GVHD & GVL in the lymphoma setting: The case of CLL Peter Dreger Dept. Internal Medicine V University of Heidelberg
EBMT: SCT for CLL 2000-2010 Update January 2012 allo auto 400 350 300 250 200 150 100 50 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 The European Group for Blood and Marrow Transplantation
Transplant activity for lymphoma EBMT 2001-2011 Absolute numbers 2011 % increase 2001 -> 2011 allo 350 300 250 200 150 100 50 0 CLL HL TCL FL DLC L MCL 200 180 160 140 120 100 80 60 40 20 0 auto 2000 1800 1600 1400 1200 1000 800 600 400 200 0 DLCL HL MCL FL TCL CLL 150 100 50 0-50 -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?
CLL: OS after allosctby EBMT score Michallet et al, Leukemia 24:1725 (2010)
Sensitivity to GVL activity allows reduction of conditioning intensity: RIC!
Myelosuppression / Toxicity Conditioning Regimens: Immunosuppressive vs anti-tumor activities (adopted from Champlin et al) Bu8/F Bu/Cy BEAM MEL150/F TBI8/F TBI12/Cy MAC NMA TBI4/F Flu/Cy TBI2/F RIC Immunosuppression
Toxicity of RIC allosct for CLL Study GCLLSG Seattle Boston FCGCLL Houston Heidelb. n 90 82 76 40 86 66 Mucositis 3-4 6% 12% na <5% na na Infection 3-4 55% 60% na 48% na na Early death (< d +100) <3% <10% <3% 0% 3% 3% NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y) 24% (3y) Ext. cgvhd 55% 49-53% 48% 42% 56% 53% Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn iwcll 2013
Percent EFS Percent EFS Survival after RIC allosct for CLL Study GCLLSG Seattle Boston FCGCLL Houston Heidelb. n 90 82 76 40 86 66 PFS 38% (6y) 39% (5y) 43% (5y) 46% (3y) 36% (5y) 49% (5y) OS 58% (6y) 50% (5y) 63% (5y) 55% (3y) 51% (5y) 62% (5y) F/U mo 72 (7-129) 11-87 61 28 (3-71) 37 (11-131) 34 (9-93) 100 100 50 50 6-y EFS 38% (27, 48) 0 0 24 48 72 96 120 Months from SCT 5-y EFS 49% (33, 65) 0 0 12 24 36 48 60 72 84 96 Months from SCT Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn iwcll 2013
GVL in CLL: Lessons to learn from MRD studies MRD = Minimal Residual Disease
CLL: Quantitative MRD assessment by 4 color flow cytometry (MRD-flow) a = CD19 + B cells b = exclude doublets c = CD5 - background d = CD5 + CD20 low e = CD43 + CD20 low f = CD43 + CD5 + 10E- 4 Sensitivity 1 in 10 4 Böttcher et al, LEUKEMIA 2004; Rawstron et al, LEUKEMIA 2007
allosct for CLL: MRD response patterns A: MRD- after CSA taper CSA taper GVHD Ritgen et al, Leukemia 22:1377 (2008)
allosct for CLL: MRD response patterns Other pattern (42%) CLL3X (n=52) MRD- immediately after SCT (16%) Heidelberg 2005-2012 (n=62) MRD- immediately after SCT (34%) MRD- after CSA taper (42%) MRD- after CSA taper (35%) Dreger et al, Blood 116:2438 (2010) Hahn et al, EBMT 2013
GVL vs GVHD in CLL: Key questions - GVL effects do exist - Are GVL effects durable?
CLL3X: Patient flow (MRD) 113 100 90 13 ineligible (no CLL, late registration, comorbidity etc.) 10 no SCT (Richter s, ED, no donor, refusal) 38 no continuous MRD sampling 52 13 event <12mo, 27 MRD-neg at +12mo 11 MRD-pos at +12mo 1 no MRD at +12mo
Percent relapsed Percent MRD or clinical relapse 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 MRD or clinical relapse 100 +12 MRD+ (10) +12 MRD- (28) 100 50 50 HR 26.2 (6-115); p 0.0001 16% (95%CI 1-50) 0 12 36 60 84 108 Months from SCT 0 36 60 84 108 Months from SCT Dreger et al, Blood 121:3284 (2013)
Clinical impact of MRD negativity at the +6mo landmark (Milan data) Farina et al, Haematologica 94:654 (2009)
MRD-level Evidence for durability of MRD response: Other intensive treatment 10 0 10-1 10-2 10-3 10-4 10-5 10-6 Dx initial dx bef. SCT bef. Campath 0-90 0-90 91-180 91-180 181-360 181-360 361-540 361-540 540-720 541-720 721-900 721-900 901-1080 1081-1260 Alemtuzumab: Hillmen JCO 2005 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?
Percent with relapse or progression CLL: Relapse risk and chronic GVHD (EBMT survey, n = 77) 100 75 cgvhd always absent 50 25 after cgvhd onset 0 0 12 24 36 48 Months from SCT Dreger et al, Leukemia 17:841 (2005)
Can we separate GVL from GVHD by T cell depletion?
AlloBMT for CLL using ex-vivo CD6 TCD (Dana Farber results, n = 25) Gribben et al, Blood 106:4389 (2005)
Percent REL Percent event-free CLL3X: Impact of TCD (CD52 vs T replete or ATG, n = 12 vs 78) REL by TCD EFS by TCD 100 100 med EFS 13 vs 33 mo HR 3.95 (1.54, 10.15); p 0.0043 50 50 HR 3.29 (.97, 11.17); p.057 0 0 12 24 36 48 60 72 84 96 Months from SCT 0 0 12 24 36 48 60 72 84 96 Months from SCT
Percent EFS CLL3X: Impact of ATG (UD w ATG vs SIB w/o ATG, n = 41 vs 36) 100 HR 0.93 (0.38-2.31); p 0.88 WMUD + ATG (12) PMUD + ATG (29) SIB (36) 50 HR 0.79 (0.4-1.54); p 0.49 0 3-y EFS 42% vs 49% vs 55% 0 24 48 72 96 Months from SCT
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 - Pre-emptive immune intervention?
Real-time MRD Immunomodulation and MRD kinetics: monitoring allowing Results of GCLLSG CLL3X trial for pre-emptive immune intervention Trial-Id: NCT00281983
CLL3X: Patient flow (MRD) 113 100 90 13 ineligible (no CLL, late registration, comorbidity etc.) 10 no SCT (Richter s, ED, no donor, refusal) 38 no continuous MRD sampling 52 Cont. MRD sampling
Percent EFS Percent Survival Percent NRM Percent progressive CLL3X (n=90) f/u 46 (7-102) mo 100 50 NRM MRD pp no (38) MRD pp yes (52) 4-y NRM 18% vs 33% (HR 0.62 (.23-1.69) 100 50 REL 4-y REL 25% vs 65%; 0.28 (0.12, 0.58) MRD pp yes (52) MRD pp no (38) 100 0 0 24 48 72 96 Months from SCT EFS 4-y EFS 59% vs 17% HR 0.31 (0.17, 0.56) 0 0 24 48 72 96 100 Months from SCT MRD pp no MRD pp yes 50 MRD pp no MRD pp yes 50 4-y OS 72% vs 55% HR 0.55 (0.29-1.12) OS 0 0 24 48 72 96 Months from SCT 0 0 24 48 72 96 Months from SCT Böttcher et al, Blood Reviews 25:91-96 (2011)
Better disease control with MRD monitoring center effect or the case for pre-emptive immunotherapy
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 - Pre-emptive immune intervention: Improves disease control w/o affecting NRM or QOL?
What does that mean in real life?
Evidence that allohct can improve the natural course of poor-risk CLL: Final results from a retrospective donor vs no donor comparison P Dreger, I Herth, A Benner, S Dietrich, M Rieger, U Hegenbart, P Stadtherr, A Bondong, TH Tran, T Zenz, AD Ho Department Medicine V, University of Heidelberg 12-ICML, 20.06.2013
Department of Internal Medicine V Study design and patients Design: Single center retrospective analysis Patient eligibility: All consecutive patients referred for allosct for CLL between June 2005 and June 2012 to the University of Heidelberg
Department of Internal Medicine V Eligibility for donor search was either one of the three EBMT consensus criteria or symptomatic 17p- fludarabine refractoriness (non-response or relapse within 6 months after the last cycle) early relapse after intensive pretreatment (relapse after intensive treatment like FR, FCR, BR, R-CHOP or similar later than 6 months but within 2 years) Richter s transformation.
Department of Internal Medicine V Study population: patients for whom a 9/10 or 10/10 matched related or unrelated donor could be found within 3 months Control population: patients without 9/10 or 10/10 matched donor found within 3 months
Department of Internal Medicine V Primary endpoint Overall survival (OS), measured from the 3-month landmark after donor search initiation (to eliminate the early relapsemortality favoring the donor group).
Patient flow: Matches / Controls MCL 2, MZL 1 Observe OS R E F E R R A L 3 134 8 No search 5 refusal, 1 comorbidity, 2 lost to f/u Donor search indication (=EBMT risk or Richter s)? no 21 yes 113 105 SEARCH 8 lost w/i 3 months (6 dead PD, 1 refusal, 1 lost to f/u ) B 83 compatible donor within 3 Mo 14 no compatible donor within 3 Mo Observe OS Herth et al, Ann Oncol in press
Percent alive OS from 3-month landmark after start of search by compatible donor availability (primary endpoint; study population: matches vs controls, n=97) 100 75 50 55% (34%-90%) 78% (95%CI 69%-88%) Median follow-up 28 months 25 donor yes (83) donor no (14) Herth et al, Ann Oncol in press 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
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 - Pre-emptive immune intervention: Improves disease control w/o affecting NRM or QOL? - Perspectives?
2013: We are moving towards a new CLL treatment landscape with the advent of BTK inhibitors and BH3 mimetics ABT-199 From Wiestner et al, Blood 2012 From Souers et al, Nat Med 2013
Disease control by novel drugs in HR CLL (monotherapy) Drug Ibrutinib Idelalisib ABT-199 n 85 54 56 ORR 71%/88%* 44%/56%* 85% CR 2% 4% 13% PFS 75% (26mo) 50% (17mo) 9 PDs (1y) F/U mo 21 (1-27) 9 (0-40) 8 (0-17) * ORR according to iwcll / OR incl. PR with persistent lymphocytosis Byrd NEJM 2013; Byrd ASCO 2013; Seymour ICML 2013
PFS Probability OS Probability PCYC-1102-CA: Ibrutinib (All relapsed/ refractory) 1.0 PFS 1.0 OS 0.8 0.8 0.6 0.4 0.2 0.0 + Censored Logrank p=0.0437 del17p (n=28) Est. PFS at 26 mo is 57% del11q (n=23) Est. PFS at 26 mo is 73% No del17p or del11q (n=29) Est. PFS at 26 mo is 93% Months on Study Data cut-off of 19OCT2012 0 5 10 15 20 25 0.6 0.4 0.2 0.0 + Censored Logrank p=0.1482 del17p (n=28) Est. OS at 26 mo is 70% del11q (n=23) Est. OS at 26 mo is 85% No del17p or del11q (n=29) Est. OS at 26 mo is 93% Data cut-off of 19OCT2012 0 5 10 15 20 25 Months on Study Byrd et al, NEJM 369:32 (2013)
HSCT algorithm for HR-CLL 2014 Re-try HR-CLL, need for treatment, gogo, donor available yes no Richter? no Novel drug available? yes no Response to immuno-chemo salvage? yes no Ongoing response to novel drug? yes 2nd novel drug or immunochemo salvage Road construction ahead Discuss scenarios with patient Perform HSCT Postpone HSCT
Proposal: EBMT Slide template Barcelona 7 February 2008 Survey on the use of B cell receptor kinase inhibitors / BCL2 inhibitors in the context of HSCT for B cell lymphoma EBMT Lymphoma Working Party, Barcelona, October 2013 The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
Objectives To assess the safety and efficacy of (intended?) auto- and allohsct for B cell lymphoma for after previous exposure to MTD To assess the safety and efficacy of MTD if used for prophylactic, preemptive or therapeutic application following auto- or allohsct The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
GVL vs GVHD in CLL: Conclusions - GVL effects do exist - GVL effects are mostly durable - Can we have GVL w/o GVHD: not yet - Pre-emptive immune intervention: Improves disease control w/o affecting NRM or QOL? - Perspectives New drugs will re-shape the stage for HSCT in CLL and B cell lymphoma??
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 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!