Free PowerPoint poster templates

1
Features of Epstein Barr Virus (EBV) reactivation
after reduced intensity conditioning (RIC)
unrelated umbilical cord blood transplantation
(UCBT)

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
Discussion
Results
The absence of EBV-specific memory T cells in UCB
grafts, more frequent use of HLA-mismatched
grafts, and use of ATG inducing in vivo T-cell
depletion all contribute to a higher risk of
EBV-related complications in the subset of
patients after UCBT.(3) However, as we observed
no increased risk of EBV complications in our
group of patients, even when ATG used, other
factors may modify the risk. Recent
evidence-based guidelines from the European
Conference on Infections in Leukemia recommended
weekly screening of EBV-DNA for at least 3 months
in high risk allo-HSCT recipients. In addition,
other studies suggest that preemptive therapy
with rituximab may be highly effective in
controlling viral proliferation and avoiding
progression into EBV-related LPD (4). In the
current series, the response rate to pre-emptive
rituximab appeared to be similar to that
previously reported in the literature.(5) In
rituximab-resistant patients, options include
chemotherapy regimens such as CHOP or EBV
specific CTL lines generated using
EBV-transformed lymphoblastoid B-cell lines.
Patients' characteristics are summarized in Table
1. The median age was 50 (range, 18-66) years.
58 (n19) of the patients had a myeloid
malignancy, 36 (n12) had a lymphoid malignancy
and 6 (n2) had severe aplastic anemia. 91
(n30) of the patients received 2 CB units and 9
(n3) received a single CB. Patients received a
median of 4.0x107/kg (range, 2.2-5.8) total
nucleated cells and a median of 0.9x105/kg
(range, 0.2-3.7) CD34 cells. Donors and
recipients were mismatched with one mismatch in
43 of cases and 2 mismatches in 57. A RIC
including fludarabine (200 mg/m2 total dose),
cyclophosphamide (50 mg/Kg) and low dose TBI (2
Gy.) was used in 29 cases (88), while 8 patients
(24) who were not heavily pretreated before UCBT
received ATG.
Unrelated umbilical cord blood (UCB) is now being
increasingly used as an alternative stem cell
source for allogeneic stem cell transplantation
(allo-SCT). Because of the slow kinetics of
immune reconstitution after UCBT, previous
studies showed that EBV reactivation and EBV
induced lymphoprolipherative disease (LPD) may be
of matter of concern.(1) However,more recent
studies reported an infectious-related mortality
(IRM) incidence similar to that of allo-SCT using
HLA-matched unrelated donor. (2) This single
centre study assessed incidence and predictive
factors of EBV reactivation and LPD in 33
consecutive patients undergoing RIC UCBT.
Engraftment occurred at a median of 12 (range,
8-60) days and 15 of patients developed grade
2-4 acute GVHD. The median follow-up for
surviving patients was 468 (range, 92-1277) days.
EBV reactivation was observed in 5 patients (15)
at a median of 132 (range, 85-438) days after
UCBT. The cumulative incidence of EBV viremia is
shown in Figure 1. Among the 5 patients
experiencing EBV reactivation, 2 patients
received ATG as part of their RIC. Four patients
were treated with a median of 3 (range, 1-8)
rituximab infusions. Two patients responded to
rituximab, but 2 patients developed LPD. One of
these 2 patients died before receiving any other
anti-EBV therapy. In the other patient, LPD could
be controlled after additional chemotherapy and 2
infusions of EBV specific cytotoxic
T-lymphocytes. Of note, there was no significant
difference in overall survival between patients
with or without EBV reactivation (p0.33).
Patients and methods
Table 1. Patients characteristics
In all, 33 consecutive patients who received a
RIC UCBT for hematological malignancies in a
single institution (University Hospital of
Nantes) between January 2005 and June 2009 were
included in this retrospective study. 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 viremia gt1000 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).
Patient age (median, range) 50 (18-66)
Sex ratio (MF) 18 15 (5545)
CMV seronegative recipient EBV seropositive recipient 20 (61) 31 (94)
Diagnosis Myeloid malignancies Lymphoid malignancies Severe aplastic anemia 19 (58) 12 (36) 2 (6)
Disease status Standard risk disease High risk disease 6 (18) 27 (82)
Number of CBT units Single Double 3 (9) 30 (91)
HLA matching 1 mismatch 2 mismatches 14 (43) 19 (57)
Conditioning with ATG without ATG with TBI without TBI 8 (24) 25 (76) 29 (88) 4 (12)
Imunosupression Cyclosporine (CSA) CSAmycophenolat-mophetil (MMF) 1 (3) 32 (97)
CD 34 count/105 kg Bw 0.9 (0.2-3.7)
TNC count/106 kg Bw 4.0 (2.2-5.8)
Engraftment days (ANCgt0,5) 12 (8-60)
acute GVHD Grade 0-I Grade II Grade III-IV 28 (85) 3 (9) 2 (6)
Acute GVHD days after alloSCT 34 (9-112)
Figure 1. Cumulative incidence of EBV viremia
post RIC allo-SCT
Conclusions
Overall, this study shows the rate of EBV
reactivation after RIC UCBT to be relatively low
(15) and this is comparable to the incidence
expected with PBSC or BM unrelated mismatched
transplants. However, close EBV monitoring and
the use of pre-emptive rituximab treatment
appears to be mandatory since some cases may
progress to LPD requiring additional
interventions such as EBV-specific CTLs.
Figure 2. Probability of Survival post RIC
allo-SCT
References
Without EBV reactivation

• 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.
• 2. Parody Ret al. Severe infections after
  unrelated donor allogeneic hematopoietic stem
  cell transplantation in adults comparison of
  cord blood transplantation with peripheral blood
  and bone marrow transplantation. Biol Blood
  Marrow Transplant. 200612734-748
• 3. Clave E et al. Epstein-Barr virus (EBV)
  reactivation in allogeneic stem-cell
  transplantation relationship between viral load
  EBV-specific T-cell reconstitution and rituximab
  therapy. Transplantation. 20047776-84.
• 4. Wagner HJet al. Prompt versus preemptive
  intervention for EBV lymphoproliferative
• disease. Blood. 20041033979-3981.
• 5. 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.

With EBV reactivation
P NS
CONTACT Zinaida Peric, MD University Hospital
Centre Zagreb, Croatia zina_peric_at_yahoo.com