Infections in non-myeloablativeInfections in non-myeloablative« Reduced intensity conditioning »« Reduced intensity conditioning »

stem cell transplantstem cell transplant

Catherine CORDONNIERCatherine CORDONNIER

Hôpital Henri Mondor, Créteil, FranceHôpital Henri Mondor, Créteil, France

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Reduced intensity conditioning SCTReduced intensity conditioning SCT

OBJECTIVES: OBJECTIVES:

-> Reduce the early toxicity of allogeneic SCT-> Reduce the early toxicity of allogeneic SCT

-> Keep the Graft-versus-leukemia effect-> Keep the Graft-versus-leukemia effect

Mainly proposed to:Mainly proposed to:

- older patients (> 55 y)- older patients (> 55 y)

- patients with comorbidity- patients with comorbidity Reduces the duration of neutropeniaReduces the duration of neutropenia Reduces mucosal and liver toxicityReduces mucosal and liver toxicity Does not solve the problem of GVHDDoes not solve the problem of GVHD

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Example of a RIC / non myelo-ablative regimenImmunesuppression vs Myelosuppression

Fludarabine: 30 mg/sq./d

Cyclosporine

Mycophenolate Mofetil

TBI 2 GyPB SCT

Chimerism Analyses

-3

56

0

28 84

-2 -1-4

From Niederwieser et al. 2003

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RIC: Different preparative regimensRIC: Different preparative regimensfrom Kassim AA et al. BMT 2005from Kassim AA et al. BMT 2005

MyeloAblative

MOderate intensity

MInimal intensity

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RIC reduces the Transplant (non relapse) Related Mortality RIC reduces the Transplant (non relapse) Related Mortality after Allogeneic SCT – Results of historical comparisonsafter Allogeneic SCT – Results of historical comparisons

AuthorAuthor RIC vs MARIC vs MA DiseaseDisease TRM 3 moTRM 3 mo TRM 1 yTRM 1 y

Sorror 2004Sorror 2004 60 / 7460 / 74 variousvarious 12% vs 18% 12% vs 18% p=.07p=.07

20% vs 32%20% vs 32%

p=.04p=.04

Diaconescu 2004Diaconescu 2004 73 / 7373 / 73 variousvarious 3% vs 23%3% vs 23%

p=.001p=.001

16% vs 30% 16% vs 30% p=.04p=.04

Alyea 2004Alyea 2004 71 / 8171 / 81 variousvarious 32% vs 50%32% vs 50%

P=.01P=.01

Kojima 2005Kojima 2005 70 / 13770 / 137 variousvarious 7% vs 15%7% vs 15% 22% vs 32%22% vs 32%

p=.28p=.28

Scott 2006Scott 2006 38 / 11238 / 112 AML/MDSAML/MDS TRM 3 y : 41% vs 34% TRM 3 y : 41% vs 34% p=.94p=.94

BUT TRENDS FOR HIGHER RELAPSE RATES IN MANY DISEASES

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Immune reconstitution after RIC (1)Immune reconstitution after RIC (1)NeutropeniaNeutropenia

After Fluda-TBI 2Gy in AMLAfter Fluda-TBI 2Gy in AML (Hegenbart JCO 2006):(Hegenbart JCO 2006):

No neutropenia at all (PMN > 500/µL):No neutropenia at all (PMN > 500/µL): 27%27%

Median nadir of PMN:Median nadir of PMN: 216/µL216/µL

Median No. Days with PMN<500/µL:Median No. Days with PMN<500/µL: 6 days6 days

Other RIC regimensOther RIC regimens::

VariableVariable

Never as deep and long as in MA regimensNever as deep and long as in MA regimens

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Immune reconstitution after RIC (1)Immune reconstitution after RIC (1)T and B cell PopulationsT and B cell Populations

Few comparative data with conventional transplantsFew comparative data with conventional transplants

CD4: better recovery in RIC vs MACD4: better recovery in RIC vs MA (Jimenez 2005)(Jimenez 2005)

slow recovery in RICslow recovery in RIC (Larosa 2005)(Larosa 2005)

TRECs: better recovery at 6 months in RIC vs MATRECs: better recovery at 6 months in RIC vs MA (Jimenez 2005)(Jimenez 2005)

B cells: slower recovery after RIC vs MAB cells: slower recovery after RIC vs MA (Schulenburg 2005)(Schulenburg 2005)

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EBV-specific immune reconstitution is delayed EBV-specific immune reconstitution is delayed after RICafter RIC

(Chakrabarti et al. Blood 2003)(Chakrabarti et al. Blood 2003)

Recovery of circulating antigen-specific T-cell immunity to EBV Recovery of circulating antigen-specific T-cell immunity to EBV

determined by ELIspot assays / controlsdetermined by ELIspot assays / controls

3 mo3 mo 6 mo6 mo 12 mo12 mo

After MA SCTAfter MA SCT 3/63/6 6/96/9 12/1212/12

After RICAfter RIC -- 1/91/9 7/107/10

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Reduced Intensity Conditioning Regimens Reduced Intensity Conditioning Regimens and Infections (1)and Infections (1)

Many contradictory reports at the beginningMany contradictory reports at the beginning« High rate of secondary viral and bacterial infections in patients « High rate of secondary viral and bacterial infections in patients

undergoing allogeneic bone-marrow mini-transplantation »undergoing allogeneic bone-marrow mini-transplantation »(Mohty et al. BMT 2000)(Mohty et al. BMT 2000)

« Reduced-intensity conditioning reduces the risk of severe infections « Reduced-intensity conditioning reduces the risk of severe infections

after allogeneic peripheral blood stem cell transplantation »after allogeneic peripheral blood stem cell transplantation »(Martino et al. BMT 2001)(Martino et al. BMT 2001)

« High rate of invasive fungal infections following nonmyeloablative « High rate of invasive fungal infections following nonmyeloablative

allogeneic transplantation » allogeneic transplantation » (Hagen et al. CID 2003)(Hagen et al. CID 2003)

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Reduced Intensity Conditioning Regimens Reduced Intensity Conditioning Regimens and Infections (2)and Infections (2)

No prospective study between RIC and standard SCT No prospective study between RIC and standard SCT sofar publishedsofar published

Only retrospective, case control studies, with bias of Only retrospective, case control studies, with bias of selection:selection:

- Age- Age

- Contraindication for standard conditioning- Contraindication for standard conditioning

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Fungal and Aspergillus infections Fungal and Aspergillus infections Historical comparison between RIC and Conventional SCTHistorical comparison between RIC and Conventional SCT

AuthorAuthor

No. No.

RIC SCTRIC SCT % with IFI% with IFI

% with % with AspAsp

No.No.

ConventConvent

SCTSCT

% with IFI% with IFI

% with % with AspAsp

Martino 2001Martino 2001 7171 11%11% 5%5% 123123 14%14% 8%8%

Junghanss 2002Junghanss 2002 5656 -- 15%15% 112112 -- 9%9%

Fukuda 2003Fukuda 2003 163163 19%19% 14%14% 16731673 -- 10%10%

Kojima 2004Kojima 2004 178178 -- 8.2%8.2% 486486 -- 4.5%4.5%

Sorror 2004Sorror 2004 6060 12%12% -- 7474 14%14% --

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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

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Risk factors, timing, and mortality of aspergillosis Risk factors, timing, and mortality of aspergillosis after RIC vs conventional SCTafter RIC vs conventional SCT

Daly 2003, Fukuda 2004, Kojima 2004Daly 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

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Should a RIC be prefered in case of previous Should a RIC be prefered in case of previous severe infection?severe infection?

To be taken in consideration: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- risk of infection relapse Previous bacterial infection:Previous bacterial infection:

- No if cured, without persistent focus- No if cured, without persistent focus

Current bacterial infection:Current bacterial infection:

- Probably Yes is transplant is urgent, and the infectious - Probably Yes is transplant is urgent, and the infectious situation is uncontrolledsituation is uncontrolled

Previous Fungal infection ?Previous Fungal infection ?

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Allogeneic SCT and previous Invasive Allogeneic SCT and previous Invasive aspergillosisaspergillosis

Risk of IA relapse estimated at # Risk of IA relapse estimated at # 30%30%

(Nosary 1994, Cowie 1994, Martino 1997, Offner 1998, Cornelly 2002, Fukuda 2004)(Nosary 1994, Cowie 1994, Martino 1997, Offner 1998, Cornelly 2002, Fukuda 2004)

Probable protective effect of Probable protective effect of RICRIC, no TBI, secondary prophylaxis, , no TBI, secondary prophylaxis,

>> 1 mo of AF therapy, and resolution of imaging before transplant 1 mo of AF therapy, and resolution of imaging before transplant(Offner 1998, Fukuda 2004)(Offner 1998, Fukuda 2004)

Parody et al, EBMT 2006Parody et al, EBMT 2006: Retrospective survey from 23 centers on : Retrospective survey from 23 centers on

pts transplanted with previous proven or probable IA pts transplanted with previous proven or probable IA

129 pts : 57 RIC and 72 MA129 pts : 57 RIC and 72 MA

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Progression of IA Progression of IA before Day 30before Day 30 of an allogeneic of an allogeneic SCT in patients with previous IA SCT in patients with previous IA

(Parody et al. EBMT 2006)(Parody et al. EBMT 2006)

RISK FACTORS Univariate P Multivariate P

Conventional vs RIC 0.02 

0.06HR 2.5 (0.9-3.1)

Time of neutropenia (every 5 day period) <0.001 NT

 < 6 weeks between Dg of IA and AlloHSCT

0.04 NT

≥ 2 post-HSCT serum positive GM ( ≥ .8) No Yes Not done

0.03  

2/43 (5%)11/24(46%)14/62(23%)

NT 

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Days after transplant3020100

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]

Inci

den

ce o

f p

rogr

essi

on o

f IA

< +

30d

P=0.06

Parody et al. EBMT 2006

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Progression of IA Progression of IA after Day 30after Day 30 of an allogeneic SCT in of an allogeneic SCT in patients with previous IA patients with previous IA (Parody et al. EBMT 2006)(Parody et al. EBMT 2006)

RISK FACTORS Univariate P Multivariate P

BMT/CBT vs PBSCT 

<0.0001 0.001HR 98(9-990)

aGVHD ≥ 2 (high-dose steroids > 7ds &/or ATG) 

0.01 0.04HR 100(3.7-2900)

CMV disease 

0.0001 0.01HR 4.2(1.4-17)

Advanced disease status 0.0008 NT

Duration of neutropenia (every 5 day)

0.02 NT

< 6 w between IA-SCT 0.06 0.1

Response status of IA at SCT

0.04 Not included

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CMV infection and diseaseCMV infection and diseaseRetrospective comparisons between RIC and Retrospective comparisons between RIC and

myeloablative transplantsmyeloablative transplants

AuthorAuthor No. PtsNo. Pts

RIC / MARIC / MA

Mean ageMean age

RIC / MARIC / MA

CMV InfCMV Inf CMV diseaseCMV disease

Martino 2001Martino 2001 71 / 12371 / 123 54 / 3854 / 38 21% vs 39%21% vs 39%

p=.03p=.03

1% vs 9.5%1% vs 9.5%

p=.05p=.05

Junghanss Junghanss 20022002

34 / 6834 / 68 54 / 4654 / 46 (Ag) 53% vs 69% (Ag) 53% vs 69% (ns)(ns)

6% vs 19% 6% vs 19%

(ns)(ns)

Sorror 2004Sorror 2004 60 / 7460 / 74 54 / 4154 / 41 45% vs 35%45% vs 35%

nsns

Norasetthada Norasetthada ASH 2005ASH 2005

342 / 2154342 / 2154 53 / 4053 / 40 49% vs 55%49% vs 55%

(ns)(ns)

« High grade Inf»« High grade Inf»

12% vs 23%12% vs 23%

(ns)(ns)

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CMV infection and disease in R+ patients CMV infection and disease in R+ patients

Comparison RIC (n = 34) vs MA (n=68)Comparison RIC (n = 34) vs MA (n=68)Junghanss, C. et al. Blood 2002

CMV Ag « tends » to be less frequent in RICCMV Ag « tends » to be less frequent in RIC

(53% vs 69%; p = .11)(53% vs 69%; p = .11)

CMV viremia « tends » to be less frequentCMV viremia « tends » to be less frequent

(3% vs 13%; p=.16)(3% vs 13%; p=.16) and to occur later and to occur later

(d60 vs d43; p=.40)(d60 vs d43; p=.40) in RIC in RIC

CMV disease « tends » to be less frequentCMV disease « tends » to be less frequent

(6% vs 19%; p=.08)(6% vs 19%; p=.08) and to occur later and to occur later

(d85 vs d36;p=.04)(d85 vs d36;p=.04)

BUT ! Finally at 1 year:BUT ! Finally at 1 year:

No difference in the incidence of CMV combined No difference in the incidence of CMV combined manifestations manifestations

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Infections after RIC transplantsInfections after RIC transplants Conclusion Conclusion

- No prospective comparative studies sofar, but….No prospective comparative studies sofar, but….

- A clear trend for less early bacterial infectionsA clear trend for less early bacterial infections

- Comparable incidences of IFI, a trend for less in RICComparable incidences of IFI, a trend for less in RIC

- A likely protective effect of RIC in case of previous IAA likely protective effect of RIC in case of previous IA

- Comparable incidences of CMV infection and diseaseComparable incidences of CMV infection and disease

- Delayed occurrence of fungal and viral infectionsDelayed occurrence of fungal and viral infections

- No data on late infectionsNo data on late infections