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5/7/2018

Immune Based Treatment Options
in Lymphoma: CAR-t cells
Leo I. Gordon, MD, FACP

Summary
• We are entering a new era in treatment for lymphomas
• CAR T-cell therapy may represent one of the more effective
immunotherapeutic options
• Challenges
• Time to manufacture
• Patient selection and toxicity management
• integration with or replacement of existing modalities (chemotherapy, small
molecule inhibitors, autologous vs allogeneic stem transplant)
• cost

• CAR T-cell therapy likely to alter how we treat DLBCL

1

5/7/2018

The Case for Cancer Cellular Therapy

Presented By Carl June at 2016 ASCO Annual Meeting

Graft vs. Leukemia/Lymphoma:
The case for allogeneic transplant
• Presence of GvHD reduces the
likelihood of recurrence in
leukemia patients who had an
allogeneic transplant.
• Provided rationale for “mini”
transplants to take advantage of
GvL effect without high dose
chemotherapy

2

5/7/2018

CAR Design: Critical Elements

CAR T cells are genetically altered to express CAR on the cell surface.

T Cell Receptor

Chimeric Antigen Receptor

APC
scFv: recognize tumor
surface proteins

pMHC

CD28
L

TCR

T Cell

CD28

Costimulatory Signal 2:
CD28 or 4-1BB or OX40
Essential Signal 1:
CD3z

CD3z

Activation Independent of MHC
Limited to cell surface proteins

CAR Construct: CD28 vs 4-1BB

Kalawekar at el, 2016

CAR Construct: Antigen Selection

•

CD19 expression is generally restricted to B cells and B cell
precursors1

•

CD19 is expressed by most B-cell malignancies

•

•

CD19 is not expressed on hematopoietic stem cells or other tissue

CLL, B-ALL, DLBCL, FL, MCL

Hematopoietic
stem cell

Pro-B

Pre-B

CD19 expression

B cell lymphomas
and leukemias

preB-ALL

Immature
(IgM)

Mature
(IgM, IgD)

Activated
B cell

Memory
B cell
(IgG, IgA)

Plasma
cell
(IgG)

Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001:221-293;
Scheuermann RH, et al. Leuk Lymphoma. 1995;18:385-397; and Feldman M, Marini JC. Cell cooperation in the antibody response.
In: Roitt
I, Brostoff J, Male D, eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001:131-146.

3

5/7/2018

SCHOLAR-1 – Poor outcomes in R/R DLBCL

Refractory DLBCL, n=636; ORR 26%, CR 7%; median OS 6.3 months

Crump et al., Blood 2017

CAR T manufacturing and administration

*large range on timing
for processing

Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors.
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46

4

5/7/2018

JULIET: Study Status (Data cut March 2017)

Enrolled
n = 147

Enrollment began July 2015

Discontinued before infusion
Inability to manufacture
Patient-status relateda

Pending
infusion
n=5

Total = 43
n=9
n = 34

Infused
n = 99
Evaluable for response
n = 81
ASH 2017
a Death

(n = 16); physician decision (n = 12); subject decision (n = 3); adverse event (n = 2); protocol deviation (n = 1).
Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577].
Approval date 12/2017

13

M-CTL-1176725

Duration of Response, 74% Relapse-free at 6 Months

Probabilty of Relapse Free (%)

100

• Median DOR and OS not
reached
• Most patients achieving CR
at month 3 have remained in
CR
• No patients proceeded to
transplant while in response

80

60

40

20

0
0

1

Patients still at risk
n = 43
36

2

3

4

5

6

7

8

9

10

11

12

2

1

0

Time From Onset of Response (months)
25

18

16

13

9

9

5

2

CR, complete response; DOR, duration of response; OS, overall response.
Efficacy analysis set = All patients who received a tisagenlecleucel infusion at least 3
months prior to data-cut date.
Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577].

ASH 2017

Approval date 12/2017

14

M-CTL-1176725

JULIET: Adverse Events of Special Interest

(N = 99)
AESIa

All grade, %

Grade 3, %

Grade 4, %

58

15

8

21

8

4

36

15

12

Infections

34

18

2

Febrile neutropenia

13

11

2

Cytokine release

syndromeb

Neurological events
Prolonged

cytopeniac

• No deaths attributed to tisagenlecleucel, CRS or cerebral edema
• 26 (26%) patients were infused as outpatients
• 20/26 (77%) patients remained outpatient for ≥ 3 days after infusion

a

Occurring within 8 weeks of tisagenlecleucel infusion. b Cytokine release syndrome was graded using the Penn scale. c At day 28.
AESI, adverse events of special interest.
Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577].

ASH 2017

Approval date 12/2017

15

M-CTL-1176725

5

5/7/2018

Progression-free Survival, Response Duration, and Overall Survival.

Schuster SJ et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1708566

Presented by:

Objective Response Rate among the 101 Treated Patients.

Neelapu SS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707447

6

5/7/2018

Kaplan–Meier Estimates of the Duration of Response, Progression-free
Survival, and Overall Survival.

NeelapuSS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707447

Presented by:

7

5/7/2018

High CR Rates in Relapsed/Refractory Aggressive B-NHL
Treated
With the
CAR TB-NHL
Cell Product
JCAR017
High Durable
CRCD19-Directed
Rates in R/R Aggressive
Treated with
(TRANSCEND
NHL 001; maraleucel;
NCT02631044)
JCAR017 (lisocabtagene
liso-cel) (TRANSCEND NHL 001):
Defined Composition CD19-Directed CAR T Cell Product Allows for
Dose Finding and Definition of Pivotal Cohort
1 M. Lia
2 Leo I. Gordon,
4 Jon Arnason,5 Michael
1 M.
2 Leo 3I.Matthew
3 Matthew
5 Michael
Jeremy S.S.
Abramson,
Palomba,
Lunning,
Wang,6 Andres
ForeroJeremy
Abramson,
Lia Palomba,
Gordon,
Lunning,4 Jon Arnason,

Torres,7 David Maloney,8 Tina Albertson,9 Jacob Garcia,9 Daniel Li,9 Benhuai Xie,9 Tanya Siddiqi10

Wang,6 Andres Forero-Torres,7 Tina Albertson,8 Claire Sutherland,8 Benhuai Xie,8 Jacob Garcia,8
Tanya Siddiqi9
1

Massachusetts General Hospital Cancer Center, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Northwestern University Robert H. Lurie
Comprehensive Cancer Center, Chicago, IL; 4University of Nebraska Medical Center, Omaha, NE; 5Beth Israel Deaconess Medical Center, Boston, MA; 6University of

1Massachusetts General Hospital Cancer Center, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL;
Texas MD Anderson Cancer Center, Houston, TX; 7University of Alabama at Birmingham, Birmingham, AL; 8Fred Hutchinson Cancer Research Center, Seattle, WA;
4University of Nebraska Medical Center, Omaha, NE; 5Beth Israel Deaconess Medical Center, Boston, MA; 6University of Texas MD Anderson Cancer Center, Houston, TX; 7University of Alabama at Birmingham,
10
Therapeutics,
Seattle, WA;
Hope
National
Center,
Duarte,
Birmingham,
AL; 8Juno Therapeutics,
Seattle,City
WA; 9of
City
of Hope
NationalMedical
Medical Center,
Duarte,
CA CA

9 Juno

Multicenter, Seamless Design Pivotal Trial
(TRANSCEND NHL 001; NCT02631044)
Dose Findinga
(DF) Cohorts

Dose Expansiona
(DE) Cohorts

5 × 107 cells (DL1),
single dose (S)b
DL1S
5 × 107 cells (DL1),
double dose (D)c

Pivotal DLBCL
Cohort
Dose
Recommendation
by Steering
Committee

DL2S
DL2S

1 × 108 cells (DL2),
single dose (S)b

Data will be presented from DF and DE DLBCL cohorts

Enrollment ongoing for
pivotal patient population

• 91 patients treated (FULL)d
• 67 patients treated in identified pivotal patient population (CORE)e
Disease-specific Dose Finding and Dose Expansion cohorts enrolled [DLBCL and MCL].
Administered on Day 1.
Administered on Day 1 and Day 14.
d DLBCL FULL cohort: DLBCL, NOS de novo and transformed from any indolent lymphoma, ECOG 0-2.
e DLBCL CORE cohort: DLBCL, NOS de novo and transformed from FL, ECOG 0-1, high grade B-cell lymphoma.
a
b
c

4

8

5/7/2018

TRANSCEND NHL 001 (NCT02631044)
Enrollment &
Apheresis

PET-positive
disease reconfirmed

FOLLOW-UP

Lymphodepletion

JCAR017 (liso-cel)
2-7 days
after FLU/CY

FLU 30 mg/m2 and
CY 300 mg/m2 x 3d

Screen

Initial: 12 months
On-study: 24 months
Long-term: up to 15 years after last
JCAR017 treatment

Liso-cel Manufacturinga

ENROLLMENT COHORTS
§

§

PATIENT ELIGIBILITY

DLBCL after 2 lines of therapy:
– DLBCL, NOS (de novo or transformed FL)
– High grade B-cell lymphoma (double/triple hit)
– DLBCL transformed from CLL or MZL
– PMBCL
– FL3B
MCL after 1 line of therapy

§
§
§
§

Pivotal
population (CORE)
All enrolled DLBCL
population (FULL)

Prior SCT allowedb
Secondary CNS involvement allowed
ECOG 0-2b
No minimum absolute lymphocyte count requirement for apheresis

FLU, fludarabine; CY, cyclophosphamide.
a Therapy for disease control allowed.
b ECOG 2 and prior allogeneic HSCT excluded from pivotal cohort.

5

CONSORT Diagram: DLBCL Cohort
Leukapheresed (n = 140)
Awaiting product (n=10)
Withdrew before manufacturing (n = 2)
Product unavailable (n = 2)

§ Product available for
98% (126/128) of
patients apheresed in
DLBCL cohort

Product available (n = 18)
• Awaiting treatment (n = 4)
• Withdrew (n = 4)
• PD or died (n = 10)

§ Six MCL subjects treated
thus far with JCAR017 at
DL1S

JCAR017-Treated (n=108)
• Received JCAR017, not yet evaluable (n = 6)
• Received nonconforming JCAR017 (n = 11)a

§ Five patients treated in
outpatient setting as of
October 9 data
snapshota

Safety-Evaluable (n=91)
DL1S (n = 45)
a

DL1D (n = 6)

DL2S (n = 40)

For further details, see Maloney et al (abstract 1552).

Data as of October 9, 2017 6

TEAEs and Lab Abnormalities in DLBCL Cohort (FULL, N=91)
TEAEs and Laboratory Abnormalities Occurring in ≥ 20% of Patientsa
Any TEAEb,c
Any related TEAEc
Neutropeniad
Thrombocytopeniad
Anemiad
Fatigue
Cytokine release syndrome
Nausea
Diarrhea
Constipation
Decreased appetite
Headache
Dizziness

Grade

Hypotension

0

10

20

30

40

50

60

70

1

2
80

3

4
90

5
100

Percentage of Patients
TEAE, treatment-emergent adverse event.
a Data for 5 patients with MCL treated with conforming product at DL1 with at least 28 days of follow-up are not reported.
b One grade 5 AE of septic shock, unrelated to JCAR017, occurred in the setting of disease progression.
c One grade 5 AE of diffuse alveolar damage, investigator assessed as related to fludarabine, cyclophosphamide, and JCAR017, occurred on day 23 in a patient who refused mechanical ventilation for progressive
respiratory failure while neutropenic on growth factors and broad-spectrum antibiotics and antifungals.
d Laboratory abnormalities.
Data as of October 9, 2017 8

9

5/7/2018

High Rates of Response in FULL DLBCL Population
Homogeneous Patient Population Moving Forward in Pivotal Cohort
By B-NHL Subtype

FULL
BOR, na

tFL

DLBCL, NOS

tCLL/MZL

FL3B/PMBCL

88

57

19

10

2

ORR, % (95% CI)

74 (63, 83)

74 (60, 85)

84 (60, 97)

50 (19, 81)

100 (16, 100)

CR, % (95% CI)

52 (41, 63)

51 (37, 64)

63 (38, 84)

30 (7, 65)

100 (16, 100)

≥ 3-mo f/u, nb

72

46

15

9

3-mo ORR, % (95% CI)

53 (41, 65)

54 (39, 69)

67 (38, 88)

22 (3, 60)

50 (1, 99)

3-mo CR, % (95% CI)

44 (33, 57)

43 (29, 59)

60 (32, 84)

22 (3, 60)

50 (1, 99)

2

54

37

10

6

2

6-mo ORR, % (95% CI)

35 (23, 49)

35 (20, 53)

50 (19, 81)

0 (0, 46)

50 (1, 99)

6-mo CR, % (95% CI)

31 (20, 46)

32 (18, 50)

40 (12, 74)

0 (0, 46)

50 (1, 99)

≥ 6-mo f/u, nc

BOR, best overall response; NOS, not otherwise specified.

Homogeneous CORE patient population
identified and will move forward in pivotal trial
a
b
c

Includes patients with event of PD, death, or 28-day restaging scans. Two patients did not have restaging scans available.
The denominator is number of patients who received JCAR017 ≥ 3 months ago, prior to data snapshot date, with an efficacy assessment at month 3 or prior assessment of PD or death.
The denominator is number of patients who received JCAR017 ≥ 6 months ago, prior to data snapshot date, with an efficacy assessment at month 6 or prior assessment of PD or death.

Data as of October 9, 2017 10

Overall Survival (OS)
Early OS Encouraging in High-Risk DLBCL Patient Population
mOS (95% CI); 6 mo OS (95% CI)

FULL
100

CORE

100

CR : NR (NR, NR); 94% (78, 98)

80

80

All : NR (NR, NR); 86% (73, 93)

60

60

All : NR (9.0, NR); 78% (66, 86)

40

PR : 9.0 mos (3.8, NR); 75% (40, 91)

20
0

Median F/U=6.2 months

3

6

12

53
35
12
6

37
25
8
4

20
16
2
2

13
12
0
1

15

18

4
4

0
0

0

PR : 9.0 mos (4.9, NR); 81% (44, 95)
Nonresponders: 6.2 mos (0.6, NR); 66% (33, 86)

0
9

Overall Survival (months)
88
46
19
23

40
20

Nonresponders: 5.4 mos (1.5, NR); 46% (21, 68)

0
At Risk
All
CR
PR
Nonresponder

% Survival

% Survival

CR : NR (13.7, NR); 92% (78, 98)

Median F/U=6.2 months

0

3

At Risk
All 65
CR 36

39
26

6

9

12

PR 16

11

8

2

0

Non- 13
responder

2

2

1

0

15

18

3
3

0
0

Overall Survival (months)
30
20

15
12

mOS, median OS; mos, months.

9
9

Data as of October 9, 2017 14

TRANSCEND NHL 001: Conclusions
§ JCAR017 (lisocabtagene maraleucel; liso-cel), a CD19-directed CAR T cell product with defined
composition, shows potent and durable responses in poor-prognosis patients with R/R aggressive NHL
§ The pivotal cohort has begun enrollment in the CORE population based on encouraging durable
response rate at dose level 2
– 74% ORR and 68% CR rate at 3 months and 50% CR at 6 months
– Across dose levels, 80% of patients in CR at 3 months remain in response at month 6 and 92% of patients in CR
at 6 months remain in response

§ Liso-cel toxicities have been manageable at all dose levels tested with a favorable safety profile that
may enable outpatient administration
– Low rates of severe CRS (1%) and NT (12%)
– Evaluation of outpatient administration is ongoing in pivotal cohort (Maloney et al, abstract 1552)

§ Optimized, commercial-ready liso-cel defined cell product being utilized for pivotal cohort with expected
apheresis to product release < 21 days

15

10

5/7/2018

CAR T Toxicities

Challice L Bonifant, published online
20 April 2016. doi:10.1038/mto.2016.11

DLBCL AFTER CAR-T THERAPY
BASELINE

Day +30

11

5/7/2018

Summary
• We are entering a new era in treatment for lymphomas
• CAR T-cell therapy may represent one of the more effective
immunotherapeutic options
• Challenges
• Time to manufacture
• Patient selection and toxicity management
• integration with or replacement of existing modalities (chemotherapy, small
molecule inhibitors, autologous vs allogeneic stem transplant)
• cost

• CAR T-cell therapy likely to alter how we treat DLBCL

12

5/8/2018

Treatment of Newly Diagnosed DLBCL in 2018

John Pagel, M.D., Ph.D.
Chief of Hematologic Malignancies
Director of Hematopoietic Stem Cell Transplantation Program
CENTER FOR BLOOD DISORDERS AND STEM CELL TRANSPLANTATION
SWEDISH CANCER INSTITUTE

COI
• Consultant for Pharmacyclics and Gilead Sciences

WHO Classification of Aggressive B- Cell Lymphoid Neoplasms 2008 v
2016
2008

2016

Diffuse large B-cell lymphoma (DLBCL), NOS
− OPTIONAL Germinal Center/Activated B cell
− T cell/histiocyte-rich large B-cell lymphoma
− Primary DLBCL of the CNS
− Primary cutaneous DLBCL, leg type
− EBV positive DLBCL, NOS
− EBV+ Mucocutaneous ulcer
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK positive large B-cell lymphoma
Plasmablastic lymphoma
Primary effusion lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman Dis

Diffuse large B-cell lymphoma (DLBCL), NOS
− REQUIRED Germinal Center DLBLC
− REQUIRED ABC DLBCL
− T cell/histiocyte-rich large B-cell lymphoma
− Primary DLBCL of the CNS
− Primary cutaneous DLBCL, leg type
− EBV positive DLBCL, NOS
− EBV+ Mucocutaneous ulcer
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK positive large B-cell lymphoma
Plasmablastic lymphoma
Primary effusion lymphoma
HHV8 positive DLBCL, NOS

High grade B-cell lymphoma, NOS

High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
High grade B-cell lymphoma, NOS
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL
and classical Hodgkin lymphoma

Swerdlow et al. Blood (2016) http://dx.doi.org/10.1182/blood-2016-01-643569 *Excluding Precursor Neoplasms

1

5/8/2018

International Standard of Care: R-CHOP
Rituximab 375 mg/m2 day 1
Cyclophosphamide 750 mg/m2 day 1
Doxorubicin 50 mg/m2 day 1
Vincristine 1.4 mg/m2 day 1 (2 mg max)
Prednisone 40 mg/m2 (or 100 mg) daily x 5
Age > 60 Pegfilgrastim 6 mg subcut day 2
Original Gela LNH 98-5 confirmed in multiple studies

Coiffier et al. ASCO 2007. Abstract 8009.

GOYA R-CHOP v G-CHOP for DLBCL: Study design
Previously untreated DLBCL
Age ≥18 years
IPI 2 or IPI 1 (not age) or IPI 0
with bulky disease 7.5cm
ECOG PS ≤2

G-CHOP (N=706)
G 1000mg C1 D1/8/15 and C2–8 D1

CHOP 6 or 8 cycles every 21 days
Randomized 1:1

R-CHOP (N=712)
R 375mg/m2 C1–8 D1
CHOP 6 or 8 cycles every 21 days

Target enrolment: 1400

Primary endpoint
• PFS (INV-assessed)

•
•
•
•
•

Secondary and other endpoints
• PFS (IRC-assessed)§
• OS, EFS, DFS, DoR, TTNT

• CR/ORR at EOI (+/− FDG-PET)
• Safety

Statistical assumption for primary endpoint: G-CHOP v R-CHOP HR = 0.75
Number of CHOP cycles pre-planned in advance for all pts at each site
Stratification factors: number of CHOP cycles, IPI, geographic region
§Confirmatory endpoint
Exploratory endpoint: PFS by cell of origin

Vitolo U, et al. ASH 2016 Abstract 470

GOYA: Investigator-assessed PFS and OS
PFS

1.0

0.8

Probability

Probability

OS

1.0

0.8
0.6
0.4
0.2

0.6
0.4
0.2

R-CHOP (n=712)
G-CHOP (n=706)

R-CHOP (n=712)
G-CHOP (n=706)

0

0
0

6

No. of patients at risk
R-CHOP
712
616
G-CHOP
706
622

12
527
540

18
488
502

Pts with event, n (%)
1-yr PFS, %

24
30
36
Time (months)

42

413
425

96
102

227
240

142
158

48
41
39

54
6
2

60

0

6

No. of patients at risk
R-CHOP
712
663
G-CHOP
706
659

12

18

24
30
36
Time (months)

42

48

54

617
616

586
582

540
552

138
138

71
67

9
8

R-CHOP,
n=712

G-CHOP,
n=706

215 (30.2)

201 (28.5)

79.8

81.6

1-yr OS, %

Pts with event, n (%)

319
316

190
201

R-CHOP,
n=712

G-CHOP,
n=706

126 (17.7)

126 (17.8)

89.9

90.7

2-yr PFS, %

71.3

73.4

2-yr OS, %

83.7

83.9

3-yr PFS, %

66.9

69.6

3-yr OS, %

81.4

81.2

HR (95% CI), p-value*

0.92 (0.76, 1.11),
p=0.3868

HR (95% CI), p-value*

1.00 (0.78, 1.28),
p=0.9982

Vitolo U, et al. ASH 2016 Abstract 470

60

*Stratified analysis; stratification factors: IPI score, number of
planned chemotherapy cycles. Median follow-up: 29 months

2

5/8/2018

Dose-Adjusted (DA)-EPOCH-R
Drug

Dose

Rituximab

375 mg/m2 day 1 IVPB

Doxorubicin

10 mg/m2/day x 4 by CI

Vincristine

0.4 mg/m2/day x 4 by CI

Etoposide

50 mg/m2/day x 4 by CI

Cyclophosphamide

750 mg/m2 day 5 IVBP

Prednisone

60 mg/m2 BID days 1-5 oral

Filgrastim*

Weight-adjusted dose starting day 5 until ANC > 5000/μL

*Data from MSKCC showed identical rate of dose-adjustment with filgrastim or
pegfilgrastim

•
•

Dosed every 21 days if ANC > 1/μL and PLTS > 100KμL
Dose-adjusted based on ANC nadir:
– >500/μL, increase cytotoxic drugs by 20%
– <500/μL for 1-3 days, no change
– <500/μL for >3 days or FN, decrease cytotoxic drugs by 20%

Wilson, J Clin Oncol 2008 26: 2717-2724; Lunning et al. SHO, abstract

CALGB 59910: Multi-Center DA-EPOCH-R, Outcomes

Wilson W H et al. Haematologica 2012;97:758-765

CALGB 50303: DA-EPOCH-R vs RCHOP21
DeNovo DLBCL
No discordant
disease
CS IIX-IV

•

OBJECTIVES:

R
A
N
D
O
M
I
Z
E

DA-EPOCH-R
R-CHOP

n= 478 patients (239 per treatment arm)

– Primary
• EFS untreated de novo DLBCL treated with RCHOP vs DA-R-EPOCH
• Determine molecular predictors of outcome (using molecular profiling) in patients treated with these regimens.

– Secondary
• Compare ORR and OS
• Compare the toxicity of these regimens in these patients.
• Correlate the clinical parameters (i.e., toxicity, response, survival outcomes, and laboratory results) with molecular
profiling in patients treated with these regimens.
• Determine the use of molecular profiling for pathological diagnosis
• PET/CT parameters as potential biomarker, predictive value of interim PET, reproducibility and standardization of PET/CT
Wilson et al. ASH 2016, Abstract 489

3

5/8/2018

CALGB 50303: Event-Free and Overall Survival
PFS
0.8
0.6
0.2

0.4

Survival Probability

0.6
0.4
0.2

Probability event free

0.8

OS

HR=1.14 (0.82-1.61)
p = 0.4386

1

2

3

4

0

5

1

2

Years from Study Entry

Arm

HR=1.18 (0.79-1.77)
p = 0.42

R-CHOP
DA-EPOCH-R
0.0

0.0

R-CHOP
DA-EPOCH-R
0

3

4

5

Years from Study Entry

N

Events

3 Y (95% CI)

5 Y (95% CI)

R-CHOP

233

64

0.81 (0.75-0.85)

0.69 (0.62-0.75)

DA-EPOCH-R

232

70

0.79 (0.73-0.84)

0.66 (0.59-0.72)

Arm

N

Events

3 Y (95% CI)

5 Y (95% CI)

R-CHOP

233

44

0.85 (0.80-0.89)

0.80 (0.74-0.85)

DA-EPOCH-R

232

50

0.85 (0.79-0.89)

0.76 (0.70-0.71)

Additional analyses pending including outcome by COO, DH and DE
Wilson et al. ASH 2016, Abstract 489

CALG 50303: PET Sub-study n=171
PET neg = Deauville 1-3

EOT
Post Cycle 6

Events= 23
Events= 19

p-value= 0.0339

4

PET-negative
PET-positive

N= 121
N= 29

Events= 25
Events= 10

p-value= 0.0567

0.0

2

0.6
0.2

N= 104
N= 55

0.0

PET-negative
PET-positive

0

0.4

Probability event free

0.6
0.4
0.2

Probability event free

0.8

0.8

Interim
Post Cycle 2

6

0

Years from Study Entry

2

Timing of PET

3 year EFS

Interim

81% (-) vs 69% (+)

0.034

p

End of treatment

80% (-) vs 72% (+)

0.057

4

6

Years from Study Entry

Treatment arms combined for analysis
Schoder, H, Menton, France 2016; Wilson et al. ASH 2016, Abstract 489

Methods for determination of COO
•

Gene Expression Profiling on fresh tissue
– ‘The gold standard’
– Not practically applicable in clinical practice

•

Immunohistochemistry
– Widely available
– Reproducibility may be difficult
– Many assays (Hans, Choi, Muris, Natkurman, Tally)
– Lack of correlation with GEP in many studies

•

GEP of formalin-fixed paraffin-embedded (FFPE) tissue
– Multiple platforms
– Hybrid capture/fluorescent reporter emerging as a widely validated assay

4

5/8/2018

GOYA: COO is prognostic
ABC

Unclassified
1.0

0.8

0.8

0.6
0.4
0.2

Probability

1.0

0.8

Probability

Probability

GCB
1.0

0.6
0.4
0.2

R-CHOP (n=269)
G-CHOP (n=271)

0
0

6

12
200
217

18

24 30 36 42
Time (months)

191
207

166
178

HR (95% CI)†

94
113

64
75

48

46
50

19
22

54
2
1

60

0.72 (0.50, 1.01)

R-CHOP (n=75)
G-CHOP (n=75)

0
0

6

No. of patients at risk
R-CHOP 118 101
G-CHOP 125 106

71% vs 79%,
R-CHOP vs G-CHOP

3-yr PFS

0.4
0.2

R-CHOP (n=118)
G-CHOP (n=125)

0

No. of patients at risk
R-CHOP 269 234
G-CHOP 271 246

0.6

12
84
90

18

24 30 36 42
Time (months)

77
84

HR (95% CI)†

65
79

36
42

21
31

15
17

48
5
8

54
1
1

0.86 (0.57, 1.29)
58% vs 61%,
R-CHOP vs G-CHOP

3-yr PFS

60

6

12

18

No. of patients at risk
R-CHOP
75
65
G-CHOP 75
63

0

54
57

52
51

HR (95% CI)†
3-yr PFS

24 30 36 42
Time (months)
43
43

36
28

25
17

15
10

48

54

6
3

1

60

1.02 (0.60, 1.75)
64% vs 62%
R-CHOP vs G-CHOP

*Exploratory analysis; COO classification available in 933 pts; missing COO classifications due to: restricted
Chinese export license, n=252; CD20+ DLBCL not confirmed, n=102; missing/inadequate tissue, n=131; PFS
HR=0.82 (0.64, 1.04) in pts with COO classification; PFS HR=1.18 (0.85, 1.64) in pts without COO classification
†Unstratified analysis
Vitolo U, et al. ASH 2016 Abstract 470

Double-Hit B-cell Lymphomas

Translocation of BCL2
and/or BCL6 is seen in
a subset of GC DLBCL;
simultaneous
translocation of MYC
is seen in ~6% of cases
of GC DLBCL.

MYC

Expression of MYC
and BCL2 is a
consequence of the
biology of ABC
DLBCL

Reclassified in WHO as
HGBCL with
rearrangement of MYC
and BCL2 and/or BCL6

BCL2

Mottock & Gascoyne, CCR 2014

MYC Translocation in DLBCL Associated with Poor Outcomes
with CHOP-based Therapy
MYC+ DLBCL

“Double Hit” BCL2/MYC Translocated

R-CHOP
treated

Savage KJ et al. Blood 2009; Johnson NA et al. Blood 2009

5

5/8/2018

DA-EPOCH-R for DLBCL with translocation of MYC and BCL2 and/or BCL6

Progression-Free Survival of DH Case (n=14)*
100

Characteristic
52

Median age

61 y (29-80)

IPI Score
0-2
3-5

35%
65%

Histology
DLBCL
BCL-U

86%
14%

BCL2 translocated
by FISH

14/31*

*31 of 52 tested

90

*

80

Proportion
Progression free

Number

70
60
50
40
30
20
10
0

6

12

18

24

30

36

42

48

54

Months

*Cases were censored if they were transplanted;
number censored for transplant NOT REPORTED

Dunleavy, ASH 2015

Impact of induction regimen and SCT on outcomes in DH lymphoma: a multicenter
retrospective analysis

Adam M. Petrich et al. Blood 2014;124:2354-2361

Lenalidomide for DLBCL: Impact of Cell of Origin

CD10

BCL6

Lenalidomide cycles
Median (Range)
Response
CR
PR
SD
PD
Unknown
ORR (CR + PR)
PFS, mo
Median
95% CI

All

GCB

2 (1-35)

2 (1-21)

Non-GCB

4 (1-35)

6 (15.0)
5 (12.5)
7 (17.5)
21 (52.5)
1 (2.5)
11 (27.5)

1 (4.3)
1 (4.3)
7 (30.4)
14 (60.9)
0
2 (8.7)

5 (29.4)
4 (23.5)
0
7 (41.2)
1 (5.9)
9 (52.9)

2.6

1.7

6.2

0.9-4.2

0.3-3.1

2.9-9.6

IRF4

Hernandez-Ilizaliturri et al, Cancer 2011 117:5058

6

5/8/2018

Mayo Series: Outcomes for RL-CHOP v R-CHOP Case Match Control by
Cell of Origin

Non-GC DLBCL

GC DLBCL

Nowakowski et al. ASH 2012, ASCO 2014

ROBUST (NCT02285062): Lenalidomide Plus R-CHOP Chemotherapy (R2-CHOP) Versus Placebo Plus RCHOP Chemotherapy in Subjects With Untreated ABC-DLBCL, Phase 3, double-blind, placebocontrolled
Inclusion
DLBCL, ABC-type, untreated
COO by Lymph2Cx
Measurable disease by CT/MRI

ECOG 0-2
Age 18-80

IPI ≥2

Double-blind, placebo
controlled
Randomization 1:1

Placebo +
R-CHOP × 4

Placebo +
R-CHOP × 2

Lenalidomide +
R-CHOP × 4

Lenalidomide +
R-CHOP × 2

Lymphoma other than DLBCL
HIV, HBV, HCV active infections
LVEF <45%

⇑

Interim Evaluation
NR off study

Exclusion

Study Start Date:
January 2015
Estimated Study Completion Date:
Estimated Primary Completion Date:

⇑

EOT Evaluation
IWG 2007 with
Deauville PET

September 2022
June 2018

Peripheral neuropathy, grade ≥2
Other malignancies < 5 years disease free

Clinical Endpoints

Sample Size/Statistical Plan

Evaluation

Sample size: 560

Interim evaluation after cycle 4

90% to detect increase in PFS of 60%

EOT (6 cycles) FDG-PET

Primary: Progression-free survival
Secondary: OS, CRR, Duration of CR,
TTNT, ORR, QOL

Conclusions
•

DLBCL should always be approached with curative intent
– The majority of patients will be cured with R-CHOP
– R-CHOP remains the standard of care for de novo DLBCL in most situations
– DA-R-EPOCH is a reasonable alternative with OS ~80% at 5 years
• No difference in EFS and OS
– G-CHOP does not appear to be better than R-CHOP for newly diagnosed DLBCL

•

Not all DLBCL are created equally
– GCB versus non-GCB
• Data is limited for GCB versus non-GCB

•

MYC alteration and Double Hit DLBCL remain challenging

•

Many novel agents and approaches are in development and warrant further investigation

7

5/7/2018

Jasmine Zain, M.D.
Director, T-Cell Lymphoma Program
City of Hope National Medical Center

NOVEL TREATMENTS OF DIFFUSE
LARGE B-CELL LYMPHOMA

Click to edit Master Presentation Date

NO NEW FDA-APPROVED AGENTS SINCE RITUXIMAB!

Fisher RI et al. N Engl J Med 1993;328:1002-1006.

Coiffier B, et al. NEJM. 2002.

POTENTIAL TARGETS FOR TREATING B-CELL MALIGNANCIES

1

5/7/2018

BROAD CATEGORIES FOR TARGETED AGENTS FOR DLBCL

• Immune modifiers Lenalidomide
• Molecualar targets- Ibrutinib,
Venetoclax, Idelalisib
• Antibodies and antibody drug
conjugates – anti CD37
• Blinotumumab and other
bispecific antibodies
• Immune-check point inhibitors
• Microenvoirnment targets- Anti
CD47
• Epigenetic agents

IMPROVE ON R-CHOP?

• HDAC inhibitors = no
• Bortezomib = no
• Next up:
– Lenalidomide (immunomodulator)
– Polatuzumab vedotin (anti-CD79b ADC)
– Venetoclax (BCL2 inhibitor)
– SGN-CD19A (anti-CD19 ADC)

LENALIDOMIDE

Lenalidomide has an ORR of 19% and 28% in RR.
Witzig, et al. Zinzani, et al. 2008.

More effective in non-GCB subtype- ORR 53% vs
9%. Hernandez, et al. Cancer. 2011.
Tested in combination with Rituximab, RICE and as
maintenance post transplant. Feldman, et al. 2014.
Lenalidomide maintenance vs placebo in elderly
patients after RCHOP. PFS was not reached in the
Len arm vs 58.9 months in the placebo arm. Diff was
notable in the GCB subtype. Thieblemont, et al. Blood. 2017.

2

5/7/2018

TARGETED TERAPIES – PI3K INHIBITORS

Idealisib, TGR1202, copanlisib

B-cell

Herrera AF and Jacobsen EJ. CCR. 2014.

IBRUTINIB

• Selective and irreversible inhibitor of BTK
• Modest clinical activity in DLBCL as a single agent - 23% seen mostly
in the ABC-subtype.
• Phase 1b/2 study of Ibrutinib plus lenalidomide and Rituximab is
underway. Preliminary results show a RR of 44%.
• RCHOP vs RCHOP+ibrutinib for non-GCB subtype of DLBCL.
• Most common side effects are rash and diarrhea.

BCL-2 INHIBITION - VENETOCLAX

SINGLE AGENT
RESPOSNE RATE IN R/R
DLBCL WAS 18%

Konopleva M, et al. Cancer Discovery. 2016.

3

5/7/2018

POLATUZUMAB VEDOTIN- ADC TARGETS CD79B CONJUGATED TO MMAE

POLATUZUMAB VEDOTIN IN R/R DLBCL

Treatment Regimen

Best Overall Response

Pola 1.8–2.4 mg/kg

51%1

Pola 1.8–2.4 mg/kg + rituximab

56%2

R/R DLBCL from the ROMULUS trial: pola + rituximab:
Best SPD Change from Baseline

Progression-Free Survival

Morschhauser F, et al. Blood 2014; 124:4457.

Palanca-Wessels MCA, et al. Lancet Oncol 2015; 16: 704-15.

POLATUZUMAB VEDOTIN PLUS OBINUTUZUMAB

FL
(N=35)
Objective response, n (%)

24 (69)

DLBCL
(N=43)
17 (40)

Complete Response

11 (31)

9 (21)

[90% CI]

[19–47]

[11–34]

Partial Response

13 (37)

8 (19)

[90% CI]

[24–52]

[10–31]

Stable disease, n (%)

4 (11)

0

Progressive disease, n (%)

1 (3)

18 (42)

Unable to evaluate, n (%)

6

(17)b

8 (19)c

aPatients

who received ≥1 dose of study treatment; assessment per Lugano Criteria (Cheson 2014)
bNo Pola dose due to IRR from G, taken off-study (n=2); no PET assessment (n=2); taken off-study due to neutropenia before assessment (n=1); fatal pneumonia
before assessment (n=1)
c Died before assessment (n=1); PD not by PET (n=4); not assessed due to hospitalization / taken off study (n=2);
W/D consent / not dosed (n=1)

Data Cut-Off: 26 JUL 2016
Download this presentation: http://tago.ca/TPHI

4

5/7/2018

POLA + R/G-BENDAMUSTINE

Investigator-Assessed Response by PET/CTa
FL

DLBCL

Pola + BR
(n=6)

Pola + BG
(n=26)

Pola + BR
(n=6)

Pola + BG
(n=27)

6 (100)
4 (67)
2 (33)
0
0
0

23 (89)
17 (65)
6 (23)
0
1 (4)
2 (8)

3 (50)
2 (33)
1 (17)
0
2(33)
1 (17)

16 (60)
11 (41)
5 (19)
2 (7)
6 (22)
3 (11)

Best Objective Response
ORR, n (%)
CR
PR
SD
PD
UE
Objective Response at End of Treatment
5 (83)
4 (67)
1 (17)

21 (81)
17 (65)
4 (15)

3 (50)
2 (33)
1 (17)

10 (37)
9 (33)
1 (4)

Median duration of response, mo (range)b

ORR, n (%)
CR
PR

16.1
(3.8–16.3)

NR
(15.2–20.6)

NR
(0.03–14.5)

NR
(0.03–15.7)

Median PFS, mo
(range)b

18.4
(7.2–18.9)

NR
(1.4–17.1)

NR
(1.5–22.7)

5.4
(0.03–17.6)

aModified

Lugano 2014 response criteria: for CR, repeat bone marrow biopsy required to confirm clearance of bone marrow if involved at
screening. bKaplan-Meier method; range data are at clinical data cut-off.
CT, computed tomography; ORR, objective response rate; PD, progressive disease; PET, positron emission tomography; PFS,
progression-free survival; PR, partial response; SD, stable disease; UE, unable to evaluate.

EZH2 - INHIBITORS

Enhancer of zeste homolog 2 (EZH2)
results in methylation of the histone H3associated with gene repression
EZH2 activating mutations and
overexpression is seen in cancers, GCB
type of DLBCL not ABC subtype
EZH2 inhibitor Tazemostat is in clinical
trials- first in class inhibitor of mutated and
wild type EZH2.
Initial trials showed promising activity in Bcell lymphomas.

CHECKPOINT INHIBITION: PD-1 PATHWAY

Pardoll DM. Nature Reviews Cancer. 12, 252-264 (April 2012).

Effects of PD-L1 binding:
Inhibits T-cell activation
Inhibits cytokine production
Decreased cytolytic activity of CD4+ and CD8+ cells

5

5/7/2018

CHECK POINT INHIBITORS IN DLBCL

• CTLA-4 AND PD-1 are being
targeted.
• CT-011 (pidilizumab) in post
ASCT- 16 mo PFS 72% including
high risk patients. Armand, et al.
2013.

• Nivolumab- ORR 36% Lesokin, et al.
2016.

• Pembrolizumab- in trials –
encouraging rates in PMBCL and
CNS.
• Combinations with other
therapies especially CAR-T.

Juarez-Salcedo, et al. 2017.

BISPECIFIC ANTIBODIES

Phase II study of single agent bispecific
engager (BiTE®) antibody
Blinatumomab– ORR was 43% including
19% CRs. Viardot, et al. 2016.
Trials ongoing with lenalidmide and
alternative strategies of administration
(subcutaneous) using Blinatumomab,
lenalidmide.

Other targets – CD 20 bispecific engager
antibodies- encouraging RR and do not
require CD19.

CONCLUSION

• Many promising strategies to treat RR DLBCL
• Combination therapies are likely to win
• Attempts to improve upon RCHOP continue especially for double hit
and ABC subtypes

6



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