Hematopoietic Stem Cell Transplantation:
High Risk Diffuse Large Cell Lymphoma:
Ginna G. Laport, MD
Associate Professor of...
Diffuse Large B-Cell Lymphoma:
Stem Cell Transplantation for High Risk
Patients
• Identifying “High Risk” Patients
• Autol...
Transplants
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
'68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '...
Indications for Hematopoietic Stem
Cell Transplants in the U.S.
NumberofTransplants
0
500
1,000
1,500
2,000
2,500
3,000
3,...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
 Most common NHL: 31%
– Peak inciden...
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....
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Yrs
OS
Diffuse Large
B-Cell Lymphoma
...
Prognosis By Interim PET Scanning
- Mixed results seen in 4 studies
- 2 studies confirm predictive value, 2 studies did no...
High Risk Diffuse
Large Cell Lymphoma
Autologous
HSCT in First CR/PR
High Risk Diffuse Large B Cell NHL:
Frontline Autologous HCT
Phase II Trials containing rituximab
Group n
aaIPI
>2
Therapy...
Cochrane Database Sys Rev 2008;CD004024
Meta-analysis:
Autologous HSCT as Front Line Therapy
N = 2228
No survival advantag...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Pts with
≥ PR after CHOP
RTX x 5
(N =...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Stiff PJ, et al. ASCO 2011. Abstr 800...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Newly
diagnosed
DLBCL,
aaIPI > 2
n = ...
Italian Lymphoma Foundation
2 x 2 Randomized Trial with Autologous HCT in High Risk Patients
(median followup = 23 mos)
PF...
High Risk Diffuse
Large Cell Lymphoma
Is there a role for allogeneic HSCT??
Years
0 2 61 3 4 5
Survival after Allogeneic HCT for Diffuse
Large B-Cell Lymphoma, 2000-2009
- By Disease Status -
0
20
4...
Reduced Intensity Allogeneic HSCT
(after autologous HSCT relapse)
n Ablat/RIC OS PFS NRM F/U
EBMT 101 37%; 64% 53% 41% 28%...
• Need better tools to identify high risk patients
• Current studies suggest that high-IPI subtype may
benefit from autolo...
Stanford University
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Relapsed/
refractory
DLBCL
n = 396
R
...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Overall Survival Event Free Survival
...
CORAL Trial:
EFS by relapse time after initial therapy
Relapse > 12 mos from dx Relapse < 12 mos from dx
Relapse < 12 mos ...
JCO 2012, In press
EFS
RTX
Obs
p=.74
PFS
Female
Male
p=.04
Female pts benefited from RTX maintenance
CORAL: Factors affecting survival in
relapsed DLCL patients
EFS OS
Prior rituximab .0007 .01
Relapse < 12 mos <.0001 <.000...
clinicaloptions.com/oncology
Evolving Options and Challenges in Mantle Cell Lymphoma
Philip T, et al. N Engl J Med. 1995;3...
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Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:

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  • 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.
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  • Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:

    1. 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. 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
    3. 3. Transplants 0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 '68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12 Autologous Allogeneic Transplant Activity Worldwide 1968-2012
    4. 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. 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. 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. 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. 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
    9. 9. High Risk Diffuse Large Cell Lymphoma Autologous HSCT in First CR/PR
    10. 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. 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. 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. 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. 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. 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
    16. 16. High Risk Diffuse Large Cell Lymphoma Is there a role for allogeneic HSCT??
    17. 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. 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. 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
    20. 20. Stanford University
    21. 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. 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. 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. 24. JCO 2012, In press EFS RTX Obs p=.74 PFS Female Male p=.04 Female pts benefited from RTX maintenance
    25. 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. 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

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