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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48

Months

MPV-A

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

0.0

00

.25

0.5

00

.75

1.0

0

0 20 40 60 80analysis time

Kaplan-Meier survival estimate

0.0

00

.25

0.5

00

.75

1.0

0

0 20 40 60 80analysis time

Kaplan-Meier survival estimate

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

Antonio.Omuro@Yale.edu

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