Title: Strategies for CMV management in haematopoietic stemcell transplant patients
1Strategies for CMV management in haematopoietic
stem-cell transplant patients
- Per LjungmanProfessor of HaematologyHuddinge
University HospitalKarolinska InstitutetStockhol
m, Sweden
2Important 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)
3Risk 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)
4Influence of the donors and recipients CMV
serological status
Ljungman P et al. Transplantation
19986613301334.
(see notes)
5Influence 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)
6Donor 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.
7Why 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.
8Effect 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)
9CMV in non-myeloablative SCT
(see notes)
10Autologous 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)
11Prevention 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)
12Screened 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)
13Leukocyte-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)
14Strategies 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)
15Treat all patients
- Use of immunoglobulin
- Use of prophylactic antiviral agents
- Low potency
- Aciclovir
- Valaciclovir
- High potency
- Ganciclovir
- Foscarnet
(see notes)
16Immunoglobulins
- 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)
17Aciclovir/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)
18Risks of CMV viraemia with aciclovir versus
valaciclovir prophylaxis
(see notes)
19IV 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)
20Treat some patients pre-emptive therapy
- Which patients?
- Which monitoring method?
- Which antiviral agent(s)?
(see notes)
21Diagnostic 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)
22Pre-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)
23Pre-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)
24Comparison 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)
25Randomized study comparing ganciclovir and
foscarnet
(see notes)
26How 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)
27Prevention 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)
28What 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)
29Possible 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)
30Autologous 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?
31Treatment 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)
32Cidofovir 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)
33Survival in CMV GI disease
Ljungman P et al. BMT 199821473-476.
34Summary
- 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