MANTLE CELL LYMPHOMA · Derriford Hospital and Peninsula Medical School ... and Growth Pattern in Mantle Cell Lymphoma (MCL): Results from Randomized ... Sureda A, Smith P, Patrick

MANTLE CELL LYMPHOMA

Simon Rule

Professor of Clinical Haematology

Derriford Hospital and Peninsula Medical School Plymouth

UK

Outline

• Biological aspects

• Risk stratification

• Management in 2018

• Young / older patients

• Relapse

• Novel agents

• Ibrutinib

• Combinations

• Second generation BTKi

Presenting Features of MCL

• Approximately 550 – 600 new patients per year (UK)

• Median age of presentation around 70

• Male > female (up to 4:1)

• Invariably stage IV (gut / marrow involved)

• Unusual sites of involvement

• GI tract / skin / lung / conjunctiva / breast etc

Bowel Involvement with MCL

MCL Biological Aspects

Banding analysis FISH

Cyclin D1 staining

Mantle zone, Nodular,

Diffuse

Classic (centrocytic)

Small cell, MZL,

pleiomorphic, blastic

Immunphenotype

sIg++, λ > κ, CD19/20/22+,

CD5+, CD10–, CD23–,

CD11c–,

HLA-DR++, CD43+

t(11;14)(q13;q32)

International Cytomorphology Study of

MCL: Panel review of 304 cases

Tiemann et al. Br J Haematol 2005; 131(1):29-38

Classical (87.5%) Small Cell (3.6%)

Pleomorphic (5.9%) Blastic (2.6%)

Low Risk

High Risk

85% concordance

Primary

aberrations

Secondary

aberrations

Morphological

transformation

Blastoid

MCL

Survival

Number of genetic alterations

Conventional

MCL

“in situ“ MCL

Indolent MCL

t(11;14) or

Variants

(light IG, CycD2)

TP53 mut /del (17p13)

CDKN2A del (9p21)

MYC ampl/rearr (8q24)

High genomic instability

3q,7p, 8q

1p, 6q, 8p, 9,11q2, 13q

BM

Naïve B-cell

(Royo et al, Sem Can Biol 2011)

Staging

PET scanning does not

upstage

Hoster, ASH 2006(PALL: PS, age, LDH, leucocyte count)

Clinical risk factors: MIPI

Prognostic Value of Proliferation (Ki-67), Cytology, and Growth Pattern in Mantle Cell Lymphoma (MCL): Results from Randomized Trials of the European MCL Network

E. Hoster, A. Rosenwald, F. Berger, H. W. Bernd, S. Hartmann, C. Loddenkemper, T. Barth, N. Brousse, S. Pileri, G. Rymkiewicz, R. Kodet, S. Stilgenbauer, R. Forstpointner, C. Thieblemont, M. Hallek, B. Coiffier, U. Vehling-Kaiser, V. Ribrag, M. Unterhalt, W. Hiddemann, J. C. Kluin-Nelemans, O. Hermine, M. Dreyling, W. Klapper

On Behalf of European MCL Pathology Panel and European MCL Network

Hoster et al., Hematol Oncol 2015; 33: 100–180 (abstract 58, oral presentation)

Alternative Combined MIPI: MIPI-c

Multivariable Cox Regression

MIPI and Ki-67 index consistently seen as the independent prognostic factors and should be combined for improved risk stratification

MIPILow

MIPIIntermediate

MIPIHigh

Ki-67 <30%

Ki-67 ≥30%

Ki-67 <30%

Ki-67 ≥30%

MIPI-cLow

MIPI-cHigh

MIPI-cHigh-Intermediate

MIPI-cLow-Intermediate

Ki-67 <30%

Ki-67 ≥30%


OS According to MIPI-c

GLSG1996/2000 MCL Younger/MCL Elderly


Pitfalls in the selection of representative areas for the Ki-67

index in MCL

arrow: residual

germinal

centers

asterisk: hot

spots of

proliferation

arrow head:

proliferating

interfollicular

T-cells

circles:

representative

areas

circles:

representative

areas

Molecular assay for proliferation signature in routine FFPE MCL samples

Scott DW et al JCO, In press

Prognostic value of FDG-PET parameters at time of diagnosis

SUVmax

(p<0.001,

cutoff=11.4)

SUVmean

(p<0.001,

cutoff=7.7)

SUVpeak

(p<0.001,

cutoff=8.7)

Le Gouill et al., ASH 2015 (abstract 335, oral presentation)

Current treatment 2018

MCL treatment algorithm

Adapted from Campo & Rule Blood 2015 Jan 1;125(1):48-55

Require Therapy?

Fit for autograft? Consider watch & wait

Rituximab and HD-AraC

containing regimenFit for CHOP?

Autograft

Maintenance

R-CHOP or

(R-Bendamustine)

based therapy

R-Maintenance

R-Bendamustine

R-CVP

R-Cbl

Other?

? Maintenance

Yes No

Treat

YesNo

Yes NoCR/PR

Require Therapy?




Autograft

? Maintenance

R-CHOP

(R-Bendamustine)

R-Maintenance

R-Bendamustine

R-CVP

R-Cbl

Other?

? Maintenance

Yes No

Treat

Yes No

Yes NoCR/PR

OS according to type of treatment.

Anna Abrahamsson et al. Blood 2014;124:1288-1295

©2014 by American Society of Hematology

Treatment may be safely deferred in some patients with MCL

1-Martin JCO 2009, 2-Abrahamsson Blood 2014, 3-Abrisqueta ASH abstract 2015, 4-Cohen ASH abstract 2015, 5-Orchard Blood 2003, 6-Ondrejka Haematologica 2011, 7-Eve JCO 2009, 8-Budde JCO 2010

0.0

00

.25

0.5

00

.75

1.0

0

0 50 150 200100Months

Observation group Early treatment group

Overall Survival by Treatment Group

N=31

OS=64 mo.

N=68

OS=55 mo.

Center N Defn. of deferred tx. TTT Impact on OS

Derriford7 16/52 3 mo. 11.1 mo. No difference

FHCRC8 13/118 3 mo. 5 mo. No difference

Nordic2 29/1389 NR NR 79% vs. 61%

BCCA3 74/439 3 mo. 35.5 mo. 66 mo. vs. 50 mo.

NCDB4 492/8029 90 days NR HR 0.79

What characteristics are define these patients?

Not blastoid morphology1

Normal LDH2

Ki67 <30%3

No B symptoms4

Mutated IGHV5

SOX11-

Non-nodal6

MIPI is NOT a defining characteristic

ESTABLISHING A BIOBANK AND DATABASE AS A

NATIONAL RESOURCE FOR CHARACTERISING

INDOLENT AND AGGRESSIVE FORMS OF MANTLE

CELL LYMPHOMA

Professor Simon Rule

University of Plymouth, Schools of Medicine and Dentistry

Derriford Hospital, Plymouth Hospitals NHS trust

Study design

Patient diagnosed with MCL

Register with studyUpfront therapy Central data collection

Clinical data &

diagnostic samples

Tissue repository &

laboratory studies;

-Genetic

-Molecular

-Immunological

‘Watch & Wait’Data on date / type of

therapy & reason to

treat Data on date of

treatment / type &

reason to treat

date & cause of

death

Study design

Patient diagnosed with MCL

Register with studyUpfront therapy Central data collection

Clinical data &

diagnostic samples

Tissue repository &

laboratory studies;

-Genetic

-Molecular

-Immunological

‘Watch & Wait’Data on date / type of

therapy & reason to

treat Data on date of

treatment / type &

reason to treat

date & cause of

death

395 patients

UK MCL Biobank 2015-2016

Watch-and-wait for >

1year

38 (26.6%)Intermediate intensity

therapy

53 (37.1%)

High intensity

therapy

28 (19.6%)

Localised radiotherapy

14 (9.8%)

Intermediate intensity therapy: R-CHOP, R-Bendamustine or R-Ibrutinib; High intensity therapy: High dose cytarabine based induction +/- BEAM AutoSCT.

1 yr FU = 143 patients

Management of young

patients

Require Therapy?




Autograft

? Maintenance

R-CHOP

(R-Bendamustine)

R-Maintenance

R-Bendamustine

R-CVP

R-Cbl

Other?

? Maintenance

Yes No

Treat

Yes No

Yes NoCR/PR

Week: 1 4 7 10 13 16 19 20

R

A

r

a

C

B

E

A

M/C

RE-

STAGE

STEM-CELL

HARVEST REINFUSIONINDUCTION

NORDIC MCL2 200-2006:

C

H

O

P

A

r

a

C

A

r

a

C

R

C

H

O

P

C

H

O

P

RR

No. Eval. CR/CRu ORR

160 54% 96%

0.0 2.5 5.0 7.5 10.0 12.50.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival (53 deaths)

MCL2 Update 2010:- Overall and Event-freeSurvival.- Response Duration

EFS (79 events)RD (145, 54 progressions)

Years

Fra

cti

on

su

rviv

al

RR

PR, CR

Cyclo 120mg/kg+ TBI 12 Gray

PBSCT

PR, CR

R-CHOP/R-DHAPalternating

stem cell mobilizationafter course 6

PBSCT

TBI 10 GrayAra-C 4x1.5 g/m2Melphalan 140 mg/m2

4 x R-CHOP

2 x R-CHOP

DexaBEAM(stem cell mobilization)

Intensive schemes including ASCTMCL Network younger Trial

Hermine O, et al. Lancet 2016 388;565-75

Figure 2. (A) Time to treatment failure in primary analysis and (B) overall survivalHR=hazard ratio.

Olivier Hermine et al. Lancet 2016;388:565-575

LyMa trial

OS from Randomisation

OS

Obs (95%CI) vs Rituximab (95%CI)

24m: 93.3 % (87.0-96.6) 93.3 % (87.1-96.6)

36m: 85.4 % (77.5-90.7) 93.3 % (87.1-96.6)

48m: 81.4 % (72.3-87.7) 88.7 % (80.7-93.5)

OS (months) from randomization

mFU: 50.2m (46.4-54.2)

Nordic Protocol 15 Year Follow up

Eskelund Br J Haematol 2016

CYTOLOGY

Ibrutinib bridging to allogeneic hematopoietic cell transplantation: Non-

relapse mortality in patients with CLL (n=48) and MCL (n=22)

Dreger et al., BMT 2018 [Epub ahead of print]

Progression-free survival Overall survival

• In the CLL group PFS and OS were 60% and 72%, respectively

• In the MCL group PFS and OS were 76% and 86%, respectively.

The impact of ibrutinib failure on PFS in 22 patients with MCL

pre-treated with ibrutinib

Dreger et al., BMT 2018 [Epub ahead of print]HCT allogeneic hematopoietic cell transplantation, HR hazard ratio

Fig. 1

Best Practice & Research Clinical Haematology 2018 31, 90-98DOI: (10.1016/j.beha.2017.10.008)

McCullough and Rule 2017

REDUCED INTENSITY CONDITIONING TRANSPLANTATION AS PART

OF FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA:

RESULTS FROM THE PHASE II MINI ALLO TRIAL

(CRUK: C7627/A9080)

Peggs KS, Cook G, S Robinson, Russell N, Hunter A,

Morley NJ, Sureda A, Smith P, Patrick P, Braganca N,

Stevens L, Adedayo T, Kirkwood AA, Rule S

MCL MiniAllo

NCRN / BSBMT

Phase II study of low intensity allogeneic transplantation in Mantle Cell Lymphoma

Trial Sponsor: University College London

Trial Sponsor ID: BRD/07/137

Trial Funder: Cancer Research UK

Funder reference: C7627/A9080

Clinicaltrials.gov no: NCT00720447

EUDRACT no: 2007-003081-18

CTA no: 02666/0001/001

Protocol version no: Version 5.0

Protocol version date: 12.09.2012

MCL MiniAllo

NCRN / BSBMT

Phase II study of low intensity allogeneic transplantation in Mantle Cell Lymphoma

Trial Sponsor: University College London

Trial Sponsor ID: BRD/07/137

Trial Funder: Cancer Research UK

Funder reference: C7627/A9080

Clinicaltrials.gov no: NCT00720447

EUDRACT no: 2007-003081-18

CTA no: 02666/0001/001

Protocol version no: Version 5.0

Protocol version date: 12.09.2012

MCL MiniAllo: Overall Survival

KM 2 year OS = 80%

Require Therapy?




Autograft

? Maintenance

R-CHOP

(R-Bendamustine)

R-Maintenance

R-Bendamustine

R-CVP

R-Cbl

Other?

? Maintenance

Yes No

Treat

Yes No

Yes NoCR/PR

Kluin-Nelemans HC et al. NEJM 2012;367:520-31

ORR

(%)

CR

(%)

R-CHOP 86 34

R-FC 78 40

R-CHOP vs R-FC in

elderly patients with MCL

Cause of death R-FC R-CHOP

Died in CR/PR 10% 4%

Infections 7% 4%

Second cancer 3% 1%

P=0.06 P=0.10

MCL Elderly: overall survival related to induction regimen

After R-CHOP After R-FC

Kluin-Nelemans HC et al. NEJM 2012;367:520-31

Updated results 2017: Maintenance part (R2)

– after R-CHOP

PFS

O

SGroup

5-year

rate 95% CI

R 79% 67%-86%

IFN 59% 48%-69%

Group

5-year

rate 95% CI

R 51% 40%-62%

IFN 22% 14%-32%

Rummel MJ et al, Lancet 2013

R-Bendamustine

PFS

MCL

Two Years Rituximab Maintenance vs. Observation

after 1st-line treatment with Bendamustine plus Rituximab in

pts with Mantle Cell Lymphoma

Results of a prospective, randomized, multicentre phase 2 study

(a subgroup study of the StiL NHL7-2008 MAINTAIN trial)

Mathias Rummel, Wolfgang Knauf, Martin Goerner, Ulrike

Soeling, Elisab. Lange, Bernd Hertenstein, Jochen Eggert,

G. Schliesser, R. Weide, Kl. Blumenstengel, N. Detlefsen,

Axel Hinke, Frank Kauff, Juergen Barth on behalf of StiL

Study group indolent Lymphomas, Giessen, Germany

Overall survival (58.6 months median follow-up)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84 96

Pro

babili

ty

Months since registration

OS (randomized pts)

Hazard ratio, 1.51 (95% CI 0.70 – 3.25)

p = 0.2974

months events

(median) (n)

Observation n.y.r. 11

R maint. n.y.r. 15

N = 122

Pts at risk

Observ 62 58 57 52 43 21 8

R maint 60 59 53 44 38 23 5

StiL NHL 7-2008 Kluin-Nelemans et al

n = 122 (of 168) n = 184 (of 280)

Rate of randomized patients 73 % 66 %

B-R B-R CHOP-R CHOP-R

+ R + INF + R

Remission duration

median (months) since randomization 57 68 23 n.y.r

rate at 72 months (estimated) 49% 40% 12% 50%

OS

median (months) since randomization n.y.r. n.y.r. 64 n.y.r.

rate at 72 months (estimated) 70% 66% 50% 71%

Cross study comparison

RBAC500 as induction therapy for elderly patients

• Rituximab 375 mg/m2 on day 1; Bendamustine 70 mg/m2 days 2 and 3; Cytarabine (dose

reduced) 500 mg/m2 days 2-4

• Included previously untreated patients aged >65 years or 60-65 unfit for ASCT with no

history of indolent disease (non-nodal leukemic disease)

• Primary objectives: CR rate and safety

Visco et al., ASH 2016 (abstract 472, oral presentation))

End of treatment PET/CT

N=57 %

ORR 52 91

CR 52 91

PD 2 4

NA 3 5

MRD by n-PCR (n=45, 79%)

Timepoints n MRD- BM/PB

After cycle 2 45 54/62

End of therapy 45 55/79

+12 months 28 57/75

Require Therapy?




Autograft

? Maintenance

R-CHOP

(R-Bendamustine)

R-Maintenance

R-Bendamustine

R-CVP

R-Cbl

Other?

? Maintenance

Yes No

Treat

Yes No

Yes NoCR/PR

Treatment at relapse

Table of Various Treatment for R/R MCL

Treatment Study or

Literature

Reference

N ORR CR Median

DOR

(months)

Median

PFS

(months)

Median

OS

(months)

Ibrutinib PCYC-1104-

CA

111 68% 21% 17.5 13.9 Not

reached

Bortezomib Fischer 2006

Goy 2009

155a 33% 8% 9.2 6.5 23.5

Lenalidomide Goy 2012 134 28% 8% 16.6 4.0 19.0

Temsirolimusb Hess 2009 54 22% 2% 7.1 4.8 12.8

CR=complete response; DOR= duration of response; ORR=overall response rate; OS=overall survival;

PFS= progression-free survival.a Of the 155 patients enrolled, 141 were assessable for response.

b Results are presented for temsirolimus 175/75 mg dose group.

53

Campo & Rule Blood 2015 Jan 1;125(1):48-55

BORTEZOMIB

No difference in OS.

VR-CAP was more effective than R-CHOP in patients

with newly diagnosed MCL but at the cost of increased

hemo-toxicity.

Robak T et al, NEJM 2015

ORR

(%)

CR

(%)

R-CHOP 89 42

VR-CAP 92 53

LENALIDOMIDE

IBRUTINIB

Bruton’s Tyrosine Kinase (BTK):A Critical Kinase for Lymphoma Cell Survival and Proliferation

EHA 2013, PCYC-1104 Rule et al.2

• Bruton’s tyrosine kinase (BTK) is an essential element of the BCR signaling pathway (Niiro, NRI 2002)

• Inhibitors of BTK block BCR signaling and induce apoptosis

• BTK also acts downstream of certain chemokine receptors impacting integrin molecules that help in promoting egression from the lymph node environment

PCYC-1104-CA Phase 2 Study of Ibrutinib in R/R MCL

48.7

53.250.5 47.8

46.0 47.3

0

10

20

30

40

50

60

70

80

90

100

2 4 6 9 12 15

Re

spo

nse

rat

e, %

Time, months

66.7 68

52.3

62.264 64.9

3.6 9.0 13.5 17.1 20.7 20.7

CRPR

Rule et al. Oral presentation at EHA 2013, Abstract S1178.Wang et al. Poster presentation at ICML 2013, Abstract 293.

60

Median 3.5-Year Follow-Up of Ibrutinib Treatment

in Patients With Relapsed/

Refractory Mantle Cell Lymphoma:

A Pooled Analysis

Simon Rule,1 Martin Dreyling,2 Andre Goy,3 Georg Hess,4 Rebecca Auer,5 Brad Kahl,6 Jose Hernandez-Rivas,7 Anil Londhe,8 Fong Clow,9 Sanjay Deshpande,8

Lori Parisi,8 Michael Wang10

1Plymouth University Medical School, Plymouth, UK; 2Department of Medicine III, Klinikum der Universität München, LMU, Munich, Germany; 3John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ,

USA; 4Department of Hematology, Oncology and Pneumology, University Medical School of the Johannes Gutenberg University, Mainz, Germany; 5Barts Cancer Institute, London, UK; 6Department of Medicine, Washington University, St. Louis, MO, USA; 7Hematology Department, Hospital Universitario Infanta Leonor, Madrid, Spain; 8Janssen Research &

Development, Raritan, NJ, USA; 9Pharmacyclics, Sunnyvale, CA, USA; 10The University of Texas MD Anderson Cancer Center, Houston, TX, USA

• Discontinuation rates due to AEs at time of primary analysis (median follow-up):

• PCYC-1104 (15.3 months): 7%

• SPARK (14.9 months): 7%

• RAY (20 months): 6%

Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory MCL: A

pooled analysis - Patient disposition

Total (Pooled)

(N = 370)

Study, n (%)

PCYC-1104

SPARK

RAY

111

120

139

Patients rolled over to CAN3001, n (%) 87 (23.5)

Median duration of follow-up, months (range) 41.1 (0.2-72.1)

Treatment discontinuation, n (%)

AE

Disease progression

Death

Other*

316 (85.4)

37 (10.0)

218 (58.9)

19 (5.1)

42 (11.4)

*Includes: alternative access to ibrutinib (n = 1); physician decision (n = 14); withdrawal of consent (n = 24); other reasons (n = 3).

Rule et al., ASH 2017 (abstract 151, oral presentation)

64

Pooled MCL Analysis:

Improvement in Response Rates Over Time

0

10

20

30

40

50

60

70

80

90

100

2 4 6 9 12 15 18 21 25

OR

R (

%)

45.7

Months

CR

PR

15.7

47.3

54

60.564 64.6 64.9 65.1 65.7

PR, partial response.N = 370

1.6 5.9 10.015.4 18.4 18.9 19.2 19.5 20.0

45.745.745.745.745.1

44.041.4

14.1

OS

Median

NR

(36.0-NE)

Median 22.5

mo

(16.2-26.7)

65

PFS and OS by Prior Line of Therapy

PFS

Median 25.4 mo

(17.5-57.5)

Median 10.3

mo

(8.1-12.5)

Median PFS overall (95% CI): 12.5 (9.8-16.6)

months

Median OS overall (95% CI): 26.7 (22.5-38.4)

months

Median PFS was just over 2 years in patients with 1 prior line of

therapy

Patients at risk

1

prior> 1 prior

99

271

81

193

66

147

61

117

55

97

51

79

47

67

38

60

36

54

31

47

27

43

16

30

12

22

5

12

3

5

2

2

2

1

2

1

0

0

Patients at risk

1

prior> 1 prior

99

271

88

227

81

186

70

158

66

139

66

12

2

59

103

50

83

46

68

41

59

36

50

20

37

15

29

8

16

4

8

3

3

3

2

2

2

0

1

0

0

Patients censored from OS analysis upon study discontinuation.

CI, confidence interval; NE, not estimable.


PFS by Baseline Patient Characteristics

66

**

*

*

HR (95% CI) p value


OS by Baseline Patient Characteristics

67

**

*

*

Significant in univariate analysis

Significant in multivariate analysis*

HR (95% CI) p value

Median 3.5-Year follow-up of ibrutinib treatment in patients with

relapsed/refractory MCL: a pooled analysis


In this pooled analysis of 370 patients:

– Approximately one-third (n = 115, 31.1%)

were treated with ibrutinib for ≥ 2 years

– 54 remained on ibrutinib at time of

analysis, with a median exposure of 46.3

months (range 28.8-72.1)

– Maximum treatment exposure was

72 months

Ibrutinib Exposure in Patients With≥ 2 Years of Exposure (N = 115)

2 to < 3

yrs

32

(27.8%)

≥ 4 yrs

40

(34.8%)

3 to < 4

yrs

43

(37.4%)

43.2% 41.4% 43.9%

26.5% 36.4%22.9%

0%

20%

40%

60%

80%

100%

ITT 1 prior line > 1 prior line

Ibrutinib in MCL: Overall response and PFS/OS by best response

N = 370

ORR:

69.7%

(n = 258)

N = 99CR PR

N =

271

ORR

ORR:

77.8%

(n = 77) ORR:

66.8%

(n = 181)

Kaplan-Meier estimate of median.

Median, Months

(95% CI)

Best Response

CR

(n = 98)

PR

(n = 160)

PFS 46.2

(42.1-NE)

14.3

(10.4-17.5)

OS NE

(59.9-NE)

26.2

(21.6-34.7)

ITT, intent-to treat; ORR, overall response rate; PR, partial response.

CR rate was 36% in patients with 1 prior line of therapy

Median PFS was nearly 4 years in patients who achieved a CR


Ibrutinib in MCL: DOR by best response and line of therapy

Median DOR,

Months (Range)

Overall

(n = 258)

Prior Lines of Therapy

1

(n = 77)

> 1

(n = 181)

Overall

(n = 258)

22.2

(16.5-28.8)

34.4

(23.1-NE)

16.0

(12.9-23.5)

CR

(n = 98)

55.7

(55.7-NE)

55.7

(33.1-NE)

NE

(40.7-NE)

PR

(n = 160)

10.4

(7.7-14.9)

22.1

(10.6-34.4)

8.5

(6.2-12.1)

Median DOR was 4.5 years in patients achieving a CR

Patients with 1 prior line had 2× longer DOR than patients with > 1 prior line

DOR, duration of response.


71


PFS and OS by Blastoid Histology

CI, confidence interval.

*Statistically significant.

0 5 10 15

Months

Nonblastoid (n = 326) Blastoid (n = 44)

20 25 30

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

urv

ivin

g w

ith

ou

t p

rogr

ess

ion

MonthsP

rop

ort

ion

aliv

e

5.09 months

14.59 months

12.75 months

Median OS, not reached2-year OS, ~ 55%

0 5 10 15 20 25 30 35

0.2

0.4

0.6

0.8

1.0

+ Censored

PFS* OS*

TOXICITY

0% 10% 20% 30% 60%50%40%

Grade 1/2

Grade 3/4

Grade 5

Thrombocytopenia

Neutropenia

Anemia

FatigueDiarrhea

Cough

NauseaMuscle spasms

Pyrexia

DyspneaRash

Upper respiratory tract infection

VomitingArthralgia

PneumoniaContusion

Constipation

SinusitisStomatitisBack pain

Decreased appetiteHypokalemia

HypertensionAtrial fibrillation

MyalgiaAbdominal pain

Urinary tract infectionPain in extremity

Headache

SPARK trial Wang et al ASH 2015

0% 10% 20% 30% 60%50%40%

Grade 1/2

Grade 3/4

Grade 5

Thrombocytopenia

Neutropenia

Anemia

FatigueDiarrhea

Cough

NauseaMuscle spasms

Pyrexia

DyspneaRash

Upper respiratory tract infection

VomitingArthralgia

PneumoniaContusion

Constipation

SinusitisStomatitisBack pain

Decreased appetiteHypokalemia

HypertensionAtrial fibrillation

MyalgiaAbdominal pain

Urinary tract infectionPain in extremity

Headache

SPARK trial Wang et al ASH 2015

Ibrutinib in MCL: Grade ≥ 3 treatment-emergent AEs over time and

by line of therapy

79.7%

67.8%

47.8%

34.8%36.1%

20.0%

68.7%

55.6%

34.4%29.8%29.4%

7.1%

83.8%

72.3%

54.6%

38.2%40.8%

26.9%

0%

20%

40%

60%

80%

100%

1

29

525

1

40 3

0

8

86

ITT 1 Prior Line > 1 Prior Line

68

55

14 1021

22

7196

26 20

7

65

Overall Yr 1 Yr 2 Yr 3 Yr 4 Yr > 4 Overall Yr 1 Yr 2 Yr 3 Yr 4 Yr > 4 Overall Yr 1 Yr 2 Yr 3 Yr 4 Yr > 4

370 370 180 115 83 40 99 99 61 47 34 14 271 271 119 68 49 26N =

New onset grade ≥ 3 TEAEs generally decreased after the first year of treatment

– Similar trend was seen for atrial fibrillation (AF) and bleeding

New onset grade ≥ 3 TEAEs were generally lower in patients with 1 vs > 1 prior line

Number of patients with event shown on bars.


Bleeding with procedures

Ibrutinib for CNS mantle cell NHL

Next generation BTKi’s

Tirabrutinib Acalabrutinib

M 7583

Zanubrutinib

Acalabrutinib (ACP-196)

BLK = B lymphocyte kinase; BMX = bone marrow tyrosine kinase gene in chromosome X; BTK = Bruton tyrosine kinase; EGFR = epidermal growth factor receptor; ERBB2 = erb-b2 receptor tyrosine kinase; ERBB4 = erb-b4 receptor tyrosine kinase; IC50 = inhibitory concentration of 50%; ITK = interleukin-2-inducible T-cell kinase; JAK3 = Janus kinase 3; TEC = tyrosine kinase expressed in hepatocellular carcinoma; TXK = T and X cell expressed kinase.

Barf T, et al. J Pharmacol Exp Ther. 2017;363(2):240-252.

Kinase Inhibition

Average IC50 (nM)

Kinase Acalabrutinib Ibrutinib

BTK 5.1 1.5

TEC 126.0 10

ITK >1000 4.9

BMX 46 0.8

TXK 368 2.0

EGFR >1000 5.3

ERBB2 ~1000 6.4

ERBB4 16 3.4

BLK >1000 0.1

JAK3 >1000 32

Kinase

Selectivity

Profiling at

1 M

Larger red circles represent stronger inhibition

IbrutinibAcalabrutinib

• Acalabrutinib is more selective for BTK with less off-

target kinase inhibition compared with ibrutinib in vitro

Byrd et al., ASH 2017 (abstract 498, oral presentation)

Table of Various Treatment for R/R MCL

Treatment Study or

Literature

Reference

N ORR CR Median

DOR

(months)

Median

PFS

(months)

Median

OS

(months)

Ibrutinib PCYC-1104-

CA

111 68% 21% 17.5 13.9 Not

reached

Bortezomib Fischer 2006

Goy 2009

155a 33% 8% 9.2 6.5 23.5

Lenalidomide Goy 2012 134 28% 8% 16.6 4.0 19.0

Temsirolimusb

Acalabrutinib

Hess 2009

Wang 2017

54

124

22%

81%

2%

40%

7.1

Not

reached

4.8

Not

reached

12.8

Not

reachedCR=complete response; DOR= duration of response; ORR=overall response rate; OS=overall survival;

PFS= progression-free survival.a Of the 155 patients enrolled, 141 were assessable for response.

b Results are presented for temsirolimus 175/75 mg dose group.

81

WHERE NEXT?

Comparison of the 4 drugs licensed for the use

in MCL: data as single agents and in

combination with rituximab

Treatment No. Patients ORR CR Median

DOR

(months)

Median

PFS

(months)

Median

OS

(months)

Ibrutinib 111 68% 21% 17.5 13.9 Not reached

+ rituximab 50 87% 38% NR 15 month

PFS 69%

15 month

OS 83%

Bortezomib 155 33% 8% 9.2 6.5 23.5

+ rituximab 19 58% 16% NR NR NR

Lenalidomide 134 28% 8% 16.6 4 19

+ rituximab 44 57% 36% 19 11.1 24.3

Temsirolimus 54a 22% 2% 7.1 4.8 12.8

+ rituximab 69 59% 19% 10.6 9.7 29.5CR=complete response; DOR= duration of response; ORR=overall response rate; OS=overall survival;

PFS= progression-free survival; NR=not reported.

83

Jain P et al 2018

Jain P et al BJHaem 2018

Jain P et al. BJHaem 2018

Study Therapy PART I: Chemo-free Ibrutinib +

Rituximab

R-I 2 cycles 2 cycles

=CR

=PR

/SD#

=PD

=CR

=PR

=SD#

/PD

Part 2

Part 2

2 cycles

=CR

=PR

=SD#

/PD

Part 2

Part 2

2 cycles

Part 2

Part 2

Cycles continue up

to 12 cycles until

no more PR or

best response (As

long as patient has

PR from last

restaging. R-I

continues

• Oral ibrutinib at 560 mg daily, each cycle is 28 days

• 4 weekly loading doses IV rituximab at 375 mg/m² in Cycle 1, then 1 dose/cycle in

Cycles3-12

• Restage every 2 cycles

• Any time CR in PART I, will enter PARTII

• Up to 12 months to reach bestresponse.

Oral Presentation ASH 2016Wang

Window I/II Study: the Best ResponseRate

90100

10

0

20

40

60

80

100

Part I

(N =50)

Part II

(N =47)

CR

PR

%o

fp

ati

en

tsORR100% ORR100%

ENRICH – NCRI MULTICENTRE RANDOMISED

OPEN LABEL PHASE II/III TRIAL OF RITUXIMAB

& IBRUTINIB VS RITUXIMAB & CHEMOTHERAPY

IN ELDERLY MANTLE CELL LYMPHOMA

ENRICH – NCRI multicentre Randomised open

label phase III trial of Rituximab & Ibrutinib vs

Rituximab & CHemotherapy in Elderly mantle

cell lymphoma

IR/RIntervention

R-CHEMO/RStandard care

Ibrutinib daily

+ Rituximab (every 21 days)

for 8 cycles

R-CHEMO

(every 21 days)

for 6-8 cycles

Rituximab

(every 56 days)

for 2 years

Ibrutinib daily

+ Rituximab (every 56 days)

for 2 years

Ibrutinib to

continue until

disease

progression

Follow-up

until disease

progression

R

CI S Rule

Triangle

Courtesy of the European MCL Network

ObservationR-CHOP/

R-DHAP x 6ASCT

2 yrs I-maintenance

2 yrs I-maintenance

R R-CHOP/

R-DHAP x 6 + I

R-CHOP/

R-DHAP x 6 + I

ASCT Observation

Observation

A:

A + I:

I:

superiority/non-inferiority: time to treatment failure

HR: 0.60; 65% vs. 77% vs. 49% at 5 years

HOW TO TREAT POST

IBRUTINIB?

ABSOLUTELY NO IDEABut it almost certainly depends on when it is used

RAY: Efficacy of subsequent anticancer therapy

Dreyling M et al. Lancet 2016; 387(10020):770-8


Progression-free survival 2 (PFS2)

CRPR

0

20

40

Prior Ibrutinib (n = 40)

Prior Temsirolimus

(n = 50)

4.0%7.5%

12.5% 16.0%

After EXCLUDING patients who

received crossover treatment with

either drug, ORR was 20% in both

groups

Response to subsequent therapy

% o

f p

ati

en

ts

% w

ith

ou

t ev

en

t

Ibrutinib

TemsirolimusTemsirolimus

Ibrutinib

Ibrutinib Temsirolimus

Median PFS2

(months)19.1 11.3

HR 0.49

95% CI 0.36-0.69

Log-rank p value < 0.0001

95

Next Treatments and Response Rates in Patients Randomized

to Ibrutinib 139 patients randomized to ibrutinib

63 ibrutinib patients received subsequent anticancer therapy on study

Of those, 29 (46.0%) ibrutinib patients received rituximab-based

chemotherapy as 1st subsequent anticancer therapy

Summary of Rituximab-Based

Chemotherapy (N = 29)

BR 15 (51.7%)

R-chemo 9 (31.0%)

R-chemo + bortezomib or

temsirolimus or lenalidomide

5 (17.2%)

Response, n (%) N = 29

Overall response rate 12 (41.4%)

CR 7 (24.1%)

PR 5 (17.2%)

SD 2 (6.9%)

PD 4 (13.8%)

Not evaluable/applicable 11 (37.9%)

Venetoclax monotherapy in patients with relapsed/refractory mantle cell

lymphoma post BTK inhibition therapy

Eyre et al., EHA 2018; S855 (oral presentation)

• Retrospective, multicentre study of 20 R/R

MCL patients treated with venetoclax

monotherapy at major UK centres

Median PFS to prior BTKi of 4.8

months

(95% CI 3.1-29.2 months)

All patients (N=20) n (%)

Response rate to prior BTK inhibitor ORR 11/20 (55%)

CR 3 (15%)

PR 8 (40%)

SD 4 (20%)

PD 5 (25%)

Duration of exposure to BTK inhibitor

(months; range)4.8 months

(range 0.7 – 34.8 months)

Reason for BTK inhibitor

discontinuation

Progressive disease 17

Stable disease 1

Toxicity 2

ibrutinib (n=17), ibrutinib with donor lymphocyte infusion

(n=1), tirabrutinib (n=2)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35

PFS on IBR (months)

Venetoclax monotherapy in patients with R/R MCL post BTKi:

Response

Eyre et al., EHA 2018; S855 (oral presentation)

• 20 patients evaluable for response assessment

• Median follow up from the start of venetoclax:

5.1 months.

• ORR 60% (CR 20%, PR 40%)

• Median 3.75 x 28-day cycles (range 0.5-13).

• ORR according to prior BTKi response:

• primary BTKi resistance (n = 9): ORR

44.4% vs response to prior BTKi (n = 11):

ORR 72.7%

Treatment post venetoclax n (%)

Allogenic stem cell transplantation->

PEP-C1

R-BAC 2*

R-Bendamustine 2

Lenalidomide-based+/-R 2

Ibrutinib 2

Nil 12

*1 patient R-BAC given with aim to bridge to allogenic

SCT (developed secondary AML)

ABT + BTK TRIALS

Plasma DNA

AIM (ABT-199 & Ibrutinib in MCL)

Study Schema

Primary Endpoint

Tam et al. N Engl J Med 2018 378(13);1211-1223

AIM Study: Response Rates (PET)

Week 16,

CT only

Week 16,

PET/CT

Complete Response (CR) 10 (42%) 15 (63%)

CR, unconfirmed 4 (17%) -

Partial Response (PR) 4 (17%) 2 (8%)

Stable Disease (SD) 1 (4%) 1 (4%)

Progressive disease (PD) 3 (13%) 4 (17%)

Not Evaluable 2 (8%) 2 (8%)

OR = 71%

CR = 63%

Wk 16

Patients were restaged at week 16 using CT, PET, double endoscopy (if baseline

involvement), and BMAT with MRD studies.

patients were not evaluable due to early death (n=1), and target lesions judged on central

review to be too small and poorly FDG avid for reproducible measurement (n=1). Tam et al. N Engl J Med 2018 378(13);1211-1223

AIM Study: Response Rates (PET)

Week 16,

CT only

Week 16,

PET/CT

Complete Response (CR) 10 (42%) 15 (63%)

CR, unconfirmed 4 (17%) -

Partial Response (PR) 4 (17%) 2 (8%)

Stable Disease (SD) 1 (4%) 1 (4%)

Progressive disease (PD) 3 (13%) 4 (17%)

Not Evaluable 2 (8%) 2 (8%)

OR = 71%

CR = 63%

Wk 16

Patients were restaged at week 16 using CT, PET, double endoscopy (if baseline

involvement), and BMAT with MRD studies.

patients were not evaluable due to early death (n=1), and target lesions judged on central

review to be too small and poorly FDG avid for reproducible measurement (n=1). Tam et al. N Engl J Med 2018 378(13);1211-1223

50% TP53 aberrations

Half achieved CR

AIM Study : Marrow Flow MRD Kinetics*

* 3 patients had no marrow involvement

z Complete Response

z Partial Response

z Progressive Disease

Flow MRD-neg

10 of 13 (77%)

assessable CR

Tam et al. N Engl J Med 2018 378(13);1211-1223

Campos, PNAS 2014

Subclonal architecture and clonal evolution in MCLTwo different subclones in different topographic sites

Summary

• Treat when clinically indicated

• Young patients

• Cytarabine is the key drug

• What you add to it is not clear

• Older patients

• CHOP or Bendamustine based treatment appropriate

• New agents are rapidly moving into the front line

• Likely to be part of the standard of care soon

• Clinical trials are how we improve outcomes

Documents

MANTLE CELL LYMPHOMA · Derriford Hospital and Peninsula Medical School ... and Growth Pattern in Mantle Cell Lymphoma (MCL): Results from Randomized ... Sureda A, Smith P, Patrick