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

Ginna G. Laport, MDAssociate Professor of Medicine

Division of Blood & Marrow TransplantationStanford University Medical Center

Diffuse Large B-Cell Lymphoma:Stem Cell Transplantation for High Risk

Patients

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

Transp

lants

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 Worldwide1968-2012

Indications for Hematopoietic Stem Cell Transplants in the U.S.

Num

ber

of

Transp

lants

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

MultipleMyeloma

NHL AML HD ALL MDS/MPD AplasticAnemia

CML OtherLeuk

Non-Malig

Disease

OtherCancer

Allogeneic (Total N=7,012)

Autologous (Total N=9,778)

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

clinicaloptions.com/oncology

Evolving Options and Challenges in Mantle Cell Lymphoma

5Yrs

P < .001

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 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

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

00 2 4 6 8 10

Rosenwald A, et al. J Exp Med. 2003;198:851-862.

Survival by Gene Expression Profiling: DLBCL

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 Survivaln= 98

0

0.2

0.4

0.6

0.8

1.0

0 1 3 5 6 7Time (years)

PET Positive

P=0.146

PET Negative

2 4

Moskowicz et al. J Clin Oncol 2010;11: 1896

Progression Free Survivaln= 112

High Risk DiffuseLarge Cell Lymphoma

High Risk DiffuseLarge 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 CR

RatePFS/EFS OS Follow

upTarella2007 112 100 Mod R-HDS 80 73 76 4 yrs

Vitolo2009 97 100 R-mega CEOP x

BEAM/HCT 82 73 80 4 yrs

Dilhudy2010 42 100 R CEEP BEAM

HCT 55 55 74 5 yrs

Fitoussi2011 209 100 R-ACVBP +

BEAM/HCT 60 76 78 4 yrs

Cochrane Database Sys Rev 2008;CD004024

Meta-analysis:Autologous HSCT as Front Line Therapy

N = 2228No survival advantage for autologous HSCT in CR1

Haematologica 2003;88:1304

N = 3079Overall survival advantage for autologous HSCT in CR1

compared to chemotherapy

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

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

clinicaloptions.com/oncology

Evolving Options and Challenges in Mantle Cell Lymphoma

Newly diagnosedDLBCL,aaIPI > 2n = 399

RANDOMIZE

R-CHOPx 3

R-megaCHOP

SD, PDoff study

PR, CR

Ann Oncol 2011; 22 suppl 4: abstr 72.

RANDOMIZE

BEAM AutoHCT

Observation only

Italian Lymphoma Foundation2 x 2 Randomized Trial with Autologous HSCT in

High Risk Patients

Italian Lymphoma Foundation2 x 2 Randomized Trial with Autologous HCT in High Risk Patients

(median followup = 23 mos)

PFS OSNo 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

High Risk DiffuseLarge 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

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

babili

ty o

f Surv

ival, %

P < 0.0001

Sensitive (N=383)

Resistant (N=124)

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;91:931van Kampen et al. JCO 2011;29:1342

• 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

Stanford University

clinicaloptions.com/oncology

Evolving Options and Challenges in Mantle Cell Lymphoma

Relapsed/ refractoryDLBCLn = 396

RANDOMIZE

R-ICEx 3

R-DHAPx 3

AutoSCT

SD, PDoff study

PR, CR

J Clin Oncol 2010; 28:4184–4190.

Which salvage regimen is the best?

RANDOMIZE

Rituximab q2mos x 6

Observation only

Role of maintenance rituximab

CORAL Trial:Collaborative Trial in Relapsed Aggressive Lymphoma

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

0P = .27

Mos

0 12 24 36

0.8

0.6

0.4

0.2

0

1.0R-ICER-DHAP

60 724824 48 72

CORAL TrialSurvival 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%

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

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 <.0001

sIPI <.0004 <.0001

R-DHAP vs R-ICE 0.3 0.7(Except for GCB pts)

p

clinicaloptions.com/oncology

Evolving Options and Challenges in Mantle Cell Lymphoma

Philip T, et al. N Engl J Med. 1995;333:1540

P = .0010

20

40

60

80

100

EF

S (

%)

0 15 30 45 60 9075

Mos After Randomization

P = .0380

20

40

60

80

100

OS

(%

)0 15 30 45 60 9075

Mos After Randomization

TransplantationConventional treatment

PARMA Study: BMT vs Salvage Chemotx for Relapsed DLBCL

Event Free Survival Overall Survival