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Features of Epstein-Barr
Virus (EBV) reactivation after reduced intensity
conditioning (RIC) allogeneic
stem cell transplantation (allo-SCT)

Z Peric,1,2 X Cahu, 1 P Chevallier,1 E
Brissot, 1 T Guillaume,1 J Delaunay,1 S Ayari,1 V
Dubruille,1 S Le Gouill,1 B Mahe,1 T Gastinne,1
N Blin,1 B Saulquin,1 N Milpied,1 R Vrhovac, 2
JL Harousseau,1 P Moreau,1 M Coste- Burel,3 BM
Imbert-Marcille,3 and M Mohty 1
1 CHU de Nantes, Hematology
Department, Nantes, France 2 University
Hospital, Hematology Department, Zagreb, Croatia
3 CHU de Nantes, Laboratoire de virology,
Nantes, France
Introduction
Results 2
Discussion
Results
Previous studies reported an EBV reactivation
incidence ranging between 0.6 and 26, even
higher in the context of T-cell depletion and
with mortality rates following development of an
EBV-related LPD between 50 and 80. (1,2) The
current study reports a cumulative incidence of
EBV reactivation of 21 (95 CI, 15-28), but
none of the patient experienced EBV-related LPD
signs or mortality. In this series, the absence
of EBV-related severe complications is likely due
to both strict policy of EBV monitoring during
first months after allo-HSCT and the systematic
use of pre-emptive rituximab in those patients
experiencing a viral load gt1000 copies/105 cells.
In the current series, the response rate to
pre-emptive rituximab appeared to be similar to
that previously reported in the literature(3),
with efficient and sustained control of EBV viral
load in the great majority of cases. In our
series, the incidence of EBV reactivation in the
subgroup of patients receiving ATG was 24 as
compared to 5 in the remaining patients and
showed that the use of ATG as part of the
preparative regimen was the most significant risk
factor for EBV reactivation. This data supports
the well established role of ATG for in-vivo
partial T cell depletion.(4)
Patients' characteristics are summarized in Table
1. In 141 patients (81), the EBV load remained
less than 1000 EBV copies/105 cells at all time,
and none of these patients experienced any sign
or symptom of EBV-related LPD. The remaining 34
patients (19) experienced at least one EBV
viremia episode. The cumulative incidence of EBV
viremia is shown in Figure 1. EBV viremia was
observed at a median of 58 (range 0-930) days
after allo-HSCT, with 79 (n27) of reactivations
occurring during the first 6 months. The highest
viral loads were measured between the 2nd and
12th week after transplantation (Figure 2). Of
note, in 17 of the 34 patients who experienced
EBV reactivation, the EBV load was elevated only
once, and this was not accompanied by any
clinical symptom, and normalized spontaneously.
Most importantly, none of the patients from this
series developed EBV-induced LPD. The 17 patients
who had EBV DNA levels exceeding 1000 copies/105
cells on 2 or more occasions were pre-emptively
treated with a median number of 3 (range, 1-4)
rituximab infusions which resulted in complete
clearance of EBV viremia in all, but one patient
(97). Only the use of ATG as part of the RIC
regimen prior to allo-HSCT was significantly
associated with the risk of EBV reactivation
(P0.007). In the Cox multivariate analysis, the
use of ATG stayed an idepedent risk factor
associated with EBV reactivation (P0.0027).
There was no statistically significant difference
in terms of overall survival (OS) between those
patients who experienced an EBV reactivation
after allo-HSCT and those who did not (p 0.62,
Figure 3).
Following allo-HSCT, EBV viremia and EBV-related
proliferations are well recognized complications.
Established LPD post-allo-HSCT is associated with
significant mortality and morbidity. On the other
hand, early detection strategies with serial
measurement of EBV-DNA load in peripheral blood
samples have helped to identify high-risk
patients and to diagnose early lymphoproliferation
. Moreover, pre-emptive anti-B-cell therapies are
increasingly used and have been shown to be
successful in preventing LPD. To date, few data
has been reported regarding the incidence and
features of EBV-related disease following RIC
allo-HSCT in adult patients with hematological
diseases.The aim of this analysis was to define
incidence and potential risk factors predicting
the development of EBV reactivation in the first
6 months following RIC allo-HSCT in adult
patients, and to assess its impact on clinical
outcome.
Figure 1. Cumulative incidence of EBV viremia
post RIC allo-SCT
Table 1. Patients characteristics
Patient age (median, range) 56 (18-71)
Sex ratio (MF) 106 69 (6139)
CMV serostatus Seronegative recipient Seronegative donor 98 (56) 101 (58)
Diagnosis Myeloid malignancies Lymphoid malignancies Severe aplastic anemia 85 (49) 86 (49) 4 (2)
Disease status Standard risk disease High risk disease 30 (17) 145 (83)
Stam cell source Bone marrow Peripheral blood 10 (6) 165 (94)
Donor Matched related Matched unrelated Mismatched unrelated 84 (48) 80 (46) 11 (6)
Conditioning with ATG Condtioning without ATG 134 (77) 41 (23)
Imunosupression Cyclosporine (CSA) CSAmycophenolat-mophetil (MMF) CSAmetothrexate (MTX) 77 (44) 93 (52) 5 (4)
CD 34 count/106 kg Bw 6.1 (0.7-36.7)
Engraftment days (ANCgt0.5) 17 (6-48)
acute GVHD Grade 0-I Grade II Grade III-IV 114 (65) 24 (14) 37 (21)
Acute GVHD days after alloSCT 34 (6-181)
Patients and methods
In all, 175 consecutive patients who received a
RIC allo-HSCT for hematological malignancies in a
single institution (University Hospital of
Nantes) between January 2005 and June 2009 were
included in this retrospective study. Patients
receiving RIC allo-HSCT using unrelated cord
blood cells were excluded from this analysis.
During the first six months after allo-HSCT and
in patients treated for GVHD, all patients were
weekly DNA-PCR screened in the peripheral blood
for EBV reactivation and were clinically
monitored for clinical features attributable to
EBV. EBV viremia was defined as 1000 copies of
EBV DNA/105 cells. EBV LPD was defined as biopsy
or autopsy proven post-transplantation lymphoma,
or viremia along with computerized tomography
nodal or soft-tissue abnormalities consistent
with LPD. Patients with EBV viremiagt1000 copies
on at least two consecutive occasions were
treated with rituximab at a dose of 375 mg/m2
weekly until clearance of EBV viremia (usually
for a maximum of 4 infusions).
Conclusions
We conclude that patients undergoing RIC
allo-HSCT using ATG as part of the preparative
regimen are at higher risk for EBV reactivation.
However, this did not translate into a
significant impact on outcome since monitoring of
EBV viral load using quantitative PCR and early
systematic preemptive rituximab therapy allowed
for significantly reducing the risk of
EBV-related LPD.
Figure 2. Median of copies of EBV DNA when EBV
reactivation
Figure 3. Probability of Survival post RIC
allo-SCT
1. Cohen J et al. Increased incidence of
EBV-related disease following paediatric stem
cell transplantation with reduced-intensity
conditioning. Br J Haematol.2005129229-239. 2.
Brunstein CG et al. Marked increased risk of
Epstein-Barr virus related complications with the
addition of antithymocyte globulin to a
nonmyeloablative conditioning prior to unrelated
umbilical cord blood transplantation. Blood 2006
108(8)2874-2880. 3. Faye, A et al. Chimaeric
anti-CD20 monoclonal antibody (rituximab) in
post-transplant B-lymphoproliferative disorder
following stem cell transplantation in children.
BrJ Haematol 2001 115, 112118. 4. Mohty M.
Mechanisms of action of antithymocyte globulin
T-cell depletion and beyond. Leukemia 2007 21,
1387-1394.
Without EBV reactivation
With EBV reactivation
P NS
CONTACT Zinaida Peric, MD University hospital
centre Zagreb, Croatia zina_peric_at_yahoo.com