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 French series N=111 MSKCC series N=153 Moskowitz, Blood, 2010 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 CORAL sub-analysis: - N = 28 (16% original study) 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 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 % 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 ‘CUP’ trial – improves PFS & OS - no benefit from purging - prior to Rituximab era Schmitz, Lancet, 2002

Follicular: AutoSCT vs conventional chemo EFS OS p=0.05 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 DFCI/St Bart series Vose, BBMT, 2008 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)