Management of Primary CNS Lymphoma

Presenter: Dr. Narayan Adhikari

Junior Resident

Moderator: Dr. Ahitagni Biswas

Department of Radiation Oncology

Dr. B. R. Ambedker Institute Rotary Cancer Hospital

AIIMS, New Delhi

Overview

• Introduction

• Management• Approach

• Investigations

• Treatment

• Review of literature

• Recent advances

Introduction

Primary Spinal Lymphoma

Primary Leptomeningeal Lymphoma

Primary Intraocular Lymphoma

Primary Cerebral Lymphoma

Epidemiology

1% of all intracranial tumours

4% of all intracranial tumours

Sarkar C, Sharma MC, Deb P, Singh R, Santosh V, Shankar SK. Primary central nervous system lymphoma--a hospital based study of incidence and clinicopathological features from India (1980-2003). J Neurooncol. 2005;71(2):199-204

Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer. 2011;105(9):1414-1418

Pathogenesis

Local malignant transformation

Systemic transformation?

• Focal deficits (70%)• Neuropsychiatric symptoms (43%)• Raised intracranial pressure (33%)• Seizures (14%)• Ocular Symptoms (4%)• Headache• Confusion• Lethargy

Clinical Features

Bataille B, Delwail V, Menet E, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 2000; 92:261

NeuroimagingSites of DiseaseBrain hemispheres (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%)

Kuker W, et al: Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 72:169-177, 2005

• Tumefactive demyelination• Glial tumours• Brain Metastasis• Cerebral Abscess• Secondary CNS lymphoma

Differentials

Stereotactic biopsy followed by histopathological examination

Diagnosis

• 95% DLBCL• Molecular subtypes

Germinal center, Activated B cell and Type 3

• Overlapping state of differentiation

• EBV associated in immunocompromised

Histopathological findings in primary CNS lymphoma. (A) Hematoxylin and eosin stain demonstrates a population of mitotically active medium-to-large-sized lymphoid cells with large vesicular nuclei and prominent nucleoli mixed with small mature lymphocytes with a distinct propensity to cluster around medium-sized vessels. (B) Immunohistochemistry using a monoclonal anti-CD20 antibody reveals clusters of highly pleomorphic B lymphocytes. (C) Immunohistochemistry using an anti-CD3 antibody highlights the dense T-cell infiltrate within B-cell PCNSL. Tumor cells are indicated by black arrows. (D) The large fraction of mitotically active cells within the tumor can be visualized by immunohistochemistry with the Ki-67 antibody

Workup

Central review of pathologyImmunophenotypingEBV-LMP-1Bone Marrow Biopsy+ Aspirate CSF cytology+ Biochemistry

History and Clinical examinationOphthalmic examination (Slit lamp and indirect ophthalmoscopy)Neuropsychological evaluation

Complete blood countsLiver function Tests, Kidney Function Tests, ElectrolytesSerum LDHHIV serology and viral markers

Contrast enhanced MRI brainCECT neck+ chest+ abdomenUltrasonography of testis in male

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

• Age ≤60 vs >60 years• PS 0-1 vs ≥2• Serum LDH (normal vs elevated)• CSF protein (normal vs elevated)• Deep regions (no vs yes)

Prognostic Factors

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 years0 or 1 80%

2 or 3 48%

4 or 5 15%

• Exclusion of Systemic disease• Extension of the disease to eyes, CSF• Treatment feasibility in view of patient

characteristics• Prognostic factors• Recurrence

Therapeutic Decision

• The optimal treatment strategy is controversial• High dose methotrexate based polychemotherapy

is the mainstay of treatment• Role of radiation has been argued upon but it is

recommended in young patients• The role of rituximab is investigational

Treatment

Ferreri, how I treat PCNSL, bloodjournal, 2015

• Inj Methotrexate 2.5 gm/m 2 IV on weeks 1, 3, 5, 7 and 9• Inj Vincristine 1.4 mg/m 2 IV on weeks 1, 3, 5, 7, 9• Cap Procarbazine 100 mg/m 2 /day per oral for 7 days on

weeks 1, 5, 9• Inj Methotrexate 12 mg intrathecal on weeks 2, 4, 6, 8, 10• Tab Leucovorin 20 mg per oral every 6 h for 12 doses on

weeks 1, 3, 5, 7 and 9 following high dose methotrexate• Tab Dexamethasone per oral tapering dose for 7 days (16,

12, 8, 6, 4, 2 mg on weeks 1-6)• Whole brain radiotherapy (WBRT) 45 Gray in 25 fractions

over 5 weeks (weeks 11-15)• Inj Cytarabine 3 gm/m 2 /day IV for 2 days on weeks 16 and

19

DeAngelis Protocol

Radiation Therapy

German Helmet technique

• Whole Brain is treated due to multifocal and infiltrative nature of tumour

• Left and right opposed lateral fields with 6-10mv photons

• Anterior temporal lobe, cribiform plate, posterior aspect of eyes included

• Divergence beam to lens reduced by placing isocenter anteriorly between the lateral canthi or if anterior fields are made coplanar

• Inferior field edge in lower border of C2 vertebrae

• If ocular involvement both globes included for a portion of treatment to receive a dose of 30-36 Gy

• No role of CSI except for palliation in case of spinal involvement

Radiation Therapy

• Acute Adverse Effects- alopecia, erythema and dry desquamation of the scalp. Some experience fatigue, headache and inflammation of the external auditory canal or middle ear

• Patients requiring treatment of the eye are likely to experience conjunctival irritation and dry eye.

• These acute effects typically resolve within 6 – 8 weeks of completion of WBRT

Radiation Toxicity

• Late adverse effects: neurocognitive decline, sensorineural hearing loss, permanent alopecia

• Those whose eyes are treated- cataracts, chronic dry eye

• The risk of neurocognitive dysfunction increases with age, total RT dose and co-administration of chemotherapy

Radiation Toxicity

Review of literature

Review of literatureSN Study N Median

Age (years)

Chemotherapy WBRT/ Boost (Gy)

Response PFS OS Neurotoxicity

Results and Conclusions

1 RTOG 83-15, 1992

41 66 None 40/20 CR=62% NS 48% 1 year, 28% 2 years

NS KPS (p<0.001) and age (p=0.001) significant prognostic factors

2 RTOG 88-06, 1996

54 NS (>60) CHOD (2-3 cycles)

41.4/ 18

CR=19%, PR=48%, SD=6%, PD=15%

Median 9.2 months

42% 2 years

1 grade 5 encephalomalacia

Age (p=0.005 and KPS (p=0.057) were significant prognostic factors, no survival benefit of adding CHOD chemotherapy to RT, compared with RTOG 83-15, p=0.53)

3 Batchelor et al, 2003

23 60 MTX 8gm/m2, upto 8 cycles, maintenance upto 11 cycles

- CR=52%PR=22%

12.8 months

>23 months

modest Radiological response of 74% with grade 3 toxicity 8/25 and grade 4 toxicity 4/25

4 Abrey et al, 2000

52 65 MTX(3.5gm/m2) ,Vin(1.4mg/m2), Pro(100mg/m2), Cyt

45 vs none

Objective response rate to induction chemotherapy=90%

NS Median 60 months

13 In patients >60 yrs, OS similar with or without RT, late neurotoxicity more common in those who received RT (p=0.00004), young patients both OS and PFS not reached during publication but they fared well

SN Study N Median Age (years)

Chemotherapy WBRT/ Boost (Gy)

Response PFS OS Neurotoxicity Results and conclusions

5 RTOG 93-10, 2002

102 56.5 MTX (IV 2.5gm/m2 and IT 12mg), Vin,Pro, Cyt

45 later amended to 36 in CR group

CR=58%, PR=36% to chemotherapy Response rate=94%

Median 2 years

36.9 months 64% 2 years, 52% 3 years,32% 5 years

12 (15%) severe delayed neurotoxicity, 8Deaths

HDMTX- high response rate, plus RT- improved survival compared to previous studies of RT alone

6 Bessell et al, 2002

57

59 CHOD x 1, BVAM x 2

45 vs. 30.6

CR at the end of all t/t 68% and 77%

NS 36% 5 years

In 1-year survivors: 0/13 (30.6 Gy);1/12 (45 Gy and <60 years old);6/10 (45 Gy and ≥ 60 years old)

In <60 years who achieved CR, 3-year OS 92% v 60%, P =.04), 3 year relapse risk 25% vs 83% (p=0.01)

7 Ferreri et al, 2009

79 18-75 MTX 3.5g/m2 d1, Cyt 2g/m2 bd d2-3

36-45 CR 18% vs 46%, ORR 40% vs 69% in MTX only vs MTX+Cyt resp.

4 vs 8 months (median failure free survival)

10 vs 32 months

NS Combination of methotrexate with cytarabine produces better CR (0.006) ORR (p=0.009), with increased toxicity

8 RTOG 02-27, 2013Phase II results

53 57.5 HDMTX(3.5g/m2), TMZ, RTX

36hyperfractionated

ORR 37.7% post chemo

63.6% 2 years

80.8% 2 years

NS Compared to RTOG 93-10, significant benefit in OS(0.006) and PFS (p=0.03)

SN Study N Median Age (years)

Chemotherapy WBRT/ Boost (Gy)

Response PFS OS Neurotoxicity Results and conclusions

9 Rubenstein et al(CALGB50202), 2013

44 NS MTX (8g/m2), TMZ(150mg/m2 day7-11, odd cycles), RTX(375mg/m2, d3), only CR- consolidtn with EA

- CR 66% 52 m, 64%, 57% 47% at 1,2 and 4 years resp.

Estimated 75%, 70% and 65% at 1,2 and 4 years resp.

NS High Bcl6 expression correlated with shorter survival, patient above 60 did as well as younger patients

10 Ferreri et al, 2011 retrospective

33 55 MTX based Whole brain: 30-45 Gy, tumour bed: 36 to 54 Gy

5 year failure free survival 51%

5 year OS 54%

Significantly less neurologic impairment, as measured by MMSE, in patients treated with 30 – 36Gy vs. ≥ 40 Gy WBRT( p = 0.05)

WBRT doses ≥40 Gy not asso. with improved disease control compared to dose of 30 - 36 Gy, 5-year FFS, 51% vs. 50%; p = 0.26), WB and tumour bed RT doesnot have impact on survival

11 Omuro et al, 2011

64 47 (all <60, young), median KPS 70

MTX (3 g/m2), CCNU, pro, methylpred and IT MTX, cyt, and methylpred

CR-5 more cycles of CT, <CR, 27 WBRT, 29 HDC with SC rescue

ORR after induction chemo 87% (CR 54%, PR33%)

12 m 63 m 5 (none treated with chemo only)

Deferring WBRT in chemosensitiv pts compromises PFS not OS. As objective is cure in this age group, omitting WBRT may not be best strategy

• 280 receiving HDMTX (>1gm/m2) from 19 prospective series• No difference in OS between mono CHT and combination CHT

(p=0.38)• MTX ≥3gm/m2 (p=0.04), thiotepa (p=0.03) and intrathecal CHT

(p=0.03) improved survival and nitrosoureas (p=0.01) correlated with worse survival

• In multivariate analysis, limited to patient receiving ≥ 3 gm/m2 MTX, only the addition of cytarabine improved OS

• A RT dose ≥ 40 Gy to the whole brain or tumor bed did not improve OS• RT delay had no negative impact on survival• Similar findings were reported in another restrospective analysis by

Ferrari et al on 370 patients

Findings

• 81 patients analysed, 54 HDMTX only, 27 HDMTX+R• CR- 36% vs 73% (p=0.0145)• Median PFS 4.5 months vs 26.7 months (p=0.003)• Median OS 16.3 months vs not reached (p=0.01)• A retrospective study by Gregory et al in 120 patients

published in Neuro Oncol showed addition of rituximab is associated with increased OS.

• Care must be given to chances of Hepatitis B reactivation in HBsAg positive patients when given Rituximab

Findings

3

Limitations• Poor protocol adherence• 40% excluded from primary analysis• Low statistical power (60%)• Low accrual period• Suboptimal chemotherapy use• Inclusion of small centers with low experience in treating PCNSL• Lack of quality assurance• Insufficient neuropsychological evaluation• Dr. Lisa DeAngelis pointed out that competing risks analysis,

adjusting for the effect of relapse, demonstrates that approximately 24% of patients develop neurotoxicity at 5 years after WBRT, while the risk of PCNSL recurrence is twice the risk of neurotoxicity, so WBRT cannot be safely excluded from upfront management.

Study N Median Age (years)

Chemotherapy WBRT/ Boost (Gy)

Response PFS OS Neurotoxicity Results and conclusions

Shah et al, 2007

30 57 RTX, HDMTX, Pro,Vin, Cyt

23.4 vs. 45

ORR 93% 2 year PFS 57%, median PFS= 40 months

2 year OS 67%

None In CR patients with rdWBRT, 2 year PFS and 2 year OS 79% and 89% resp.

Study N Median Age (years)

Chemotherapy WBRT/ Boost (Gy)

Response PFS OS Neurotoxicity Results and conclusions

Morris et al, 2013

52 60 RTX, HDMTX, Pro,Vin, Cyt

23.4 vs. 45

CR 60%Objective response rate 95%

Median 3.3 years (7.7years for CR/23.4 Gy)

Median 6.6 years (notreached for CR/23.4 Gy)

None, except decreased motor speed(CR/23.4 Gy)

R-MPV with rdWBRT in CR is associated with high responserates, long-term disease control, and minimal neurotoxicity

HDC+ASCTStudySoussain et al

Soussain et al

Brevet et al

Colombat et al

Abrey et al

Montemurro et al

Cheng et al

Illerhaus et al

Illerhaus et al

araC indicates cytarabine; BCNU, carmustine; BEAM, carmustine, etoposide, cytarabine, and melphalan; Bu, busulfan; Cy, cyclophosphamide; IFO, ifosfamide; MBVP(regimen), methotrexate, carmustine, etoposide, and methylprednisolone; OS, overall survival; TRM, treatment-related mortality; TT, thiotepa; VP16, etoposide; and WBRT,whole-brain irradiation.*Only for patients not achieving a complete remission.†One patient received the treatment as salvage therapy

• Systemic high dose methotrexate based chemotherapy + Local therapy

• Local therapy either intravitreal chemotherapy with methotrexate or rituximab or ocular radiation upto 40 Gy

Primary Intraocular Lymphoma

Domain Test DescriptionAttention/Executive (Digits Forward

And Backward; WAIS-III)

Auditory attention

Trail Making Test (Parts A and B) Psychomotor speed (A); sequencing (B)-alternate form available(flexibility index = B-A)

Brief Test of Attention Auditory working memoryVerbal memory Hopkins Verbal Learning Test—Revised 12-word list:

Three learning/recall trialsDelayed recallRecognition (discrimination index)Six alternate forms

Motor Grooved Pegboard Test Motor speed and dexterity (dominant and nondominant hand)

Quality of life EORTC-QLQ 30 30-item self-report scale (physical, social, emotional, cognitive status)

BCM 20 20-item self-report scale (tumor and treatment-related symptoms)

Premorbid IQ Estimation Barona Index Weighted composite score on the basis of age, gender, race, residence, education, and occupation

Neurocognitive assessment

Correa DD, Maron L, Harder H, et al. Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2007;18(7):1145-1151

• CR- complete disappearance and not receiving corticosteroids in last 2 weeks, no ocular lymphoma, negative CSF in previously positive patients

• CRu- Meets criteria of CR but continues to require corticosteroids

• PR- at least 50% decrease in contrast enhancing lesion, decrease in vitreal cell count, retina/optic nerve infiltration, CSF may show malignant disease

• SD- not meeting criteria of CR, CRu, PR, PD• PD- >25% increase in CE lesions, new site, increase in

vitreal cell count

Response Criteria

Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005; 23:5034

• Leptomeningeal disease- MTX 12mg weekly intrathecally or through ommaya reserviour

• Older patients- dose adjustment, RT may be deffered till progression, proper monitoring of kidney functions

• In HIV positive: MTX based chemotherapy with anti retroviral therapy with or without radiation

Special scenarios

• Retreatment with methotrexate (ie, 3 to 8 g/m2 ) or methotrexate based combination chemotherapy if there has been a prior complete remission with this agent

• Alternative chemotherapy regimens (eg, topotecan, cytarabine, temozolomide, thiotepa, pemetrexed including high dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT)

• Whole brain radiation therapy in previously nonirradiated patients, stereotactic radiotherapy may be an option for patients who have received whole brain radiation

Treatment of refractory or relapsed disease

Targeted therapies

Primary CNS

Lymphomapathways

B-cell receptor

NFkB

IRF4

PIM kinase

s

JAK/STAT

BCL-6

Ponzoni M, Issa S, Batchelor TT, Rubenstein JL. Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2014;25(2):316-322.

Conclusions• High dose methotrexate based chemotherapy with

consolidation cytarabine is the mainstay of treatment• WBRT should be included in the treatment especially in

young patients (<60 years), response adapted approach may be beneficial

• Rituximab may be tried in upfront management or can be reserved for recurrence

• Local therapy is recommended for Intraocular lymphoma, or leptomeningeal involvement along with systemic therapy

• Targeted therapies are investigational

Immuno-competent patients of newly diagnosed primary CNS lymphoma

Five 14-day cycles of induction chemotherapy with methotrexate, procarbazine, and vincristine (MVP)

Investigations

Response AssessmentNeuropsychological & QoL assessment

Complete Response Partial Response/Stable Disease/Progressive disease

Reduced dose WBRT 23.4Gy/13#/2.5 weeks

Standard dose WBRT 45Gy/25#/5 weeks

Consolidation ChemotherapyInj cytarabine (Ara-C), 2 cycles 1 month apart

Response assessment-CMRI brain every 3 monthsNeuropsychological & QoL assessment 6 monthly post T/t completion