Updates In Lymphoma - The University of Kansas Cancer Center

Transcription

Updates in Lymphoma
Siddhartha Ganguly, MD, FACP
Director, Lymphoma/Myeloma and
Autologous Transplantation Program;
Associate Professor of Medicine;
Blood & Marrow Transplant Program,
Division of Hematology/Oncology
Conflict of Interest Disclosure
• Research Funding: Novartis, Janssen and Sanofi‐Aventis
• Speaker: Seattle‐Genetics
1
• 45 year old male with axillary and cervical lymphadenopathy
• Biopsy diagnosis of diffuse large cell lymphoma
Case I:
• Initially treated with combination of Rituximab and CHOP chemotherapy 6 cycles
• Remained in remission for 6 months
• Now presents with abdominal pain
2
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%
3
AUTOLOGOUS TRANSPLANTATION
IS THE STANDARD OF CARE IN
RELAPSED CHEMO-SENSITIVE
DIFFUSE LARGE
B-CELL
LYMPHOMA
Dose-Response Linearity
100
BEAM
ICE
Tumor Cell
Kill
0
CHOP
Increasing Myeloablative Potential
4
Dose-Response Linearity
100
Tumor Cell
Kill
0
CHOP
ICE
BEAM
Increasing Myeloablative Potential
Salvage Regimens:
5
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
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
R-ICE
R-DHAP
0.2
P = .49
P = .27
0
0
0
12
24
36
Mos
48
60 72
0
12
24
36
48
60
72
Mos
6
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)
7
MYC+ Patients do Worse with ASCT than MYC-
PFS
OS
IPI 2-3 pts
Cuccini et al, Blood, 2012
DOUBLE HIT (BCL2+C-MYC)
TRIPLE HIT (BCL-2+ C-MYC+BCL-6)
• Worse Prognosis
• ?Auto SCT in CR1
8
Are We Really Doing Well with Our
Choice of Salvage?
• 58 year old, C‐myc positive, Relapsed within 8 months, saaPI 2, High LDH, Stage III disease
At best response rate is 50%; 20% cure and 40% 3‐year PFS
Need to do better
1. Better salvage‐ ?R‐Gem‐Ox; RDHAX; R‐GDP
– R‐GDP(n=310) vs. R‐DHAP (n=309) [ASH 2012 Crump et al]
– GDP is not inferior to the standard regimen DHAP prior to ASCT
– similar rates of transplantation, EFS and OS.
– significantly less toxicity, superior QoL scores 2. O‐DHAP vs. R‐DHAP and Auto SCT‐ HOVON international Trial. Available at KUMC
3. Add BCR signaling inhibitors‐Ibritinib, PI3Kinase inhibitor
4. Antibody Drug Conjugate‐Inotuzumab/Calichaemycin
Plerixafor
9
A Novel Hematopoietic Progenitor Cell (HPC)
Mobilization regimen, utilizing Bortezomib
(Bor) and Filgrastim (G-CSF), for patients
undergoing Autologous HPC Transplant
(AHPCT) for Multiple Myeloma (MM) and
Non-Hodgkin’s Lymphoma (NHL).
Sunil Abhyankar MD, Shaun DeJarnette MT, Dean
Merkel MT, Jennifer Bunch, Kelly Daniels RN, Omar
Aljitawi MD, Sid Ganguly MD, Joseph McGuirk DO.
ASBMT/CIBMTR Tandem meeting, Salt lake City,
Utah Feb 2013
What is the Value of Different
Conditioning Regimens in
Autologous Stem Cell
Transplants
Is any regimen better than the standard BEAM or BEAC?
10
Bu-CY-E vs BEAM
No difference in OS or PFS
Kim et al , Leukemia Research 2011
How about adding Radiation?
(TBI is too toxic)
• Radio-Immunotherapy
11
Bexxar-BEAM vs R-BEAM as Conditioning
Regimen Therapy in Relapsed DLBCL BMT CTN
0401
R-BEAM: R=375 mg/m2 on days -19 and -12
Bexxar-BEAM: 75 cGy dose of 131I on day -12
Both regimens included standard BEAM conditioning on days -6 to -1.
224 randomized patients
#
Length of f/u
Median age
B-BEAM
111
25.5
56.8
R-BEAM
113
24.7
58.8
Vose et al , ASH abstr 661, 2011
Bexxar-BEAM vs R-BEAM as Conditioning
Regimen Therapy in Relapsed DLBCL BMT CTN
0401
#
2 yr PFS (%)
2 yr OS (%)
Relapse at 2 yrs (%)
Maximum mucositis (OMAS)
B-BEAM
111
47.9
61.0
45.0
.72
R-BEAM
113
48.6
65.6
48.1
.31 (p<.0001)
No difference in TRM, time to engraftment of platelets or WBC, rates of
AML or MDS, or immunologic recovery out to two years
Vose et al , ASH abstr 661, 2011
12
OUTSIDE A CLINICAL TRIAL BEAM
OR BEAC REMAINS THE STANDARD
PREPARATIVE REGIMEN FOR
RELAPSED AGGRESSIVE NHL
OTHER LYMPHOMAS
13
PHASE II TRIAL OF HIGH-DOSE
RITUXIMAB WITH THIOTEPA /
BUSULFAN / CYCLOPHOSPHAMIDE
(TBC) AUTOLOGOUS STEM CELL
TRANSPLANTATION FOR PATIENTS
WITH CNS INVOLVEMENT BY NONHODGKIN LYMPHOMA
Yi-Bin Chen, Tracy Batchelor, Ephraim Hochberg, Mark
Brezina, Erin Coughlin, Sooae Jones, Candice Del Rio,
Karen K. Ballen, Jeffrey Barnes, Andrew Chi, Jessica
Driscoll, Fred Hochberg, Ann S. LaCasce, Steven McAfee,
Laskhmi Nayak, Philippe Armand
February 13th, 2013
ASBMT
Study Schema - Mobilization
Stem cell pheresis
when WBC appropriate
Day: 1
2
4
8
14
GCSF
begins
Optional LP 24-36 hours after
Day 1 Rituximab dose
14
Study Schema – High Dose
Therapy
Day: -12-10 -9
-8
-7
-6
-5
-4
-3
-2
Autologous
stem cell
transplant
-1
0
Objectives
• Primary Objective
– To assess the proportion of patients who are alive and progression‐free at one year after R‐HiDAC‐R mobilization and R‐
TBC ASCT
• Secondary Objectives
– To examine the safety and toxicities of this treatment program
– To assess 1‐year event‐free survival (EFS), overall survival (OS), and overall response rate (complete and partial response) in this patient population
30
15
Patients
23 out of 30 planned patients enrolled at the time of abstract submission
• 12 patients with primary CNS NHL
– 7 patients in CR1, 5 patients with relapsed disease in PR/CR
– All were DLBCL by histology including 1 case of EBV‐PTLD
• 11 patients with secondary CNS NHL
– Histology:
• 2 cases of CLL
• 2 cases of transformed follicular NHL
• 7 cases of DLBCL with spread to CNS
– 5 patients were in CR1, 6 patients with relapsed disease in PR/CR
31
Transplant Characteristics
Outcomes
• Engraftment
– All patients engrafted neutrophils (median 9 days, range 8‐12)
– All patients engrafted platelets (median 12 days, range 8‐40)
• Toxicities
– No issues with high‐dose Rituximab
– Most common were diarrhea and mucositis
– Neurotoxicity (n=2)
• 1 patient who had previously had WBRT, eventually died 5 months after ASCT from this
• 1 patient with TMA from high‐grade candidemia
32
16
Transplant Characteristics
Survival
• Transplant‐related mortality
– No cases by day +100 after ASCT
– Only one case thus far – from neurological complications
• Median follow‐up of 399 days (3 mo. – 2 yr.)
– Only one patient has died (TRM as above)
– Only one patient has relapsed
• 73 yo F with multiply relapsed cutaneous DLBCL with CNS disease since the 1990s relapsed 9 months after ASCT in the skin. Remains alive in remission after salvage chemotherapy
33
Next Steps
30 patients enrolled
• Accrual finished
– Should have at least 9 individual samples of CSF to confirm levels of rituximab observed • Longer follow‐up needed
– Will such high‐doses translate into less relapses?
– Heterogeneity of this study makes any comment on efficacy difficult
• Does having such high systemic levels slow CSF elimination of Rituximab?
– Does it make sense to combine high‐dose IV with intrathecal administration?
34
17
Diffuse Large Cell Lymphoma
Auto-HSCT in First Remission?
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. Stiff, J.M. Unger J.R. Cook, L.S. Constine, S. Couban,
T.C. Shea, J.N. Winter, T.P. Miller, R.R. Tubbs, D.C.
Marcellus, J. Friedberg, K. Barton, G. Mills, M. LeBlanc, L.
Rimsza, S.J. Forman, R.I. Fisher
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
Stiff, et al: JCO 8001a, 2011
18
Overall Outcome : PFS
Overall Outcome: Survival
19
Outcome of All Randomized Patients Based on
IPI: PFS/OS
RELAPSE IS THE MOST
COMMON CAUSE OF FAILURE
OF AUTO TRANSPLANTATION
IN NHL
20
Maintenance Therapy
Following ASCT for
DLBCL
EFS
PFS
Female
RTX
Obs
p=.74
Male
p=.04
Female pts benefited from RTX maintenance
21
Monoclonal Antibodies of Lymphoma
Killers
Enhancers/Modulators
CD20
CD19
CD22
CD23
CD30
CD40
CD52
CD79
TRAIL-R1 and R2
4-1BB
OX40
CTLA4
PD-1
CD40
VEGF
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]
22
Anti-PD-1 CT-011 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
Gordon et al, Lugano 2011
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
23
CT-011 following HDT/ASCR for DLBCL:
Preliminary Efficacy Data: PFS and OS
1
@ 18 months 0.70
(95% C.I. [0.57-0.79])
Probability of PFS
0.8
PFS
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
CT-011 following HDT/ASCR for DLBCL:
Preliminary Efficacy Data: PFS and OS
1
OS
@ 18 month 0.84
(95% C.I. [0.72-0.91])
Probability of OS
0.8
0.6
0.4
0.2
0
0
2
4
6
8
Study OS
10
12
Months
14
16
18
20
Historical OS
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
24
B Cell Receptor Signaling Inhibitors
Bruton’s Agammaglobulinemia
Bronchiectasis in 14 yo male
Ogden Car Bruton
25
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
BTK P
P
PIP3
JAK1
DAG
AKT
P
PLCγ
BLNK
MYD88
IP3--Ca++
PKCβ
P
CARD11
ERK
Bcl10
MALT1
IkB
IkB
Proteosomal
Degradation
NFkB
Transcriptional Activation
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
Limited to patients with measurable disease at baseline (n=55)
26
Response in ABC and GCB DLBCL
Conclusions
• Ibrutinib, a selective covalent inhibitor of BTK,
induced a high response rate in relapsed/refractory
ABC DLBCL in addition to CLL, MCL and FL
• Ibrutinib had marginal activity in GCB DLBCL,
supporting the use of the ABC DLBCL molecular
subtype as a biomarker for activity
• Ibrutinib was associated with a favorable safety
profile
27
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
Ibrutinib
Maintenance
ASCT: CBV or BEAM
<60 d
Follow Up
Placebo
Maintenance
Follow Up
Summary of Maintenance Regimens after
Auto Transplantation in Aggressive NHL
Interventions
Outcomes Maintenance Regimens
Ibrutinib, Inotuzumab Ozogamicin
Future
Anti‐PD1 antibody, CT‐011
Promising
Rituximab
Overall ineffective in Phase III trial
28
Hodgkin’s Disease:
Transplant Everybody beyond CR1
Hodgkin Lymphoma Progressive Despite Primary Treatment
4 Cases
34 yo Stage IVB
ABVD x 6 => CR
34 yo Stage IVB
ABVD x 6 => CR
34 yo Stage IVB
ABVD x 6 => CR
2 months => Prog
8 years => Prog
thorax nodes only
2 months => Prog
GDP X 2 => PR
GDP X 2 =>
thorax nodes only
GDP X 2 => PR
thorax nodes only
34 yo Stage IVB
ABVD x 6 => Prog
thorax nodes only
GDP X 2 => Prog
Progression
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
D. HDC + auto SCT
D. HDC + auto SCT
D. ICE +/- RT & SCT
only if PR
E. HDC + auto SCT
D. ICE +/- RT & SCT
only if PR
E. HDC + auto SCT
58
29
Hodgkin Lymphoma Progressive Despite Primary Treatment
4 Cases
34 yo Stage IVB
ABVD x 6 => CR
34 yo Stage IVB
ABVD x 6 => CR
34 yo Stage IVB
ABVD x 6 => CR
2 months => Prog
8 years => Prog
thorax nodes only
2 months => Prog
GDP X 2 => PR
GDP X 2 =>
thorax nodes only
GDP X 2 => PR
34 yo Stage IVB
ABVD x 6 => Prog
thorax nodes only
thorax nodes only
GDP X 2 => Prog
Progression
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
A. Mantle RT
B. MOPP +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
C. COPP/ABV +/- RT
D. HDC + auto SCT
D. HDC + auto SCT
D. ICE +/- RT & SCT
only if PR
E. HDC + auto SCT
D. ICE +/- RT & SCT
only if PR
E. HDC + auto SCT
59
German HDSG and EORTC HD-R1
German Hodgkin’s Study Group, Schmitz, Lancet 2002;359:2065
Relapsed HD:
A
®
B
Dexa
BEAM
n 161
Dexa
BEAM
Dexa
BEAM
CR
or
PR
117
CR
Dexa
BEAM or
PR
Dexa
BEAM
Dexa
BEAM
Radiotherapy to
residual disease
HSC/BM BEAM
harvest HSCT
30
HSCT
Chemo
German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065
Primary progressive, early and late relapsed HL
Outcome after Secondary Tx
GHSG 1988 - 1999
n = 3809; relapses = 513 (13%)
1,0
Probability
,8
,6
late relapse 169 (33%)
early relapse 138 (27%)
refractory 206 (40%)
,4
,2
p < 0.0001
0,0
0
12
24
36
48
60
72
84
96
108
120
Overall Survival (Months)
31
Late relapse > 12 months (n = 55)
HSCT
Chemo
Early relapse < 12 months (n = 38)
HSCT
Chemo
32
Hodgkin's Lymphoma: Tx HDC/HSCT
By Disease Status at HDC/HSCT
1.0
Cum Survival
.8
REL-1
n = 133
REL-2
n = 18
REL-3
n=9
.6
.4
.2
0.0
0
20
10
Post SCT Survival (y)
Prognosis for HL Patients who Relapse after ASCT
Note the very poor prognosis for the 72% of patients whose relapse
occurs in the first 12 months after ASCT
1-yr mortality 40%
100
TTR, mo N
Probability, %
80
> 12
0 - 12
60
% Median OS, yr
214 28
542 72
4.6
1.2
N = 756
p < 0.001
40
20
0
0
5
10
15
20
Time from relapse, y
TTR = Time to relapse.
Horning et al. 10th International Conference on Malignant Lymphoma; Lugano, Switzerland; 2008.
33
How Can We Improve our Auto SCT
results in HD?
Autologous stem cell transplantation for refractory or poor‐
risk relapsed Hodgkin's lymphoma: effect of the specific high‐dose chemotherapy regimen on outcome.
Nieto Y, Popat U, Anderlini P, Valdez B, Andersson B, Liu P, Hosing C, Shpall EJ, Alousi A, Kebriaei P, Qazilbash M, Parmar S, Bashir Q, Shah N, Khouri I, Rondon G, Champlin R, Jones RB. Biol Blood Marrow Transplant. 2013 Mar;19(3):410‐7
COMPARISON OF GEMCITABINE, BUSULFAN
AND MELPHALAN (GEMBUMEL) WITH BEAM
AND BUSULFAN/MELPHALAN (BUMEL) IN
CONCURRENT COHORTS OF REFRACTORY
HODGKIN’S LYMPHOMA PATIENTS RECEIVING
AN AUTOLOGOUS STEM-CELL TRANSPLANT
Y Nieto, R Jones, P Anderlini, U Popat, B Andersson, P
Thall, B Valdez, EJ Shpall, A Alousi, P Kebriaei, C Hosing,
M Qazilbash, G Rondon, R Champlin
Depts of Stem Cell Transplantation and Biostatistics,
UT MD Anderson Cancer Center, Houston, TX
34
GemBuMel vs BuMel vs BEAM for Refractory HL
Contemporaneous Matched Cohorts (N=201)
1. GemBuMel (N=80)
• HL patients treated with GemBuMel (Jan’07- July ‘11)
• All had high-risk disease, defined as:
• Primary refractory tumor
• Poor-prognosis relapse:
• CR1 <6 months
• >1 relapse/PD
• PET+ tumor at HDC
• Median follow-up: 20 (6-60) months
2. BuMel (N=38)
• All pts meeting high-risk disease criteria enrolled in a phase 2 trial of
Busulfan/Melphalan (Jan ‘05 – Dec ’09)
• 78% of all HD pts in this trial
• Median f/u: 34 (17-74) months
3. BEAM (N=83)
• All pts with high-risk disease treated with BEAM (Jan ‘05 – July ’11)
• 40% of all HD pts receiving BEAM
• Median f/u: 17 (6-74) months
EFS analysis
% EFS
Median EFS
P Value
GemBuMel
61%
NR
BuMel
35%
14 months
BEAM
43%
13 months
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
GemBuMel
0.5
0.4
Cox (Proportional hazard
regression)
0.04
0.9
Probability
Probability
Log rank
0.0006
0.6
GemBuMel
0.5
0.4
BEAM
0.3
0.3
BuMel
0.2
BEAM / BuMel
0.2
0.1
0.1
0.0
0.0
0
10
20
30
40
50
Months post-HDC
60
70
80
90
0
10
20
30
40
50
60
70
80
90
Months post-HDC
35
OS analysis
% OS
Median OS
P Value
Log rank
GemBuMel
84%
BuMel
62%
NR
BEAM
60%
71 mo
Cox (Proportional
hazard regression)
NR
0.1
0.006
0.5
1.0
1.0
0.9
0.9
0.8
0.8
GemBuMel
GemBuMel
0.7
BuMel
0.6
Probability
Probability
0.7
0.5
0.4
BEAM
0.6
0.5
0.4
BuMel/BEAM
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0
10
20
30
40
50
60
70
80
90
0.0
Months post-HDC
0
10
20
30
40
50
60
70
80
90
Months post-HDC
Refractory HL - Subgroup Analyses
Patients in CR at HDC
PET Negative
PET Positive
1.0
1.0
0.9
0.9
0.8
0.8
GemBuMel (74% EFS)
0.7
0.6
Probability
Probability
0.7
0.5
0.4
0.6
GemBuMel (48% EFS)
0.5
0.4
BuMel/BEAM (46% EFS)
0.3
P=0.06
0.3
0.2
0.2
P=0.01
0.1
0.1
0.0
0
10
20
30
40
50
Months post-HDC
60
70
80
90
0.0
0
10
20
30
40
50
60
70
80
Months post-HDC
36
Patients with Active Disease at HDC
PR
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
GemBuMel (60% EFS)
0.6
Probability
Probability
PD/SD
0.5
0.4
P=0.01
0.3
0.6
0.5
0.4
0.2
0.2
0.1
0.1
0.0
0.0
0
10
20
30
40
50
Months post-HDC
60
GemBuMel (30% EFS)
0.3
70
80
BuMel/BEAM (0% EFS)
0
5
10
15
20
25
30
35
40
45
50
55
Months post-HDC
Conclusions
• In this nonrandomized comparison, the cohort of refractory HL pts receiving GemBuMel showed, despite its worse prognostic features, superior outcome compared to two contemporaneous cohorts of refractory HL pts receiving BEAM or BuMel
• The superiority of GemBuMel was seen across the different prognostic categories • This benefit was detected despite most, if not all, GemBuMel patients receiving a dose of Gemcitabine below its MTD
• These results warrant further study of GemBuMel in HL. – A phase 2 trial at dose level 9 is actively accruing patients at MDA
37
Mantle Cell International Prognostic Index
(MIPI)
Survival After Diagnosis by MIPI
• 4 factors independently associated with OS
1.0
Probability of OS
– Age
– Perf Status
– LDH
– WBC 0.8
0.6
0.4
0.2
0
Risk
Survival
Low
Int
High
not reached
51 mos
29 mos
0
12
24
36
48
60
Months
72
84
96
Hoster E, et al. Blood. 2008;111:558-565.
Nordic Group: AutoSCT for newly diagnosed MCL
5-Yr Outcomes
100
75%
Patients (%)
80
60
63%
OS
EFS
MCL-2
40
15%
20
EFS MCL-1
EFS, P < .0001
0
0.0
2.5
5.0
7.5
10.0
Yrs
2012 update
‐ Median OS: >10 yrs Prognostic Factors: MIPI, Ki‐67
‐ Median EFS: 7.4 yrs Follow‐up: 6.6 yrs
Geisler et al. Blood. 2008;112:2687
Geisler et al. Brit J Heme 2012;158:355
38
HCT for Mantle Cell Lymphoma
• Younger pts with good perf status:
– R-hyperCVAD or RCHOP-like regimen with HD Arac Æ autoSCT
– Maintenance therapy after SCT?
• Auto SCT has minimal benefit in relapsed or refractory pts
• Allogeneic HCT is only known cure
– Pts who failed prior autoSCT
– Pts with high MIPI score or Ki67 (or novel therapies)
Poor Outcome For Most Subtypes with Standard Tx
International PTCL Project
Vose et al. J Clin Oncol, 2008
39
• 166 pts enrolled
• Histologies:
• PTCL NOS
• Alk- ALCL
• AITL
• EATL
• Induction: CHOEP x 6
(39%)
(19%)
(19%)
(13%)
PFS (all pts)
• 115 pts Æ autoHCT
• Results:
• 5 yr PFS and OS = 51%
• Alk- ALCL has best survival
PFS by histology
JCO Sept 2012
Hematopoietic Stem Cell Transplantation:
PTCL
• Autologous HSCT more efficacious in early disease
• Myeloablative allogeneic SCT associated with high TRM
• Reduced intensity conditioning promising
• Histologies to consider for alloSCT in CR1/PR1
• Hepatosplenic T cell • Enteropathy associated T cell • Gamma delta T cell
40
Cancer patient
Personalized
Cancer
Diagnostics
Tumor analysis
Whole-genome
sequencing
Whole-exome
sequencing
Corless CL Science
334:1217, 2011
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
Acknowledgement
•
•
•
•
•
•
•
•
Our BMT Team
Dr. Tom Shea, UNC Chapel Hill, NC
Dr. Moskowitz, Sloan Kettering, NYC
Dr. Gisselbrecht, France
Dr. Gina Laport, Stanford, CA
Dr. Yago Nieto, MD Anderson Cancer Center, Houston, TX
Dr. Julie Vose, UNMC, Omaha, NE
Dr. Y‐Bin Chen, MGH, Harvard, Boston, MA
41
Questions?
83
42