1. Infections in non-myeloablative « Reduced intensity conditioning » stem cell transplant Catherine CORDONNIER Hôpital Henri Mondor, Créteil, France

2. 2 Reduced intensity conditioning SCT OBJECTIVES: -> Reduce the early toxicity of allogeneic SCT -> Keep the Graft-versus-leukemia effect n Mainly proposed to: - older patients (> 55 y) - patients with comorbidity n Reduces the duration of neutropenia n Reduces mucosal and liver toxicity n Does not solve the problem of GVHD

3. 3 Example of a RIC / non myelo-ablative regimen Immunesuppression vs Myelosuppression Fludarabine: 30 mg/sq./d Cyclosporine Mycophenolate Mofetil TBI 2 Gy PB SCT Chimerism Analyses -3 56 0 2884 -2 -4 From Niederwieser et al. 2003

4. 4 RIC: Different preparative regimens from Kassim AA et al. BMT 2005 MyeloAblative MOderate intensity MInimal intensity

5. 5 RIC reduces the Transplant (non relapse) Related Mortality after Allogeneic SCT – Results of historical comparisons Author RIC vs MA Disease TRM 3 mo TRM 1 y Sorror 2004 60 / 74 various 12% vs 18% p=.07 20% vs 32% p=.04 Diaconescu 2004 73 / 73 various 3% vs 23% p=.001 16% vs 30% p=.04 Alyea 2004 71 / 81 various 32% vs 50% P=.01 Kojima 2005 70 / 137 various 7% vs 15% 22% vs 32% p=.28 Scott 2006 38 / 112 AML/MDS TRM 3 y : 41% vs 34% p=.94 BUT TRENDS FOR HIGHER RELAPSE RATES IN MANY DISEASES

6. 6 Immune reconstitution after RIC (1) Neutropenia After Fluda-TBI 2Gy in AML (Hegenbart JCO 2006): No neutropenia at all (PMN > 500/µL):27% Median nadir of PMN:216/µL Median No. Days with PMN<500/µL:6 days Other RIC regimens: Variable Never as deep and long as in MA regimens

7. 7 Immune reconstitution after RIC (1) T and B cell Populations n Few comparative data with conventional transplants n CD4: better recovery in RIC vs MA (Jimenez 2005) slow recovery in RIC (Larosa 2005) slow recovery in RIC (Larosa 2005) n TRECs: better recovery at 6 months in RIC vs MA (Jimenez 2005) n B cells: slower recovery after RIC vs MA (Schulenburg 2005)

8. 8 EBV-specific immune reconstitution is delayed after RIC (Chakrabarti et al. Blood 2003) Recovery of circulating antigen-specific T-cell immunity to EBV determined by ELIspot assays / controls 3 mo 6 mo 12 mo After MA SCT 3/66/912/12 After RIC -1/97/10

9. 9 Reduced Intensity Conditioning Regimens and Infections (1) Many contradictory reports at the beginning « High rate of secondary viral and bacterial infections in patients undergoing allogeneic bone-marrow mini-transplantation » (Mohty et al. BMT 2000) « Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation » (Martino et al. BMT 2001) « High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation » (Hagen et al. CID 2003)

10. 10 Reduced Intensity Conditioning Regimens and Infections (2) n No prospective study between RIC and standard SCT sofar published n Only retrospective, case control studies, with bias of selection: - Age - Contraindication for standard conditioning

11. 11 Fungal and Aspergillus infections Historical comparison between RIC and Conventional SCT AuthorNo. RIC SCT % with IFI % with Asp No.ConventSCT % with IFI % with Asp Martino 2001 7111%5%12314%8% Junghanss 2002 56-15%112-9% Fukuda 2003 16319%14%1673-10% Kojima 2004 178-8.2%486-4.5% Sorror 2004 6012%-7414%-

12. 12 Comparison of invasive fungal infection after nonmyeloablative and myeloablative HCT (1993-1998) Fukuda, T. et al. Blood 2003;102:827-833 N=163 N=1673 ns N=163 All IFI Aspergillosis

13. 13 Risk factors, timing, and mortality of aspergillosis after RIC vs conventional SCT Daly 2003, Fukuda 2004, Kojima 2004 Aspergillosis occurs LATER after RIC (d120 vs d90) Case FATALITY rates are comparable RISK FACTORS are comparable: age > 50 y acute/chronic GVHD CMV Aspergillosis is the first cause of non-relapse (or infectious) mortality ALSO after RIC

14. 14 Should a RIC be prefered in case of previous severe infection? n To be taken in consideration: - underlying disease: risk to go to RIC vs MA - underlying disease: risk to go to RIC vs MA - risk of infection relapse n Previous bacterial infection: - No if cured, without persistent focus - No if cured, without persistent focus n Current bacterial infection: - Probably Yes is transplant is urgent, and the infectious situation is uncontrolled n Previous Fungal infection ?

15. 15 Allogeneic SCT and previous Invasive aspergillosis n Risk of IA relapse estimated at # 30% (Nosary 1994, Cowie 1994, Martino 1997, Offner 1998, Cornelly 2002, Fukuda 2004) n Probable protective effect of RIC, no TBI, secondary prophylaxis, > 1 mo of AF therapy, and resolution of imaging before transplant (Offner 1998, Fukuda 2004) n Parody et al, EBMT 2006: Retrospective survey from 23 centers on pts transplanted with previous proven or probable IA 129 pts : 57 RIC and 72 MA 129 pts : 57 RIC and 72 MA

16. 16 Progression of IA before Day 30 of an allogeneic SCT in patients with previous IA (Parody et al. EBMT 2006) RISK FACTORSUnivariate PMultivariate P Conventional vs RIC0.02 0.06 HR 2.5 (0.9-3.1) Time of neutropenia (every 5 day period)<0.001NT < 6 weeks between Dg of IA and AlloHSCT 0.04NT 2 post-HSCT serum positive GM (.8) No Yes Not done 0.03 2/43 (5%) 11/24(46%) 14/62(23%) NT

17. 17 Days after transplant 3020100 20 15 10 5 0 RIC (4 / 57) CONV (9 / 72) Progression of IA BEFORE day 30 in recipients of a RIC or a conventional myeloablative regimen (CONV) [n=13 cases] Incidence of progression of IA < +30d P=0.06 Parody et al. EBMT 2006

18. 18 Progression of IA after Day 30 of an allogeneic SCT in patients with previous IA (Parody et al. EBMT 2006) RISK FACTORSUnivariate PMultivariate P BMT/CBT vs PBSCT <0.00010.001 HR 98(9-990) aGVHD 2 (high-dose steroids > 7ds &/or ATG) 0.010.04 HR 100(3.7-2900) CMV disease 0.00010.01 HR 4.2(1.4-17) Advanced disease status 0.0008 NT Duration of neutropenia (every 5 day) 0.02NT < 6 w between IA-SCT0.060.1 Response status of IA at SCT 0.04Not included

19. 19 CMV infection and disease Retrospective comparisons between RIC and myeloablative transplants Author No. Pts RIC / MA Mean age RIC / MA CMV Inf CMV disease Martino 2001 71 / 123 54 / 38 21% vs 39% p=.03 1% vs 9.5% p=.05 Junghanss 2002 34 / 68 54 / 46 (Ag) 53% vs 69% (ns) 6% vs 19% (ns) Sorror 2004 60 / 74 54 / 41 45% vs 35% ns Norasetthada ASH 2005 342 / 2154 53 / 40 49% vs 55% (ns) « High grade Inf» 12% vs 23% (ns)

20. 20 CMV infection and disease in R+ patients Comparison RIC (n = 34) vs MA (n=68) Junghanss, C. et al. Blood 2002 CMV Ag « tends » to be less frequent in RIC (53% vs 69%; p =.11) CMV viremia « tends » to be less frequent (3% vs 13%; p=.16) and to occur later (d60 vs d43; p=.40) in RIC CMV disease « tends » to be less frequent (6% vs 19%; p=.08) and to occur later (d85 vs d36;p=.04) BUT ! Finally at 1 year: No difference in the incidence of CMV combined manifestations

21. 21 Infections after RIC transplants Conclusion - No prospective comparative studies sofar, but…. - A clear trend for less early bacterial infections - Comparable incidences of IFI, a trend for less in RIC - A likely protective effect of RIC in case of previous IA - Comparable incidences of CMV infection and disease - Delayed occurrence of fungal and viral infections - No data on late infections