Controversies in Transplant for Lymphoma

Andy Chen, MD PhDCenter for Hematologic MalignanciesOregon Health & Science University

chenan@ohsu.eduSeptember 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)