primary cns lymphoma (pcnsl) what is the optimal...

Primary CNS Lymphoma (PCNSL)

What is the optimal treatment?

Dr Kate Cwynarski

Consultant Haematologist

UCLH

LONDON

Outline: PCNSL

●Induction

–Chemoimmunotherapy

●Consolidation

–PBSCT

–WBRT

●Relapsed disease

–Chemotherapy

–Non-chemotherapy

–Immunotherapy

PCSNL is rare but incidence is increasing

● Represents approx 2-4% extra-nodal NHL

5% Primary CNS tumours

● Incidence about 1 / 100 000 / year

About 60% of patients > 60 years at diagnosis

Makino et al, Surg Neurol 2006; Olson et al, Cancer 2002; Panageas et al, Cancer 2007

Primary CNS Lymphoma (PCNSL)

Aggressive lymphoma entity with a unique

localisation

Drug delivery to CNS

Surrounding brain tissue is highly vulnerable

The Blood Brain Barrier

Mechanisms That Prevent

Drug Delivery To The CNS

1. Plasma protein binding

2. Endothelial tight junctions

3. Active drug efflux

Factors Influencing BBB

Penetration

1. Plasma concentration

2. Lipid solubility

3. Hydrostatic pressure

within tumour

4. Route of administration

(IV vs IA)

5. Disruption of BBB

6. Drug metabolism

Prognosis In PCNSL

● IELSG Score

– Age >60

– ECOG >0

– Elevated LDH

– Elevated CSF protein

– Deep brain lesions

● MSKCC Score

– Age >50

– KPS <70

Therapy Of PCNSL

● High dose methotrexate

● Cytarabine

● Ifosfamide

● Temozolamide

● Thiotepa

● Rituximab

● Whole Brain Radiotherapy

● Conventional Chemotherapy

● High Dose Therapy + Auto-SCT

Induction Consolidation

●

PCNSL [≤ 65 ys. + PS 0-3] or [65-70 ys. + PS ≤2]

®

® WBRT 36 Gy

± boost 9 Gy

BCNU 400 mg/m2 d.1

Thiotepa 5 mg/Kg x 2/d; d.2-3

+ APBSCT www.ielsg.org

4 c. MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

every 3 weeks

ARM A

4 c. rituximab 375 mg/m2 d-5 & 0

MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

every 3 weeks ARM B


MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

Thiotepa 30 mg/m2 d.4

every 3 weeks ARM C

Response assessment after 2° & 4° courses and after consolidation

CR – PR - SD PD – tox

SC harvest

WBRT 40 Gy

± boost 9 Gy

IELSG-32

Feasibility and Toxicity

A (n= 75) B (n= 69) C (n= 75) p

Actually delivered courses 223 (74%) 236 (86%) 274 (91%)

RDI Methotrexate 92% 84% 85% NS

RDI Cytarabine 87% 81% 80% NS

RDI Rituximab - 82% 83% NS

RDI Thiotepa - - 76% -

G4 neutropenia 99 (44%) 119 (50%) 153 (56%) 0.01

G4 thrombocytopenia 116 (52%) 140 (59%) 200 (73%) 0.0001

G4 anemia 9 ( 4%) 6 ( 3%) 14 ( 5%) NS

G≥3 febrile neutrop./infections 43 (19%) 31 (13%) 45 (16%) NS

G4 hepatotoxicity 6 ( 3%) 3 ( 1%) 1 ( 1%) NS

G4 nephrotoxicity 0 ( 0%) 0 ( 0%) 1 ( 1%) NS

Interruptions x toxicity (/pts) 9 (12%) 5 ( 7%) 4 ( 5%) NS

Toxic deaths (/ pts) 7 ( 9%) 3 ( 4%) 3 ( 4%) NS

Autologous stem cell collection 48/51 (94%) 44/46 (96%) 60/64 (94%) NS

Median APBSC (x 106 c/kg bw) 12.3 15 8.2 NS

MATRix: Efficacy

0 12 24 36 48 60

Months

0,0

0,2

0,4

0,6

0,8

1,0

Pro

babili

ty,

PF

S

Arm A

Arm B

Arm C

A

A vs. B= 0·06, HR= 0·68, 95%CI=0·45 - 1·02

A vs. C= 0·0001, HR= 0·66, 95%CI=0·53 - 0·81

B vs. C= 0·049, HR= 0·63, 95%CI=0·40 - 0·99

0 12 24 36 48 60

Months

0,0

0,2

0,4

0,6

0,8

1,0

Pro

babili

ty,

OS

Arm A

Arm B

Arm C

B

A vs. B= 0·14, HR= 0·73, 95%CI=0·48 - 1·11

A vs. C= 0·0004, HR= 0·65, 95%CI=0·52 - 0·83

B vs. C= 0·02, HR= 0·57, 95%CI=0·35 - 0·93

Ferreri, Cwynarski, Pulczynski et al, Lancet Haematology 2016

Median follow up 40 (19-76) months

Therapy Of PCNSL

● High dose methotrexate

● Cytarabine

● Ifosfamide

● Temozolamide

● Thiotepa

● Rituximab

● Whole Brain Radiotherapy

● Conventional Chemotherapy

● High Dose Therapy + Autologous Stem Cell Transplant

Induction Consolidation

Neurotoxicity

● Causes

– Lymphoma

– Chemotherapy

– WBRT Post chemotherapy (even worse pre-)

● Clinical Irreversible leukoencephalopathy

● Radiological

● Neurocognitive MMSE, Neuropsychological

● Quality of life Correa 2012, Abrey 2005

The role of whole brain radiation in primary CNS lymphoma.

Kasenda B et al, Blood. 2016

●

PCNSL [≤ 65 ys. + PS 0-3] or [65-70 ys. + PS ≤2]

®

® WBRT 36 Gy

± boost 9 Gy

BCNU 400 mg/m2 d.1

Thiotepa 5 mg/Kg x 2/d; d.2-3

+ APBSCT www.ielsg.org

4 c. MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

every 3 weeks


MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

every 3 weeks


MTX 3.5 g/m2 d.1

araC 2 g/m2 x 2/d, d. 2-3

Thiotepa 30 mg/m2 d.4

every 3 weeks

Response assessment

CR – PR - SD PD – tox

SC harvest

WBRT 40 Gy

± boost 9 Gy

IELSG-32

R2:

CR vs PR/PD

A vs B vs C

EFFICACY: PFS

0 12 24 36 48 60

Months

0,0

0,2

0,4

0,6

0,8

1,0

Pro

babili

ty,

PF

S

arm D

arm E

A

p= 0.17

Randomization Primary

endpoint

P0* P1 α 1 - β Estimated

sample

Minimum N° of

progression-free

survivors at 2 ys.

2nd 2-yr PFS 65% 85% 5% 95% 52/ arm 40

ITT Arm D Arm E

First 104 pts (52/ARM) 40 (77%) 40 (77%)

0 12 24 36 48 60

Months

0,0

0,2

0,4

0,6

0,8

1,0

Pro

babili

ty,

PF

S

WBRT

ASCT

B

p= 0.62

ITT PP

EFFICACY: OS

102 (47%) pts are alive:

- 44 (75%) in arm D

- 37 (63%) in arm E

- 21 pts excluded from R2.

Causes of death Arm D Arm E Non R2

lymphoma 11 15 62

treatment toxicity 0 2 13

toxicity during salvage therapy 1 1 0

neurocognitive decline while NED 0 1 1

late infective complications 3 1 2

car accident 0 0 1

acute erythroid leukaemia 0 1 0

sudden death (> 1 yr) 0 1 0

unknown 0 0 1

ITT

PP

Progression free and overall survival:

UK Experience Auto-SCT in PCNSL

(n=78)

● Median PFS and OS not reached

PFS % OS %

1 year 86 86

2 year 76.6 82

5 year 71.8 74.5

Kassam et al, BMT 2017

Management challenges in treating

older patients

● - High proportion of elderly pts

- Poor PS at presentation

- Biopsy not performed

- Palliative treatment considered

- Therapeutic consensus is lacking

PRIMAIN Trial

Kasenda, et al. Leukemia 2016

PRIMAIN Trial - Efficacy

Kasenda et al, Leukaemia 2016

HDT And AutoSCT In Older Patients

With PCNSL?

● 50% of patients with PCNSL >65yrs

● Prognosis of older patients worse

● Ability to tolerate intensive therapy restricted

● WBRT associated with greater neurotoxicity in

older patients


With PCNSL

Schorb et al BMT 2017

• Retrospective, multicentre

• Germany/France/UK

• Median age 68.5 (65-77)

• n=52

• KPS 80% (30-100%)

• 71% first line

• Median F/U 20/12

• Thiotepa based HDT


With PCNSL

Schorb et al BMT 2017

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

Survival Time (Months)

Su

rviv

al p

rob

ab

ility

PFS2: 2.2 months [0-29.6]

OS2: 3.5 months [0-29.6]

Management and outcome of Primary CNS

Lymphoma at first relapse/progression: Analysis of

256 patients from the French LOC NetworkSSION

Langnier-Lemercier et al, Neuro-Oncol 2016

Prognosis of relapses/refractory PCNSL OS according to duration of first remission

LOC data base (N = 256 R/R patients)

Langnier-Lemercier et al, Neuro-Oncol 2016

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

Survival Time (Months)

Su

rviv

al p

rob

ab

ility

Relapsed patients

Refractory patients

PFS 1 ≥ 1 year

PFS 1 < 1 year

OS2= 2.1mo

OS2= 3.7mo

OS2= NR

A Phase I/II Study of Thiotepa, Ifosphamide, Etoposide

and Rituximab (TIER) for the treatment of relapsed and

refractory PCNSL

Rituximab 375mg/m2

Etoposide 250mg/m2

Ifosphamide 2g/m2

Thiotepa 20-50mg/m2

GCSF(mobilising)

q21d

0 1 2 3 5

8

GCSF

CI: Chris Fox Bloodwise TAP Study

PCNSL previously treated with a

HD-MTX-based therapy

Relapsed/refractory disease

Eligible for TIER

2 cycles of protocol

treatment

Response

assessment:

multimodal MRI

PBSC mobilisation

PD Off-

study

F/U data

≥SD 3rd cycle

TIER

Local decision re

consolidation

therapy

- Thiotepa/BCNU

HDT-ASCT

recommended

Illerhaus et al. Manuscript in prep

Relapsed PCNSL: The German Approach

(Kasenda et al, Leukemia 2017

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

after1stR/ AraC/TT

after2nd R/AraC/TT

afterHD (d30)

offStudy

n.d.

PD

SD

PR

CR




Med FU: 45.2 Mo

Med OS: n.r

3y OS: 50.9 %

50.9%




iLOC: Ibrutinib Monotherapy in Relapse or Refractory

Primary CNS Lymphoma (PCNSL) and Primary

Vitreo-Retinal Lymphoma (PVRL). Results of the final

analysis of the primary end-point

Sylvain Choquet, Caroline Houillier, Fontanet Bijou, Roch Houot, Eileen Boyle, Remy Gressin, Emmanuelle Nicolas-Virelizier, Maryline Barrie, Cécile Moluçon-Chabrot, Marie Blonski, Abderrazak El Yamani, Marie-Laure Lelez, Aline Clavert, Solène Coisy, Marjan Ertault de la Bretonnière, Valérie Touitou, Nathalie Cassoux, Sami Boussetta, Florence Broussais, Benedicte Gelas-Dore, Noélie Barzic, Hervé Ghesquières, Khê Hoang-Xuan, Carole Soussain

Rationale

1. PCNSL: ABC-DBCL

2. Mutations of MYD88

and CD79b

3. Unmet medical needs

4. Activity of Ibrutinib in

systemic ABC-

DLBCL

HE

S

CD 10 BCL6 MUM1

4%

51 %

45 %

96 %

Camilleri-Broët S, Blood 2006; Montesinos-Rongen,

Leukemia 2008; Gonzalez-Aguiar, Clin Cancer Res 2012;

Advani, J Clin Oncol 2013; Chapuy, Blood 2016

iLOC study: Main Features

● Prospective multicenter phase II.

● Relapse/Refractory DLBCL- PCNSL or PVRL

● > 18 y

● ECOG PS < 2

● 1-4 previous lines of chemotherapy

● Corticosteroids allowed during the first cycle

Schedule: Ibrutinib in relapsed PCNSL

Ibrutinib : 560 mg/day until disease progression or TRT

Therapeutic Response Evaluations: IPCG criteria

Soussain et al, ICML 2017

Primary Objective

● DC rate (CR + CRu + PR + SD) after 2 cycles of treatment or at treatment discontinuation.

● Response evaluation according to IPCG criteria

– Evaluated locally by investigators.

– Central review of MRI

Methods

● Two-stage Simon’s design

– Ineffective treatment if the DC rate < 10% (H0)

– Effective treatment if the DC rate > 30% (H1)

– Risk 1-sided α = 0.05 and power = 80%

● Sample size

– Stage 1: 18 patients with an efficacy threshold of 3 patients (ASH abstract # 784): DC in 15/18 patients

– Stage 2: 35 patients with an efficacy threshold of 7 patients

Patients are evaluable for response if they received 90 % of the planned dose for the first month of treatment

iLOC

Patients evaluable for response

N=43 patients

Patients Enrolled

N=52 patients

Early treatment discontinuation < 1 month : N = 9 (PD in 8, toxicity in 1)

End of treatment : N = 32

On going treatment

N=11 patients

Sept 30, 2015 – July 6, 2016

May 2017

Patient characteristics

Age (range) 70 (range 52-81)

Gender ratio M: F 19: 24

PS 0-1

PS 2

33 (77%)

10 (23%)

> 2 lines of treatment 26 (60%)

ASCT n=4; WBRT n=1

Relapse vs refractory disease 30 (70%) vs 13 (30%)

Disease assessment at start of

treatment:

Brain parenchyma/Spinal cord

Intraocular

29 (inc 5 with IO)

14 (inc 2 with CSF)

Corticosteroids during Course 1 14

Results (1)

Therapeutic response

DC @ 2 cycles

DC = 30/43 (70%)

ORR = 26/43 (60%)

N = 43

CR + uCR 10 (23.2 %)

PR 16 (37.2%)

SD 4 (9.3 %)

PD 13 (30.2 %)

Results (2)

Previous corticosteroids therapy

DC @ 2 cycles

N = 43

CR + uCR 10 (23.2 %)

PR 16 (37.2%)

SD 4 (9.3 %)

PD 13 (30.2 %)

Corticosteroid

No

(n = 29)

Yes

(n = 14)

CR + uCR 10 0

PR 12 4

SD 2 2

PD 5 8

DC according to site of disease

● Brain or spinal cord involvement at baseline : N = 29

DC @ 2 cycles = 16/29 (55 %)

– CR : 4; PR: 10 (ORR = 14/29, 48 %), including 5 nearly CR

– SD: 2

– PD: 13

● IO involvement at baseline: n = 19

DC @ 2 cycles = 16 (84 %)

– CR : 10; PR: 4 (ORR = 14/19, 74%)

– SD: 2; ND: 1; inconclusive : 2

● CSF involvement at baseline: n = 4

– CR: 3

– Not done in 1

Duration of Ibrutinib treatment

● Median follow-up = 9.2 m

● DC rate (70%) @ 2 months

● Median number of cycles = 6

21 patients > 6 months

11 patients > 12 months

● Discontinations of treatment

in 32 patients

– PD: N = 25

– Toxicity of study treatment: N =3

– Other : N = 4 0 2 4 6 8 10 12 14 16 18 20 22

Cycle evaluable

Progression evaluable

EOT Evaluable

Death Evaluable

Duration of treatment according to site of

disease involvement at baseline

No parenchyma involvement

(n = 14)

Parenchyma Involvement

(n = 29)

12 months 6 months

Before @ 2

months

@ 18 months

Adverse events

N=52 AE Intensity

1 3 (5.7%) 2 25 (47.2%) 3 16 (30.2%) 4 5 (9.4%) 5 4 (7.5%) Missing 1

Relationship with Ibrutinib Related 15 (28.3%) Unrelated 37 (69.8%) Not applicable 1 (1.9%) Missing 1

N=52 Patients Events

Ae 22 (42.3%) 54 Infection 7 (13.5%) 11

General Disorders 5 (9.6%) 5

Blood And Lymphatic System Disorders 4 (7.7%) 7

Nervous System Disorders 4 (7.7%) 4 Cardiac Disorders 3 (5.8%) 3 Gastrointestinal Disorders 3 (5.8%) 8

Vascular Disorders 3 (5.8%) 3 Psychiatric Disorders 2 (3.8%) 2 Respiratory, Disorders 2 (3.8%) 3

Eye Disorders 1 (1.9%) 3 Hepatic Disorder 1 (1.9%) 1 Metabolism And Nutrition Disorders 1 (1.9%) 1

Renal And Urinary Disorders 1 (1.9%) 1 Surgical And Medical Procedures 1 (1.9%) 1

SAE of special interest

● Ventricular hemorrhage (n= 2)

● Hyphema (n = 1)

● Atrial fibrillation (n =2)

● Two cases of Pulmonary Aspergillosis

– At 1 months with a favourable outcome

– After a severe flu and 21 days of ibrutinib with a

fatal outcome

Conclusions

1. Manageable toxicity

2. ‘Proof of concept’ of activity of ibrutinib in R/R

PCNSL with a DC rate (70%) @ 2 months

– Responses in the brain, IO, CSF, spinal cord

3. Single agent ibrutinib can be considered as a

treatment alternative in selected patients

4. Benefit of ibrutinib in combination with

chemotherapy at relapse and in first-line treatment of

PCNSL

5. Role of ibrutinib monotherapy in first-line PVRL

CheckMate 647: A Phase 2, Open-Label Study of

Nivolumab in Relapsed/Refractory PCNSL or

Relapsed/Refractory Primary Testicular

Lymphoma

Lakshmi Nayak,1 Fabio M Iwamoto,2 Andrés José María Ferreri,3 Armando Santoro,4 Samuel

Singer,5 Connie Batlevi,6 Tracy T. Batchelor,7 James Rubenstein,8 Patrick Johnston,9

Radhakrishnan Ramchandren,10 Carole Soussain,11 Jan Drappatz,12 Kevin Becker,13 Mathias

Witzens-Harig,14 Gerald Illerhaus,15 Alex F. Herrera,16 Aisha Masood,17 Margaret Shipp1

1Dana-Farber Cancer Institute, Boston, MA, USA; 2Columbia University Medical Center, New York, NY, USA; 3IRCCS

San Raffaele Scientific Institute, Milan, Italy; 4Humanitas Cancer Center – Humanitas University, Rozzano–Milan, Italy; 5Hackensack University Medical Center, Hackensack, NJ, USA; 6Memorial Sloan Kettering Cancer Center, New York,

NY, USA; 7Massachusetts General Hospital, Boston, MA, USA; 8University of California San Francisco Medical Center,

San Francisco, CA, USA; 9Mayo Clinic, Rochester, MN, USA; 10Barbara Ann Karmanos Cancer Institute, Detroit, MI,

USA; 11Institut Curie, Hôpital René-Huguenin, Saint-Cloud, France; 12Hillman Cancer Center, University of Pittsburgh

Medical Center, Pittsburgh, PA, USA; 13Yale Cancer Center, New Haven, CT, USA; 14University Hospital Heidelberg,

Heidelberg, Germany; 15Klinikum Stuttgart, Stuttgart, Germany; 16City of Hope, Duarte, CA, USA; 17Bristol-Myers

Squibb, Princeton, NJ, USA

Presented at the 14th International Conference on Malignant Lymphoma (ICML); Lugano, Switzerland; June 14–17, 2017

Preclinical & clinical studies have shown that

lymphoid malignancies with 9p24.1/PD-L1/PD-L2

alterations are genetically predisposed to rely on

PD-1 mediated immune evasion

Immune evasion in lymphoid malignancies

PD–L1 and PD-L2 protein expression is increased

via PD–L1 and PD-L2 copy gain and transcription

is further induced via JAK2/STAT signaling

1. Green et al. Blood 2010;116:3268–77; 2. Hao et al. Clin Cancer Res 2014;20:2674–83; 3. Roemer et al. J Clin Oncol 2016; 34:2690.

9p24.1 Amplicon Block

1) JAK2 amplification

3) JAK-2-induced

PD-1 ligand

transcription and

cellular proliferation

2) Increased JAK2

protein expression

and kinase activity

–log10

(Q value) 2 4

p24.2

p24.2

JAK2 PD-L1/2

0

p24.1

PD-L1/PD-L2 Genetic Alterations in PCNSL and PTL

EBV = Epstein-Barr virus; PD-1 = programmed death-1

Chapuy B et al. Blood 2016;127:869–81.

PCNSL and PTL genetic signatures exhibit frequent PD-L1 and PD-L2 copy number gain

resulting in increased protein expression

2

0

EBV- (n=42)

PTL (n=43) PCNSL (n=50)

EBV+ (n=8)

35% (15/43) 67% (28/42) 63% (5/8)

PD-L1 copy number gain

0

4

6

8

16

Co

py N

um

ber

No

rmals

L

428

S

UP

DH

1

HD

LM

2 1 7 22 41 43

2

4

6

8

16

Co

py N

um

be

r

No

rma

ls

L428

S

UP

DH

1

HD

LM

2 4 15 39 44 49

case #7

PD

-L1

case #43

PD

-L1

case #4 case #39 case #49

Cases with copy gain are highlighted in blue. Error bars reflect standard

deviation

Targeting the PD-1 Pathway in PCNSL and PTL with Nivolumab

PD-1 = programmed death-1

1. Chapuy B et al. Blood 2016;127:869–81; 2. Roemer M et al. J Clin Oncol 2016;34:2690–7; 3. Ansell SM et al. N Engl J Med

2015;372:311–9; 4. Younes A et al. Lancet Oncol 2016;17:1283–94;

Nivolumab is a fully-human immunoglobulin G4 monoclonal antibody targeting the

programmed death-1 (PD-1) receptor immune checkpoint pathway

PD-L1/PD-L2 genetic alterations in PCNSL and PTL1 suggest targeting the PD-1

pathway may be a promising therapeutic strategy, as seen in classical Hodgkin

lymphoma2–4

Clinical Case Series With Off-Label Nivolumab

Characteristics N=5

Tumor type

• Primary refractory PCNSL = 1

• Recurrent PCNSL = 3

• CNS recurrence of PT = 1

Median age (range), years 64 (54–85)

Median KPS (range), % 70 (40–80)

Treatment history

All pts treated with standard regimens

including HD-MTX based chemotherapy, ASCT

and WBRT

Nayak L et al. Blood 2017; doi: 10.1182/blood-2017-01-764209

Case Series: Responses to Nivolumab in R/R PCNSL or PTL

Patient #1 #2 #3 #4 #5

Disease

Primary

refractory

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

CNS recurrence

of PTL

Presenting

symptoms

Visual field deficit

& cognitive

change

Cognitive change

Nausea,

vomiting,

ataxia

Asymptomatic Aphasia,

impaired LOC

KPS, % 70 80 50 80 40

Radiographic

response CR CR PR CR CR

Neurologic/

clinical

response

Complete

Resolution

Complete

Resolution Resolution

Stable

(asymptomatic) Resolution

KPS, % 90 80 70 80 80

PFS, months 13+ 17 17+ 14 14+


Nayak L et al. Blood 2017; doi: 10.1182/blood-2017-01-764209


Median number of treatments to objective radiographic response was 3 (range, 2–4)

Persistent ocular disease was observed in 1 patient


Patient #1 #2 #3 #4 #5

Disease

Primary

refractory

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

CNS recurrence

of PTL

Presenting

symptoms


& cognitive

change

Cognitive change

Nausea,

vomiting,

ataxia


impaired LOC

KPS, % 70 80 50 80 40

Radiographic


Neurologic/

clinical

response

Complete

Resolution

Complete


Stable


KPS, % 90 80 70 80 80

PFS, months 13+ 17 17+ 14 14+

KPS = Karnofsky performance status; LOC = level of consciousness; PFS = progression-free survival, CR = complete response, PR = partial

response

Nayak L et al. Blood 2017; doi: 10.1182/blood-2017-01-764209 [Epub ahead of print]


All patients were alive at a median follow-up of

17 months

KPS = Karnofsky performance status; LOC = level of consciousness; PFS = progression-free survival, CR = complete response, PR = partial

response Nayak L et al. Blood 2017; doi: 10.1182/blood-2017-01-764209 [Epub ahead of print]


Patient #1 #2 #3 #4 #5

Disease

Primary

refractory

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

Recurrent

PCNSL

CNS recurrence

of PTL

Presenting

symptoms


& cognitive

change

Cognitive change

Nausea,

vomiting,

ataxia


impaired LOC

KPS, % 70 80 50 80 40

Radiographic


Neurologic/

clinical

response

Complete

Resolution

Complete


Stable


KPS, % 90 80 70 80 80

PFS, months 13+ 17 17+ 14 14+

Case Series: Complete Radiographic Response to

Nivolumab in a Patient With Primary Refractory PCNSL

Baseline Post-nivolumab

CR at 2 months

CR sustained at 13 months

Primary refractory PCNSL

Head CTs with contrast, #1

CR = complete response

Nayak L et al. Blood 2017; doi: 10.1182/blood-2017-01-764209 [Epub ahead of print]

CheckMate 647

Study design A phase 2, open-label, single-arm, 2-cohort study

of nivolumab in R/R PCNSL or R/R PTL

Primary objective ORR by BICR

Secondary objectives

• PFS

• DOR

• OS

Planned enrollment

Total: 65 patients

• PCNSL : 45 patients

• PTL : 20 patients

Estimated completion December 2019

ClinicalTrials.gov ID NCT02857426

BICR = blinded Independent Central Review; DOR = duration of response; ORR = overall response rate; OS = overall survival.

CheckMate 647: Study Design

Endpoints

Primary

• ORR

Secondary

• PFS

• DOR

• OS

Nivo 240 mg IV

Q2W

Cycles 1–8

Treatment until disease progression, unacceptable toxicity, or 2-year maximum duration

Follow-up

RR PCNSL N≈45

RR PTL N≈20

Nivo 480 mg IV

Q4W

Cycle 9+

Nivo = nivolumab; Q2W = every 2 weeks; Q4W = every 4 weeks

Month

Cycle 8

4

Treatment

end

24

Treatment

start

0

CheckMate 647: Key Eligibility Criteria

Inclusion Criteria

• Adults aged ≥18 years

• Progressed on or did not respond to ≥1 line of

standard of care therapy

• PCNSL patients: Measurable disease on MRI with

≥1 extranodal lesion

• PTL patients: ≥1 extranodal or nodal lesion

• Karnofsky performance status of ≥70

• Dose of dexamethasone or equivalent ≤ 2 mg/day

allowed 14 days prior to first dose of nivolumab

CheckMate 647: Key Eligibility Criteria

Exclusion Criteria

• Prior treatment with checkpoint inhibitors or T cell co-stimulatory drugsa

• Intraocular PCNSL with no evidence of measurable brain disease

• Patients with brain stem lesions

• PTL patients with prior history of allogeneic transplantation <6 months

before screening

• Dexamethasone requirement of >2mg/day within the 14 days prior to

first dose of nivolumab

• Prior active malignancy within 3 years

• Concurrent autoimmune disease

aIncludes antibodies that target PD-1, PD-L1, PD-L2, CD137, CTLA-4, or any agent targeting T-cell co-stimulation

or checkpoint pathways

CheckMate 647 Study Sites

United States

Canada

Russia

Japan Italy

Germany

Czech Republic

Hungary

Israel

Singapore

Brazil

France

Hong Kong

Switzerland

52 Sites in 14 Countries

Summary

● PCNSL and PTL are rare, aggressive B-cell NHLs with limited treatment

options and high unmet need

– Patients experience high relapse rates and poor outcomes

● Nivolumab is a checkpoint inhibitor that targets PD-1 to restore T-cell

antitumor immune responses

● Genetic alterations prevalent in PCNSL and PTL indicate targeting the

PD-1 pathway may be a promising therapeutic strategy

● A case series in 5 patients with R/R PCNSL or R/R PTL suggested

nivolumab may be an effective treatment option for these patients

● The Phase 2 CheckMate 647 study (NCT02857426) is currently enrolling

patients with R/R PCNSL and R/R PTL

Relapse of PCNSL

1. Decreased incidence of R/R with the new generations of induction treatment?

2. Repeated MRIs optimal for follow-up?

3. Strong biomarkers are needed to assess minimal residual disease (MRD)

4. Long survivors with salvage chemotherapy followed by ASCT

5. On going studies are testing new drugs as an alternative consolidation treatment

6. Strong signals of activity of iMids (Lenalidamide) and BTK-inhibitors (Ibrutinib) and PD1-inhibitors

Key points and outstanding issues

● PCNSL is potentially curable

● Performance score is prognostic

● Chemotherapy should be considered for ‘all’

● Role of immunotherapy is clear

● In whom/How can we avoid radiotherapy?

● Role of stem cell transplantation? When?

● Effective salvage strategies emerging

● Long term neurocognitive sequaele

primary cns lymphoma (pcnsl) what is the optimal...

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