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Controversies in Transplant for Lymphoma

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.

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Controversies in Transplant for Lymphoma

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  1. Controversies in Transplant for Lymphoma Andy Chen, MD PhD Center for Hematologic Malignancies Oregon Health & Science University chenan@ohsu.edu September 2013

  2. Disclosures • Clinical trials - Genentech, Otsuka, Seattle Genetics • Advisory boards - Genentech, Seattle Genetics

  3. 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

  4. 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

  5. Hodgkins: pre-SCT disease status PFS French series N=111 MSKCC series N=153 Moskowitz, Blood, 2010 Devillier, Haematologica, 2012

  6. Hodgkins: PET negativity & AutoSCT MSKCC study - GVD salvage if PET+ after ICE Should PET negativity be the goal before AutoSCT? Moskowitz, Blood, 2012

  7. 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 2ndsalvage to achieve PETneg before SCT? - Use as 1st salvage – with or without chemo? - Maintenance after autoSCT?

  8. 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

  9. 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

  10. CORAL • DHAP vs ICE • maintenance Rituximab • modern efficacy of salvage+Auto Gisselbrecht, JCO, 2010

  11. DLBCL: R-DHAP vs R-ICE (CORAL) No difference overall between R-ICE and R-DHAP Gisselbrecht, JCO, 2010

  12. 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

  13. 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

  14. 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

  15. 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

  16. DLBCL: BEXXAR-BEAM (CTN 0401) No difference in PFS or OS Significant increase in mucositis with BEXXAR Vose, JCO, 2013

  17. 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?

  18. DLBCL: Consolidative AutoSCT Stiff, ASCO, 2011 Vitolo, ICML, 2011

  19. 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

  20. Follicular: AutoSCT vs conventional chemo OS PFS ‘CUP’ trial – improves PFS & OS - no benefit from purging - prior to Rituximab era Schmitz, Lancet, 2002

  21. 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

  22. Follicular: Timing of AutoSCT Nebraska series DFCI/St Bart series Vose, BBMT, 2008 Rohatiner, JCO, 2007

  23. Follicular: Maintenance Rituximab post-SCT EBMT randomized study: relapsed chemosensitive FL Caveat: No prior rituximab Pettengell, JCO, 2013

  24. Follicular Auto vs Allo Adjusted OS CIBMTR series Similar results in EBMT series van Besien, Blood, 2003

  25. Follicular Allo: Ablative vs Reduced intensity PFS OS CIBMTR series: HLA matched siblings Hari, BBMT, 2008

  26. Transformed Follicular: R-chemo vs Auto vs Allo PFS OS Canadian retrospective series: N 172, median f/u 7 yrs Villa, JCO, 2013

  27. 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

  28. Mantle: Upfront AutoSCT PFS OS MCLnetwork randomized study - CHOP induction (No Rtx) Dreyling, Blood, 2005

  29. 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

  30. Mantle: MRD status AutoSCT effect on MRD rate in DHAP arm: 73% -> 83% Similar impact of MRDneg in R-CHOP + Rtxmaint (no SCT) Pott, ASH, 2010 & Blood, 2010

  31. Mantle: Allogeneic SCT • European multicenter • - N 70, median f/u 24 mos • relapsed/refractory • 67% prior auto • reduced intensity Le Gouill, Ann Onc, 2012

  32. AlloSCTafter 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

  33. 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)

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