Mantle Cell Lymphoma - European Society for Medical Oncology
Transcript of Mantle Cell Lymphoma - European Society for Medical Oncology
MANTLE CELL LYMPHOMA
Dr Tobias Weiglein, MD, MHBA & Prof Dr Martin Dreyling, MD
Ludwigs-Maximilians University Munich, Medical Department for
Hemathology and Oncology,
Campus Groβhadern, Munich, Germany
1. To understand the biology of MCL
2. To understand the diagnostic and prognostic factors in MCL
3. To choose the most appropriate first line treatment for different subsets of patients
4. To know about molecular targeted substances and therapy concepts at relapse
and refractory disease
LEARNING OBJECTIVES
Accounts for approximately 6% of all NHL cases
Median age 60-70 years
Male predominance (men > women 3:1)
Very frequent extranodal disease manifestation
Since its worldwide recognition in 1994, it has been known to have a dismal
prognosis (“the worst lymphoma to have”), with a median overall survival (OS) rate
of 3 years only
MANTLE CELL LYMPHOMA
Epidemiology and characteristics
PROGNOSIS OF MANTLE CELL LYMPHOMA
PROGNOSIS OF MCL
Overall survival of MCL compared to other B-NHL entities
Survival of B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland,1980-2006.
Republished with permission of American Society of Hematology, from Blood, Ghielmini M, et al., Blood, 114, 8, 2009, permission conveyed through Copyright
Clearance Center, Inc.
MANTLE CELL LYMPHOMA
HISTOLOGY
A classical; B small cell; C pleomorphic; D: blastoid; E: classical & pleomorphic; F: classical/pleomorphic
Tiemann M, et al., Br J Haematol 2005;131(1):29–38. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma
(MCL): a clinicopathological study from the European MCL Network. © 2005 Blackwell Publishing Ltd.
MANTLE CELL LYMPHOMA BIOLOGY
RB signal pathway in MCL I
G1
S
G2
MRB
RB P
cdk4/
cyclin D1
MANTLE CELL LYMPHOMA:
A SPECTRUM OF DISEASE
“Indolent” MCL (15%) “Classical” MCL (80%) “Transformed” (5%)
Dreyling M, ASCO Educational 2014. Courtesy of Prof Martin Dreyling
MANTLE CELL LYMPHOMA:
TWO KINDS OF DISEASE?
Dreyling M, ESMO CR 2017. Courtesy of Prof Martin Dreyling
PROGNOSIS OF MCL
In 1980 -1990s overall median survival (OS) was
dismal with 2-4 years at time of diagnosis
Prognosis depending on clinical variables
Age
Stage
Performance Score
LDH
And biological features
Proliferation Index (Ki67)
growth pattern (blastoid vs. classical)
Tiemann M, et al., Br J Haematol 2005;131(1):29–38. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma
(MCL): a clinicopathological study from the European MCL Network. © 2005 Blackwell Publishing Ltd.
PROGNOSIS OF MCL
Risk factor proliferation: MCL 35
Scott DW, J Clin Oncol, 35(15) 2017: 1668–77. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
MIPI:
Age
ECOG Performance status
LDH level
WBC count
MIPI-c:
MIPI + Ki-67 index
The more refined combined MIPI (MIPI-c) classifies MCL patients into four prognostic groups
dependent on MIPI group and Ki-67 index
According to MIPI-c, patients are assigned to the low, low-intermediate, high-intermediate, or
high risk group
PROGNOSIS OF MCL
MIPI and MIPI-c
Dreyling M, et al., Haematologica 2016;101(2):104–114. Obtained from the Haematologica Journal website http://www.haematologica.org;
Hoster, J Clin Oncol 2016;34(12):1386-94.
MIPI
high
MIPI
low
MIPI
intermediate
MIPI-c
high
MIPI-c
high-intermediate
MIPI-c
low-intermediate
MIPI-c
low
Ki67
<30%
Ki67
≥30%
Ki67
<30%
Ki67
≥30%
Ki67
<30%
Ki67
≥30%
PROGNOSIS OF MCL
Combined MIPI (MIPI-c)
Patients >65 years Patients <65 years
Hoster E, J Clin Oncol, 34(12), 2016:1386-94. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved.
MANTLE CELL LYMPHOMA TREATMENT
MANTLE CELL LYMPHOMA
TREATMENT
Optimal treatment for MCL?
=> MRD elimination=> lymphoma remission
Immuno-chemotherapy !
Maintenance
+/-
SCT
Induction Consolidation
MANTLE CELL LYMPHOMA
TREATMENT
Young, fit patients
Young Fit Patient (<65)Organ Function
Comorbidity
Performance Status
Old Fit Patient (>65)Organ Function
Comorbidity
Performance Status
Old Unfit Patient (>65)Organ Function
Comorbidity
Performance Status
First Line Therapy*
Mild Therapy
e.g. R-Chlorambucil
B-R
R-CVP
Best Supportive Care?
Conventional
Immunochemotherapy
e.g. R-CHOP, B-R
VR -CAP
+ Rituximab Maintenance
Dose-intensified
Immunochemotherapy
R-CHOP / R- DHAP followed by
Autologous SCT
+ R- Maintenance
Intensive Therapy:
Long Term Survival
Less Intensive Therapy:
Remission and Better Survival
Mild Supportive Therapy:
Symptom Control , Survival
*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible
MANTLE CELL LYMPHOMA
TREATMENT
Role of anti-CD-20 antibody rituximab
Adding rituximab to CHOP clearly
improves PFS an ORR, (ORR 94%
vs. 75%, CR 34% vs. 7%)
Improvement of ORR and PFS with
addition of rituximab to
polychemotherapy have been
confirmed in successive trials
R-Chemo standard of care in first
and successive treatment lines
1. Hoster E, et al., Blood 2008;112(11):3049. Presented at ASH Annual Meeting 2008. Courtesy of Prof Martin Dreyling;
2. Buske C, et al., 2009 Leukemia 2009;23:153–161.
MANTLE CELL LYMPHOMA
TREATMENT
Why CHOP?
From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of older patients with mantle-cell lymphoma, 367,520–31. Copyright © 2012 Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
MANTLE CELL LYMPHOMA TREATMENT
Autologous SCT and IFN survival rates
Treat-
ment
Hazard
Ratio 95% CI p
R 0.70 0.44 1.12 0.14
ASCT 0.63 0.41 0.97 0.0379
Treat-
ment
Hazard
Ratio 95% CI p
R 0.60 0.42 0.86 0.0056
ASCT 0.50 0.35 0.70 0.0001
Remission duration Overall survival
Dreyling M, et al., Blood 2005;105:2677–2684; Hoster E, et al. Blood 2009;114(22):880.
Presented at ASH Annual Meeting 2008 Courtesy of Prof Martin Dreyling.
MANTLE CELL LYMPHOMA
TREATMENT
Young fit patients <65 years
PR, CR!3 x R-CHOP
DexaBEAM(stem cell mobilisation)
Cyclo 120 mg/kg
+ TBI 12 Gy
PBSCT
3 x R-CHOP
PR, CR!
3 x R-CHOP
3 x R-DHAP
alternating
(stem cell mobilisation
after course 4)
PBSCT
TBI 10 Gy
Ara-C 4 x 1.5 g/m2
Melphalan 140 mg/m2
Hermine O, et al., Lancet 2016;388(10044):565–75.
MANTLE CELL LYMPHOMA
TREATMENT
Time to treatment failure in “MCL younger” trial
From The Lancet, 388(10044), Hermine O, et al. ( Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients
aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network,
388:565–75. Copyright © 2016 with permission from Elsevier.
MANTLE CELL LYMPHOMA
TREATMENT
MRD at end of induction: Effect of ASCT
R-CHOP R-DHAP
PB BM PB BM0
25
50
75
100
% M
RD
neg
ativ
e
58%
70%
p = 0.08 p = 0.007
37%
60%
83% 79% 70%
85%
ns
**
* *
* p = 0.03
Hermine O, et al., Lancet. 2016;388(10044):565–75.
MANTLE CELL LYMPHOMA
TREATMENT
Post ASCT rituximab maintenance: “LyMa” trial
R-BEAM
Rituximab maintenance
every 2 months during 3 years
Observation
R-DHAP R-DHAPR-DHAP R-DHAP
If < VGPR
W1 W4 W7 W10
R-DHAP: Rituximab 375 mg/m2; aracytine 2 g/m2 x2 IV 3 hours injection 12 hours interval; dexamethasone 40 mg d1-
4; Cisplatin 100 mg/m2 d1 (or oxaliplatin or carboplatin)
R-BEAM: Rituximab 500 mg/m2 d-8; BCNU 300 mg/m2 d-7; Etoposide 400 mg/m2/d d-6 to -3; aracytine 400 mg/m2/d d-6
to d-3; melphalan 140 mg/m2 d-2
If > VGPR
R-CHOP
Le Gouill S, et al. N Engl J Med. 2017;377(13):1250-1260
MANTLE CELL LYMPHOMA
TREATMENT
Post ASCT rituximab maintenance: “LyMa” trial
From N Engl J Med, Le Gouill S, et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma, 377, 1250–60. Copyright © 2017
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
MANTLE CELL LYMPHOMA
TREATMENT
First line treatment young patients: Conclusion
Watch and wait strategy in indolent, low tumour burden patients possible
Rituximab – chemo is standard of care in any induction therapy
Induction-regimes containing high-dose cytarabin seem to further improve PFS, OS and MRD
negativity. ORR is 80-90% with 40-50% CR
High-dose chemotherapy, followed by autologous stem cell transplantation prolongs PFS and
OS and is the current standard of care for younger patients, generally providing high responses
and long survival rates, but is hampered by acute and long-term toxicity
R-hyper-CVAD or R-HD-MTX-Ara-C regimen, followed by a consolidation with BEAM and ASCT
is an alternative dose intensified (and toxic) approach and are debated, especially between
European and American clinical groups
Rituximab maintenance every 2 months for 3 years after ASTC improves OS
MANTLE CELL LYMPHOMA
TREATMENT
Older patients / Unfit patients
Young Fit Patient (<65)Organ Function
Comorbidity
Performance Status
Old Fit Patient (>65)Organ Function
Comorbidity
Performance Status
Old Unfit Patient (>65)Organ Function
Comorbidity
Performance Status
First Line Therapy*
Mild Therapy
e.g. R-Chlorambucil
B-R
R-CVP
Best Supportive Care?
Conventional
Immunochemotherapy
e.g. R-CHOP, B-R
VR -CAP
+ Rituximab Maintenance
Dose-intensified
Immunochemotherapy
R-CHOP / R- DHAP followed by
Autologous SCT
+ R- Maintenance
Intensive Therapy:
Long Term Survival
Less Intensive Therapy:
Remission and Better Survival
Mild Supportive Therapy:
Symptom Control , Survival
*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible
IMMUNO-CHEMOTHERAPY IN
ELDERLY >65 YEARS
Progression-free survival
• Bendamustine in combination with rituximab can be applied with comparable ORR
and OS rates as R-CHOP, but with lesser side effects
Reprinted from The Lancet, 381(9873), Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent
and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial, 1203–10. Copyright 2013, with permission from Elsevier.
MANTLE CELL LYMPHOMA
TREATMENT
MCL elderly survival rates (R-CHOP)
Remission duration Overall survival
• Rituximab as maintenance therapy every two months following R-CHOP chemotherapy
significantly improves PFS
From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of Older Patients with Mantle-Cell Lymphoma, 367:520–31. Copyright © 2012 Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
BORTEZOMIB IN MCL
VR-CAP vs. R-CHOP
No maintenance Therapy after induction!
59% improvement with VR-CAP vs. R-CHOP (hypothesised: 40% improvement)
Median PFS by investigator was 16.1 vs. 30.7 months with R-CHOP vs. VR-CAP
From N Engl J Med, Robak T, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma, 372:944–53. Copyright © 2015 Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
FIRST LINE ELDERLY PATIENTS
Conclusion
In elderly patients with compromised organ function and performance score, conventional
immuno-chemotherapy is the first choice with ORR of ~90%
Fludarabin-containing regimens are inferior to R-CHOP in terms of OS
Rituximab as maintenance therapy every two months following R-CHOP chemotherapy
significantly improves PFS
Bendamustin in combination with Rituximab can be applied with comparable ORR and OS rates
as R-CHOP, but with lesser side effects
Bortezomib in combination with R-CAP (VR-CAP) shows better PFS compared to R-CHOP with
more (haemoto-) toxicity and may be a good option for aggressive (e.g. blastoid) MCL in elderly
patients not eligible for ASCT
In very frail patients Rituximab mono or Rituximab and oral Chlorambucil is an effective and well
tolerated regime, especially in low risk or rather indolent cases
MANTLE CELL LYMPHOMA
TREATMENT
First Relapse / Refractory Disease
Immunochemotherapy
e.g. B-R
R-BAC
Targeted Approaches
Repeat First Line?
Consider: Allogeneic SCT
Immunochemotherapy
e.g. B-R, R-CHOP, R-BAC
Targeted Approaches
Repeat First Line?
Consider: R- Maintenance
Radioimmunotherapy
Immunochemotherapy
e.g. B-R (dose reduced)
Targeted Approaches Best
Supportive Care?
Higher Relapse
Targeted Approaches: Ibrutinib, Lenalidomide,
Temsirolimus, Bortezomib (preferable in combination with chemotherapy)
Alternatively: repeat previous therapy (long remissions)
Young Fit Patient (<65)Organ Function
Comorbidity
Performance Status
Old Fit Patient (>65)Organ Function
Comorbidity
Performance Status
Old Unfit Patient (>65)Organ Function
Comorbidity
Performance Status
R, Rituximab, B-R, Bendamustine-Rituximab, R-CHOP, Rituximab/ Cyclophosphamide/ Doxorubicin/ Vincristine/Prednisone,
VR-CAP, Bortezomib/Rituximab/Cyclophosphamide/Doxorubicin/Prednisone
R-DHAP, Dexamethason/high-dose Cytarabine/Cisplatin, R-CVP- Rituximab/Cyclophosphamide/Prednison
R-BAC, Rituximab/Bendamustine/Cytarabine, SCT- Stem-Cell Transplantation
TARGETED SUBSTANCES
AT RELAPSE
Temsirolimus is registered in EU and has shown superiority over other agents in
heavily pre-treated patients with ORR of 23%, and PFS of 4.8 months
Hess G, et al. J Clin Oncol 27(23), 2009:3822–9. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.
TARGETED SUBSTANCES
AT RELAPSE
Lenalidomide
Lenalidomide
(n = 170)
IC
(n = 84)
Median PFS, mo (95% CI) 8.7 (5.5-12.1) 5.2 (3.6-6.9)
HR (95% CI) 0.61 (0.44-0.84); P = 0.004
Number of patients at riskLenalidomide
IC
170
84
86
31
63
15
36
7
27
5
20
4
16
4
12
2
7
0
1 1 0
1.0
0.8
0.6
0.4
0.2
0.0
Sur
viva
l pro
babi
lity
Progression-free survival, months
0.1
0.3
0.5
0.7
0.9
0 5 10 15 20 25 30 35 40 45 50 55
LenalidomideIC
Lenalidomide
8.7 mo
Control
5.2 mo
Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell
transplantation have longer progression-free survival with lenalidomide compared to investigator's choice of monotherapy
Reprinted from The Lancet Oncol, 17(3), Trněný M, et al. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002;
SPRINT): a phase 2, randomised, multicentre trial, 319–31, Copyright 2016, with permission from Elsevier.
TARGETED SUBSTANCES
AT RELAPSE
Ibrutinib
TARGETED SUBSTANCES
AT RELAPSE
At a 2-year landmark, the PFS rate was 41% for ibrutinib versus 7% for temsirolimus
Investigator-assessed HR for ibrutinib versus temsirolimus was 0.43 (95% CI, 0.32-0.58)
ITT population
Median follow-up: 20 months
Ibrutinib Temsirolimus
Median PFS (months) 14.6 6.2
Hazard ratio (HR) 0.43
95% confidence interval (CI) 0.32-0.58
Log-rank p value < 0.0001
0 3 6 129 15
Months
18 21 24 27 30
0
30
10
20
40
50
60
70
80
90
100
% a
live
with
out p
rogr
essi
on
Temsirolimus
Ibrutinib
Reprinted from The Lancet, 387(10020), Dreyling M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an
international, randomised, open-label, phase 3 study, 770–8, Copyright 2015, with permission from Elsevier.
Patients at riskIbrutinib 139 114 101 83 77 45 34 8 5 0 0Temsirolimus 141 93 69 45 33 19 11 3 1 0 0
TARGETED SUBSTANCES
AT RELAPSE
Adverse events ibrutinib
*AEs were updated with an estimated median follow-up of 26.7 months
Republished with permission of American Society of Hematology, from Blood, Wang ML, et al. 126(6), 2015, permission conveyed through Copyright Clearance Center, Inc.
OUTLOOK: TAILORED MEDICINE
First line MCL suggested therapeutic algorithm
High Highintermediate
Lowintermediate
Low
Mutational screening
MIPI-c risk
ASCTPost-treatment risk
evaluation: MRD
TP53,NOTCH1,
other
SOX11 negativewithout adverse
mutations
HD AraC +anthracyclin
+ biological agent
HD AraC +biological agent
HD AraC
MRD+ MRD-
Conventional treatment(low tumour load:watch and wait)
MRD+ MRD-Consolidation/maintenance
Observation
Dreyling M, et al. Haematologica 2016;101(2):104–14. Obtained from the Haematologica Journal website http://www.haematologica.org
THERAPY AT RELAPSE
Conclusion I
Immuno-chemotherapy is standard of care at relapse and is chosen depending on
patient fitness and age, comorbidities, earlier therapy and duration of response
The mTOR-inhibitor temsirolimus can achieve better ORR, PFS and OS compared to
mono-chemotherapy at relapsed or refractory disease
In relapsed or refractory disease ibrutinib increases ORR from 40% to 72% and PFS
(hazard ratio 0,43; median 8,4 months) compared to temsirolimus. OS is not affected
by ibrutinib (due to crossover)
Lenalidomide also increases ORR and PFS compared to physicians choice in relapsed
and refractory disease
THERAPY AT RELAPSE
Conclusion II
Bortezomib also shows promising activity in MCL as monotherapy or in combination,
yet no Phase III data is available in refractory or relapsed disease, e.g. a combination
of bortezomib and bendamustin + rituximab (BERT) shows high activity in a
Phase II study
Rituximab maintenance therapy after salvage immunochemotherapy leads to improved
PFS and can be discussed
If HD-Ctx and ASCT has not been performed as first line therapy, eligible patients
should be offered a HD-Ctx and ASCT after lymphoma remission in relapse
Young fit patients relapsing after HD-Ctx and ASCT should be offered an allogenic
transplantation if a donor is available
OUTLOOK: BCL-2 INHIBITION
Venetoclax
75%
(21%)
OR 38%
(CR 11%)
18%
(12%)
Davids MS, et al. J Clin Oncol, 35(8), 2017:826–33. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
OUTLOOK: CHEMOTHERAPY
FREE COMBINATIONS?
First line: Rituximab-lenalidomide
From N Engl J Med, Ruan J, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma, 373:1835–44. Copyright © 2015 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
Progression-free survival
OUTLOOK:
COMBINATION THERAPY
European MCL Network Study generation 2017
< 65 years > 60 years
R-HAD +/- Bortezomib
1. Relapse
2. Relapse (or not qualifying for R-HAD)
BeRT
BR-temsirolimusIbrutinib vs. temsirolimus
MCL elderly R2:
R-CHOP vs. R-CHOP/Ara-C
=> Rituximab M
+/-Lenalidomide
MCL younger:
R-CHOP/DHAP =>ASCT
R-CHOP/DHAP+I =>ASCT => I
R-CHOP/DHAP + I => I
MCL elderly I:
BR +/- Ibrutinib
=> Rituximab M
+/- Ibrutinib
> 65 years
THANK YOU!