Advances in the Treatment of Lymphoma

Transcription

4/28/2014
Updates in Lymphoma
Siddhartha Ganguly, MD, FACP
Director, Lymphoma/Myeloma and
Autologous Transplantation Program
Professor of Medicine
Blood & Marrow Transplant Program,
Division of Hematology/Oncology
• 45 year old male with axillary and cervical lymphadenopathy, High LDH, Para‐Vertebral and splenic masses, poor performance status
• Biopsy diagnosis of diffuse large cell lymphoma
• Age
• Performance Status
• LDH
• Extra nodal sites
• Stage
4 out of 5
High IPI
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Our Patient:
• Initially treated with combination of Rituximab and CHOP chemotherapy 6 cycles
• Attained remission
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QUESTION 1
Would you recommend
autologous transplantation in
1st Complete Remission?
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Randomized phase III US / Canadian Intergroup trial (SWOG
S9704) comparing CHOP±R x 8 vs CHOP±R x 6 followed by
high dose therapy and auto transplant for patients with diffuse
aggressive non-Hodgkin’s lymphoma (NHL) in highintermediate (H-Int) or high IPI risk groups.
P.J. Stiff1, J.M. Unger2 J.R. Cook3, L.S. Constine4, S. Couban5,
T.C. Shea6, J.N. Winter7, T.P. Miller8, R.R. Tubbs3, D.C.
Marcellus9, J. Friedberg4, K. Barton1, G. Mills10, M. LeBlanc2, L.
Rimsza8, S.J. Forman11, R.I. Fisher4
1Loyola
University Medical Center, Maywood, IL; 2SWOG Statistical Center, Seattle,
WA; 3Cleveland Clinic Foundation, Cleveland, OH; 4University of Rochester,
Rochester, NY; 5Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, CAN;
6University of North Carolina at Chapel Hill, Chapel Hill, NC; 7Northwestern University,
Chicago, IL; 8University of Arizona, Tucson, AZ; 9Margaret and Charles Juravinski
Cancer Centre, Hamilton, Ontario, CAN; 10Louisiana State University Medical Center,
Shreveport, LA; 11City of Hope Medical Center, Duarte, CA
5
Stiff, et al: NEJM Oct 2013
Schema
CHOP/CHOP-R x 5
PR or CR
PR or CR
Randomize
CHOP/CHOP-R x 1
+ Auto transplant
<PR
Off Protocol therapy
CHOP/CHOP-R x 3
Transplant regimens: SWOG TBI (12Gy / 8 Fx) or BCNU (150mg/m2 x 3d) +
VP16 (60mg/kg) + Cyclophosphamide (100mg / kg)
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Overall Outcome : PFS
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Overall Outcome: Survival
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Outcome of All Randomized Patients Based on
IPI: PFS/OS
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AUTOLOGOUS SCT FOR
NHL: DLBCL IN CR1
Consider in High-IPI and individual
case based scenarios
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Our Patient:
• Initially treated with combination of Rituximab and CHOP chemotherapy 6 cycles
• Remained in remission for 6 months
• Now presents with abdominal pain
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Autologous Transplant for NHL
“Parma trial”
• 1987‐1994, n=215
• Prospective, randomized
• Chemo x 4
• Auto BMT
• 5yr EFS: 12% vs. 46%
• 5 yr OS: 32% vs. 53%
Philip, NEJM 1995; 333: 1540‐5
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AUTOLOGOUS
TRANSPLANTATION IS
THE STANDARD OF CARE
IN RELAPSED CHEMOSENSITIVE DIFFUSE
LARGE B-CELL
LYMPHOMA
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RITUXIMAB ERA
What is after PARMA?
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CORAL (Collaborative Trial in Relapsed Aggressive
Lymphoma Trial) of RICE v DHAP

Which salvage regimen is the best?
R
A
N
AB
SE
CA
TM
D
CD20+ DLBCL
O
Relapsed/Refractory
M
I
Z
E
SD/POD → Off
R-ICE x 3
R
A
D
PR/CR →
R-DHAP x 3
Rx6
N
O
M
I
Obs
Z
E
N=400

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Place of immunotherapy post transplantation?
CORAL Trial
Survival according to Salvage Regimen
Overall Survival
Event Free Survival
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0
R-ICE
R-DHAP
0.2
P = .49
0
12
24
36
Mos
48
60 72
0
P = .27
0
12
24
36
48
60
72
Mos
20
10
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64%
N=160
31%
N=228
PROGRESSION-FREE
SURVIVAL ACCORDING TO
FAILURE FROM DIAGNOSIS
(INDUCTION ITT)
62%
N=147
30%
N=241
PROGRESSION-FREE
SURVIVAL ACCORDING TO
PRIOR RITUXIMAB
(INDUCTION ITT)
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Prior Exposure to Rituximab and Relapse within 12 mo.
of diagnosis
Gisselbrecht C et al. JCO 2010;28:4184-4190
©2010 by American Society of Clinical Oncology
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No Doubt We Need to Improve!!
• Improve in salvage
• Improve in transplantation • Not all lymphomas are same‐
personalized treatment
• Post remission therapy
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Ofatumumab versus Rituximab Salvage Chemoimmunotherapy
followed by ASCT in Relapsed or Refractory DLBCL
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A Phase II Randomized Open Label Study of MEDI-551 in
Patients with Relapsed or Refractory DLBCL
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NHL subtype Karyotype
Molecular
Burkitt’s
Lymphoma
t(8;14)
Alt-t(8;22), t(2;8)
Activation of MYC
Follicular
Lymphoma
t(14;18)
Activation of BCL2
Mantle Cell
Lymphoma
t(11;14)
Activation of cyclin
D1
Double and
triple hit
DLBCL
Complex—partners
variable
Activation of MYC,
and other(s)
MYC, BCL2, BCL6 with many
other abns
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PFS and OS according to the presence (MYC+) or the
absence (MYC−) of MYC aberration.
Cuccuini W et al. Blood 2012;119:4619-4624
©2012 by American Society of Hematology
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MYC and BCL2 overexpressors have an inferior
outcome
S. Hu et al. Blood 2013
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What is the best treatment for these patients?
•
•
•
•
R‐EPOCH
RHCVAD or other Burkitt’s‐like regimens
Aggressive induction followed by HDT/ASCT
Addition of novel agents
– Proteasome inhibition
– BTK inhibitors
– BCL2 inhibitors
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DOUBLE HIT LYMPHOMA:
POOR LONG-TERM SURVIVAL
• Needs Clinical Trial
• ? ASCT in 1st Remission
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Our Patient
•
•
•
•
Received RICE as salvage
Attained partial remission
Autologous Stem Cell Transplantation
Relapsed after 6 months
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RELAPSE IS THE MOST
COMMON CAUSE OF FAILURE
OF AUTO TRANSPLANTATION
IN NHL
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Maintenance Therapy
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RITUXIMAB MAINTENANCE
IN FOLLICULAR LYMPHOMA
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PRIMA: study design
INDUCTION
MAINTENANCE
Rituximab maintenance
375 mg/m2
Immunochemotherapy
every 8 weeks
High
8 x Rituximab
for 2 years‡
tumor burden
+
CR/CRu
Random 1:1*
untreated
8 x CVP or
PR
follicular
6 x CHOP or
lymphoma
6 x FCM
Observation‡
PD/SD
Registration
off study
* Stratified by response after induction, regimen of chemo, and geographic region
‡ Frequency of clinical, biological and CT-scan assessments identical in both arms
Five additional years of follow-up
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PRIMA 6 years follow-up
Progression free survival from randomization
6 years = 59.2%
HR= 0.57
P<0001
6 years = 42.7%
Median follow-up since randomization : 73 months
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PRIMA 6 years follow-up: Overall Survival
6 years = 88.7%
6 years = 87.4%
HR= 1.027
P=.885
Median follow-up since randomization : 73 months
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RITUXIMAB MAINTENANCE
IN NHL: DLBCL
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EFS
PFS
Female
RTX
Obs
p=.74
Male
p=.04
Female pts benefited from RTX maintenance
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Our Patient
•
•
•
•
Received RICE as salvage
Attained partial remission
Autologous Stem Cell Transplantation
Relapsed after 6 months
Options: • Clinical Trials or • Allogeneic transplantation
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OPTIONS
Newer Drugs
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Bruton’s Agammaglobulinemia
Ogden Car Bruton
Bronchiectasis in 14 yo male
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B-Cell Receptor Signaling
Antigen
CK
B Cell Receptor
Cytokine Receptor
C
D
7
C
D
7
9
9
A
PB
SYK
P
P
LYN
TLR
C
D
1
9
PI3K
P
BTK P
PIP3
JAK1
DAG
AKT
P
PLCγ
BLNK
MYD88
IP3--Ca++
PKCβ
P
CARD11
ERK
Bcl10
MALT1
IkB
IkB
NFkB
Transcriptional Activation
Proteosomal
Degradation
46 46
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Maximum Change in Tumor Burden in CLL
e SPDBaselinehange from% Ch
m
50
*
25
420 mg/d
840 mg/d
0
‐25
‐50
‐75
‐100
*Patient developed progressive disease, but did not have tumor measurements available
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Limited to patients with measurable disease at baseline (n=55)
Ibrutinib
On November 13, 2013, the U. S. Food and Drug Administration granted accelerated approval to Ibrutinib (IMBRUVICA, Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. And now in CLL 48
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Gene Expression Profiling
Dave SS, et al. N Engl J Med 2006
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Response of Ibrutinib in ABC and GCB DLBCL
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Proposed Study Schema Alliance/BMT-CTN: Andreadis et al.
Relapsed/Refractory DLBCL-ABC
Salvage PR, stem cells collected
Randomization
Stratify by response, TTR, regimen
Arm A
Arm B
ASCT: CBV or BEAM
ASCT: CBV or BEAM
<60 d
Ibrutinib
Maintenance
Placebo Maintenance
Follow Up
Follow Up
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Monoclonal Antibodies in Lymphoma
Naked
Monospecific
RIT
131I-Tosotumomab
90Y-Ibritumomab
Bispecific
Tiuxetan
ADC
CD19
CD22
CD30
CD79
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Monoclonal Antibodies of Lymphoma
Enhancers/
Modulators
Killers
CD20
CD19
CD22
CD23
CD30
CD40
CD52
CD79
TRAIL-R1 and R2
4-1BB
OX40
CTLA4
PD-1
CD40
VEGF
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Clinical application of PD-1 agonists and
antagonists
(rejection)
(Tolerance)
Okazaki T , Honjo T Int. Immunol. 2007;19:813-824
The Japanese Society for Immunology. 2007. All rights reserved. For permissions,
please e-mail: [email protected]
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Anti-PD-1 CT-011 (Pidilizumab) to Augment Post Transplant
Immunity:
CT-2007-01
ASCR
1-3 m
CT-011
Follow up
6wk 6wk
18 months
Hypothesis: Anti‐PD‐1 antibody (CT‐011) can elicit tumor‐immune control leading to favorable clinical outcome in DLBCL patients following HDT/ASCR
55
Armand et al, JCO Nov 30, 2013
Most Frequent Adverse Events (≥2% of events): Number
of patients (percent of total events)
Adverse Event
Severity Grade
All
1
2
3
4
5
Neutropenia
19 (4.2)
3 (0.4)
8 (1.2)
9 (1.6)
5 (0.8)
0
Fatigue
19 (3.5)
17 (3.2)
2 (0.3)
0
0
0
Thrombocytopenia 10 (3.5)
6 (1.1)
4 (0.9)
4 (0.8)
2 (0.6)
0
Diarrhea
12 (3.2)
10 (2.4)
4 (0.8)
0
0
0
WBC count
decreased
Upper respiratory
tract infection
Cough
9 (2.4)
7 (1.6)
4(0.6)
1 (0.1)
0
0
13 (2.2)
9 (1.6)
4 (0.6)
0
0
0
12 (2.2)
11 (2.1)
1 (0.1)
0
0
0
Hyperglycaemia
9(2.2)
8 (1.9)
2 (0.3)
0
0
0
Haemoglobin
decreased
8 (2.1)
7 (1.3)
3 (0.8)
0
0
0
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CT-011(Pidilizumab) following HDT/ASCR for
DLBCL: Preliminary Efficacy Data: PFS and OS
1
PFS
@ 18 months
0.70
Probability of PFS
0.8
(95% C.I. [0.57-0.79])
0.6
0.4
0.2
0
0
2
4
6
8
Study PFS
10
12
Months
14
16
18
20
Historical PFS
Historical Control is the median of:
Fenske TS; Biol. Blood & Marrow Transpl, (2009), 15(11),1455-1464
Chen, Yin-Bin; Leuk & Lymph, (2010), 51(5), 789-796
Gisselbrecht C. et al. JCO, (2010), 28 (27), 4184-4190
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CT-011(Pidilizumab) following HDT/ASCR for
DLBCL: Preliminary Efficacy Data: PFS and OS
OS
@ 18 month 0.84
(95% C.I. [0.72-0.91])
Historical Control is the median of:
Fenske TS; Biol. Blood & Marrow Transpl, (2009), 15(11),1455-1464
Chen, Yin-Bin; Leuk & Lymph, (2010), 51(5), 789-796
Gisselbrecht C. et al. JCO, (2010), 28 (27), 4184-4190
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Our Patient
• Clinical Trial with PI3Kinase inhibitor and no response
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Allogeneic HCT for B-NHL: Overall Survival
100
US patients only
Diseases:
DLBCL / Foll. NHL/ Mantle Cell
Probability, %
80
60
40
1996-1999 (n=725) Median from Diagnosis 15 mo
2000-2003 (n=1007) Median – 21 mo
20
2004-2007 (n=1117) Median – 25 mo
2008-2011 (n=1383) Median – 25 mo
0
0
1
2
3
4
5
Years
60
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AlloHCT Conditioning Regimen for DLBCL
100
PFS
5 year PFS 25%
80
Bacher et al Blood 2012:4256
60
40
NST
20
Myeloablative
RIC
0
0
1
2
3
4
5 0
Years
61
AlloHCT Conditioning for refractory disease
Adjusted Probability, %
100
80
60
FL-III MA
40
FL-III RIC
20
DLBCL MA
DLBCL RIC
0
0
2
4
6
8
10
Years
Hamadani et al BBMT 2013
62
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Our Patient
• Reduced Intensity Allogeneic Stem Cell Transplantation
• Matched Sibling Donor
• In remission with minimal Graft Versus Host Disease
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MANTLE CELL LYMPHOMA
No Randomized Study
Between Transplant versus
No Transplant
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Mantle Cell NHL
Overall Survival and timing of transplant
100
N - 250
Early Auto
Probability, %
80
Early Allo (N– 50)
60
Late Auto(N-132)(
40
Late Allo N - 88
20
0
0
1
From Transplant
2
3
Years Post-transplant
4
5
65
J Clin Oncol. 2014 Feb 1;32(4):273-81 –
Fenske et al
Who benefits from an early Auto?
PFS By Disease Status at HCT
100
Early Auto CR1 (1 line)
N- 97
Probability, %
80
60
Early Auto CR1 (2 lines)
N- 79
Early Auto - PIF sens N - 73
40
20
0
0
1
2
3
Years Post-transplant
J Clin Oncol. 2014 Feb 1;32(4):273-81 –
Fenske et al
4
5
66
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Overall Survival for AlloHCT
after Relapse from prior Autograft
100
80
Probability, %
100
Survival
5 yr ------ 37 (26-49) %
Non Relapse Mortality
31% at 1 year
46% at 5 years
80
30% were chemo refractory at allograft
60
60
RIC/NST (N=91)
40
40
Relapse after AutoHCT – Significant proportion
(40%) still alive at 5 years
20
20
In Multivariate : KPS and Age <60 yrs predicted Survival
0
0
1
2
3
4
0
5
Years
Ann. Oncol. 22 (Suppl. 4) , (Abstract 018) Hari et al
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Frontline Treatment of Mantle Cell Lymphoma (nonIndolent variety)
• R‐Hyper CVAD/MTX‐Ara‐C times 8 cycles
Epner EM, et al. A multicenter trial of hyper‐CVAD + rituxan in patients with newly diagnosed mantle cell lymphoma. Blood2007;110:121a. Abstract 387
• R‐Hyper CVAD 4 cycles followed by consolidating autologous stem cell transplantation Institutional algorithm; Extrapolated from hyper CVAD times 4 cycles followed by SCT‐Khouri et al. Hyper‐CVAD and high‐dose methotrexate/cytarabine followed by stem‐cell transplantation: an active regimen for aggressive mantle‐cell lymphoma. J Clin
Oncol1998;16:3803‐3809. How I Treat mantle Cell Lymphoma. Ghielmini et al. Blood August 20, 2009 vol. 114 no. 8 1469‐1476. Dreyling M, Hoster E, Hermine O, et al. European Mantle Cell Lymphoma Network: an update on current first line trials [abstract]. Ann Oncol.2008;19:300.
• BR
BRIGHT Trial‐Lancet. 2013 Apr 6;381(9873):1203‐10
• Maintenance Rituximab in Transplant ineligible patients‐ 4 weekly doses every 6 months for 2 years
Kahl BS, Longo WL, Eickhoff JC, et al. Maintenance rituximab following induction chemoimmunotherapy may prolong progression‐
free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Ann Oncol. 2006; 17:1418–1423.
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Relapsed Mantle Cell Lymphoma
• Single agent Bortezomib
Fisher RI, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin
Oncol 2006;24:4867‐4874.
• BR with Bortezomib (VBR)
Blood. 2011 Mar 10;117(10):2807‐12
• RICE
Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):475‐82
• Ibrutinib
Wang L, et al. The Bruton’s tyrosine kinase inhibitor PCI‐32765 is highly active as single‐agent therapy in previously‐treated mantle cell lymphoma (MCL): preliminary results of a phase II trial [abstract]. Blood 2011;118(21). Abstract 442.
• Allogeneic Stem Cell Transplantation in suitable patient
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T-CELL LYMPHOMA
70
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PTCL-NOS, AITL, and ALK- Systemic ALCL
CHOP with (<60 yrs) or without etoposide (>60 years) 6‐8 cycles and consider autologous stem cell transplantation in first complete remission (Except localized disease)
Prognostic factors and treatment of patients with T‐cell non‐Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Escalón MP, et al. Cancer. 2005;103(10):2091. Treatment and prognosis of mature T‐cell and NK‐cell lymphoma: an analysis of patients with T‐cell lymphoma treated in studies of the German High‐Grade Non‐Hodgkin Lymphoma Study Group. Schmitz N, et al. Blood. 2010;116(18):3418.. Hematopoietic cell transplantation for systemic mature T‐cell non‐Hodgkin lymphoma. Smith SM, et al. J Clin Oncol. 2013;31(25):3100.
Relapsed PTCL‐NOS or AITL: Salvage regimen with:
– single agent Gemcitabine, Pralatrexate, Romidepsin, or Belinostat
Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T‐cell lymphoma: U.S. Food and Drug Administration drug approval summary. Malik SM, et al. Clin Cancer Res. 2010;16(20):4921.
Results from a pivotal, open‐label, phase II study of romidepsin in relapsed or refractory peripheral T‐cell lymphoma after prior systemic therapy. Coiffier B, et al. J Clin Oncol. 2012;30(6):631.
– Combination‐ ICE or Gemcitabine, Dexamethasone, Cis‐Platin (GDP)
Ifosfamide, carboplatin, etoposide (ICE)‐based second‐line chemotherapy for the management of relapsed and refractory aggressive non‐Hodgkin's lymphoma. Zelenetz AD, et al. Oncol. 2003;14 Suppl 1:i5.
– Followed by stem cell transplantation (auto or allo) in suitable patients.
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Special T-cell NHL Cases
• Hepato‐Splenic Gamma/Delta Lymphoma: Hyper CVAD/MTX‐Arac‐ 4‐6 cycles followed by allogeneic stem cell transplantation
• T cell PLL‐Intravenous Alemtuzumab followed by allogeneic stem cell transplantation
• Sub acute Panniculitic Type T cell Lymphoma‐
CHOP for 6‐8 cycles. In gamma variant consider autologous stem cell transplantation in first complete remission
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Cancer patient
Personalized
Cancer
Diagnostics
Corless CL Science
334:1217, 2011
Tumor analysis
Whole-genome
sequencing
Whole-exome
sequencing
Whole-transcriptome
sequencing
Combine information
Chromosomal changes
Gene copy number alterations
Gene mutations
Gene fusions
Sequencing tumor board
Clinicians, geneticists, pathologists,
biologists, bioinformaticians, bioethicists
Distill information
for clinical use
Personalized patient treatment
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Acknowledgement
•
•
•
•
•
CIBMTR
P.Hari, MD‐ Medical College of Wisconsin
Martin Dreyling, MD‐University of Munich
Andrei Shustov, MD‐Seattle, WA
Christian Gisselbrecht, MD‐ Paris, France
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Advances in the Treatment of Lymphoma

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