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Controversies in Transplant for Lymphoma. Andy Chen, MD PhD Center for Hematologic Malignancies Oregon Health & Science University [email protected] September 2013. Disclosures. Clinical trials - Genentech, Otsuka, Seattle Genetics Advisory boards - Genentech, Seattle Genetics. - PowerPoint PPT Presentation
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Controversies in Transplant for Lymphoma
Andy Chen, MD PhDCenter for Hematologic MalignanciesOregon Health & Science University
[email protected] 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
MSKCC series N=153
Moskowitz, Blood, 2010
French series N=111
Devillier, Haematologica, 2012
PFS
Hodgkins: PET negativity & AutoSCT
Moskowitz, Blood, 2012
MSKCC study - GVD salvage if PET+ after ICE
Should PET negativity be the goal before AutoSCT?
Hodgkins: Brentuximab & autoSCTBrentuximab (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
OSEFS
Philip, NEJM, 1995
‘PARMA’ study: N 215, median f/u 5 yrs - randomized chemosensitive patients
Prior to Rituximab era
Gisselbrecht, JCO, 2010
CORAL- DHAP vs ICE- maintenance Rituximab- modern efficacy of
salvage+Auto
DLBCL: R-DHAP vs R-ICE (CORAL)
Gisselbrecht, JCO, 2010
No difference overall between R-ICE and R-DHAP
DLBCL subtype: DHAP vs ICE
Thieblemont, JCO, 2011
cell of origin by Hans IHC
R-DHAP may be superior for germinal center type DLBCL
R-ICER-DHAP
PFS PFS
DLBCL: Relapse ≤ 1 yr
Gisselbrecht, JCO, 2010
60% of early relapse do not respond to 1st salvage
- If respond & proceed to autoSCT, then 3 yr EFS = 39%
Myc+ and AutoSCT
Cuccuini, Blood, 2012
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+
From start of salvage
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)
Vose, JCO, 2013
No difference in PFS or OSSignificant increase in mucositis with BEXXAR
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 AutoSCTSWOG 9704 Italian DLCL04
Criteria IPI 3-5 aaIPI 2-3
Chemo (R)-CHOP x8 R-CHOP-14 x8
BMT CBV, BEAM or TBI R-MAD + BEAM
N 370 392
PFS 2 yr: 69 vs 56 % 2 yr: 71 vs 59 %
OS 2 yr: 74 vs 71 % 2 yr: 83 vs 83 %
Vitolo, ICML, 2011Stiff, ASCO, 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
‘CUP’ trial – improves PFS & OS- no benefit from purging- prior to Rituximab era
Schmitz, Lancet, 2002
OSPFS
Follicular: AutoSCT vs conventional chemo
Impact of AutoSCT at 1st relapse on Pts in FL2000 studyFrontline R-CHVP, N=70
Caveat: AutoSCT not randomized
Le Gouill, Haematologica, 2011
OSEFS
p=0.05 p=0.05
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 rituximabPettengell, JCO, 2013
Follicular Auto vs AlloAdjusted OS
CIBMTR series
Similar results in EBMT series
van Besien, Blood, 2003
Follicular Allo: Ablative vs Reduced intensity
CIBMTR series: HLA matched siblings
PFS
Hari, BBMT, 2008
OS
Transformed Follicular: R-chemo vs Auto vs Allo
Canadian retrospective series: N 172, median f/u 7 yrs
PFS
Villa, JCO, 2013
OS
NMDP Guideline for Mantle Cell• Following initial therapy
Not specify Auto vs AlloNot discuss relapse/refractory
NCCN guidelines:- Auto in CR1- Allo in CR2
Mantle: Upfront AutoSCT
MCLnetwork randomized study- CHOP induction (No Rtx)
Dreyling, Blood, 2005
OSPFS
Mantle: Induction chemo pre-SCT
MCLnet ‘Younger’ trial- improved MRD- trend for OS- updated 4 yr f/u median PFS 88 vs 46 mos
Hermine, ASH, 2010 & 2012
PFS
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
CIBMTR series- N 263- median f/u 68 mos
Freytes, BBMT, 2012
Prognostic factors:- early failure of auto- disease status- performance status
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)