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Strategies for CMV management in haematopoietic stemcell transplant patients

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Important topics in the management of CMV after stem-cell transplant (SCT) ... Nichols WG et al. J Infect Dis 2002;185:273 282. (see notes) Slide No. Slide 6 ... – PowerPoint PPT presentation

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Title: Strategies for CMV management in haematopoietic stemcell transplant patients


1
Strategies for CMV management in haematopoietic
stem-cell transplant patients
  • Per LjungmanProfessor of HaematologyHuddinge
    University HospitalKarolinska InstitutetStockhol
    m, Sweden

2
Important topics in the management of CMV after
stem-cell transplant (SCT)
  • To understand the risk factors for CMV disease
  • To prevent CMV infection and disease
  • Early after SCT
  • Late after SCT
  • To treat established CMV disease

(see notes)
3
Risk factors for CMV disease
  • Pre-transplant factors
  • Patients CMV serological status
  • Donors CMV serological status
  • Type of transplant performed (allogeneic,
    autologous, with reduced conditioning)
  • Type of stem-cell donor (sibling, unrelated,
    haplo-identical)
  • Post-transplant factors
  • CMV viraemia
  • Poor immune reconstitution to CMV
    (graft-versus-host disease)

(see notes)
4
Influence of the donors and recipients CMV
serological status
Ljungman P et al. Transplantation
19986613301334.
(see notes)
5
Influence of donor seropositivity in CMV
seronegative patients
  • CMV CMV
  • Cause of death donor donor
  • Septicaemia 6.9 3.7 P0.037
  • Aspergillosis 8.0 3.5 P0.004
  • All invasive moulds 8.8 4.0 P0.004
  • All bacterial/fungal 18.3 9.7 Plt0.001
  • CMV 0.4 0.2 Pns
  • All deaths 48.0 39.0 P0.02

ns, not significant. Nichols WG et al. J Infect
Dis 2002185273282.
(see notes)
6
Donor influence in CMV-seropositive patients
  • No effect in HLA-identical sibling transplants
  • Unrelated donors
  • 5-year overall survival estimates (KM)
  • 36 CMV donor
  • 28 CMV donor P0.006
  • Transplant-related mortality
  • 39 CMV donor P0.006
  • 52 CMV donor

(see notes)
Ljungman et al. ASH 2001.
7
Why would use of a CMV-seropositive donor reduce
mortality?
  • Patients receiving CMV-seropositive grafts less
    likely to die from infections
  • 22.9 versus 27.6 (P0.07)
  • However, not specifically from viral infections
  • 9.7 versus 12.5 (P0.15)
  • Effect mediated through donor T cells
    protective effect not found in T-cell depleted
    grafts

(see notes)
Ljungman et al. ASH 2001.
8
Effect of donor type on mortality in CMV
Risk for death in CMV disease
0.1
Mismatched or unrelated donors
HLA-identical sibling donors
0
0
100
200
300
400
500
600
700
Days after SCT
Ljungman P et al. Transplantation
19986613301334.
(see notes)
9
CMV in non-myeloablative SCT
(see notes)
10
Autologous SCT
  • Patients undergoing autologous SCT generally have
    a lower risk of CMV disease than allogeneic
    patients
  • However, some regimens/procedures might increase
    the risk for CMV disease
  • Holmberg LA et al. Blood 19999440294035.
  • The prognosis for established CMV disease is poor
  • Ljungman P et al. BMT 199413209212.

(see notes)
11
Prevention of primary CMV infection
  • CMV-seronegative marrow donors
  • Bowden RA et al. N Engl J Med 198631410061010.
  • Screened CMV-seronegative blood products
  • Bowden RA et al. N Engl J Med 198631410061010.
  • Filtered blood products
  • Bowden RA et al. Blood 19958635983603.
    Ljungman P et al. Scand J Infect Dis
    200234347350.
  • Immunoglobulin?
  • Bowden RA et al. J Infect Dis 1991,164483487.
  • Ruutu T et al. BMT 199719233236.

(see notes)
12
Screened or filtered blood products
  • Filtered Screened
  • CMV infection 2.4 Pns, 1.3
  • CMV disease d 21-100 2.4 Pns, 0
  • CMV disease d 0-100 2.4 P0.03, 0

ns, not significant. Bowden RA et al. Blood
19958635983603.
(see notes)
13
Leukocyte-depleted (LD) versus CMV negative and
LD blood products
  • Non-randomized study using sequential cohorts
  • No patient in either arm developed CMV disease
  • 3 of 33 (10.4) patients in the combination group
    became CMV (using polymerase chain reaction
    PCR)
  • Pns
  • 6 of 48 (12.5) patients in the LD group became
    PCR

ns, not significant. Ljungman P et al. Scand J
Infect Dis 200234347350.
(see notes)
14
Strategies for prevention of CMV
reactivation/disease
  • Treat all patients universal prophylaxis
  • Treat selected patient populations
  • Pre-emptive strategies
  • Prophylaxis for high-risk patients
  • Use combination strategies

(see notes)
15
Treat all patients
  • Use of immunoglobulin
  • Use of prophylactic antiviral agents
  • Low potency
  • Aciclovir
  • Valaciclovir
  • High potency
  • Ganciclovir
  • Foscarnet

(see notes)
16
Immunoglobulins
  • Immunoglobulins are safe but expensive
  • Protective effect is modest, at best
  • Studies were performed before modern diagnostic
    techniques available immunoglobulins not
    compared with antiviral chemoprophylaxis
  • Role for immunoglobulin as CMV prophylaxis is now
    very limited

(see notes)
17
Aciclovir/valaciclovir prophylaxis studies in SCT
patients (IV and oral formulations)
  • Aciclovir versus placebo (no pre-emptive therapy
    strategy)
  • Reduced risk of CMV infection and viraemia
  • No difference in CMV disease but reduced
    mortality in CMV
  • Improved survival
  • Prentice HG et al. Lancet 1994343749753.
  • Valaciclovir versus aciclovir (pre-emptive
    therapy given)
  • Reduced CMV infection and viraemia
  • No difference in CMV disease
  • No difference in survival
  • Reduced use of pre-emptive therapy (23 versus
    37 Plt0.001)
  • Ljungman P et al. Blood
    20029930503056.

(see notes)
18
Risks of CMV viraemia with aciclovir versus
valaciclovir prophylaxis
(see notes)
19
IV ganciclovir prophylaxis
  • Two randomized studies found
  • Reduced risk of CMV disease
  • No effect on survival
  • Goodrich JM et al. Ann Intern Med
    1993118173-178
  • Winston DJ et al. Ann Intern Med
    1993118179-184
  • Ganciclovir prophylaxis associated with increased
    risk of late CMV disease
  • Li CR et al. Blood 1994831971-1979.

(see notes)
20
Treat some patients pre-emptive therapy
  • Which patients?
  • Which monitoring method?
  • Which antiviral agent(s)?

(see notes)
21
Diagnostic tests for CMV
  • Shell vial culture Insensitive
  • Antigenaemia (detection of pp65) Semi-quantitative
  • Qualitative PCR for DNA Very sensitive
  • Quantitative PCR for DNA Allows diffentiation
    into risk groups
  • Detection of mRNA (NASBA) Ongoing studies

(see notes)
22
Pre-emptive therapy
Design Test of strategy, any culture Randomized,
IV ganciclovir versus placebo Ganciclovir
Placebo CMV disease d 100 1/37 Plt0.0001
15/35 CMV disease d 180 6/37 P0.01
15/35 Death due to CMV 4/37 P0.03
11/35 Subjects with known CMV disease before
study 12
  • Goodrich GM et al. N Engl J Med
    19913251601-1607.

(see notes)
23
Pre-emptive therapy
  • Design Randomized test of technique IV
    ganciclovir on positive shell vial/rapid culture
    or PCR result
  • PCR Rapid culture
  • CMV disease 5 P 0.02 23
  • CMV-associated death 0 P 0.02 14

Einsele et al. Blood 1995862815-2820.
(see notes)
24
Comparison of CMV preventive strategies in SCT
patients
IV ganciclovir at engraftment 2.7
16.5 16 87 71
Pre-emptive therapy 14.1 8.3
6 84 73
Modified strategy 3.6 13.1
6 83 77
  • CMV disease d 100
  • After d 100
  • Invasive fungal disease
  • Survival d 100
  • Survival d 180

Boeckh M et al. Blood 1996884063-4071. Boeckh
M et al. Blood 1999,931781-1782.
(see notes)
25
Randomized study comparing ganciclovir and
foscarnet
(see notes)
26
How to improve predictions of CMV disease
  • Initial viral load correlates with CMV disease
  • per 0.25 log10 increase in viral load (OR 1.52
    1.13-2.05, P0.006)
  • Rate of increase in CMV load correlates with CMV
    disease
  • 0.33 versus 0.19 log10 genomes/ml daily, Plt0.001

Emery VC et al. Lancet 20003552032-2036.
(see notes)
27
Prevention of late CMV disease in SCT patients
  • The risk of late CMV disease has increased
  • We have started to see new forms retinitis
  • What are the causes of these developments?

(see notes)
28
What causes late CMV disease?
  • Transplant-related factors?
  • Increased number of unrelated or mismatch donor
    transplants
  • Chronic graft-versus-host disease
  • Lymphocytopaenia
  • The common risk factor is lack of a specific
    immune response
  • Drug resistance
  • Relatively infrequent in transplant patients

(see notes)
29
Possible strategies for prevention of late CMV
disease
  • Prolonged monitoring for CMV reactivations and
    repeated pre-emptive therapy
  • Immunological monitoring
  • Adoptive transfer of immunity
  • CMV specific cytotoxic T lymphocytes
  • CMV specific helper T cells

(see notes)
30
Autologous SCT patients
  • Prevention of CMV in seronegative patient
  • Filtered blood products makes sense but no
    data
  • Prevention of CMV in seropositive patients
  • Aciclovir not effective
  • Ganciclovir not tested, indicated?
  • Pre-emptive therapy not tested, indicated?

31
Treatment of CMV pneumonia
  • Published Phase II studies show good results with
    ganciclovir and high-dose intravenous
    immunoglobulin in combination, compared to
    earlier results with either therapy alone
  • This combination was originally regarded as
    standard therapy for CMV pneumonia
  • However, Machado et al. (2001) found no
    differences in outcomes in patients treated
    with ganciclovir with or without immunoglobulin

(see notes)
32
Cidofovir for treatment of CMV pneumonia
30-day survival 87 180-day survival 55
1.0
0.8
Cumulative survival
0.6
0.4
0.2
0.0
0
100
200
300
400
500
600
700
800
900
Days after diagnosis of CMV pneumonia
Ljungman P et al. Blood. 200197388-392.
(see notes)
33
Survival in CMV GI disease
Ljungman P et al. BMT 199821473-476.
34
Summary
  • CMV remains an important complication after
    allogeneic SCT
  • Donor and recipient CMV serostatus are important
    risk factors for CMV disease
  • Both prophylactic and pre-emptive strategies can
    reduce the risk for CMV disease
  • Delayed immune reconstitution increases the risk
    for late-occurring CMV disease
  • Adoptive immunotherapy may become an important
    tool for prevention of CMV disease
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