Controversies in Transplant
for Lymphoma
Andy Chen, MD PhD
Center for Hematologic Malignancies
Oregon Health & Science University
chenan@ohsu.edu
September 2013
Disclosures
 Clinical trials - Genentech, Otsuka, Seattle Genetics
 Advisory boards - Genentech, Seattle Genetics
NMDP Guidelines for Hodgkins
AutoSCT indicated for:
• No initial CR
• First or subsequent relapse
NCCN guidelines:
AutoSCT for relapsed/refractory Hodgkins not amenable
to radiation therapy
Hodgkins: AutoSCT vs conventional chemo
GHSG randomized trial
- 3 yr FFTF 55 vs 34%
- No difference in OS
Similar results in BNLI study
Schmitz, Lancet, 2002
Hodgkins: pre-SCT disease status
PFS
MSKCC series
N=153
Moskowitz, Blood, 2010
French series
N=111
Devillier, Haematologica, 2012
Hodgkins: PET negativity & AutoSCT
MSKCC study
- GVD salvage if PET+ after ICE
Should PET negativity be the goal before AutoSCT?
Moskowitz, Blood, 2012
Hodgkins: Brentuximab & autoSCT
Brentuximab (SGN-35): antibody drug conjugate against CD30
• Approved for relapse after auto or failure of 2 chemo regimens
• Response rate >70% including >30% CR
-
Use as 2nd salvage to achieve PETneg before SCT?
-
Use as 1st salvage – with or without chemo?
-
Maintenance after autoSCT?
ASBMT Key Guidelines for DLBCL
• AutoSCT recommended for chemosensitive relapse
• AutoSCT not recommended as first line therapy
• Age is not contraindication for autoSCT
• Auto vs Allo SCT: competing risks & selection bias
NCCN guidelines similar
Oliansky, BBMT, 2011
DLBCL: Conventional Tx vs BMT
EFS
OS
‘PARMA’ study: N 215, median f/u 5 yrs
- randomized chemosensitive patients
Prior to Rituximab era
Philip, NEJM, 1995
CORAL
- DHAP vs ICE
- maintenance Rituximab
- modern efficacy of salvage+Auto
Gisselbrecht, JCO, 2010
DLBCL: R-DHAP vs R-ICE (CORAL)
No difference overall between R-ICE and R-DHAP
Gisselbrecht, JCO, 2010
DLBCL subtype: DHAP vs ICE
cell of origin by Hans IHC
R-DHAP
R-ICE
PFS
PFS
R-DHAP may be superior for germinal center type DLBCL
Thieblemont, JCO, 2011
DLBCL: Relapse ≤ 1 yr
60% of early relapse do not respond to 1st salvage
- If respond & proceed to autoSCT, then 3 yr EFS = 39%
Gisselbrecht, JCO, 2010
Myc+ and AutoSCT
From start of salvage
CORAL sub-analysis:
- N = 28 (16% original study)
- Myc single vs double hit same
- R-DHAP & R-ICE same
- GCB vs ABC same if Myc+
Cuccuini, Blood, 2012
AutoSCT and Radioimmunotherapy
• RIT: antibody conjugated to radiation
– Beta emitter: Yttrium-90 Ibritumomab tiuxetan (Zevalin)
– Gamma emitter: Iodine-131 Tositumomab (Bexxar)
• Does RIT improve efficacy of high dose conditioning regimen?
– BMT CTN 0401: R-BEAM vs BEXXAR-BEAM
DLBCL: BEXXAR-BEAM (CTN 0401)
No difference in PFS or OS
Significant increase in mucositis with BEXXAR
Vose, JCO, 2013
AutoSCT in 1st Response for DLBCL
• Multiple (>10) randomized studies in pre-Rituximab era
– Two meta-analyses: No benefit in EFS or OS
– Controversial whether benefit in high risk IPI
– Not recommended in ASBMT policy guidelines
• What is role of AutoSCT in PR/CR1 after R-CHOP for DLBCL?
DLBCL: Consolidative AutoSCT
SWOG 9704
Italian DLCL04
Criteria
IPI 3-5
aaIPI 2-3
Chemo
(R)-CHOP x8
R-CHOP-14 x8
CBV, BEAM or TBI
R-MAD + BEAM
370
392
PFS
2 yr: 69 vs 56 %
2 yr: 71 vs 59 %
OS
2 yr: 74 vs 71 %
2 yr: 83 vs 83 %
BMT
N
Stiff, ASCO, 2011
Vitolo, ICML, 2011
ASBMT Guidelines for Follicular lymphoma
• AutoSCT improves PFS and OS as salvage therapy based
on pre-Rituximab data
• AutoSCT recommended for transformed Follicular based
on expert opinion and accepted practice
• Not recommend as first line therapy/consolidation
• Auto vs Allo: competing risks & selection bias
• Reduced intensity conditioning acceptable for Allo
Oliansky, BBMT, 2010
Follicular: AutoSCT vs conventional chemo
PFS
OS
‘CUP’ trial – improves PFS & OS
- no benefit from purging
- prior to Rituximab era
Schmitz, Lancet, 2002
Follicular: AutoSCT vs conventional chemo
EFS
p=0.05
OS
p=0.05
Impact of AutoSCT at 1st relapse on Pts in FL2000 study
Frontline R-CHVP, N=70
Caveat: AutoSCT not randomized
Le Gouill, Haematologica, 2011
Follicular: Timing of AutoSCT
Nebraska series
Vose, BBMT, 2008
DFCI/St Bart series
Rohatiner, JCO, 2007
Follicular: Maintenance Rituximab post-SCT
EBMT randomized study: relapsed chemosensitive FL
Caveat: No prior rituximab
Pettengell, JCO, 2013
Follicular Auto vs Allo
Adjusted OS
CIBMTR series
Similar results in EBMT series
van Besien, Blood, 2003
Follicular Allo: Ablative vs Reduced intensity
PFS
OS
CIBMTR series: HLA matched siblings
Hari, BBMT, 2008
Transformed Follicular: R-chemo vs Auto vs Allo
PFS
OS
Canadian retrospective series: N 172, median f/u 7 yrs
Villa, JCO, 2013
NMDP Guideline for Mantle Cell
• Following initial therapy
Not specify Auto vs Allo
Not discuss relapse/refractory
NCCN guidelines:
-
Auto in CR1
Allo in CR2
Mantle: Upfront AutoSCT
PFS
OS
MCLnetwork randomized study
- CHOP induction (No Rtx)
Dreyling, Blood, 2005
Mantle: Induction chemo pre-SCT
PFS
MCLnet ‘Younger’ trial
- improved MRD
- trend for OS
- updated 4 yr f/u
median PFS 88 vs 46 mos
Hermine, ASH, 2010 & 2012
Mantle: MRD status
AutoSCT effect on MRD rate in DHAP arm: 73% -> 83%
Similar impact of MRDneg in R-CHOP + Rtx maint (no SCT)
Pott, ASH, 2010 & Blood, 2010
Mantle: Allogeneic SCT
European multicenter
- N 70, median f/u 24 mos
- relapsed/refractory
- 67% prior auto
- reduced intensity
Le Gouill, Ann Onc, 2012
AlloSCT after Auto failure in NHL
Prognostic factors:
- early failure of auto
- disease status
- performance status
CIBMTR series
- N 263
- median f/u 68 mos
Freytes, BBMT, 2012
Future directions: NHL & SCT
• Identification of high risk patients
– Alternative chemo and/or Allo
• Novel therapies
– Better disease control before SCT
– Maintenance after SCT
– Critical need in DLBCL, especially Myc+/double hit
Next gen Antibodies & Antibody drug conjugates
Signaling inhibitors (BTK, Syk, PI3K)