Inibitori del Proteosoma e Trapianto Allogenico B. Bruno University of Torino – School of Medicine – Torino, Italy Udine 21.1. 2016
NF-kB Negative Feedback Immunity Antiapoptosis Proliferation Chemokines, Bcl-2, XIAP, cytokines, IkB, A20 cIAP-1, cIAP-2 Cyclin D1 Adhesion FLIP, Bcl-XL molecules
TNF a p65 Protein kinases P P IkB p65 P P p50 IkB P p50 P p65 IkB TNF a R p50 Degradation of IkB by P p65 NFkB -IkB P 26S proteasome IkB complex P p50 NFkB Nuclear PS 341 translocation NFkB binding site p65 p50 Increase in Increase in Cytokine adhesion production molecules NFkB Induced proteins Block of programmed cell death
TNF a p65 Protein kinases P P IkB p65 P P p50 IkB P p50 P p65 IkB TNF a R p50 Degradation of IkB by P p65 NFkB -IkB P 26S proteasome IkB complex P p50 NFkB Nuclear PS 341 translocation NFkB binding site p65 p50 Increase in Increase in Cytokine adhesion production molecules NFkB Induced proteins Block of programmed cell death
TNF a p65 Protein kinases P P IkB p65 P P p50 IkB P p50 P p65 IkB TNF a R p50 Degradation of IkB by P p65 NFkB -IkB P 26S proteasome IkB P p65 complex P IkB P p65 P P IkB p50 P p50 P p50 NFkB Nuclear PS 341 translocation NFkB binding site Increase in Increase in Cytokine adhesion production molecules NFkB Induced proteins Block of programmed cell death
TNF a p65 Protein kinases P P IkB p65 P P p50 IkB P p50 P p65 IkB TNF a R p50 Degradation of IkB by P p65 NFkB -IkB P 26S proteasome IkB P p65 complex P IkB P p65 P P IkB p50 P p50 P p50 NFkB Nuclear PS 341 translocation Increase in Increase in Cytokine adhesion production molecules NFkB Induced proteins Block of programmed cell death
TNFa p65 Protein kinases P P IkB p65 P P p50 IkB P p50 P p65 IkB TNFaR p50 Degradation of IkB by P p65 NFkB -IkB P 26S proteasome IkB P p65 complex P IkB P p65 P P IkB p50 P p50 P p50 NFkB Nuclear PS 341 translocation Increase in Cytokine production Increase in adhesion Anti-myeloma effect molecules NFkB Induced proteins GVHD prevention Block of programmed cell death
Topics • GVHD • Background : allografting in myeloma and new drugs • Current studies: proteasome inhibitors and allografting
Suggested readings: • Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Sun K, et al. Proc Natl Acad Sci U S A. 2004;101:8120-5. • Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity.Sun K, et al. Bood. 2005;106:3293-9. • Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. Koreth J, et al. J Clin Oncol. 2012;30:3202-8. . • Treatment of chronic graft-versus-host disease with bortezomib. Pai CC, et al. Blood. 2014;124:1677-88. • Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Pai CC, et al. Biol Blood Marrow Transplant. 2014;20:1899-904. • Proteasome: target for acute and chronic GVHD? Magenau JM, Reddy P.Blood. 2014;124:1551-2.
Pai et al. Blood 124, 1677-1688, 2014
Pai et al. Blood 124, 1677-1688, 2014
Pai et al. Blood 124, 1677-1688, 2014
Pai et al. Blood 124, 1677-1688, 2014
Pai et al. Blood 124, 1677-1688, 2014
Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and Graft-versus-host Disease in Allogeneic Hematopoietic Cell Transplantation for High-risk Hematologic Malignancies Methotrexate will be administered at 5 mg/m2 IV per day on day +1, +3, +6 and +11 as standard graft-versus-host disease prophylaxis. Tacrolimus will be administered at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis. Experimental: CarfilzomibPatients will receive standard fludarabine- based conditioning regimen (fludarabine + busulfan or fludarabine + melphalan), followed by an allogeneic hematopoietic cell transplantation, with the addition of carfilzomib. Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7. ClinicalTrials.gov Identifier: NCT02145403
Multiple Myeloma: EBMT/GITMO-Data 200 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0 GITMO 81 115 128 129 103 94 94 70 86 85 71 86 55 73 ITALY MIS 1 12 4 10 APLO EBMT 393 405 523 573 594 565 494 498 525 567 614 601 668 606 ALLO EBMT 352 4283 4843 5487 5926 6374 6564 6743 6833 6874 7260 8536 9214 9794 AUTO 0
Timeline showing advances in myeloma treatment FDA approvation of Bu-Cy Bortezomib in patients Cy-TBI who had received at least Seattle one prior therapy Montreal TBI-based Toronto non-myeloablative allogeneic michigan Introduction of FDA approvation of SCT in hematological Bologna Lenalidomide in malignancies non-myeloablative TBI Surrey (McSweeney ) patients who had recived at allogeneic SCT regimens in Arkansas least one prior therapy MM Boston (Maloney) Vancouver FDA approvation of FDA approvation of 1996 – Bortezomib in Bortezomib in Autolougous refractory patients first line therapy SCT is superior to standard chemotherapy (Attal) Introduction of RIC- allogeneic SCT regimens in FDA approvation MM of Thalidomide (Kroger )
Figure 2. An Approach to the Treatment of Newly Diagnosed Multiple Myeloma. Kyle,Rajkumar NEJM 2004
New drugs after allografting in myeloma Median OR PFS after OS after Median Disease Pts Drug time to (at least salvage salvage age status salvage PR) treatment treatment Mohty et al 54 Relapse/ 50% 31 Thal NR 29% NR 2004 (39-64) refractory ~ 15 mo Bruno et al 64 Relapse/ Vel 50% 23 20 mo 61% NR 2006 (48-85) refractory Vel+Dex (6 mo) El-Cheikh et 49 Relapse/ Vel 65% 37 20 mo 73% NR al 2008 (27-64) efractory Vel+Dex (18 mo) Thal 58% vs. 90% vs. Kroger et al 50 No CR after 25/32 Vel NR 59%** 35%*** 62%*** 2009 (35-68) DLI * Len (56 mo) (56 mo) Minnema et 58 Relapse/ Len 50% 50% al 16 NR 87% (43-67) refractory Len+Dex (11 mo) (13 mo) 2008 Kroger et al 49 SD, PR or 89% 95% 18 Vel 8 mo NR 2006 (32-68) CR ^ (7 mo) § (7 mo) Thal Schmitt et al 56 Relapse/ 17% 32% 23/36 Vel - NR 2008 (44-64)) refractory ^^ (36 mo) ^^^ (36 mo) ^^^ Len Vel Niels et al No response 21/63 NR Thal NR NR § NR NR 2006 to DLI Vel+Thal Lehmann et 59 Relapse/ Len 50% al 24 NR 66% NR (37-70) refractory Len+Dex (20 mo) 2008 NR: not reported; * DLI was administrated in 32 patients who achieved only partial remission after allogeneic SCT; ** percentage of CR obtained after DLI and treatment with new drugs; *** patient who achieved CR versus patients who did not achieve CR; ^ obtained after RIC allogeneic SCT; ^^ obtained before RIC allogeneic SCT; ^^^ calculated on all 36 patients.
Number of Allo / year / type Allo beyond 2nd line Auto-allo 2nd line after auto Allo for rel after 2 auto Allo for rel post 1 auto Auto-allo 1st line Allo 1st line Leukemia, 2016 submitted
OS (after 2004) Courtesy of Dr Kroger
PFS (after 2004) Courtesy of Dr Kroger
Sinergy between residual donor T cells and “ new drugs ”
Sinergy between residual donor T cells and “new drugs” Bruno B NEJM 2007 Giaccone et al. Blood 2011
Post-relapse Survival Rates after Tandem Auto-HSCT vs. Auto/Allo-HSCT in Multiple Myeloma Endpoint: Compare clinical outcomes (overall survival, event free survival and time-to next therapy)in patients at first relapse after autologous transplantation or allogeneic transplantation when the transplant procedure was employed as first line treatment. All intensities of conditionings and stem cell source are included A Krishnan, MD (City of Hope National Medical Center) P Hari, MD, MRCP, MS (Medical College of Wisconsin) B Bruno, MD, PhD (University of Torino) N Tank, MD (City of Hope National Medical Center) Minneapolis, October 2014
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