PRIMARY CNS DLBCL (PCNSL) (BSH 2018)
Epidemiology
1% of all NHL, 3% of all brain tumours
Clinical Presentation
Varied – Behavioural change, memory or language impairment, focal motor deficits, seizures, raised intracranial pressure, neuropsychiatric symptoms
Uveitis – 20% of patients have intraocular involvement resembling chronic uveitis
assessment
Fitness assessment - e.g. Charlson Comorbidity Index (CCI), G8 screening tool, Cumulative Illness Rating Scale
Biopsy – intra-operative rapid cytology may avoid extensive surgery
Effect of steroids prior to biopsy – up to 1/3 of biopsies non-diagnostic after <1 week of steroids
CSF – 3-10ml for protein, cytology and immunophenotyping (Alternative: PCR for IGHV rearrangement)
MRI – imaging modality of choice but appearances not to be confused with neurosarcoidosis, multiple sclerosis, glioblastoma and vasculitis which may all share similar features
PET-CT – to look for systemic involvement (CT if PET unavailable)
Testicular USS – PET-CT may not detect testicular involement
Bone marrow biopsy? – not essential if FBC normal & no paraprotein detected
LDH – forms part of prognostic scores
Mini Mental State Examination (MMSE) +/- more detailed neuropsychological assessments
Ophthalmology review – Slit Lamp examination
Other – U&E, LFT, Creatinine Clearance, HIV & Hep B/C prior to chemotherapy
MDT – review of the above at lymphoma MDT
MANAGEMENT
General Considerations
Fitness for treatment
Assess physiological fitness over chronological age
High dose methotrexate requires adequate renal, liver and cardiac function for safe delivery
Performance Status likely to be impaired at diagnosis, may improve with initial treatment
Offer clinical trial where available
Remission Induction
Combination chemotherapy regimen that includes high dose methotrexate (HD-MTX)
MATRix
HD-MTX, Cytarabine, Thiotepa & Rituximab
69% 2 year OS in IELSG32 (International Extranodal Lymphoma Study Group) trial, 56% at 7yrs.
4-7% treatment-related mortality (TRM), mostly in first cycle
MATRix preferred in UK, but other available regimens include:
MT-R – HD-MTX, Temozolimide & Rituximab
R-MPV – Rituximab, HD-MTX, Procarbazine & Vincristine
R-MBPV – Rituximab, HD-MTX, Carmustine, Etoposide, Prednisolone
Less Fit Patients:
Patients considered not fit for MATRix but still able to receive HD-MTX
Several regimens available, most combing HD-MTX with oral alkylating agents
Palliative therapy
Patients unfit to receive HD-MTX have a very poor prognosis
Whole brain radiotherapy, steroids and oral chemotherapy are all options
Consolidation
Chemotherapy Consolidation
i.e. Autologous Stem Cell Transplant
70-80% 3-5 year OS in prospective trials, only a minority of patients also received WBRT
PRECIS Trial – 2-year PFS 86% Autograft vs 63% WBRT, no difference in OS
Whole Brain Radiotherapy (WBRT)
30-45Gy
Causes irreversible, potentially debilitating, neurocognitive dysfunction. Esp. if >60 y.o.
Some evidence to suggest of less benefit with modern induction regimens
Decision to use requires MDT discussion including neuroradiology
Follow-Up
MRI 1-2 months after completion of consolidation
MRI Surveillance?
Consider 3-4 monthly MRI for 2 years is patient would be fit for salvage chemotherapy
Rationale: Higher OS rates when patients salvaged for asymptomatic relapse
Relapsed/Refractory Disease
Median survival – 3.5 months
Re-biopsy
Offer clinical trial wherever possible
Options
Ifosfomide-based regimens: R-ICE (Rituximab, Ifosfomide, Carboplatin, Etoposide)
Re-treatment with HD-MTX if good first remission
Novel agents: Ibrutinib, Nivolumab, Lenlidomide, Tafasitamab
primary intraocular lymphoma (piol)
Variant of PCNSL
High rate of CNS relapse post treatment and CNS lymphoma is primary cause of death in PIOL
Drugs that cross blood-brain barrier also cross blood-ocular barrier
Fit Rx: MATRix or similar, followed by ocular radiotherapy +/- WBRT or Autograft
Unfit Rx: Intravitreal methotrexate
A Few Trial notes
IELSG32 2016
219 patients. Phase 2 randomised trial for 1st treatment of primary CNS lymhpoma
HD-MTX + Cytarabine vs additional Rituximab vs additional Rituximab and Thiotepa (MATRix)
Followed by Whole Brain Radiotherapy vs High Dose Autograft
CR of 23%, 30% and 49% respectively for the induction regimens given above
69% 2 year OS
6% treatment-related mortality (TRM)