Download Prophylaxis of CMV infection and disease

Prophylaxis with oral valganciclovir
or intravenous ganciclovir to prevent
cytomegalovirus infection and
disease after umbilical cord blood
transplantation
Pau Montesinos, Jaime Sanz, Susana Cantero, Ignacio Lorenzo,
Guillermo Martín, Silvana Saavedra, Javier Palau, Mónica Romero,
Alberto Montava, Leonor Senent, Jesús Martínez, Isidro Jarque,
Miguel Salavert, Juan Córdoba, Lola Gómez, Shirley Weiss,
Federico Moscardó, Javier de la Rubia, Luis Larrea, Miguel A. Sanz
and Guillermo F. Sanz
Sesión monográfica, 6 Nov 2008
Backgound (1)
• CMV = major cause of therapeutic failure after allo-SCT.
• Major advances in the prevention and treatment of CMV
disease after allo-SCT:
• Ganciclovir, a potent anti-cytomegalovirus (CMV) agent.
• Rapid initiation of treatment based on detection assays, such as DNA
polymerase chain reaction (PCR) or pp65 antigenemia (pp65 Ag)
• However, CMV infection and disease remain a significant
cause of morbidity and mortality.
• UCBT = subset with a high risk of CMV infection and disease
 poor immune reconstitution
• The incidence and outcome of, and risk factors for, CMV
infection and disease after UCBT have been scarcely
addressed
Backgound (2)
• Risk factors for CMV = patient’s and donor’s CMV serological
status, unrelated donor, GVHD, T cell depletion  allowing
risk-adapted strategies.
• Strategies in high-risk patients include:
• Preemptive therapy with IV ganciclovir as soon as CMV+ in the blood;
• IV ganciclovir prophylaxis initiated (form engraftment until day +100.
• Randomized study comparing both preventive strategies:
• a lower incidence of CMV infection and a similar incidence of disease and
survival
• a higher incidence of neutropenia and fungal and bacterial infections in
patients under prophylaxis
• Preemptive therapy with ganciclovir = most frequently used
after allo-SCT. Prophylaxis in patients with a very high risk?
(such as CMV-seropositive UCBT).
Backgound (3)
• Valganciclovir = oral prodrug of ganciclovir with excellent
bioavailability
• Similar efficacy to IV ganciclovir for prophylaxis of CMV
infection in organ-solid transplant recipients.
• Early studies also showed a similar efficacy to IV ganciclovir
as preemptive therapy in allo-SCT
• Oral valganciclovir  potential to replace IV ganciclovir:
• making outpatient care possible, which should provide more comfort
for the patient and reduce the use of hospital resources.
• especially valuable when prophylaxis for CMV infection and disease is
considered.
• No information on the efficacy and safety of valganciclovir as
prophylaxis after allo-SCT.
Objectives
• Evaluate and compare the efficacy, toxicity, and
hospital resource use of prophylaxis of CMV
infection and disease with IV ganciclovir or oral
valganciclovir in two consecutive cohorts of CMVseropositive adult patients undergoing UCBT at a
single center.
• Assess the rates of CMV infection and disease in
the group of CMV-seronegative patients, in whom
prophylaxis comprised low-dose acyclovir.
• Analyze the characteristics, outcome, and risk
factors for CMV infection and disease.
Patients and Transplant
Charactheristics
• From May 1997 to January 2008, 143 adults UCBT
• Median age and weight were 31 years (range, 15–62
years) and 70 kg (range, 34–112), respectively.
• Underlying diseases: ALL (33%), AML (31%), others.
• Early disease stages in 65% of patients.
• HLA matching: 6/6 in 9 patients, 5/6 in 53, and 4/6 in 81.
• Median number of nucleated, CD34+, and CD3+ cells
infused were: 2.26  107/kg recipient’s body weight, 1.18 
105/kg, and 0.55  107/kg.
Preparative regimens and GVHD
prophylaxis
• BUCYTT and ATG in 72 patients (50%) (29 horse ATG
(Lymphoglobulin®) and 40 rabbit ATG (Thymoglobulin®).
• BUFLUTT and Thymoglobulin in 61 other patients (43%).
• A reduced-intensity conditioning regimen was used in the
remaining 10 patients (FLU, CY, and Thymoglobulin with or
without TT in nine patients, and FLU, TT and Lymphoglobulin in one
patient).
• Acute GVHD prophylaxis = CsA+PDN (87%) and
CsA+MMF (13%).
Risk stratification
• CMV serology from the mother or cord blood unit
(CBU) and the recipient were assessed before
UCBT.
• None of the CBU or mothers was positive for IgM
antibody to CMV.
• The CBU was considered CMV seronegative
regardless of the serostatus of the mother.
•  risk stratification for CMV infection and disease
was based only on the patient’s CMV serostatus.
Monitoring and diagnosis of CMV
• In CMV-seronegative (low-risk) patients: no CMV
monitoring.
• In CMV-seropositive (high-risk) patients: PB samples twice
weekly from +7 to +100, every 15 days until +180, monthly
until +365, and weekly for patients taking more than 15 mg
daily of prednisone for chronic GVHD.
• pp65 Ag in PB leukocytes in the first 63 CMV-seropositive
patients (56%), and plasma quantitative LC-PCR in the
next 49 patients (44%).
• Diagnosis of CMV infection = pp65 Ag assay (> 1 infected
cell of 50,000 cells) or PCR (> 500 CMV DNA copies).
• Diagnosis of CMV disease = standard clinical and
microbiological criteria.
Prophylaxis of CMV infection and disease
•
31 CMV-seronegative patients (22%)  IV acyclovir (250 mg/m2 twice
daily) from–5 until +30, followed by oral acyclovir (400 mg three times
daily) until +100.
•
CMV-seropositive patients  intravenous ganciclovir (first cohort) or
oral valganciclovir (second cohort).
•
First cohort of 38 CMV-seropositive patients (27%) IV acyclovir (500
mg/m2 three times daily) from day –5 until engraftment, followed until
day +100 by IV ganciclovir (5 mg/kg daily from Monday to Friday) and
oral acyclovir (800 mg three times daily on weekend).
•
From October 2003, the second cohort of 74 CMV-seropositive
patients (52%)  prophylaxis with IV acyclovir followed by oral
valganciclovir (900 mg once daily) until day +120-180.
G-CSF to maintain neutrophil count above 1.2  109/L.
All patients IgIV (0.5 g/kg weekly through day +100 and then monthly
until +365).
•
•
•
All transfused products were irradiated and depleted of leukocytes but
were not tested for CMV.
Treatment of CMV infection and disease
•
IV ganciclovir 5 mg/kg twice daily or oral valganciclovir 900 mg twice
daily.
•
Foscarnet 90 mg/kg twice daily was used if severe neutropenia.
•
For 14–21 days after the first of two consecutive negative tests of PB.
•
Maintenance (every 24 hours) for 14–21 days or until the completion of
the originally scheduled prophylaxis.
•
When CMV disease (suspected or diagnosed)  IgIV (every 48 hours)
until resolution of symptoms.
•
Ganciclovir and valganciclovir were discontinued temporarily and
substituted with foscarnet in patients with a neutrophil count < 0.5–1 
109/L despite the administration of G-CSF.
•
If renal failure, ganciclovir and valganciclovir were reduced to 50%
(clearance < 70 mL/min) or to 25% (clearance < 50 mL/min).
•
Second-line with foscarnet was generally started in case of persistence of
CMV positive tests in PB after 3-4 weeks of first-line antiviral therapy, or
in case of non-responding/progressing CMV disease.
Incidence and time of diagnosis of CMV infection
and disease
•
CMV infection occurred at a median of 45 days (range, 14–239).
•
CMV disease occurred at a median of 183 days (range, 65–355).
•
Second recurrent CMV infection at a median of 156 days (range, 64–
338).
Cumulative Incidence of CMV infection
1
P < 0.001
0,8
CMV-seropositive recipients
0,6
0,4
CMV-seronegative recipients
0,2
0
0
30
60
90
120
150
180
210
Days after UCBT
240
270
300
330
360
Sites of CMV disease
• 13 CMV disease: 7 under ganciclovir prophylaxis, 4
patients under valganciclovir prophylaxis, and 2
CMV-seronegative under acyclovir prophylaxis.
• Gastrointestinal in 6 patients, pneumonia in 5,
retinitis in 1, and pancytopenia and fever in 1.
• 2 gastrointestinal disease without detectable CMV
PCR or pp65 Ag in PB.
• 5 recurrent CMV disease: 3 pneumonia, 1
gastrointestinal, 1 retinitis.
• 2 patients died from CMV disease (pneumonia).
Prognostic factors and efficacy of prophylaxis
Prognostic factors and efficacy of prophylaxis
Cumulative Incidence of CMV infection
1
P = 0.52
0,8
Intravenous ganciclovir
0,6
0,4
Oral valganciclovir
0,2
0
0
30
60
90
120
150
180
210
Days after UCBT
240
270
300
330
360
Multivariate analyses
• CMV infection and disease in the entire cohort:
CMV serostatus of the recipient for infection (hazard ratio
[HR], 6.26;P < 0.001).
No factor was associated clearly with CMV disease.
• CMV infection and disease in CMV-seropositive:
Grade III–IV acute GVHD for infection (HR, 2.45;P =
0.02).
CMV monitoring by pp65 Ag for CMV disease (HR, 8.35;
P = 0.008).
Toxicity
• Less frequent in the group of ganciclovir compared with
valganciclovir, but not significant (3% vs 8%, P = 0.48).
• Ganciclovir group, one patient required dose adjustment due
to renal toxicity.
• Valganciclovir group, six patients switched to foscarnet
because of neutropenia. 5 patients (7%) switched to
ganciclovir prophylaxis because of the impossibility of oral
intake.
• None developed secondary graft failure after starting
valganciclovir or ganciclovir.
Efficacy of preemptive therapy
Use of hospital resources
CI of infection-related mortality
1
P = 0.62
0,8
0,6
CMV-seropositive recipients
0,4
0,2
CMV-seronegative recipients
0
0
60
120
180
240
300
360
420
Days after UCBT
480
540
600
660
720
CI of infection-related mortality
1
P = 0.46
0,8
0,6
Intravenous ganciclovir
0,4
0,2
Oral valganciclovir
0
0
60
120
180
240
300
360
420
Days after UCBT
480
540
600
660
720
Conclusions
• Prophylaxis with oral valganciclovir is as
effective as intravenous ganciclovir for
reducing the incidence of CMV infection and
disease in CMV-seropositive recipients of
UCBT.
• Oral valganciclovir has an acceptable
toxicity profile and leads to a significant
reduction of the use of hospital resources
when
compared
with
intravenous
ganciclovir.