Bahlis, N.

Balogh, A.

Brown, C.

Chaudhry, A.

Daly, A.

Duan, Q.

Duggan, P.

Geddes, M.

Larratt, L.

Quinlan, D.

Russell, J.

Savoie, L.

Stewart, D.

Storek, J.

Turner, R.

Zacarias, N.

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Poster Session IIALLOGENEIC TRANSPLANTS275
GRAFT REJECTION FOLLOWING DOG LEUKOCYTE ANTIGEN
(DLA)-IDENTICAL NONMYELOABLATIVE HEMATOPOIETIC CELL TRANS-
PLANTATION (HCT) RESULTS IN LONG-TERM INCREASES IN HOST
T REGULATORY (TREG) CELLS
Georges, G.E.1,2, Lesnikova, M.1, Hwang, B.1, Abrams, K.1,
Nash, R.A.1,2. 1Fred Hutchinson Cancer Research Center, Seattle, WA;
2University of Washington, Seattle, WA.
In the canine HCT model, graft rejection occurred immediately
with no evidence of transient donor chimerism among all recipients
who were sensitized with whole blood transfusions given prior to
conditioning from their respective DLA-identical HCT donor. In
a separate study, in order to identify alternative nonmyeloablative
conditioning regimens such as 1 Gy total body irradiation (TBI)
with post-grafting pharmacological immunosuppression, we ob-
served a cohort of recipient dogs (not previously sensitized with
transfusions), who had transient donor/host mixed chimerism fol-
lowed by graft rejection. To evaluate if these recipients were now
sensitized to donor antigens, 27 dogs who had transient mixed chi-
merism followed by graft rejection after 1st HCT were re-condi-
tioned with 2 Gy TBI and given a second HCT from the original
donor. Recipient dogs developed either transient or stable mixed
chimerism in 37% and 19%, respectively. We hypothesized that
themechanism for donor-specific tolerance seen following rejection
of a hematopoietic cell graft was due to a sustained increase of host
Treg cells. We evaluated the induction of Treg in the peripheral
blood of 10 dogs conditioned with 0.5, 1 or 2 Gy TBI that had tran-
sient donor chimerism followed by rejection of a DLA-identical
HCT compared to 10 normal (not transplanted) dogs. We devel-
oped a quantitative PCR assay, using canine specific foxP3 primers
to amplify cDNA from sorted T cells. Recipient T cells were cul-
tured with the respective DLA-identical donor dendritic cells to in-
duce allostimulation andwere assessed forCD41CD251FoxP31 by
flow cytometry. Also, intracellular T cell interferon-g and TNF-
a was measured by flow cytometry. We determined that indepen-
dent of the time after HCT rejection (range, 4–96 weeks) or dura-
tion/degree of transient mixed chimerism, Treg cells were
significantly increased in dogs that had graft rejection compared
to untreated dogs. There was a 4-fold increase in foxP3 tran-
scripts/cell, consistent with the induction of CD41CD251FoxP31
Treg cells in dogs with prior transient mixed chimerism and graft re-
jection. However CD41TNFa1 and Inf-g1 cells were also in-
creased, reflecting activation of allo-immune effector cells
induced by HCT rejection. The results are consistent with the hy-
pothesis that acceptance of second HCT grafts may occur after 1st
transient mixed chimerism because of immune mechanisms favor-
ing Treg induction over pro-inflammatory cytokine producing im-
mune cells.T Cell Regulatory and Effector Phenotype in Dogs
Previously Rejected102HCT* Untreated p-valueT Cell Assay Mean ± Standard Deviation t-testfoxP3 transcripts/105 T cells 14,208 ± 6886 3,475 ± 1973 #0.0001% CD41CD251 6.9 ± 5.4 1.1 ± 0.3 #0.047% CD41CD251FoxP31 7.2 ± 6.1 0.8 ± 0.4 #0.048% CD41TNFa1 18.1 ± 5.1 7.7 ± 4.7 #0.001% CD41Infg1 17.7 ± 5.1 12.6 ± 4.0 #0.031% CD81Infg1 25.3 ± 7.8 17.1 ± 4.6 #0.014*Dogs with graft rejection after transient mixed chimerism follow-
ing 1st nonmyeloablative HCT.276
MYELOABLATIVE TRANSPLANTATION FROMMATCHED SIBLINGS (MSD)
USING A DAILY INTRAVENOUS BUSULFAN (BU)/FLUDARABINE (FLU)
REGIMEN WITH THYMOGLOBULIN (TG): ANALYSIS INVOLVING 200
PATIENTS INDICATES LOW TRANSPLANT-RELATED MORTALITY (TRM)
IN ALL BUT OLDER PATIENTS WITH HIGH-RISK DISEASE
Russell, J.1, Duan, Q.1, Chaudhry, A.1, Brown, C.1, Bahlis, N.1,
Savoie, L.1, Daly, A.1, Geddes, M.1, Storek, J.1, Balogh, A.1,
Zacarias, N.1, Duggan, P.1, Quinlan, D.1, Turner, R.2, Larratt, L.2,
Stewart, D.1. 1Tom Baker Cancer/Foothills Hospital, Calgary, AB,
Canada; 2Cross Cancer Institute, Edmonton, AB, Canada.
We aimed to identify MSD transplant recipients given Flu/Bu
andGVHDprophylaxis incorporatingTGwhomay be at particular
risk of TRM and perhaps merit some modification of the protocol.
Between 1999 and 2005 200 patients (pts) aged 18–65 (median 46)
received Flu 50 mg/m2 daily 5 and IV Bu 3.2 mg/kg daily 4. 46
had additional total body irradiation 200 cGy 2. GVHD prophy-
laxis was CSA, methotrexate and TG (Genzyme) 4.5 mg/kg total
dose. Cell source was mobilized blood cells in 172 and marrow in
28. At follow-up of survivors of 13–87 months (median 42) low-
risk (LR, acute leukemia CR1/CR2, CML CP1) pts had projected
5 year TRM and overall survival (OS) of 4% and 76% for pts
#45 years old (n 5 54) vs 6% and 83% for those .45 (n 5 31).
For high-risk (HR) pts TRM was 6% vs 27% (18% at one year)
(p 5 0.04) and OS 64% vs 37% (p 5 0.47) in younger (n 5 40)
and older (n 5 75) pts respectively. To correct for imbalance in
HR diagnoses we matched each of 17 younger HR pts with 2 older
HR (OHR) pts by diagnosis and details of stage and thereafter for
other risk factors. OS was 70% vs 37% (p 5 0.02), TRM 0 vs
34% (p5 0.02) and relapse 63% (48% at 3 years) vs 46% at 5 years
(p 5 ns) respectively. For a more robust analysis OHR pts were
compared with the other 3 groups combined giving TRM of 27%
vs 5% respectively (p 5 0.002). Incidence of aGVHD grade II-
IV, aGVHD grade III-IV and cGVHD was 23% vs 10% (p 5
0.02), 4% vs 2% (p5 ns) and 66% vs 41% (p5 0.001) respectively.
Nine of 14 non-relapse deaths in the OHR group were related to
GVHD or its treatment compared with 3 of 6 in all others (p value
for GHVD related death 5 0.01). Multivariate analysis of OS and
DFS correcting for potentially confounding pretransplant factors
idenitified only the HRO patients as having significantly increased
risk (RR 3.32, CI 1.71–6.47, p\ 0.0001 and RR 3.32, CI 1.71–
6.43, p\ 0.0001 respectively). We conclude that the effect of age
on TRM is only apparent in HR pts and is not explained by hetero-
geneity in diagnoses. HRO pts experience more GVHD and more
GVHD related death than others. TRM is no higher than reported
with many non-myeloablative regimens, justification for our prac-
tice of treating all pts with the same regimen. Additional GVHD
prophylaxis might help the HRO pts.277
A PROSPECTIVE EVALUATION OF THE EFFECT OF POLYOMA (BK) VIRUS
INFECTION ON THE INCIDENCE OF HEMORRHAGIC CYSTITIS (HC)
AFTER UNRELATED DONOR ALLOGENEIC HEMATOPOIETIC STEM
CELL TRANSPLANTATION (UD HSCT)
Silva, L.1, Patah, P.1, Szewczyk, N.1, Saliba, R.M.1, Gilman, L.1,
Gulbis, A.1, Neumann, J.1, Walker, J.A.1, Petropoulos, D.1, El-
Zimaity, M.1, Anderlini, P.1, Tarrand, J.2, Ciurea, S.O.1, Shpall, E.1,
Popat, U.1, Jones, R.1, Giralt, S.1, Champlin, R.E.1, de Lima, M.1.
1The University of Texas MD Anderson Cancer Center, Houston, TX;
2The University of Texas MD Anderson Cancer Center, Houston, TX.
Background: BK virus infection is highly prevalent in humans,
and has been associated with development of HC after UD
HSCT. Previously we determined that UDHSCT is independently
associated with higher prevalence of HC (El-Zimaity et al. Blood
2004). In order to further investigate the association of BK with
HC, we hypothesized that the presence of BK virus in the urine as


276: Myeloablative Transplantation from Matched Siblings (MSD) using a Daily Intravenous Busulfan (Bu)/fludarabine (Flu) Regimen with Thymoglobulin (TG): Analysis Involving 200 Patients Indicates Low Transplant-related Mortality (TRM) in all but Older Patients with High-risk Disease 

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276: Myeloablative Transplantation from Matched Siblings (MSD) using a Daily Intravenous Busulfan (Bu)/fludarabine (Flu) Regimen with Thymoglobulin (TG): Analysis Involving 200 Patients Indicates Low Transplant-related Mortality (TRM) in all but Older Patients with High-risk Disease

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