2. PRIMARY CNS LYMPHOMA
• PCNSL is an extranodal non hodgkins lymphoma confined to the craniospinal
axis (Brain, leptomeninges, spinal cord or eyes) without evidence of systemic
spread
• Primary intraocular lymphoma (PIOL)
• Neurolymphomatosis (NL) / Nerve-seeking lymphoma
3. EPIDEMIOLOGY
• 2% of all primary brain tumors
• 1% of all lymphomas
• 4-8% of all extranodal lymphomas
• Risk factors : Congenital immunodeficiency syndromes, AIDS (3600 times risk), organ
transplant recipients
• Male : Female = 1:1
• Median age of Non HIV related CNS 55-65 years
4. ETIOPATHOLOGY
• Precise etiology is not known
• Role of Epstein-Barr virus (EBV) genome: 0-20% in immunocometent & 100% in AIDS related
PCNSL
• 90% are DLBCL
• WHO 2016 Classification of lymphoma: Primary DLBCL of the central nervous system
• 10% are poorly characterized: Low-grade lymphomas, Burkitt’s lymphomas & T-cell
lymphomas
5. PATHOGENESIS
DLBCL cell of origin
Germinal center B cell Activated B cell Unclassifiable
9% 91%
• Activated B cell DLBCL are frequently associated with mutations in the B-cell
receptor (BCR) pathway & Nuclear factor kappa-B inhibitor zeta (NFKBIZ)
amplification pathway.
• Mutations targeting the CD79B subunit and the Toll-like receptor adaptor
protein MYD88 are most prevalent & considered as hallmark of PCNSL.
Mutation Reported Prevalence
CD79B 83%
MYD88 76%
PIM 1 71-77%
KMT 2D 50%
6. PATHOGENESIS
• Whether PCNSL arises inside or as transformed B cells originating outside the brain is unclear.
• Functional lymphatic vessels are present in the dural venous sinuses but brain parenchyma itself lacks classic
lymphatics and normally contains very few lymphocytes
• The observation that systemic dissemination of PCNSL is rare suggests that the cells of origin in PCNSL may be
derived from neoplastic lymphocytes that are eradicated from the periphery by an intact immune system, but which are
able to survive in an immunologically aberrant CNS.
• Facilitated through the expression of specific cell-surface adhesion molecules, CD44,CD18 and various chemokine
receptors (e.g. CXCL)
7. PATHOLOGY :GROSS
• Well demarcated single or multiple hemispheric masses with a
"fish flesh" consistency
• Solid, pale lesions with occasional necrosis & small hemorrhagic
foci.
MICROSCOPY
•Highly cellular tumor
•Large atypical cells with large round to irregular nuclei with
prominent nucleoli
•MIB-1 is high, often exceeding 50%.
•Angiocentric" clustering
•CD20 and CD45 positive
9. International PCNSL Collaborative group Guidelines
for baseline evaluation
Abrey LE, et al: Report of an international workshop to standardize baseline evaluation and response
criteria for primary central nervous system lymphoma. J Clin Oncol 23:5034-5043, 2005
10. Clinicoradiological Features of PCNSL
Immunocompetent Immunocompromised
Age 55-60 years 30 years
Multiple lesions 30-50% 63-81%
Necrosis, Haemorrhage & Calcification Rare Common
Location Supratentorial fronto-parietal white
matter, Periventricular regions, deep
gray nuclei and corpus callosum
Atypical locations such as
intraventricular
CT Imaging
Density Iso-Hyperdense Iso-Hyperdense
Enhancement Homogenous Heterogenous
MRI Imaging
T1 signal & T2 signal Iso-Hypo Iso-Hypo
Enhancement Homogenous Heterogenous
Perfusion Low relative Cerebral Blood volume (rCBV)
MRS High Cho/Cr ratio, low NAA, High lipid peaks
11. S. Jaggi Changing Face of Primary CNS Lymphoma, ECR 2013 10.1594/ecr2013/C-2632
12. S. Jaggi Changing Face of Primary CNS Lymphoma, ECR 2013 10.1594/ecr2013/C-2632
13. Kuker W, et al: Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 72:169-177, 2005
1. Healthy volunteer spectrum with normal
metabolite concentrations
2. A typical lymphoma spectrum:
a. Decreased N-acetylaspartate (NAA)
b. Decrease of creatine (Cr)
c. Massive increase of choline (Cho), lactate (Lac)
as well as of resonances of lipids/macromolecules
(Lip/MM).
d. Reversed choline/creatinine ratio
MRI spectroscopy in PCNSL
14. PET CT for the diagnosis of PCNSL
PCNSL Other Histology
Mean
SUVmax
27.5% 18.2% (p 0.001)
Mean
T/N Ratio
2.34 1.53 (p 0.001)
10% patients found to have extraneuaxial
disease
15. •Any involvement of extra-neuraxial disease in PCNSL is considered as systemic lymphoma with secondary CNS involvement
•4-13% of suspected PCNSL have demonstrable extra neuraxial involvement on complete imaging
•The extent of staging is controversial.
•1099 patients from 14 PCNSL studies with extensive systemic staging (Whole body CT or CT TAP + bone marrow Biopsy + USG
for testicular involvement) including 9 studies using FDG PET
•Diagnostic yield of 6% (95% CI 4%-8%) with extensive systemic staging & FDG PET
•Diagnostic yield with whole body 18F- FDG PET 5% (95% CI 3%-8%)
CONCLUSION: FDG PET serves as a one stop shop for systemic staging in suspected or proven PCNSL
16. CSF studies
• Cytology: Low sensitivity (30-40 %)
• Flow cytometry : Sensitivity and Specificity exceeds > 90%
• Biomarkers: CXCL 13, beta 2 microglobulin, IL-10, CD27 & neopterin have highest
potential of diagnosing CNSL
• CSF ctDNA: For diagnosis, tumor cell burden & response assessment
• Presence of a detectable IL10 level at the completion of therapy portends an early
recurrence
17. Abrey LE, et al: Report of an international workshop to standardize baseline evaluation and response
criteria for primary central nervous system lymphoma. J Clin Oncol 23:5034-5043, 2005
18. Prognostication- PCNSL
Ann Arbor Staging does not apply in PCNSL
Parameters associated with poor prognosis as per IELSG:
1. Age older than 60 years (most powerful prognostic factor)
2. ECOG performance status greater than 1
3. Elevated serum LDH
4. High CSF protein concentration
5. Tumor location within the deep regions of the brain (periventricular regions,
basal ganglia, brainstem, and/or cerebellum).
Biochemical markers:
• BCL-6 over-expression associated with longer survival (101 months versus
14.7 months in those in whom it is not expressed)
• P53 and c-Myc expression associated with worse prognosis
Ferreri AJ et al: Prognostic scoring system for primary CNS lymphomas: The
International Extranodal Lymphoma Study Group experience. J Clin Oncol 21:266-272, 2003
Score OS at 2 years
0-1 80%
2-3 48%
4-5 15%
19. PCNSL: Treatment aspects
• Extremely radiosensitive and chemo-sensitive tumor
• Relapses are common
• Current trials seek to identify the most appropriate combined modality treatment
• Minimizing the permanent treatment induced neurological deficits is a significant
consideration in treating PCNSL
20. Role of Surgery
• Removal of all gross tumor or debulking tumor confers no survival benefit over biopsy alone
• Survival after surgery alone is 1 to 4 months.
• Stereotactic biopsy :Gold standard for diagnosis
• Rarely considered in case of large lesions with acute symptons of brain herniation
• Resection can cause neurological deficits or delay definitive treatment
21. Role of steroids in the management of PCNSL
• Exert apoptotic effect on lymphoid cells through cytoplasmic steroid receptors.
• Dexamethasone has been associated with initial CR (15%) and PR (25%)
• Remission is only temporary although it can outlast the steroid administration.
• Resistance is common on re-exposure.
• Should be avoided during evaluation of patient and before biopsy & CSF examination
• Unclear whether steroids need to be an integral part of any regimen as is true for systemic lymphomas
22. WBRT alone in PCNSL
• PCNSL is traditionally considered as radiosensitive tumor
• PCNSL is a multifocal disease
• Historically WBRT with steroids was considered as sole
therapy
• Doses used for RT alone 45-60Gy
• High relapse rates with poor OS 4-20%
• High rates of Neurotoxicity
23. Chemotherapy in PCNSL
• Standard use of systemic NHL treatment regimens in PCNSL is associated with
transient responses of brain lesions & frequent recurrences
• Four prospective trials (one randomized)
• All failed to show an advantage of CHOP/CHOD plus WBRT over WBRT alone.
• CHOP has no role in the treatment of PCNSL
24. METHOTREXATE (MTX)
• Antitumor antimetabolite: Cornerstone for management of PCNSL
• Ability to penetrate BBB
• Rapid infusion of HD-MTX over 3 hours greatly raises the drug levels in the CSF
• Remains above minimum therapeutic concentration in the CSF upto 24 hrs
• Blood to CSF ratio 30:1
• Mean doses 3.5-8 g/m2
• ORR 35%-74%
• Median PFS 10-12.8 months & Median OS 25-55 months
• Improved outcomes with combination chemotherapy
27. 1992
Group A: 31 patients (De
Angelis regimen)
Group R: 16 patients
(refused chemotherapy or
RT initiated without prior
consultation)
Time to recurrence 41 months Vs 10 months p=0.003
Median OS 42.5 months Vs 21.7 months
CONCLUSION: Addition of chemotherapy to cranial RT for
initial treatment of PCNSL significantly improved DFS &
contributed to OS. All immunocompetent PCNL should be
considered for combined modality
28.
29. • 79 patients
• 18-75years
• ECOG 3 or less
Methotrexate 3.5g/m2 on D1
Every 3 week f/b WBRT
(n=40)
Methotrexate 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2-3
Every 3 week f/b WBRT
(n=39)
Primary Endpoint: Complete remission rate after chemotherapy 18% Vs 46% p=0.006
Secondary Endpoint:
3yr PFS 21% Vs 38% p=0.01
3yr OS 32% Vs 46% p=0.07
Grade 3-4 hematological toxicity 15% Vs 92%
2009
CONCLUSION: In patients aged 75 years and younger with
PCNSL, the addition of high dose cytarabine to HD-MTx
provides improved outcome with acceptable toxicity
compared with HD-MTX alone.
30. Group A n=75
MTX 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3
Every 3 weeks
Group B n=74
Rituximab 375mg/m2 on D-5 & 0 +
MTX 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3
Every 3 weeks
Group C n=78
Rituximab 375mg/m2 on D-5 & 0 +
MTX 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3 plus
Thiotepa 30mg/m2 on D4
Every 3 weeks
• N= 227
•Age 18-70 years
•ECOG 0-3
•53 centers from 5 countries
Second randomization in all three groups as Group D= WBRT or Group E= ASCT
Primary endpoint: Complete remission rate: At median F/up of 30 months
Group C 49% (95% CI 38-60)
Group B 30% (95% CI 21-42)
Group A 23% (95% CI 14-31)
2016
•Grade 4 hematological toxicity more frequent in group C
•Most common adverse events in all 3 groups: Neutropenia, thrombocytopenia, anaemia, febrile neutropenia or infections
•13 (6%) patients died of toxicity
31. 2 year OS in Group A 42% (95% CI 36-48)
Group B 56% (95% CI 50-62)
Group C 69% (95% CI 64-74)
2 year PFS in Group A 36% (95% CI 31-41)
Group B 46% (95% CI 40-52)
Group C 61% (95% CI 55-67)
32. 2019
•23 hospitals fromNetherlands, Australia, Newzeland
•18-70 years
•N=200
•Induction chemotherapy 2cycles of 28days
•Consolidation: High dose cytarabine in patientes or low dose WBRT
Primary endpoint Event free survival
R-MBVP Regimen n=100
•:IV MTX 3g/m2 on D1 & D15
•IV Carmustine 100mg/m2 on D4
•IV Tenoposide 100mg/m2 on D2 & D3
•oral prednisone 60mg/m2 on D1-D5
•Rituximab 375mg/m2 on D 0, 7, 14, 21 in C1 & D 0 &
14 in C2
MBVP Regimen n=100
•:IV MTX 3g/m2 on D1 & D15
•IV Carmustine 100mg/m2 on D4
•IV Tenoposide 100mg/m2 on D2 & D3
•oral prednisone 60mg/m2 on D1-D5
33. CO NCLUSION: No benefit of adding Rituximab in PCNSL
•At Median F/up 32.9months (IQR 23.9-51.5)
•Total 98 events (51 in MBVP group & 47 in R-MBVP group)
•EFS at 1 year 49% (95% CI 39-58) Vs 52% (42-61 p(0.99
HR 1)
•Grade 3 Grade 4 toxicity 58% in MBVP & 63% in R-MBVP
•Treatment related deaths 5% Vs 3%
RESULTS
34. Randomized phase III study of high dose Methotrexate and whole brain radiotherapy with or
without concomitant and adjuvant temozolamide in patients with newly diagnosed PCNSL:
JCOG 1114C – Kazuhiko Mishima ASCO MAY 2020 ABSTRACT
RESULTS:
2 yr OS 86.8% (95% CI 72.5-94) in Arm A Vs 71.4% in Arm B (95% CI 56-82.2) with HR 2.18 (95% CI 0.95-4.98)
2yr PFS 60.6% (43.6-73.8) in Arm A Vs 49.9% (34.4-63.5) in Arm B with HR 1.54 (0.88-2.70)
30 hospitals in Japan
20-70 years
N=122
Aim: To determine whether the addition of concomitant and adjuvant
TMZ chemotherapy to standard treatment of high dose methotrexate
(HD-MTX) and WBRT for PCNSL improves survival.
Arm A (62)
MTx 3.5g/m2 at day 1, 15,29
WBRT 30Gy+/- 10Gy boost
Arm B (60)
Arm A regimen +/- concomitant TMZ 75mg/m2 daily
Adjuvant TMZ 150-200mg/m2 daily for 5 days every 28 days
for 2yr after initiation of HD-MTx or until progression
CONCLUSION: No benefit of addition of TMZ to WBRT and adjuvant TMZ in newly diagnosed PCNSL
38. • 62 institutions were surveyed regarding the treatment approach of PCNSL
• In 7 institutions whole brain irradiation was not practiced
• Data of 43 patients treated from 1985 to 2000 from these institutes were collected
Pattern of recurrence Percentage
Cumulative in field recurrences at 5 year 57%
Cumulative out field recurrences at 5 year 49%
Out field recurrence rate in solitary lesion 45% (p= 0.79)
Out field recurrence rate in multiple lesions 67%
Out field recurrence rate with safety margin ≥4cm 22% (p=0.0079)
Out field recurrence rate with safety margin <4cm 83%
2002
39. CONCLUSION: Focal radiotherapy with safety margin of <4cm appears to be associated with a very high rate of out field
recurrence, but the use of radiation field with generous margins ≥4cm appears to be worth further investigation
Median & 5 yr survival 28.5 mo & 20%
Vs 15 months & 11% (p=0.057)
40. 40
• Phase II study of single agent intravenous methotrexate
• Methotrexate 8 mg/m2 every 2 weeks administered for 8 cycles or till CR
• Among 23 patients, 12 CR (52%), 5 PR (22%), 1 (4%) with stable disease,
and 5 progressions (22%) while on therapy.
• Seven patients died of tumor progression, and two died of other causes.
• Median PFS12.8 months.
• Median OS for the entire group had not been reached at 22.8 months
• Grade 3 toxicity 8/25 & Grade 4 toxicity 4/25 after 287 cycles of
chemotherapy
2003
CONCLUSION: HD-MTX is associated with modest toxicity and a radiographic response
proportion (74%) comparable to more toxic regimens
41. •HD-MTX alone in 37 patients
•Median OS 25 months & PFS 10 months
•20 patients received WBRT at relapse
•4 years rate of leukoencephalopathy in patients surviving more than 12
months was 58% with & 10% without WBRT given at relapse (p 0.11).
CONCLUSION: HD-MTX with deferred radiotherapy had only moderate efficacy
and was associated with significant neurotoxicity in long-term surviving patients.
2005
42. 2010
CHEMO Protocol
May 2000-Aug 2006: HD-MTx 4g/m2 on D1 of six 14day
cycles
Post Aug 2006: HD-MTx + Ifosfamide 1.5g/m2 on D3-5 of
six 14 day cycles
WBRT 45Gy/30# @ 1.5Gy daily on weekdays
Four cycles of high dose Cytarabine – 2 doses of 3g/m2
daily as 3hr IV infusions on D1-2 of 21 day cycle
75 centres
May 2000 to May 2009
N= 551
Hypothesis: Omission of WBRT does not compromise OS with a non inferiority margin of 0.9
551
273 278
112
118 96
85
56 98 96 112
43. RESULTS
• 551 patient randomised, 318 were treated per protocol.
• Treatment-related neurotoxicity in patients with sustained complete response was more
common in patients receiving WBRT
Per Protocol
Analysis
WBRT (154) No WBRT (164)
Median OS 32.4 37.1 (p 0.71)
Meidan PFS 18.3 11.9 (p 0.14)
CONCLUSION:
•No significant difference in OS was recorded when WBRT was omitted from first-line
chemotherapy in patients with newly diagnosed PCNSL, but primary hypothesis was not proven.
•The PFS benefit offered by WBRT has to be weighed against the increased risk of neurotoxicity in
long-term survivors.
44.
45. April 2013
• Dose intensive chemotherapeutic strategies as consolidation
• To Eliminate WBRT i/v/o Neurocognitive toxicity
Objective:
1. Rate of CR after remission induction with MT-R regimen
2. Feasibility of two step approach using high dose consolidation with
etoposide plus cytarabine
3. PFS
4. Correlation between clinical and molecular prognostic factors and
outcomes
N=44
Median age 61 year
Restaging was done by MRI at 4months of remission induction
After consolidation every 2 months for first year
Every 4 months for 2 and 3 year
Every 6 month from 3.5 year to 6.5year
46. RESULTS
• CR rate was 66%
• Median PFS was 29 months
• The median OS was not reached with a
median follow-up of 5 years.
• Results are comparable to those observed in
regimens that include consolidative
WBRT.
TTP for all
patients
For treatment protocol
completed patients 27
OS for all patients
47. Molecular Prognostic factors:
• BCL6 & MYC testing was done N=26
• High MYC expression (>50% of lymphoma nuclei) in 54% of
patients not significant
• High BCL6 Expression (>=30% of lymphoma nuclei) in (19)
59% Shorter TTP, PFS, OS
Clinical prognostic factors:
• ECOG>1 & IELSG score (4-5) shorter DFI
•Treatment delay >30days Shorter DFI
48. • N= 52
• Median age 60years (30-79)
• Median KPS 70 (50-100)
• R-MPV Regimen (5-7 cycles)
• Rituximab 500mg/m2 on D1
• MTx 3.5g/m2 over 2 hours on D2
• Vincristine 1.4mg/m2 D1-D7
• Procarbazine 100mg/m2/day on odd cycle only
• CR
• Reduced dose WBRT 23.4Gy/13#
• PR
• Standard dose WBRT 45Gy/25#
CONSOLIDATION Post RT for all patients: High dose cytarabine 3g/m2 on D1 & D2 for 2 cycles
Primary endpoint: 2 year PFS in patients receiving reduced dose WBRT
Oct 2013
49. RESULTS
• 31 (60%) achieved CR after R-MPV & received rdWBRT
• For CR 2 year PFS 77% & median PFS 7.7 years
• Median OS not reached at median F/up of 5.9 years
• 3 year OS 87%
• Cognitive assessment showed improvement in executive function (p<0.01) & verbal memory (p<0.05) after
chemotherapy and follow up scores remained relatively stable across the various domains.
CONCLUSION: R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long term
control and minimal neurotoxicity
50.
51. 2016
Phase I study: N=13
•Primary end point: Maximum tolerated dose of TMZ
•Experimental doses: from 100mg/m2 to 150mg/m2 to
200mg/m2
•Result: 100mg/m2 as MTD
•Dose limiting toxicities: Hepatic & Renal
Phase II study: N=53
•Rituximab 375mg/m2 D3 before C1
•MTx 3.5g/m2 with leucovorin on week 1,3,5,7,9
•TMZ daily for 5 days on week 4 & week 8
•Hyperfarctionated WBRT of 36Gy with1.2Gy BID on
week 11-13
•TMZ 200mg/m2 daily for 5 days every 28days on
week 14 to 50
RESULTS: Median F/up 3.6 years
•2 year OS 80.8%
•2 year PFS 63.6%
•Compared with historical controls significantly improved
control
•ORR 85.7%
TOXICITY:
•66% (35/53) Grade 3 & Grade 4 toxicity before hWBRT
•45% (24/53) of patients experienced grade 3 & Grade 4
toxicities attributable to post hWBRT chemotherapy.
•Cognitive function and QOL improved or stabilised after
hWBRT
52.
53. Phase II Randomised study of Rituximab, Methotrexate, Procarbazine, Vincristine and cytarabine
with and without Low-Dose WBRT for PCNSL RTOG 1114 ASCO 2020 update – M.P.Mehta et al
Arm B
Arm I Regimen of RMVP f/b reduced dose WBRT
23.4Gy/13#/2.5 weeks OD for 5 days a week
ASCO MAY 2020 ABSTRACT
Arm A :
Induction: Rituximab IV over 5 Hrs D1-D5
MTX IV over 2 Hrs on D2 & D16
Vincristine Sulfate IV on D2 & D16 for C1 & C2
Procarbazine hydrochloride P/o D2-D8
28 day cycle for 4 cycles
Primary End Point: PFS
RESULTS:N=87 with median f/up of 55 months
Median PFS 25 months in chemo arm Vs not reached in chemoRT arm
2 year PFS survival 54% in chemo Vs 78% in chemo RT HR 0.51 (p=0.015)
At 4.6 year median OS not reached in both arms
Neurotoxicity were not significantly different in both arms
CONCLUSION: Addition of WBRT can increase the PFS in PCNSL but long term results are awaited to
see toxicity data
Consolidation in both arms: Cytarabine IV Over 3 hours on days 1-2
Every 28 days for 2 cycles
54. •Field: CTV: Whole brain including 1 or 2 upper cervical vertebrae & posterior aspect of the eyes.
•The isocenter is set anteriorly and bisects the bony canthi.
•If the eyes were originally involved, both eyes should be included in their entirety in the WBRT field.
•The role of tumor site boost is uncertain and is not recommended by most experts.
Dose:
•Consolidation dose after CR to chemotherapy 24 Gy.
•WBRT after incomplete response to chemotherapy or salvage: 36 Gy to 45 Gy (1.5 to 1.8 Gy/fraction).
•WBRT as primary treatment for noncandidates for chemotherapy: 40 to 50 Gy (1.5 to 1.8 Gy/fraction).
•For palliation: WBRT dose is 30 to 36 Gy in 10 or 15fractions.
Jan 2015
55. Figure 1A
Typical WBRT field arrangement using German helmet bilateral field arrangements(1A) & Collimated
field arrangement(1B)
Figure 1B
Slide Courtesy: Dr Jayant Goda
Sastri
56. Figure 2A Figure 2B
Digitally Reconstructed radiographs(DRR)
showing MLC based field shaping for WBRT
planning;
Representative three dimensional multiplanar
sections (axial, coronal, sagittal) showing the
95% isodose wash);DRR showing the 95%
dose wash
Slide Courtesy: Dr Jayant
Goda Sastri
57. Role of HDCT and ASCT in PCNSL
• WBRT is associated with Neurotoxicity
• Increasing interest in high-dose chemotherapy (HDT) followed by autologous stem cell
transplantation (ASCT) as first-line consolidative approach
• Involves leukapheresis and peripheral blood stem cell harvest, followed by conditioning
chemotherapy then reinfusion of the stem cells to restore blood cell production.
• Conditioning regimens that contain CNS-penetrant agents such as carmustine, thiotepa, and
busulfan have demonstrated the most encouraging results.
58. AIM: To evaluate efficacy and safety of HD-MTX induction followed by high dose busulphan/ thiotepa (HD/BuTT) with autologous peripheral blood stem
cell transplantation (aPBSCT) and response adapted WBRT in patients with PCNSL
2006
2011
Busulfan P/o 4 doses at 4mg/kg from -D8 to –D5
Thiotepa 5mg/Kg on –D4 to –D3
aPBSCT on D0
INDUCTION:HD-MTX 8g/m2 on D1 & 10
Response assessment by MRI after second dose of MTX
If CR/PR sPBSCT (16)
If less than PR to induction or after PR post aPBSCT WBRT
45Gy/25# (6)
EARLY RESULTS: Post aPBSCT CR 69% & PR 13%
•For all 23 patients CR 70% & PR 13%
•3 treatment related deaths
•At 15 months median F/up EFS 17 months, OS 20 months
•2 year EFS & OS were 45% and 48% for all patients VS 56% &
61% for HD-BuTT group
•WBRT associated with higher neurotoxicity
LONG TERM OUTCOMES
•OS rate of 35% (8/23) after 10 years of follow up
•7/8 who were treated with chemotherapy alone developed no long-
term neurotoxicity and had excellent QOL and functional status with
KPS of 90% to 100%.
N=23
59. R-MPV Regimen (5-7 cycles)
• Rituximab 500mg/m2 on D1
• MTx 3.5g/m2 over 2 hours on D2
• Vincristine 1.4mg/m2 D1-D7
• Procarbazine 100mg/m2/day on odd cycle only
Jan 2015
N=32
Median age 57
Median KPS 80
Primary end point: 1 year PFS after HDCT-ASCT
HDC-ASCT
•Thiotepa 250mg/m2 IV on -9, -8, -7
•Busulphan 3.2 mg/Kg IV on D -6, -5, -4
•Cyclophosphamide 60mg/Kg IV on D -3 & -2
Peripheral cell harvesting after C1 or C2 of R-MPV
CR/PR on MRI after 5 cycles of R-MPV chemotherapy
If PD / SD off protocol treatment
Stem cell Reinfusion on D0
RESULTS
•ORR following R-MPV 97%
•26 (81%) proceeded with HDC-ASCT
•Median PFS & OS not reached at 45 months
•2 year PFS 79% (95% CI 58-90)
•2 year OS 81% (95% CI 63-91)
•In transplanted patients 2 year OS & PFS 81%
•3 treatment related deaths
•Stable neurocognitive status post treatment
60. CONCLUSION: Excellent disease control and survival with ASCT in younger and good PS patients with acceptable toxicity
61. July 2016
INDUCTION:
IV Rituximab 375mg/m2 D -7 & then every 10days for 5 cycles
IV MTX 8gm/m2 every 10 days for 4 cycles
AIM: To investigate the safety and efficacy of HCT-ASCT in patients with PCNSL
CONDITIONING REGIMEN (after 3 weeks of last chemo):
Rituximab 375mg/m2 on D1
Carmustine 400mg/m2 on D2
Thiotepa 2X 5mg/Kg D3 & D4
WBRT (45Gy/25#) to patients without CR post HCT-ASCT
Primary Endpoint: Complete response at day thirty after HCT-ASCT.
Reinfusion of stem cells D7, irrespective of response
status after induction
2 cycles of 21days of consolidative chemo:
IV Rituximab 375mg/m2
Cytarabine 3g/m2 D2 & D3
Thiotepa 40mg/m2 on D3
Stem cell collection in between
After 14 days
CONDITIONING REGIMEN
N=79 of 18-65years
15 hospitals from Germany
62. RESULTS:
•ORR 91%
•73 (92%) received HCT-ASCT
•61 (77.2%) patients achieved CR at D30
•5% treatment related deaths 3 during induction & one 4 weeks post ASCT
•At 3 year PFS 74 months & OS 81%
Most Common Toxicity
During Induction
Grade 3 Anaemia 37 (47%)
Grade 4 Thrmbocytopenia 50 (63%)
During HCT-ASCT
Grade 3 toxicity fever 50 (68%)
Grade 4 leucopenia 68 (93%)
CONCLUSION: HCT-ASCT with thiotepa & carmustine is an effective treatment option in young patients with newly
diagnosed PCNSL
63. Group A n=75
Mtx 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3
Every 3 weeks
Group B n=74
Rituximab 375mg/m2 on D-5 & 0 +
Mtx 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3
Every 3 weeks
Group C n=78
Rituximab 375mg/m2 on D-5 & 0 +
Mtx 3.5g/m2 on D1 +
Cytarabine 2g/m2 BID on D2 & D3
plus thiotepa 30mg/m2 on D4
Every 3 weeks
• N= 227
•Age 18-70 years
•ECOG 0-3
•53 centers from 5 countries
Second randomization in all three groups after 4th induction cycle as Group D= WBRT or Group E= ASCT
Primary endpoint: 2 year progression free survival
2017
WBRT 55
36Gy at 1.8Gy/#
Orbital shielding after 30Gy
9Gy TBB in patients with PR
ASCT 58
Carmustine 400mg/m2 on D -6
Thiotepa 5mg/Kg 12hrly on D -5 & D-4
Reinfusion of stem cells on D0
Stratification : Type of chemo and Response
64. Results
• No significant differences in 2-year PFS between WBRT and ASCT: 80% (95% CI 70–90) in group D and 69%
(59–79) in group E (HR 1·50, 95% CI 0·83–2·71; p=0·17)
• Haemotological toxicity commoner in ASCT arm, 2 toxic deaths in ASCT arm
65. CONCLUSION
• Both WBRT and ASCT were feasible and effective as consolidation after high-dose methotrexate based induction, and after
MATRix in particular (4 year OS 80% for both arms)
• Most cognitive functions recover after initial treatment in both arms
• ASCT better in cognitive flexibility, attention shifting, visuoconstructive abilities, and visuospatial configuration
66. Feb 2019
AIM: To determine efficacy and toxicity of chemoimmunotherapy followed by either WBRT or intensive chemotherapy and ASCT as first
line T/t in PCNSL
Induction:
2 cycles of R-MBVP
Rituximab 375mg/m2 on D1
Methotrexate 3g/m2 on D1, D15
Etoposide 100mg/m2 on D2
BCNU 100mg/m2 on D3
Prednisone 60mg/Kg/d D1-D5
2 R- AraC cycles of 21 days
Rituximab 375mg/m2 on D1
Cytarabine 3g/m2 D1-D2
After 4-6 weeks of induction completion
Primary End Point: 2 year PFS from the time of registration
Secondary End Point: Neuropsychological evolution, OS, ORR,
acute & long term toxicities & procedure feasibility
18-60 years
N=140
23 French centers
WBRT 40Gy at 2Gy/# 5d/wk
No Boost
N=70
IC IV Thiotepa 250mg/m2 on D -9, -8, -7
IV Busulfan 8mg/Kg D-6, -4
Cyclophosphamide 60mg/kg/d on D -3, -2
ASCT on D0
N=70
67. As per ITT consolidation group
As per primary end point in
consolidation group
As per ITT consolidation group
As per protocol consolidation group
Results
•The 2-year PFS rates were 63% (95% CI,
49% to 81%) and 87% (95% CI, 77% to
98%) in the WBRT and ASCT arms,
respectively.
•Toxicity deaths recorded in one WBRT arm
and five in ASCT arm
•Cognitive impairment was observed after
WBRT, whereas cognitive functions were
preserved or improved after ASCT
68. CONCLUSION
• WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60
years of age and younger.
• The efficacy end points tended to favor the ASCT arm (although non comparative design).
• The specific risk of each procedure should be considered (RT neurotoxicity, ASCT treatment
related mortality approx. 5-10%).
70. Treatment in the elderly
• Fivefold increased risk of neurotoxicity with combined regimen in age >60years
• Chemotherapy alone as initial treatment
• HD-MTX at doses of 3.5-8gm/m2 well tolerated
• HD-MTX combined with oral alkylating agents such as procarbazine, temozolaminde
• WBRT is considered as major risk factor for development of delayed neurotoxicity
• WBRT is usually deferred or avoided until the time of relapse
71. Treatment HIV related Lymphomas
• D/d of enhancing mass lesion or lesions in immunocompromised with surrounding
edema are toxoplasmosis, progressive multifocal leukoencephalopathy (PML),
cytomegalovirus (CMV) encephalitis, and other opportunistic infections, such as
bacterial or fungal abscesses or, in the developing world, tuberculosis.
• CD4 counts in affected patients are typically less than 50 cells/microL
• High dose MTX along with ART
• Prognosis in the high HAART era in age and PS matched individuals may be similar to
non HIV patients
72. Primary Ocular Lymphoma (PIOL)
• Management principles consist of systemic therapy and intraocular therapy
• Systemic therapy: Intrathecal MTX based combination therapy
• Intraocular therapy: Intravitreal MTX or Rituximab or Ocular RT
• Ocular RT: Bilateral orbits: 30-36 Gy
• WBRT to a dose of 30 Gy may be considered depending on risk of intraparenchymal
dissemination
73. Figure 3a Figure 3C
Typical German helmet field
arrangement using customized
blocks for intraocular lymphomas
Note: both the orbits and the
entire brain is irradiated
Typical collimated field
arrangement(without blocks) for
intraocular lymphomas
Note: both the orbits and the entire brain is
irradiated
Figure 3B
Digitally Reconstructed
radiographs(DRR) showing
MLC based field shaping for
Primary Intraocular
Lymphoma; Note: both the orbits
and the whole brain is included in the
treated volume. Slide Courtesy: Dr Jayant
Goda Sastri
74. Special Scenario: Palliation
• Based on Age, expected life expectancy, comorbid status and performance status
• Oral Chemotherapy: TMZ
• WBRT
• Steroids
75. Management of refractory or relapsed PCNSL
Choice of treament depends on
1. Age
2. Prevoius treatment & response
3. Performance status
4. Comorbidities
Salvage Options: No Consensus
1. Rechallenge with HD-MTX
2. Younger & better performance status--- HDT/ASCT
3. High dose cytarabine & etoposide f/b HDT/ASCT
4. WBRT who has not received as a part of initial therapy
5. Novel Agents: Temsirolimus, Pembrolizumab, Nivolumab, Ibrutinib, Buparlisib, Pemtrexed, Lenalidomide &
Pomalidomide
76.
77. • Ibrutinib: first-in-class Bruton tyrosine kinase (BTK) inhibitor
• Cross the blood–brain barrier
• It could mediate signals downstream of MYD88 and CD79B
• ORR Ibrutinib alone 75% & median PFS 7.3 months
• Ibrutinib + MTX ORR 80%
• Response to single-agent ibrutinib has always been in- complete and transient, lasting about 6
months, requiring combination therapy
2018
78. • Lenalidomide: an immunomodulatory agent
• Inhibit IR4downregulating the BCR dependent NFkB signalling
• Lenalidominde + Rituximab ORR 65%
• Median PFS 7.8 months
• Median OS 11.7 months
2019
79. SURVIVAL
• 5 year survival rates :20- 30% in immunocompetent individuals receiving
complete treatment
• Median survival approx. 40-44 months
• Major pattern of relapse: Subarachnoid space/ Leptomeningeal disease/
Parenchymal disease
80. Abrey LE, et al: Report of an international workshop to standardize baseline evaluation and response
criteria for primary central nervous system lymphoma. J Clin Oncol 23:5034-5043, 2005
81. TMH protocol (CALGB MTR)
INDUCTION
• MTX: 8g/m2 on days 1,15 x 8 doses
• Rituximab 375 mg/m2, weekly x 6 doses
• Temozolamide 150-200 mg/m2 on days 7-11 x 5 doses
MAINTENANCE (6 months to 1 year)
• Cytarabine 2gm/m2 twice daily on day 1-4
• Etoposide 40 mg/kg infused on day 1-4
HDC/ ASCT considered depending age, PS, Affordability
WBRT considered on the basis of response to induction
83. Algorithm for PCNSL Management
DLBCL Stage IE
Age, Co-Morbidities, Performance Status
Young (<60 years) and fit
patient
Fit, Elderly age ≥ 60 years
No co-morbidities
Any age & unfit patient
for HDMTX
HMTX+ARA-C based
regimen
CR PR, SD PD
HMTX+ARA-C based regimen
CR
WBRT± steroids
maintenance
RT dose 36-45 Gy
PR, SD
WBRT
36-45 Gy
WBRT
36 Gy
WBRT
45 Gy
WBRT
36Gy
Observation
Consolidation Chemotherapy
Or
Autologous stem cell transplant
(If feasible)
A
Individualize
therapy
*Response assessment should be done with gold standard imaging modality, Magnetic resonance imaging
using T1+Contrast, T2W, T2FLAIR, Perfusion and DWI sequences.
*Response Assessment
Consolidation
chemotherapy
Slide Courtesy: Dr Jayant Goda
Sastri (ISNO guidelines)
(2.7% of all primary brain tumors diagnosed in the US from 1995 to 1999.
Sjogren $, SLE,
Immunosuppresion chemotherapy or lomg term steroids use
EBV 10-15%
Latent membrane protein-1 IHC is positive in AIDS PCNSL compared with AIDS-related systemic non-Hodgkin`s lymphomas suggesting a potentially different pathogenesis.
MYD88 mutation and/ or nuclear factor kappa-B inhibitor zeta (NFKBIZ) amplification are found in 83% of patients and lead to Toll-like receptor signaling and BCR pathway activation.
Mutations in PIM1 (71%-77%), and MYD88 (64%-86%) are most prevalent, followed by CD79B (59%-64%%) and KMT2D (50%).
Large confluent areas of frank necrosis and gross intratumoral hemorrhage are more common in AIDS related PCNSLs
Angiocentric" clustering Have a predilection for blood vessels, resulting in lymphoid clustering around small cerebral vessels
MIB 1 signnificantly higher than GBM
Iol involvement in 8%
Ocular symptoms include floaters, blurring of vision
Most common location cerebral hemispheres 38.2% f/b basal ganglia & thalamus 15.9%, 65% lesion single, 35% multiple
Mean diam of lesion 45mm
90% have edema causing mass effect. DWI scans acquired were consistent with increased diffusion of water protons
High Lip/MM is associated with high malignancy and tissue necrosis or high lipid content of the cells
There is substantial difference in the management of PCNSL & Systemic NHL
The extent of staging required to evaluate for systemic involvement in patients with suspected or proven PCNSL remains controversial.
Extensive systematic staging: Whole body CT or CT TAP + Bone marrow Bx + USG scrotum in males fb FNA or biopsy if suspect NHL
Systematic Review & Meta-analysis of 1099 patients from 14 PCNSL studies with extensive systemic staging (Whole body CT or CT TAP + bone marrow Biopsy + USG for testicular involvement) including 9 studies using FDG PET
Diagnostic yield was defined as the proportion of patients with abnormal test results outside the neuraxis that lead to detection of concordant systemic high grade lymphoma on an individual patient basis (TP+ve)
FDG PET serves as a one stop shop for systemic staging in suspected or proven PCNSL
False positive rates of 5% (3-8%)
Even low yield is reported systemic staging is should be considered as insignificant or trivial in the clinical context of potential diagnostic, prognostic and therapeutic implications.
MRI has sensitivity of only 20% for detection of leptomeningeal disease in lymphoma
List of drugs used in chemotherapy
Began new protocol in 1985
24 centres & 6 countries
Mortality 30%
Neurotoxicity after whole brain irradiation remains a major problem in the treatment of primary central nervous system lymphoma (PCNSL)
To clarify whether WBRT is necessary for PCNSL, the authors retrospectively analysed the outcome of patients treated with partial brain irradaition.
Attention deficits-6 patients and memory deficits- 4 patients
2 patients-normal, 3 pateints - moderately restricted and one had markedly restricted QOL.
551 patient randomised, 318 were treated per protocol.
In the per-protocol population, median OS: 32·4 months (95% CI 25·8–39·0) in patients receiving WBRT (n=154), and 37·1 months (27·5–46·7) in those not receiving WBRT(n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71).
Median PFS:18·3 months (95% CI 11·6–25·0) in patients receiving WBRT and 11·9 months (7·3–16·5; p=0·14) in those not receiving WBRT
Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving WBRT (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology)
BCL6 & MYC testing was done N=26
High MYC expression (>50% of lymphoma nuclei) in 54% of patients not significant
High BCL6 Expression (>=30% of lymphoma nuclei) in (19) 59% Shorter TTP, PFS, OS
Overall PFS 3.3 year & OS 6.6year
Though good results trial was questioned bcz it was single arm phase II trial. Was this really a therapeutic benefit or in fact benefit of patient selection remains the question?
Adapted version of Patric Morris RMPV regimen where Rituximab benefitted or rdWBRT benefitted was doubt
Here Reduced dose WBRT or no RT regardless of response to chemotherapy
8 MTX cycles were given
25% of patients so far on chemotherapy alone arm have received salvage WBRT
In TMH RT is given if PR/SD
WBRT 36Gy f/b 9Gy boost
The isocenter is set anteriorly and bisects the bony canthi (to reduce divergence in possible future match to ocular field).
Alternatively, the anterior border of the PTV is set with the isocenter 5 mm behind the lens
This differentials should be excluded with appropiate diagnosis