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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%
Hoster et al., Hematol Oncol 2015; 33: 100–180 (abstract 58, oral presentation)
OS According to MIPI-c
GLSG1996/2000 MCL Younger/MCL Elderly
Hoster et al., Hematol Oncol 2015; 33: 100–180 (abstract 58, oral presentation)
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?
Fit for autograft? Consider watch & wait
Rituximab and HD-AraC
containing regimenFit for CHOP?
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?
Fit for autograft? Consider watch & wait
Rituximab and HD-AraC
containing regimenFit for CHOP?
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?
Fit for autograft? Consider watch & wait
Rituximab and HD-AraC
containing regimenFit for CHOP?
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?
Fit for autograft? Consider watch & wait
Rituximab and HD-AraC
containing regimenFit for CHOP?
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.
Pooled MCL Analysis:
PFS by Baseline Patient Characteristics
66
**
*
*
HR (95% CI) p value
Pooled MCL Analysis:
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
Rule et al., ASH 2017 (abstract 151, oral presentation)
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
Rule et al., ASH 2017 (abstract 151, oral presentation)
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.
Rule et al., ASH 2017 (abstract 151, oral presentation)
71
Pooled MCL Analysis:
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.
Rule et al., ASH 2017 (abstract 151, oral presentation)
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
Rule et al., ASH 2015 (abstract 469, oral presentation)
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