primary cns lymphoma: how i treat · primary cns lymphoma: how i treat antonio omuro, md yale brain...
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Primary CNS Lymphoma: How I treat
Antonio Omuro, MD
Yale Brain Tumor CenterYale Cancer Center and Smilow HospitalNew Haven, CT, USA
Newly Diagnosed PCNSL:Principles of Treatment
• >95% DLBCL; >80% non-GC; MYD88and CD79B mutations
• Induction treatment
• Consolidation treatment
• Maintenance treatments: No role defined to date
Age has profound prognostic and treatment implications
Induction treatment: Which regimen?
• High-dose MTX based:- Dose >= 3.5g/m2 - Rapid infusions (e.g. over 2
hours)- Multi-drug regimen- Dosing <= 2 weeks apart- Just enough leucovorin• In the US: IV rituximab used in
all regimens; G-CSF support– R-MPV (+A)– R-MT (and variations)
• Aim is to achieve response rates >90%, with no toxic deaths
Hochberg , 2007
Which Consolidation Treatment?• Starting with minimal disease is essential
• Radiotherapy:
– No role for full dose WBRT (36-42 Gy or higher) due to neurotoxicity risks
– No role for focal RT, tumor bed boost or SRS.
– Reduced dose WBRT 23.4 Gy under investigation, elderly??
• HDCASCT:
– No role for BEAM
– TBC: Best phase II results, but can be toxic
– BCNU/ Thiotepa: Milder but possibly less efficacious
– Superior cognitive outcomes
• Non myeloablative regimens:
– Cytarabine/ etoposide: Interesting results but toxic
– HD cytarabine: Not really a consolidation, complement to R-MPV
Multicenter Phase II Trial of R-MPV followed by reduced-dose WBRT (23.4 Gy) in responding patients
• ORR to induction: 95% (CR: 79%)• 2-yr PFS = 57% • mPFS = 3.3 yr
• 2-yr OS = 81% ; 5-yr OS = 70% • mOS = 6.6 yr (med follow-up= 5.6yrs)• mOS elderly= 5.5yr
• Neuropsych data: Improvement in all cognitive domains following induction chemo.• No significant cognitive decline so far, although FLAIR abnl seen on MRI.
Morris et al, JCO 2013
R-MPV + HDCASCT with thiotepa, busulfan and cyclophosphamide
OS
• N=32• ORR before transplant: 96% • N=26 (81%) transplanted• 2y and 5y PFS: 81% •Med PFS: Not reached
•2y and 5y OS: 81% •Med OS: Not reached•2 pts died from acute complications, 1 died from graft vs host • No progression or deaths in pts <50
PFS
Omuro et al, Blood 2015
Omuro et al, Blood 2015
MSK 04-129: Neuropsychological and QoL results
R-MT followed by CYVE (CALGB)
• N=44 pts; 81% ECOG 0-1
• R-MT (8 g/m2 adjusted by creatinine clearance) + CYVE
• ORR: 77% (66% CR)
• Med TTP: 4y
• 4y OS: 65%
• 50% Gr 4 thrombocytopenia
Rubenstein , JCO 2013
Phase II MPV-A vs MT in elderly pts (>60yo); No consolidation
Omuro et al, Lancet Haematol 2015
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Months
MPV-A
MT
Number at risk
MPV-A 47 27 16 15 12 8 2 0MT 48 25 17 16 11 8 2 0
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Months
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MT
Number at riskMPV-A 47 35 29 24 21 14 4 1MT 48 32 23 20 17 132 4 0
PFS
OS
MT MPV-A
PFS 6m 10m
OS 14m 31m
CR/uCR 45% 62%
Gr 3 /4 tox 71% 72%
• N= 98, 1:1 randomization, MTX 3.5g/m2; G-CSF• Non comparative “pick the winner” phase II design
Global Health Status
• Randomized phase II IELSG32: Methotrexate, cytarabine, thiotepa, and rituximab + WBRT or HDCASCT
• ORR 87% (49% CR)
• 73% gr 4 thrombocytopenia, 6% toxic death off induction
• MTX 3.5 g/m2 every 3 weeks (with frequent delays), “slow” infusion (3 hours)
• Not adopted in any major US center
Ferreri al, Lancet Haematol
Ph II IELSG32 (MATRIX) Induction Regimen
Ph II IELSG32: WBRT vs transplant
• Second randomization• 118 randomized (half were
ineligible)• WBRT 36Gy + 9 Gy boost• HDCASCT • 2 y PFS: 80% WBRT vs 69%
HDCASCT: BCNU/ thiotepa• Late progressions and 2 toxic
deaths with transplant• Neurocognitive evaluation:
Worsening in some domains with WBRT (attention and executive function) and improvements with transplant
Ferreri al, Lancet Haematol
PRECIS: Ph II trial WBRT vs Transplant• Induction: Rituximab, MTX 3
g/m2, VP16, BCNU, prednisone, Ara-C; Depocyt for CSF involvement
• ASCT (Thiotepa, busulfan, cyclophosphamide) vs WBRT 40Gy
• N=140 pts < 60 yo
• ORR to induction 70% (43% CR)
• 2y PFS:63% (WBRT) vs 87% (ASCT)
• 5 toxic deaths (11%) , 4-y OS 64% WBRT vs 66% HDCASCT
Soussain et al, JCO
HOVON trial: Rituximab • N=200 pts; MTX 3 g/m2 (4 doses), teniposide, carmustine, prednisolone, HD
cytarabine, young pts: WBRT (30 Gy, boost if PR)
• ORR: 86% (CR: 36% and 30%)
• EFS: 49% vs 52% (R), p=0.99 ; 3y OS: 61% vs 58%
Elderly PCNSL patients• High response rates but frequent relapses (but often respond
to salvage)
• Multi-drug regimens feasible, transplant challenging
• Dose adjustments according to Cr clearance
– Creatinine is not a good parameter (need the clearance)
– If clearance > 50: doses up to 3.5 g/m2 can be given without adjustment; regimens using higher MTX doses usually require adjustments
– Adjust doses of renal excreted medications (e.g. levetiracetam)
• Liberal use of G-CSF
• Glucarpidase (carboxypeptidase G2) may be used
Ongoing US randomized phase II studies
• RTOG 1114 (Omuro): R-MPV-A with or without low dose WBRT (23.4 Gy)
• Alliance 51101 (Batchelor/ Rubenstein): R-MT followed by HDCASCT (Thio/ BCNU) vs CYVE
• Univ Oregon (Doolittle): Obinutuzumabmaintenance
• Alliance (Alencar): Lenalidomide maintenance in elderly
Recurrent Disease: MTX re-challenge
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Kaplan-Meier survival estimate
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PFS
OS
Med PFS: 12m 1y PFS: 56%2y PFS: 24%
Med OS: 23m 1y OS: 74% 2y OS: 47%
• N=39 patients with relapses (8-179 months after initial diagnosis)
• ORR: 85% (75% CR)
• MSKCC RPA class predicted PFS (p= 0.02) and OS (p= 0.04)
Pentsova et al, JNO
Recurrent Disease: HDCAST with TBC for consolidation after salvage chemo
• Soussain et al: CYVE + TBC
• 63% transplanted; for those median OS 59 months
• Transplant series Cote et al; Welch et al:
• 3y OS: 93%
• 70 and 80%: Salvaged with MTX re-challenge
Welch et al, Leuk Lymph
Conclusions
• Phase II randomized trials: Insights, but not definitive answers
• I use R-MPV followed by HDC-ASCT with TBC (80% long term survival, flat PFS curve)
• Necessary for MSK RPA class I? Doable in the community?
• Questions:
– Treatment for elderly that are not candidates for transplant
– Neurotoxicity of reduced dose WBRT
• Recurrent disease: R-MTX regimens re-challenge (and transplant with TBC if not already done)
• MTX-refractory disease: Clinical trials (ibrutinib, lenalidomide, pomalidomide, nivolumab, pembrolizumab)
Acknowledgements
• Neuro-Oncology Fellows
• Denise Correa
• Tracy Batchelor
• Khe Hoang-Xuan
• James Rubenstein
• Carole Soussain
• Lauren Abrey
• Lisa DeAngelis
• Alvaro Alencar
• NRG and Alliance
Each cycle: two MTX 3.5 g/m2 doses, total of 8 treatmentsWBRT (arm B): 2340 cGy (180 cGy X 13)Neuropsychological testing throughout, including in progressing patients
RTOG 1114: Randomized Phase 2 Study of R-MPV-A with or without reduced dose WBRT
RTOG 1114 Questions
• Does low-dose WBRT improve PFS? – Primary endpoint: PFS . – N=84 eligible pts (42 pts/ arm)– 80% power, HR 0.63, significance level 0.15
• Is low-dose WBRT less neurotoxic than full-dose WBRT?
• Could low-dose WBRT improved long-term cognitive function in comparison to R-MPV alone by decreasing the cognitive deterioration from disease recurrence and multiple salvage therapies ? Competing risk methodology accounting for death
Refractory disease
• Activity with lenalidomide, pomalidomide, ibrutinib, nivolumab, CAR T cells
• Clinical trials a must
Abramson, NEJM 2017
Refractory disease: Lenalidomide
• Analog of thalidomide targeting angiogenesis, cytokines and inducing apoptosis
• Activity in Non-GC DLBCL• Evidence of activity as single-
agent in PCNSL• In combination with rituximab:
63% response rate, but PFS of 8 months.
• Role as maintenance therapy under investigation
• Also under study: Pomalidomide
Ghesquieres, Blood 2016
Refractory Disease: Ibrutinib
• Evidence of mutations in other NFkB components
• Higher frequency of MYD88 (~60%) +/- CD79B ITAM mutation (~50%)
• Phase I trials: - 10/13 PCNSL pts (but PFS 5
months)- MYD88/ CD79B association
may not be necessary for response
• Responses also seen in combination with chemo (DA-TEDDi-R)
• Concern: Aspergylosis• Study in combination with
R-MTX planned
Grommes, Blood 2017Lionakis, Cancer Cell 2017
Refractory Disease: Anti-PD1 antibodies
• PD1 and/or PD-L1 expression on tumor cells, tumor infiltrating lymphocytes or tumor associated macrophages observed in 90% of PCNSL cases.
• Anecdotal experience with responses with Nivolumaband pembrolizumab (Nayaket al)
• Phase 2 single-agent studies in recurrent/refractory PCNSL ongoing
Bergoff et al, 2013
A: Prominent PD1 expression on PCNSL tumor cells B: Prominent accumulation of PD1-positive lymphocytesin the border region of PCNSL and surroundingCNS tissue C: High density of PD1-positive tumor-infiltratinglymphocytes (TILs) in PCNSL
Refractory disease: Anti-CD19 CAR T Cells
Abramson, NEJM 2017
• Neurotoxicity a concern in DLBCL treated with CAR T cells; CAR T cells found in the CSF.
• Case report of a secondary CNS lymphoma that responded after treatment with lymphodepletion with fludarabine/ cyclophosphamide followed by anti-CD19 CAR T Cells, lasting 1y+.
• Studies planned.
RANDOMIZATION TO ARM A OR ARM B, stratified by MSK RPA
Induction (5 cycles*)
Cycle 1-4
Methotrexate 8 g/m2 , D 1 and 15
Temozolomide 150-200 mg/m2 D 7-11
Rituximab 375 mg/m2 D 3, 10, 17, 24
Cycle 5:
Cytarabine 2 g/m2 IV, Q12 hours, D 1 and 2
ARM A: CONSOLIDATION WITH STEM CELL RESCUE
Carmustine, 400 mg/m2 IV, D -6
Thiotepa 5mg/kg IV Q12 hours, D -5 and -4
Stem Cell Infusion, D 0
ARM B: CYVE CONSOLIDATION ( 1 cycle *)
Cytarabine 2g/m2 IV, Q12 hours, D 1-4
Etoposide 5 mg/kg IV over 12 hours Q12 hours x 8 doses (total dose 40 mg/kg CIVI over 96 hours), D 1-4
Alliance 51101
Courtesy Dr Tracy Batchelor
MPV vs MT in Elderly: QOL and Cognitive Function in elderly
QoL: EORTC QLQ-C30 and BN-20 Neuropsychological evaluation
Mattis Dementia Rating Scale
Global Health Status
Omuro et al, Lancet Haematol 2015