This document discusses hematopoietic stem cell transplantation for high risk diffuse large B-cell lymphoma. It describes how autologous HSCT improves progression-free and overall survival compared to chemotherapy alone in high risk patients in first complete remission based on evidence from phase II and III trials. The document also discusses the potential role of allogeneic HSCT for high risk disease, and mixed results from studies of reduced intensity allogeneic HSCT for relapsed/refractory patients after autologous HSCT failure.
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
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Blood and Marrow Transplant Program
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
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Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
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2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
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2024.06.01 Introducing a competency framework for languag learning materials ...
Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:
1. Hematopoietic Stem Cell Transplantation:
High Risk Diffuse Large Cell Lymphoma:
Ginna G. Laport, MD
Associate Professor of Medicine
Division of Blood & Marrow Transplantation
Stanford University Medical Center
2. Diffuse Large B-Cell Lymphoma:
Stem Cell Transplantation for High Risk
Patients
• Identifying “High Risk” Patients
• Autologous HSCT in High Risk Patients
• Phase II Trials
• Phase III Trials
• Allogeneic HCT
4. Indications for Hematopoietic Stem
Cell Transplants in the U.S.
NumberofTransplants
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
Multiple
Myeloma
NHL AML HD ALL MDS/MPD Aplastic
Anemia
CML Other
Leuk
Non-
Malig
Disease
Other
Cancer
Allogeneic (Total N=7,012)
Autologous (Total N=9,778)
5. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Most common NHL: 31%
– Peak incidence in 6th decade
Large cells with loss of follicular architecture of node
– 30% to 40% present with rapidly enlarging, symptomatic mass
with B symptoms
Frontline chemotherapy (anthracycline-based + RTX)
– CR 50-60%
– Long term remission -> 30-35%
Diffuse Large B-Cell Lymphoma
6. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
5
Yrs
P < .001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 1 2 3 4
Sehn LH, et al. Blood. 2007;109:1857
Legend Revised IPI
Risk Group
IPI Factors,
n
Very good 0
Good 1, 2
Poor 3, 4, 5
• Age >60
• Perf Status
• Stage 3-4
• LDH
•Extranodal
Overall Survival According to
Revised International Prognostic Index
7. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Yrs
OS
Diffuse Large
B-Cell Lymphoma
DLBCL Subgroup 5-Yr OS, %
Primary Mediastinal 64
Germinal Center B cell
like (GCB)
59
Activated B cell (ABC) 30
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10
Rosenwald A, et al. J Exp Med. 2003;198:851-862.
Survival by Gene Expression Profiling:
DLBCL
8. Prognosis By Interim PET Scanning
- Mixed results seen in 4 studies
- 2 studies confirm predictive value, 2 studies did not
Safar et al, J Clin Oncol 2012;30:184
0
20
40
60
80
100
0 20 40 60 80 100
Time (months)
PET positive (n=12)
P=0.02
PET negative (n=73)
Progression Free Survival
n= 98
0
0.2
0.4
0.6
0.8
1.0
0 1 3 5 6 7
Time (years)
PET Positive
P=0.146
PET Negative
2 4
Moskowicz et al. J Clin Oncol 2010;11: 1896
Progression Free Survival
n= 112
10. High Risk Diffuse Large B Cell NHL:
Frontline Autologous HCT
Phase II Trials containing rituximab
Group n
aaIPI
>2
Therapy
CR
Rate
PFS
/EFS
OS
Follow
up
Tarella
2007
112 100 Mod R-HDS 80 73 76 4 yrs
Vitolo
2009
97 100
R-mega CEOP x
BEAM/HCT
82 73 80 4 yrs
Dilhudy
2010
42 100
R CEEP BEAM
HCT
55 55 74 5 yrs
Fitoussi
2011
209 100
R-ACVBP +
BEAM/HCT
60 76 78 4 yrs
11. Cochrane Database Sys Rev 2008;CD004024
Meta-analysis:
Autologous HSCT as Front Line Therapy
N = 2228
No survival advantage for autologous HSCT in CR1
Haematologica 2003;88:1304
N = 3079
Overall survival advantage for autologous HSCT in CR1
compared to chemotherapy
12. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Pts with
≥ PR after CHOP
RTX x 5
(N = 253)
CHOP Rituximab x 1
+ Autologou HSCT*
(n = 125)
CHOP Rituximab x 3
(n = 128)
Stiff PJ, et al. ASCO 2011. Abst 8001.
R-CHOP x 8 vs
R-CHOP x 6 Cycles + Autologous HSCT
(SWOG S9704)
Eligibility: Bulky stage 2-4 Hi-int/High IPI
13. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Stiff PJ, et al. ASCO 2011. Abstr 8001.
Outcome, % CHOP ± R
+ AutoSCT
(n = 125)
CHOP ± R
(n = 128)
P
Value
2-yr PFS (all) 69% 56% .005
High-interm IPI 60% 63 %
High IPI 75% 47 % .02
2-yr OS (all) 74% 71% .16
High-inter IPI pts 70% 75%
High IPI pts 82% 64% .01
Autologous HSCT prolonged PFS
high-intermediate
high-IPI
Autologous HSCT prolonged OS
high-IPI
ASCT After CHOP ± Rtx Improves PFS in
Advanced High-Risk Diffuse NHL
14. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Newly
diagnosed
DLBCL,
aaIPI > 2
n = 399
R
A
N
D
O
M
I
Z
E
R-CHOP
x 3
R-mega
CHOP
SD, PD
off study
PR, CR
Ann Oncol 2011; 22 suppl 4: abstr 72.
R
A
N
D
O
M
I
Z
E
BEAM AutoHCT
Observation only
Italian Lymphoma Foundation
2 x 2 Randomized Trial with Autologous HSCT in
High Risk Patients
15. Italian Lymphoma Foundation
2 x 2 Randomized Trial with Autologous HCT in High Risk Patients
(median followup = 23 mos)
PFS OS
No BMT 59 83
BMT 72 83
P value .008 NS
- Risk of relapse was 53% lower in BMT patients
- No overall survival difference between two arms`
0 6 12 18 24 30 36 42 48
Months
0.00
0.25
0.50
0.75
1.00
HDT
No-HDT
Progression Free Survival
P=.008
17. Years
0 2 61 3 4 5
Survival after Allogeneic HCT for Diffuse
Large B-Cell Lymphoma, 2000-2009
- By Disease Status -
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
ProbabilityofSurvival,%
P < 0.0001
Sensitive (N=383)
Resistant (N=124)
18. Reduced Intensity Allogeneic HSCT
(after autologous HSCT relapse)
n Ablat/RIC OS PFS NRM F/U
EBMT 101 37%; 64% 53% 41% 28% 3 yrs
Italian 165 30%; 70% 39% 32% 28% 2 yrs
• Factors affecting outcomes
• Dz status at time of allogeneic HCT
• Time to relapse after autologous HCT (< 12 m vs
> 12 m)
• Did not affect outcome
• Prep regimen
Rigacci et al , Ann Heme 2012;91:931
van Kampen et al. JCO 2011;29:1342
19. • Need better tools to identify high risk patients
• Current studies suggest that high-IPI subtype may
benefit from autologous HCT early as front line
therapy
• More studies needed to further define role of
autologous HSCT as front line therapy
– Need study that includes only ABC-subtype
• Role of allogeneic HSCT in high risk population?
Hematopoietic SCT for
High Risk DLBCL
21. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Relapsed/
refractory
DLBCL
n = 396
R
A
N
D
O
M
I
Z
E
R-ICE
x 3
R-DHAP
x 3
Auto
SCT
SD, PD
off study
PR, CR
J Clin Oncol 2010; 28:4184–4190.
Which salvage regimen is the best?
R
A
N
D
O
M
I
Z
E
Rituximab
q2mos x 6
Observation only
Role of maintenance
rituximab
CORAL Trial:
Collaborative Trial in Relapsed Aggressive Lymphoma
22. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Overall Survival Event Free Survival
P = .49
Mos
0 12 36 60
1.0
0.8
0.6
0.4
0.2
0
P = .27
Mos
0 12 24 36
0.8
0.6
0.4
0.2
0
1.0
R-ICE
R-DHAP
60 724824 48 72
CORAL Trial
Survival according to Salvage Regimen
GCB vs ABC 3 yr PFS: 70% vs 28%
R-DHAP vs R-ICE in GCB pts: 3 yr PFS: 100% vs 27%
23. CORAL Trial:
EFS by relapse time after initial therapy
Relapse > 12 mos from dx Relapse < 12 mos from dx
Relapse < 12 mos from dx
predicted for poor outcome after autologous HCT
24. JCO 2012, In press
EFS
RTX
Obs
p=.74
PFS
Female
Male
p=.04
Female pts benefited from RTX maintenance
25. CORAL: Factors affecting survival in
relapsed DLCL patients
EFS OS
Prior rituximab .0007 .01
Relapse < 12 mos <.0001 <.0001
sIPI <.0004 <.0001
R-DHAP vs R-ICE 0.3 0.7
(Except for GCB pts)
p
26. clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Philip T, et al. N Engl J Med. 1995;333:1540
P = .001
0
20
40
60
80
100
EFS(%)
0 15 30 45 60 9075
Mos After Randomization
P = .038
0
20
40
60
80
100
OS(%) 0 15 30 45 60 9075
Mos After Randomization
Transplantation
Conventional treatment
PARMA Study: BMT vs Salvage Chemotx
for Relapsed DLBCL
Event Free Survival Overall Survival
Editor's Notes
The last decade has seen remarkable improvement in response rates and survival in patients with DLCL mainly due to the addition of RTX to standard first line chemo-immunotherapy, mainly the combination of CHOP and R.But despite the dramatic improvement in outcomes, relapse is still the main cause of death in this patient population.This had led investigators to explore if high dose chemo with autosct after conventional induction chemoimunotherapy can improve outcomes of pts who we think are destined to relapse
CNS, central nervous system; NHL, non-Hodgkin’s lymphoma. Diffuse large B‑cell lymphoma is the most common type of non‑Hodgkin’s lymphoma, representing about 30% of all non‑Hodgkin’s lymphoma. The average age at presentation is usually in the late 60s. The clinical outcomes are quite heterogeneous with respect to genetic subtypes and prognostic factors. Typically, the disease is curable in 50% or more of patients with modern therapy.
The IPI has been used for risk stratification at the time of dex for about a decade at the time of dx.However, the IPI has failed to reliably predict response to specific therapies which reflect the inherent biological heterogeneity of DLCL and highlights the need for more precise patient specific and biologically based risk factors This survival curve shows the results of applying the revised IPI to patients who received R‑CHOP chemotherapy. In the poor‑risk group, patients with 3-5 risk factors have an approximately 50% chance of disease‑free survival at 4 years.
DLCL can be stratified based on cell of origin with GEP and yields 3 categories. However, it is unclear whether molecular stratification is superior to the IPI. In the original study, gene expression profiling was correlated with survival in patients with DLBCL who were receiving CHOP without R. In this study, only 30% of patients with the activated B‑cell subtype remained alive at 5 years.
Finally, the use of interim PET scanning has been investigated to predict long term outcomes but with variable results.Some retrospective studies have suggested a benefit but small prospective trials have failed to demonstrate a true benefit.
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IPI, International Prognostic Index; PR, partial response. This recent trial evaluated high‑dose chemotherapy and autologous stem cell transplantation as part of initial therapy for patients with DLBCL and a high- or high-intermediate–risk IPI score. The patients received CHOP or R‑CHOP induction therapy and were then randomized to receive either 3 additional cycles of R‑CHOP or CHOP, or 1 cycle of high‑dose therapy and autologous stem cell transplantation. For more information, go online to http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202011/Tracks/Hematologic%20Malignancies/Capsules/8001.aspx
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IPI, International Prognostic Index; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival. The progression‑free survival data showed an improvement for high‑risk patients who received consolidation with high‑dose chemotherapy followed by autologous stem cell transplantation. Patients with a high IPI score experienced the most benefit. Of note, overall survival for all patients was not different between arms. However, patients in the high IPI category did have an improvement with consolidation therapy (ie, chemotherapy and autologous stem cell transplantation) at first complete remission. There was an expected increased incidence of toxicity in the patients who underwent transplantation. For more information, go online to http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202011/Tracks/Hematologic%20Malignancies/Capsules/8001.aspx
EFS, event-free survival; ITT, intent-to-treat; OS, overall survival; R-DHAP, rituximab plus dexamethasone, cisplatin, high-dose cytarabine; R-ICE, rituximab plus ifosfamide, carboplatin, etoposide. The initial analysis showed no overall survival difference between patients randomized to salvage chemotherapy with R‑ICE or R‑DHAP; event‑free survival was also identical.
