD-MTX Inelegible for HD-MTX
Ineligible for therapy
WBRT 2340 cGy+ Temozolomide
+ Rituximab
Temozolomidex 12 mo
RIT-MTX-PCZ x 2 c.(PRIMAIN trial)
Lenalidomidex 24 mo
PCZx 6 mo
Strategies for Future Studies
To potentiate early diagnosis
To identify new active drugs
To amply our biological and molecular knowledge
To establish reliable prognostic factors & potential targets
To enhance drug bioavailability
To improve radiation therapy
To reduce neurotoxicity and improve patients’ QoL
To improve international cooperation
Ferreri AJM, et al. JCO 2003; Ferreri AJM, et al. JCO 2013
Trend in Survival
Shields MS, et al. BJH 2016 Zeremski V, et al. Ann Hematol 2016
From SHARED IDEAS to FACTS
PCNSL
Young pts
First line
PCNSL
Elderly pts
First line
SCNSL
Young pts
First line
PCNSL
Young pts
Salvage
PCNSL
Elderly pts
Salvage
SCNSL
Young pts
Salvage
IELSG #42 (MARIETTA) trial
IELSG #32 trial IELSG #43 (MATRIX) trial
SCNSL1 Trial
IELSG #XX
(FIORELLA) trialTIER trial
European PCNSL Collaborative Group
• Our patients and their families
• National Coordinators and DMSC Offices
• Hematologists, oncologists, neuro-radiologists, radiation oncologists, pathologists,
researchers, psychologists, data managers and research nurses of participating centers
• Colleagues, data managers, co-chairs and friends of the International Extranodal
Lymphoma Study Group (IELSG)
• Institutions supporting our trials: Agenzia Italiana del Farmaco, Cancer Research UK,
Oncosuisse and Swiss National Foundation
• Colleagues, data managers and friends of the Fondazione Italiana Linfomi (FIL)
• Colleagues and friends of the European PCNSL Collaborative Group (EPCG)
• Colleagues and friends of the International PCNSL Collaborative Group (IPCG)
• Unit of Lymphoid Malignancies of the San Raffaele Scientific Institute, Milano
Acknowledgments