GVHD & GVL in the lymphoma setting: The case of CLL Peter Dreger Dept. Internal Medicine V University of Heidelberg Oct 16, 2014 1 Number of Allo-HSCT for CLL per year (Cells source) 500 475 450 431 400 387 350 299 300 308 324 348 373 251 250 197 200 202 212 160 150 122 100 81 52 50 2 5 3 3 6 13 11 13 7 16 26 31 30 0 1984 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Bone Marrow Peripheral Blood Transplant activity for lymphoma EBMT 2001-2012 Absolute numbers 2012 450 200 400 180 350 160 140 300 allo % increase 2001 -> 2011 120 250 100 200 80 150 100 50 0 60 CLL HL TCL FL DLC MCL L 2000 40 20 0 150 1800 1600 100 1400 auto 1200 50 1000 800 0 600 400 DLCL HL MCL FL TCL CLL -50 200 0 -100 Total lymphoma transplants 2011 (w/o CLL): allo 1431; auto 6125 The European Group for Blood and Marrow Transplantation GVL vs GVHD in CLL: Key questions - do GVL effects exist ? Evidence for GVL: Bullet points - Plateau after RIC ? Conditioning Regimens: Immunosuppressive vs anti-tumor activities (adopted from Champlin et al) Myelosuppression / Toxicity Bu/Cy BEAM MEL150/F TBI8/F Bu8/F Flu/Cy TBI2/F TBI4/F „RIC“ „NMA“ Immunosuppression TBI12/Cy „MAC“ Toxicity of RIC alloSCT for CLL Study GCLLS G Seattle Boston FCGCL L Housto n Heidelb. UK/IRL n 90 82 76 40 86 66 50 Mucositis 3-4 6% 12% na <5% na na na Infection 3-4 55% 60% na 48% na na na 0% 3% 3% 2% Early death (< d +100) <3% <10% <3% NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y) 24% (3y) 15% (4y) Ext. cGVHD 55% 49-53% 48% 42% 56% 53% 48% Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn EBMT 2014; Richardson BJH 2013 Survival after RIC alloSCT for CLL Study GCLLSG Seattle Boston n 90 82 76 40 2-y PFS 50% >50% n.a. 5-y PFS 42% 39% 2-y OS 75% 5-y OS F/U mo Heidelb. UK/IRL 86 77 50 57% 40%* 58% 70% * 43% 46% 36%* 52% 55%* >60% n.a. 63% 63% 78% 83% 63% 50% 63% 55% 51% 63% 75% 72 (7-129) 11-87 61 28 (3-71) 37 (11-131) 37 (12-101) 51 (11-143) 100 Percent EFS 100 Percent EFS * Current PFS FCGCLL Houston 50 6-y EFS 38% (27, 48) 50 5-y EFS 49% (33, 65) 0 0 24 48 72 96 120 Months from SCT 0 0 12 24 36 48 60 72 Months from SCT Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn DGHO 2014; Richardson BJH 2013 84 96 Evidence for GVL: Bullet points - Plateau after RIC - Efficacy of donor lymphocyte infusions ? Overall survival from relapse after HSCT (n = 19 of 77) Percent Survival 100 75 MRD-neg after DLI + R 50 25 2-y OS 52% (27, 77) Med f/u 25mo (6-57) 0 0 12 24 36 48 60 Months from Relapse after HSCT Median time from HSCT to rel 11mo (3-83) 13.09.2014 Evidence for GVL: Bullet points - Plateau after RIC - Efficacy of donor lymphocyte infusions ? - Detrimental effect of T cell depletion AlloBMT for CLL using ex-vivo CD6 TCD (Dana Farber results, n = 25) Gribben et al, Blood 106:4389 (2005) Evidence for GVL: Bullet points - Plateau after RIC Efficacy of donor lymphocyte infusions Detrimental effect of T cell depletion ? Protective effect of chronic GVHD CLL: Relapse risk and chronic GVHD Percent with relapse or progression (EBMT survey, n = 77) 100 cGVHD always absent 75 50 25 after cGVHD onset 0 0 12 24 36 48 Months from SCT Leukemia 17:841 (2005) Evidence for GVL: Bullet points - Plateau after RIC Efficacy of donor lymphocyte infusions Detrimental effect of T cell depletion Protective effect of chronic GVHD Minimal residual disease (MRD) kinetics ? CLL: Quantitative MRD assessment by 4 color flow cytometry (MRD-flow) a= b= c= d= e= f= 4 CD19+ B cells exclude doublets CD5- background CD5+ CD20low CD43+ CD20low CD43+ CD5+ 10E- Sensitivity 1 in 104 Böttcher et al, LEUKEMIA 2004; Rawstron et al, LEUKEMIA 2007 alloSCT for CLL: MRD response patterns CLL3X (n=52) Other pattern (42%) A: MRD- after CSA taper MRD- immediately after SCT (16%) CSA taper GVHD MRD- after CSA taper (42%) Dreger et al, Blood 116:2438 (2010) Ritgen et al, Leukemia 22:1377 (2008) GVL vs GVHD in CLL: Key questions - GVL effects do exist - Are GVL effects durable ? Clinical impact of MRD negativity on disease control after alloHSCT (landmark studies) UK (9-month landmark) Milan (6-month landmark) Richardson et al, Br J Haematol 160:640 (2013) Farina et al, Haematologica 94:654 (2009) CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12) Clinical Relapse +12 M RD+ (10) 100 +12 M RD- (28) 50 HR 26.2 (6-115); p 0.0001 0 12 Percent MRD or clinical relapse Percent relapsed 100 MRD or clinical relapse 50 16% (95%CI 1-50) 0 36 60 84 Months from SCT Dreger et al, Blood 121:3284 (2013) 108 36 60 84 Months from SCT 108 CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo Percent not in MRD-negative clinical remission (of 38 patients with MRD monitoring and event-free at mo +12) 100 50 TP53 mut NOTCH1 mut SF3B1 mut no marker 16% (95%CI 1-51) 0 12 36 60 84 Months from SCT Blood 121:3284 (2013) 17p- 108 Evidence for durability of MRD response: Other intensive treatment 1000 10 MRD-level 10-1-1 10 10-2-2 10 10-3-3 10 10-4-4 10 10-5-5 10 Alemtuzumab: Hillmen JCO 2005 26 0 80 81 -1 10 10 1- 90 0- 09090 91 91 -1 -1 8 80 18 1 0 1-813636 0 36 3 0 6 1- 15454 0 54 5 0 4 1- 07272 0 72 7 0 2 1- 19090 00 in be itia l D f. Ca b dx x m ef. pa SC th T 10-6-6 10 autoSCT (CLL3) FC + alemtuzumab (CLL4B) Ritgen 2005 GVL vs GVHD in CLL: Key questions - GVL effects do exist - GVL effects are mostly durable - Can we have GVL w/o (chronic) GVHD ? CLL: Relapse risk and chronic GVHD Percent with relapse or progression (EBMT survey, n = 77) 100 cGVHD always absent 75 50 25 after cGVHD onset 0 0 12 24 36 48 Months from SCT Leukemia 17:841 (2005) CLL: MRD response patterns by cGVHD (Heidelberg, n=61) Ext. cGVHD 49% DLI: 18/61 (30%) (9 pre-emptive, 8 therapeutic) Chronic GVHD yes Chronic GVHD no (n=42) (n=19) Other pattern (17%) MRD- after DLI (7%) MRD- immediately after SCT (24%) MRD- after CSA taper (52%) Other pattern (26%) MRD- after DLI (11%) MRD- immediately after SCT (47%) MRD- after CSA taper (16%) Hahn et al, unpublished Can we separate GVL from GVHD by T cell depletion? Other pattern (25%) MRD- after DLI (12%) DLI: 31/50 (62%) (19 pre-emptive, 12 therapeutic) MRD- immediately after SCT (56%) MRD- after CSA taper (2%) Ext. cGVHD 48% GVL vs GVHD in CLL: Key questions - GVL effects do exist GVL effects are mostly durable Can we have GVL w/o GVHD: not yet Does GVL help in real life ? OS from 3-month landmark after start of search by compatible donor availability (high-risk CLL; donor vs no-donor comparison, n=97) 100 Percent alive 78% (95%CI 69%-88%) 75 Median follow-up 28 months 50 55% (34%-90%) donor yes (83) 25 donor no (14) HR 0.38 (95% CI 0.17-0.85); p=0.014 0 0 12 24 36 48 60 72 Months from 3-month landmark Herth et al, Ann Oncol 25:200 (2014) GVL vs GVHD in CLL: Key questions - GVL effects do exist GVL effects are mostly durable Can we have GVL w/o GVHD: not yet Does GVL help in real life: it used to do ? Indications EBMT CLL transplant consensus H I G H R I S K V E R Y H I G H allo-SCT is a reasonable treatment option in poor-risk CLL: – .Relapse <24 mo after intensive treatment (purine analogue combinations or auto-SCT) – .p53 mutation with treatment indication – .Non-response or early relapse (<12 mo) after purine analogue-based therapy (= fludarabine resistance) Leukemia 21:12-17 (2007) EBMT-ERIC position statement - High-risk CLL definition needs to be refined - Could be 17p-/TP53mut R/R CLL in the era of small molecules - SCT indication needs to be individualized considering disease risk and transplant risk and patient‘s preferences - SCT remains the most effective tool for GVLsensitive very high-risk CLL Blood, epub Oct 9 2014 Thank you CLL3X trial S Stilgenbauer R Busch M Ritgen S Böttcher D Beelen S Cohen J Schubert N Schmitz M Hallek T Zenz H Döhner MRD P Corradini C Moreno S Böttcher M Ritgen Med V M Rieger S Dietrich AD Ho T Luft U Hegenbart LWP/CMWP A Boumendil H Finel C Kyriakou JJ Luan Anna Sureda A van Biezen R Brand D Milligan D Niederwieser M Sobh J Schetelig T de Witte M Michallet …and you for your interest!
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