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Update in Hodgkins & DLBCL

Update in Hodgkins & DLBCL. Andy Chen, MD PhD Center for Hematologic Malignancies Knight Cancer Institute Oregon Health & Science University January 2012. Disclosures. Clinical trials: Seattle Genetics, Otsuka, Genentech Advisory role*: Seattle Genetics, Novartis

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Update in Hodgkins & DLBCL

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  1. Update in Hodgkins & DLBCL Andy Chen, MD PhD Center for Hematologic Malignancies Knight Cancer Institute Oregon Health & Science University January 2012

  2. Disclosures • Clinical trials: Seattle Genetics, Otsuka, Genentech • Advisory role*: Seattle Genetics, Novartis • Honoraria*: Seattle Genetics • This presentation will discuss off-label use and investigational therapies *All personal compensation donated to charity

  3. Early stage Hodgkins: NCIC XRT vs ABVD • N 405 • Stage IA or IIA non-bulky • Poor risk: age ≥ 40, ESR ≥ 50, ≥ 4 sites, MC or LD histology • Randomization • Chemo: ABVD x4-6 (only 4 if CR by CT after c2) • XRT: STNI (+ initial ABVD x2 if poor risk) • STNI = mantle + spleen + upper abdomen • Primary endpoint: OS • Secondary endpoints: PFS, EFS • Closed early due to EORTC H8F: chemoXRT > XRT for 10 yr OS Meyer, NEJM, 2011 & ASH, 2011

  4. Early Hodgkins: NCIC XRT vs ABVD OS: 87 vs 94 at 12 yrs PFS: 92 vs 87 at 12 yrs Meyer, NEJM, 2011 & ASH 2011

  5. Early Hodgkins: NCIC ABVD vs XRT * Most XRT Deaths in ‘poor risk’ group ^ Other: Alzheimers, drowning, suicide, respiratory failure, unknown

  6. Early Hodgkins: chemo or chemoXRT ? Meyer, NEJM, 2011 Engert, NEJM, 2010 Eich, JCO, 2010 Borchmann, ASH, 2010

  7. Advanced Hodgkins: MGI ABVD vs BEACOPP • N 331 • Advanced Hodgkin (IIB, III, IV) or IPS ≥ 3 • Randomization (stratified by stage or IPS) • BEACOPP: 4 escalated + 4 basic • ABVD x6-8 (only 6 if CR by CT after c4) • Planned salvage autoBMT if relapsed/refractory • Primary endpoint: freedom from 1st progression • Secondary endpoints: OS, freedom from 2nd progression, EFS Gianni, NEJM, 2011

  8. Advanced Hodgkins: MGI ABVD vs BEACOPP Gianni, NEJM, 2011

  9. Advanced Hodgkins: MGI ABVD vs BEACOPP Gianni, NEJM, 2011

  10. Advanced Hodgkin: ABVD vs escBEACOPP *All studies allowed consolidative XRT to bulky or residual sites Rummel, JCO, 2009 Federico, JCO, 2009 Gianni, NEJM, 2011

  11. Hodgkins: Consolidative XRT Who needs consolidative XRT after chemo? • Prospective GHSG HD15 (BEACOPP): PET NPV 94% Prospective studies after ABVD • Most early stage trials pre-PET & limited to low risk patients • Meta-analysis of early stage RCT: chemoXRT > chemo • British Columbia: retrospective series – omit if PET negative • EORTC H10: ABVD ± interim PET2 guided XRT • Chemo only arm closed early for increased failure ??

  12. Hodgkins: Residual CT size in PET negative 105 negative PET post treatment 74 first line + 31 first relapse 76 CT-scan residual > 2cm 29 No residual masses 50 <4 cm 26 > 4 cm 3 (10%) relapse 11 (22%) relapse 12 (46%) relapse Single institution Italian series Balzarotti, ASH, 2011

  13. Hodgkins: Residual CT size in PET negative Balzarotti, ASH, 2011

  14. Hodgkins: Brentuximab vedotin + ABVD • Phase 1 dose escalation • Age 18-60, Stage IIa bulky or IIb-IV • Treatment Design • 28 day cycles (x6) with SGN35 on d1 & 15 with chemo • Chemo: ABVD →AVD Younes, ASH, 2011

  15. Hodgkins: Brentuximab vedotin + ABVD • All evaluable (N 10) pts reached CR • 97% PET2 negative (N 37) • No DLTs in cycle 1 in any cohort • MTD not reached Younes, ASH, 2011

  16. Hodgkins: Brentuximab vedotin + ABVD ABVD cohorts: 40% pulmonary toxicity (10 of 25 pts) • 20% severe (grade 3/4) • Occurred during c3-6 No pulmonary toxicity in AVD cohorts 7% pts in ABVD cohorts discontinued due to neuropathy • 52% incidence of any neuropathy • All grade 1/2 • Recommended dose for ph 3: 1.2 mg/kg + AVD • Note: AVD inferior to ABVD in GHSG HD13 Younes, ASH, 2011

  17. Hodgkins: Key Points • ABVD alone: option in non-bulky early stage • Consider for young women • Toxicity of more chemo vs modern XRT ? • escBEACOPP: OS benefit still uncertain • EORTC 20012 results pending • Consider XRT to residual large nodes even if PET negative • Multiple studies ongoing • Brentuximab vedotin (SGN35) + bleomycin→ high toxicity • Not ready for frontline use

  18. DLBCL: Frontline therapy R-CHOP is standard • Intensive regimens not superior to CHOP • Exception French ACVBP ? • R-EPOCH vs R-CHOP ongoing • No benefit from maintenance R • Dose dense q14 days not superior to q21 • 8 cycles not better than 6 (at least for q14) • No proven benefit to intrathecal prophylaxis Fisher, NEJM, 2003 Pfreundschuh, LancOnc, 2006 Tilly, Blood, 2003 Reyes, NEJM, 2005 Habermann, JCO, 2006 Cunningham, ASCO, 2009 Delarue, ASH, 2009 Pfreundschuh, LancOnc, 2008 Nickelsen, ASH, 2009 Milpied, ASH, 2010

  19. DLBCL: Improving R-CHOP Modifications to immuno-therapy • Dosing of Rituximab • Next generation anti-CD20 • Additional target (CD22) Modifications to chemo • Bortezomib • especially in Activated B cell (ABC) type? • ‘Targeted’ agents • Protein kinase C (PKC) inhibitor (enzastaurin) • Lenalidomide

  20. DLBCL: Consolidative autoBMT Stiff, ASCO, 2011 Vitolo, ICML, 2011 Schmitz, ASCO, 2011

  21. DLBCL: Consolidative autoBMT - Notes SWOG 9704: most benefit in high IPI (2 yr OS 82 vs 64%) - 55% pts got CHOP (no Rituximab) - No benefit from Rituximab on PFS or OS Italian DLCL04: no difference R-CHOP vs augmented R-CHOP MegaCHOEP: non-standard chemo/BMT regimen - only 4 cycles & significantly increased toxicity French GELA & British BNLI studies ongoing

  22. DLBCL: Improving Salvage - CORAL • N 398 • Median f/u 2 yrs Gisselbrecht, JCO, 2010

  23. DLBCL: Improving Salvage - CORAL Restrict to early relapse All pts by Tx Arm Gisselbrecht, JCO, 2010

  24. DLBCL: Improving Salvage - CORAL R-DHAP: PFS R-ICE: PFS • GCB by Hans IHC algorithm • CD10+ • CD10-, BCL6+, MUM1/IRF4- Thieblemont, JCO, 2011

  25. 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 DLBCL: CORAL post-BMT maintenance Observation n = 120 Rituximab n = 122 p = 0.7435 EFS (months) Gisselbrecht, ICML, 2011

  26. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 DLBCL: Improving BMT - BexxarBEAM BMT CTN 0401 No difference in PFS, OS, TRM Significant increase in mucositis Rituxan/BEAM (N=113) Bexxar/BEAM (N=111) Bexxar/BEAM @ 2 yrs: 48.6% (95% CI, 39.0%, 57.5%) p=0.65 Rituxan/BEAM @ 2 yrs: 49.0% (95% CI, 39.3%, 58.0%) 0 6 12 18 24 30 36 42 48 Months Vose, ASH, 2011

  27. DLBCL: Key Points • R-CHOP-21 still the standard • Consolidative (frontline) autoBMT remains controversial • Early relapse after R-CHOP has very poor prognosis • Consider R-DHAP to salvage Germinal Center subtype • No benefit from Rituximab maintenance after autoBMT • No benefit from radio-immunotherapy in BMT

  28. Aggressive lymphoma: Missing in Action • Effective therapy for ‘double hit’ (unclassifiable, Myc+) • Optimal treatment for Peripheral T cell lymphoma • Novel drugs for relapsed/refractory DLBCL In Rituximab era: More pts cured upfront, But - fewer pts salvaged at relapse, = NO net improvement in cure rates

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