Non-Hodgkin Lymphoma and Hodgkins Disease

From The Transplantations Point of View

Wen-Kai Weng, MD, PhD BMT/Medicine, Stanford University

Non-Hodgkins Lymphoma in United States

56,000 new cases/year B-cell
Aggressive
Burkitts lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Mantle cell lymphoma

T-cell
Aggressive
Peripheral T-cell lymphoma Anaplastic large cell lymphoma Angioimmunoblastic lymphoma Angiocentric lymphoma

Indolent
Follicular lymphoma Small lymphocytic lymphoma /Chronic lymphocytic leukemia MALT lymphoma Nodal marginal zone lymphoma Lymphoplasmacytic lymphoma

Indolent
Cutaneous T cell lymphoma /Mycosis fungoides

Transplant in Diffuse Large B Cell Lymphoma

The treatment goal is to CURE ! Only for relapsed or refractory cases High dose therapy/Autologous HCT is the standard What kind of pre-HCT salvage regimen ? Impact of post-rituximab era ? Who still have bad outcome after autologous HCT ?

Diffuse Large B Cell

R-CHOP GELA Study

Coiffer, NEJM 2002, 346:235, Feugier JCO 2005, 23:4117

5-yr DFS R-CHOP CHOP 54% 30% R-CHOP CHOP

5-yr OS 58% 45%

P < 0.00001

P = 0.0073

High Dose Therapy/Autologous BMT in Relapsed NHL

Philip et al, NEJM 1995, 333:1540

N = 215 NHL of different histologies All first treated with doxorubicin-containing regimen Relapsed or refractory to induction DHAP 109 patients responded to DHAP x 2 Randomized to have either 4 more DHAP or high dose chemo/autologous marrow infusion Preparative regimen BCNU 300 mg/m2 VP-16 200 mg/m2 x 6 Ara-C 200 mg/m2 x 6 Cytoxan 35 mg/kg x 3 days Stanford 550 mg/m2 60 mg/kg 100 mg/kg

High Dose Therapy/Autologous BMT in Relapsed NHL

Philip et al, NEJM 1995, 333:1540

N = 109

Chemo Arm (N = 54) High grade DLCL Follicular Large Diffuse SC 16 32 3 3

Transplant Arm (N = 55) 11 41 3 0

High Dose Therapy/Autologous BMT in Relapsed NHL

Philip et al, NEJM 1995, 333:1540

N = 109 Event Free Survival

High Dose Therapy/Autologous BMT in Relapsed NHL

Philip et al, NEJM 1995, 333:1540

N = 109 Overall Survival

3 transplant patients died of treatment related complication

R-ICE vs R-DHAP

CORAL Study
Gisselbrecht et al, ASH 2007 #517

N = 400 planned Relapsed/refractory DLCL, Age < 65 First randomization Salvage with R-ICE vs R-DHAP x 3 AHCT (BEAM)

Second randomization post transplant Maintenance rituximab 375 mg/m2 q2m x 6 vs observation Preparation regimen BCNU 300 mg/m2 VP-16 200 mg/m2 x 6 Ara-C 200 mg/m2 x 6 Melphalan 140 mg/m2

R-ICE vs R-DHAP

CORAL Study
Gisselbrecht et al, ASH 2007 #517

N = 400 planned Relapsed/refractory DLCL, Age < 65 Currently 194 patients R-ICE Infection With neutropenia Without neutropenia Renal Toxicity 16 (17%) 6 (7%) 0 R-DHAP 18 (21%) 8 (9%) 6 (7%)

R-ICE vs R-DHAP

CORAL Study
Gisselbrecht et al, ASH 2007 #517

N = 400 planned Relapsed/refractory DLCL, Age < 65 Currently 194 patients ORR Relapsed (n=86) Refractory (n=106) IPI 0-1 (n=112) IPI 2-3 (n=63) 88% 52% 77% 54% 2-year EFS 68% 36%

<0.0001

<0.0001

<0.001

56% 39% 0.009

R-ICE vs R-DHAP

CORAL Study
Gisselbrecht et al, ASH 2007 #517

N = 400 planned Relapsed/refractory DLCL, Age < 65 Currently 194 patients ORR All patients 68% 2-year EFS 50%

No prior rituxan (n=97) Prior rituxan (n=97)

82% 54%

<0.0001

66% 34% <0.0001

Prognostics for DLCL

Pre-ABMT PET Scan

PET+ Author Cremerius Becherer Spaepen Filmont Svoboda Reference # 22 21 19 20 23 8 8% (8) 8 8% (8) 8 7% (30) 9 2% (12) 9 4% (18)

PET3 3% (15) 1 3% (8) 1 0% (30) 1 3% (8) 4 6% (44)

Percent of Patients Relapsed (N)

Prognostics for DLCL

Pre-ABMT PET Scan

Cuenca et al, ASCO 2007, #8060

N = 60 10 Hodgkins Disease, 50 NHL (20 DLCL) Relapsed or refractory All received high dose chemotherapy and ABMT PET scan pre-ABMT and post-ABMT 2 year EFS Pre-PET negative positive Pre-PET negative positive 77% 35% 92% 53%

p = 0.0002

OS

p = 0.0009

Post-PET positivity also associate with poor EFS and OS

Transplant in Diffuse Large B Cell Lymphoma

What can we do for these high risk patients ? Post-transplant rituximab Post-transplant radioimmunotherapy Tandem transplant with Auto and NMA Allo HCT

Autologous HCT followed by Adjuvant Rituximab Stanford Experience

1998 - 2000, 35 patients Diffuse large B cell Mantle cell Transformed Other 25 3 3 4 Relapsed Refractory 1st Remission 18 10 7

BCNU (or TBI)/Etoposide/Cyclophosphamide as preparative regimens All received purged autologous peripheral blood stem cells Result published by Horwitz et al, Blood 2004, 103:777

Rituximab was Given as Adjuvant

Weekly rituximab (375 mg/m2) x 4 at Day 42 and at 6 month post-HCT

HCT

Rituximab

Disease Relapse or Death

Time to Relapse/Death

Generally Good Outcome after AHCT/Rituximab

Horwitz et al, Blood 2004, 103:777

Event Free Survival (%)

Median follow-up 2-year Event free survival

30 months 83%

Still Good Outcome with Longer Follow Up

EFS OS

100 80 60 40 20 0

Years

Median follow-up 5-year Event free survival 5-year Overall Survival

6.9 years (1.08-8.38) 73% 79%

High Incidence of Rituximab-associated Neutropenia after Autologous HCT

Rituximab-induced neutropenia (grade 3 & 4) Uncommon in non-transplant patients (~6%) Median of 40 days (7-117) after rituximab course Responded well to G-CSF Usually not associate with fever or infection Etiology unknown ? Unexpected targeting of granulocyte progenitors via ADCC ? Depletion of cytokine-producing B cells ? The role of FcR polymorphism

FcR IIIA 158 V/V Genotype is Associated with Rituximab-induced Neutropenia

57 treatment courses
FcR IIIA V/V
Neutropenia p value

V/F
9/23
(39%)

F/F
5/27
(19%)

F Carriers
14/50
(28%)

5/7
(71%)

0.204

0.014

0.035

FcR IIA H/H

Neutropenia p value*

H/R
10/27
(37%)

R/R
4/15
(27%)

R Carriers
14/42
(33%)

5/15
(33%)

1.000

1.000

1.000 * Fishers exact test

B cell NHL

Rituximab following Autologous HSCT

Rice et al, ASH 2007 #1280

N= 80 Retrospective analysis on refractory/relapsed DLCL All received salvage R-ICE x 3, followed by HDT/ASCT 4 weekly Rituximab (375 mg/m2) were given at Day 42 and 6 months in 43 patients
Number of Patients RICE RICE/ Maintenance (n = 37) Rituximab (n = 43) 52 (26-73) years 48 (22-69) years 19 18 4 years 34 9 2 years

Median Age International Prognostic Index Low/low-intermediate risk (0-2) High-intermediate/high risk (3-5) Median Follow-Up

B cell NHL

Rituximab following Autologous HSCT

Rice et al, ASH 2007 #1280

N= 80 Retrospective analysis on refractory/relapsed DLCL Using Cox Regression Analysis Observation 3 yr EFS 3 yr OS 42% 56% Maintenance rituximab 84% (P<0.0001) 86% (P=0.008)

High Risk NHL

Tandem Transplant
Stanford University

Relapsed/Refractory DLCL, PET(+) after 2 cycles salvage Tx Transformed disease from low grade Lymphoma T cell Lymphoma Treatment Plan #1 Further cytoreduction with High dose therapy (BCNU/VP-16/Cytoxan) Autologous Stem Cell Rescue #2 Graft versus Lymphoma effect with Non-myeloablative Allogeneic Transplant using Total Lymphoid Irradiation (TLI) and Anti-thymocyte Globulin (ATG)

Autologous HCT in Mantle Cell NHL

Stanford Experience

N = 36 All mantle cell lymphoma At time of Transplant CR1 19 > CR2 6 PR1/PR2 6 SD/PD 5 Preparative regimen BCNU VP-16 Cytoxan 550 mg/m2 60 mg/kg 100 mg/kg Median age 60 y/o Median follow-up 2.95 Yr

Autologous HCT in Mantle Cell NHL

Stanford Experience

N = 36

100 75 50 25 0

Auto EFS Auto OS

10

12

14

Years

Median f/u 2.95 yr

2 yr EFS 86% OS 95%

Autologous HCT in Mantle Cell NHL

Stanford Experience

N = 36
CR1 EFS CR1 OS

100 75 50 25 0

10

12

14

Years

Median f/u 1.68 yr

2 yr EFS 100% OS 100%

NMA Allogeneic HCT in Mantle Cell NHL

Stanford Experience

N = 14 All mantle cell lymphoma At time of Transplant CR1 8 > CR2 3 PR1/PR2 3 Median age 59.5 y/o Median follow-up 0.93 Yr

Preparative regimen TLI 800 cGy ATG 1.5 mg/kg x 5 days Rituximab 375 mg/m2 x 4 starting day 56

Allogeneic HCT in Mantle Cell NHL

Stanford Experience

N = 14

100 75 50 25 0 0.0

NMA Allo EFS NMA Allo OS

NRM 100 day 0% 1 yr 3% GVHD acute chronic 6% 18%

0.5

1.0

1.5

2.0

2.5

3.0

Years

Median f/u 0.93 yr

2 yr EFS 74% OS 78%

Peripheral T Cell Lymphoma

Chen et al, Bio BMT 2008, 14:741

N = 53 Histology Anaplastic PTCL Angioimmunoblastic Nasal NK/T Other Preparative regimen BCNU VP-16 Cytoxan N = 44 550 mg/m2 60 mg/kg 100 mg/kg TBI VP-16 Cytoxan N=9 18 16 9 7 3 At time of Transplant CR1/PR1 15 CR2/PR2 28 Refractory 10

Peripheral T Cell Lymphoma

Chen et al, Bio BMT 2008, 14:741

N = 53 PFS OS

years

years

Follicular Lymphoma The goal of treatment is for the Disease Control !

NMA Allo HCT a curative treatment ?

Patients either die either from refractory diseases or from treatment-related problems !
When to use transplant ? After multiple relapse Behave aggressively such as transformation Auto or Allo ? High dose therapy/Auto is not curative Allo may provide chances of long term remission

Upfront Autologous BMT in Follicular Lymphoma

Colombat et al, Blood 2005, 105:3817

N = 175 Newly diagnosed advanced stage Follicular Lymphoma Randomized to either standard chemotherapy or high dose/auto Standard Arm Cytoxan/doxorubicin/teniposide/prednisone (CHVP) x 12 plus Interferon High Dose/Auto Arm High dose CHOP x 3 Ifosfamide/MTX/VP-16 x 1 or DHAP x 3 Cytoxan (60 mg/kg) x 2 days/TBI All received purged peripheral blood stem cell

Upfront Autologous BMT in Follicular Lymphoma

Colombat et al, Blood 2005, 105:3817

N = 175 Event Free Survival Overall Survival

Upfront Autologous BMT in Follicular Lymphoma

Colombat et al, Blood 2005, 105:3817

N = 175 High FLIPI Patients Event Free Survival

No difference in OS even in this group

Allo vs Auto BMT in Follicular Lymphoma

van Besien et al, Blood 2003, 102:3521

N = 904 Retrospective analysis from IBMTR All relapsed follicular lymphoma Comparing different transplant modalities on treatment-related mortality, relapse rate and survival Myeloablative Allogeneic From HLA-matched siblings Autologous with purged stem cells Autologous with unpurged stem cells

Allo vs Auto BMT in Follicular Lymphoma

van Besien et al, Blood 2003, 102:3521

N = 904 Retrospective analysis from IBMTR Treatment Related Mortality

Allo vs Auto BMT in Follicular Lymphoma

van Besien et al, Blood 2003, 102:3521

N = 904 Retrospective analysis from IBMTR Relapse Rate

Allo vs Auto BMT in Follicular Lymphoma

Relapse Free Survival
van Besien et al, Blood 2003, 102:3521

Overall Survival

Non-Myeloalbative Allogeneic Transplant in Lymphoma

Lowsky et al, AST 2008

N = 64 Histology HD DLCL, Transformed MCL T Cell At Transplantation CR1 PR1 5 2 > CR2 > PR2 19 30 PD 7 6 19 10 6 Follicular Marginal CLL Lymphoplasma Waldenstrom 10 2 9 2

Preparative regimen TLI ATG 800 cGy 1.5 mg/kg x 5 days

Non-Myeloalbative Allogeneic Transplant in Lymphoma

Lowsky et al, AST 2008

N = 53 Event Free Survival

CR PR SD/PD

High Dose Therapy/Autologous HCT in Hodgkins Diz

Horning et al, 1997

Progression Free Survival

4 yr PFS 62%

100 day NRM 5%

35% pneumonitis with BCNU 15 mg/kg

High Dose Therapy/Autologous HCT in Hodgkins Diz

Horning et al, 1997

Three risk factors identified Lung/Marrow Involvement at presentation B symptoms at presentation Residual disease prior to transplant Progression Free Survival 3 yr PFS 0 1 2 3 Risk factor 0 85% 1 57% 2 41% 3 < 20%

High Dose Therapy/Autologous HCT in Hodgkins Diz

Arai et al, 2008

N = 92 Increase clinical efficacy by adding new agents Decrease pneumonitis by lower BCNU dose

Preparative regimen Gemcitavine Vinorelbine BCNU VP-16 Cytoxan 1250 mg/m2 30 mg/m2 350 mg/m2 or 10 mg/kg 60 mg/kg 100 mg/kg

High Dose Therapy/Autologous HCT in Hodgkins Diz

Arai et al, 2008

Progression Free Survival 0 1 2 Risk factor 0 95% 1 75% 2 64% 3 < 20% 3 yr PFS

2 yr PFS 71% 15% pneumonitis with lower BCNU

Conclusion

High dose therapy/autologous HCT is curative for aggressive NHL and HD High risk aggressive NHL/HD patients need additional NMA allo ? Maintenance rituximab ? CIK ? Graft-versus-lymphoma effect is powerful Safe when delivered via non-myeloablative regimen Curative for low grade NHL ?