Ativitavas, T.

Champlin, R.

de Lima, M.

Ghosh, S.

Saliba, R.

Sergio, G.

Elsevier - Publisher Connector 

Treatment of myelodysplastic syndromes with allogeneic Hematopoietic Stem Cell Transplantation (HSCT)—impact of non-relapse mortality on outcomes 

106 transplanted unilaterally) and single positive RT1n (4.5  106
to 9.0 106) and RT1a (6.0 106 to 12.0 106) cells transplanted
bilaterally to naive Lewis rat. Donor-speciﬁc chimerism (for MHC
class I antigens) and efﬁcacy of MACS sorting was assessed by ﬂow
cytometry. Therapeutic effect of adoptive transfer of donor chi-
meric cells was evaluated following bilateral transplantation of skin
ﬂaps of donor origin (LBN and ACI). Results: In primary trimeras
13.1% of LBN donor positive cells (RT1n) and 6.8% of ACI donor
positive cells (RT1a) was found. MACS-sorting revealed 87%-96%
purity of double positive RT1n/RT1a cells. At day 21 secondary
trimera created via double positive cell transplantation (RT1n/
RT1a) revealed 8.3% of RT1n and 11.3% of RT1a positive cells,
whereas injection of single positive cells (RT1n and RT1a) resulted
in 6.0% of RT1n and 7.6% of RT1a chimerism. Prolonged skin ﬂap
survival was achieved over 84 days after double positive RT1n/
RT1a transplant and over 120 days in single positive chimeric cells
recipients (still under observation). Conclusions: Intraosseous
transplantation of bone marrow from two different MHC mis-
matched donors under a 7-day 
-TCRmAb/CsA protocol re-
sulted in creation of donor-speciﬁc trimera. Isolation and adoptive
transfer of chimeric cells proved to be efﬁcacious in extension of
donors skin ﬂap survival without prolonged immunosuppression.
70
BONE MARROW TRANSPLANTATION (BMT) FOR HEAVILY TRANS-
FUSED PATIENTS (pts) WITH SEVERE APLASTIC ANEMIA (SAA): 147
PTS TREATED AT THE SAME INSTITUTION WITH BUSULFAN (BU) 
CYCLOPHOSPHAMIDE (CY)
Bonﬁm, C., Bitencourt, M., Funke, V., Setubal, D., Ruiz, J., Doro, M.,
Medeiros, C.R., Zanis-Neto, J., Pasquini, R. Federal University of
Parana, Curitiba, PR, Brazil.
BMT from HLA identical siblings is currently the best treatment
for young pts with SAA. However, heavily transfused pts have an
inferior survival due to an increased risk of rejection and transplant
related mortality (TRM). In developing countries not only the
number but the quality of pretransplant transfusions should be
considered because most of them are not ﬁltered or irradiated. In
1993 we introduced BU to the preparatory regimen of pts with
more than 15 pretransplant transfusions trying to reduce the ele-
vated incidence of rejection observed in pts receiving only CY. In
this study we retrospectively analyzed the results in 147 pts trans-
planted between 01/93-01/05 with BU  CY. Age: 2-46 y (M: 19).
Previous blood transfusions: 15-675 (M: 34 UI). Disease duration:
1-114 mo (M: 4). All pts received bone marrow from HLA iden-
tical siblings. Preparatory regimen: BU 12 mg/kgCY 120 mg/kg.
GVHD prophylaxis: cyclosporine  methotrexate. TNC infused:
1.17-6.55  108/kg (M: 3.01). Immediately prior to BMT, 39 pts
(26%) had active bacterial or fungal infections. One hundred and
four pts are alive with a median follow up of 2719 days (range:
189-4506). Eight pts died before day 28 and were not evaluable
for engraftment. Primary graft failure (GF) occurred in 4/139 pts
(2.8%) and all pts died. Late GF occurred in 19/135 pts (14%)
between 207-1448 days after BMT (M: 584 days). 10/19 pts are
alive (5 after a 2nd BMT and 5 after treatment with immune
suppression). Mucositis grade III-IV occurred in 80 pts (54%).
VOD: 2 pts. Hemorrhagic cystitis: 13 pts (8.8%). Acute GVHD
grade II-IV: 20/135 pts (III-IV: 11 pts—8%). Chronic GVHD:
22/128 pts (extensive: 16 pts—12.5%). Forty-three pts died be-
tween 10-3072 days after BMT (M: 154 days). Death was mainly
related to infections or bleeding. 17 pts died before day 100 and
76% of them had severe infections prior to transplant. 11/16 pts
with extensive chronic GVHD died. Pts with more than 50 previ-
ous blood transfusions had an inferior survival when compared to
those receiving between 15-50 UI (54%  74%; P  .005). 28 pts
are surviving more than 10 y after BMT with a satisfactory quality
of life. We conclude that the use of BU  CY reduced the risk of
rejection in this group of pts. Survival reached 70% in pts receiving
between 15-50 transfusions. Alternative preparatory regimens
could be offered to pts receiving 	50 UI before transplant. Infec-
tions immediately prior to conditioning increased the risk of TRM.
71
THERAPEUTIC ANTI-TUMOR IMMUNITY MEDIATED BY TRANSIENTLY
ENGRAFTING ALLOGENEIC LYMPHOCYTES: THE “ALLOGENEIC EF-
FECT” REVISITED
Symons, H.J., Levy, M.Y., Wang, J., Zhou, X., Fuchs, E.J. Sidney
Kimmel Comprehensive Cancer Center, Baltimore, MD.
The “allogeneic effect” refers to the induction of host B cell
antibody synthesis or host T cell cytotoxicity, including tumori-
cidal activity, by an infusion of allogeneic lymphocytes. We have
previously shown that treatment of mice with cyclophosphamide
(Cy) followed by infusion of CD8 T cell-depleted allogeneic
spleen cells (Cy  CD8 DLI) induces anti-tumor activity in a
model of minimal residual leukemia, even though the donor cells
are eventually rejected by the host immune system. The purpose of
the current investigation was to test the activity of Cy  CD8
DLI in the treatment of well-established cancer, and to character-
ize the mechanisms of the anti-tumor effect. BALB/c mice were
inoculated intravenously (IV) with the syngeneic A20 lymphoma/
leukemia or the RENCA renal cell carcinoma on day 0 and were
then treated with nothing, Cy alone on day 14, or Cy  CD8
DLI from MHC-mismatched C57BL/6 donors on day 15. In both
tumor models, the combination of Cy  CD8 DLI signiﬁcantly
prolonged survival compared to mice treated with nothing or with
Cy alone. While depletion of CD4 T cells from the DLI signif-
icantly diminished the beneﬁcial effect of CD8 DLI, puriﬁed
CD4 T cells alone were inactive, demonstrating that donor
CD4 T cells and another population of cells were required for
optimal anti-tumor activity. Several observations pointed to an
active role for the host immune system in the anti-tumor activity of
CyCD8DLI. First, host T cells participated in the anti-tumor
effect of treatment with Cy alone, since the drug’s activity was
diminished in tumor-bearing scid mice or in normal BALB/c mice
depleted of T cells. Second, while Cy  CD8 DLI caused no
GVHD in tumor-bearing but immunocompetent BALB/c recipi-
ents, it caused fatal acute GVHD in either tumor-bearing scid or
T-cell depleted BALB/c mice. Finally, the anti-tumor effect of Cy
and Cy  CD8 DLI was also signiﬁcantly inhibited in BALB/c
mice depleted of CD8 T cells. These results demonstrate that
transiently engrafting T cells administered after Cy can induce
signiﬁcant anti-tumor effects against solid and liquid tumors. We
propose that upon recognition of alloantigen on host antigen-
presenting cells (APCs), allogeneic donor CD4 T cells deliver
activating ligands to the APCs, thereby generating effective “help”
to break tolerance in tumor-speciﬁc host CD8 T cells. This
mechanism may correspond to the “allogeneic effect” in the anti-
tumor response described over three decades ago.
72
TREATMENT OF MYELODYSPLASTIC SYNDROMES WITH ALLOGENEIC
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)—IMPACT OF
NON-RELAPSE MORTALITY ON OUTCOMES
Ativitavas, T.1, Saliba, R.2, Sergio, G.2, Ghosh, S.2, Champlin, R.2,
de Lima, M.2 1Mahido University, Bangkok, Thailand; 2Department of
Blood and Marrow Transplantation, Houston, TX.
Introduction: Myelodysplastic syndromes (MDS) are clonal he-
matopoietic disorders potentially curable with allogeneic HSCT.
Non-relapse mortality (NRM) is a major cause of treatment failure
in this context. Preparative regimens may impact survival (S) dif-
ferently given dissimilar toxicity rates. We investigated this hy-
pothesis in a dataset of patients with MDS (as deﬁned by WHO
criteria) treated in our institution from January 1993-December
2004.Methods:We reviewed 88 patients (65% males); 30 patients
(34%) received induction chemotherapy prior to HSCT (4 RA, 4
RARS, and 22 RAEB) and 58 patients (66%) did not (30 RA, 3
RARS, 21 RAEB, and 4 refractory cytopenia). Median age was 50
years (20-69). IPSS was high risk in 27%, intermediate 2 in 40%,
intermediate 1 in 28%, and low in 5%. Cytogenetics were poor in
52%, intermediate in 17% and good in 31% of patients. 53 patients
(60%) were treated with myeloablative regimens including 12 Gy
TBI-based (11/53), Bu/Cy (17/53) and Bu/Flu (25/53). 35 (40%)
patients were treated with reduced intensity regimens (Flu/Mel,
FAI or low-dose busulfan/Flu). Donor was matched-related in
Poster Session I
28
51%, matched-unrelated (40%), or mismatched related (9%). 41
patients (47%) received PBSC and 45 patients (51%) received
BMSC. Only 2 patients received cord blood transplant. GVHD
prophylaxis was tacrolimus (89%) or cyclosporine-based (10%) in
89% and 1. Predictors of NRM and disease progression at one year
post HSCT were evaluated using Cox’s proportional hazards
model for univariate and multivariate analysis. Results: 29 of 88
patients are alive with median follow-up 22 months (1-143). Ac-
tuarial estimate of survival at 2 yrs was 29%. Cumulative incidence
of progression was 24% and NRM 47% at 2 yrs. Donor type and
preparative regimen were signiﬁcant predictors of NRM on mul-
tivariate analysis (Table 1). There was a trend for an increased rate
of progression among patients with high risk IPSS (HR  3.8), yet
this did not reach statistical signiﬁcance (P  .06). None of the
other factors evaluated had an impact on the rate of progression.
Conclusion: Allogeneic HSCT can provide long-term disease
control for a signiﬁcant proportion of patients with MDS. These
results suggest that Flu/Bu may provide optimal cytoreduction
with lower toxicity. Progression and late deaths from GVHD
remain a signiﬁcant problem. Strategies aimed at addressing these
issues are currently in development (Table 1).
Table 1. Predictors of NRM and Progression within 1 yr post
Allogeneic HSCT: Univariate Analysis
Variable
NRM Progression
N HR
95%
CI
P
Value HR
95%
CI
P
Value
IC
Yes 30 0.6 0.3–1.2 .20 1.8 0.7–4.6 .20
No 58 Ref. — — Ref. — —
Age
<50 43 Ref. — — Ref. — —
>50 45 0.9 0.5–1.8 .80 1.2 0.4–2.9 .80
IPSS
Low 4 0.2 0.03–1.7 .15 *Excluded — —
Intermediate 1 25 0.6 0.3–1.3 .20 Ref. — —
Intermediate 2 35 0.3 0.14–0.7 .01 1.2 0.3–4.7 .80
High risk 24 Ref. — — 3.8 0.97–14.7 .06
Regimen
Myeloablative 27 0.8 0.4–1.6 .50 0.6 0.1–2.4 .50
ID 01-011 (Blu/Flu) 26 0.1 0.02–0.4 .004 1.3 0.4–3.8 .60
Reduced intensity 35 Ref. — — Ref. — —
Allotype
Matched sibling 45 Ref. — — Ref. — —
Mismatched sibling 8 2.7 0.9–8.4 .90 3.3 0.8–11.3 .09
Unrelated 35 2.8 1.4–5.9 .005 1.15 0.4–3.4 .80
*Excluded because of small number.
73
WORST OUTCOME FOR PATIENTS WITH NO CHRONIC GVHD IN ALLO-
GENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTS (PBSCT) IN
ACUTE MYELOID LEUKEMIA (AML)
Vigorito, A.C.1, Penteado Aranha, F.J.1, Oliveira, G.B.1, Eid, K.A.B.1,
Zulli, R.1, Lodi, F.M.2, Bittencourt, H.2, Colturato, V.3, de Souza, M.3,
Ruiz, J.4, Pasquini, R.4, Pontes, E.R.5, Brandalise, S.R.5, Novis, Y.6,
Hamerschlak, N.6, Ferreira, E.6, Maiolino, A.7, Nucci, M.7,
de Azevedo, A.M.8, Bouzas, L.F.S.8, Ruiz, M.A.9, de Souza, C.A.1
1State University of Campinas, Campinas, SP, Brazil; 2Federal Uni-
versity of Minas Gerais, Belo Horizonte, MG, Brazil; 3Jau Cancer
Hospital, Jau, SP, Brazil; 4Federal University of Parana, Curitiba,
Parana, Brazil; 5Children Hospital Dr Boldrini, Campinas, SP, Brazil;
6Albert Einstein Hospital, Sao Paulo, SP, Brazil; 7Federal University of
Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 8Brazilian National Cancer
Institute, Rio de Janeiro, RJ, Brazil; 9Sao Jose do Rio Preto Medical
School, Sao Jose do Rio Preto, SP, Brazil.
Uncertainty still exists with the effects of allo PBSCT on the out-
come of patients with hematological malignancies. Our aim was an-
alyzed retrospectively 151 AML patients with HLA identical sibling
donors who underwent an allo PBSCT. Median age was 32 (3-64),
and advanced disease was present in 68%; GVHD prophylaxis used
was MTX/CsA in 95%; CD34 median was 3.74  106/kg (1.2-24);
the median follow-up for surviving patients was 33 mo (0.6-86);
median day for neutrophils and platelets engraftment was 15 and 14;
in univariate analyses early disease and CD34 cell dose 	3.7 
106/kg were associated with faster neutrophil engraftment, and early
disease for platelet engraftment. CI for  2 aGVHD was 34%;
extensive cGVHD 65%; however, extensive cGVHD was 58% for
other than female donors for male recipients (P  .02). OS and DFS
at 86 mo was 39% and 53%; factors associated with better OS in
univariate analyses were early disease (61%) (P  .02), no TBI con-
ditioning (41%) (P  .02), and presence of extensive cGVHD (58%)
(P  .001). Furthermore, DFS for early disease was 73% (P  .003);
and for extensive cGVHDpatients 75% (P .001). CI for relapse was
47%; but in patients with early disease it was 23% (P .001), and with
cGVHD 26% (P  .001). CI for TRM was 46%; TRM for no
aGVHDwas 20% (P .03). In multivariate analyses female donor for
male recipient had a negative impact on neutrophil engraftment (P
.03), and early disease was related with faster neutrophil and platelet
engraftment (P  .02, P  .05); female donor for male recipient was
associated with more cGVHD (P  .02); early disease was predictive
of improved OS (P  .03) and DFS (P  .01), and TBI conditioning
and no cGVHD with worst OS (P  .01, P  .001) and DFS (P 
.001, P  .001); early disease was associated with fewer relapses (P 
.01), and no cGVHD with higher relapses (P .001); aGVHD had a
positive impact on TRM (P  .03). In AML the allo PBPCT seems
to be associated with leukemia control and DFS beneﬁt.
74
REDUCED-INTENSITY ALLOGENIC HEMATOPOIETIC STEM CELL
TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME
Naing, A.1, Nakamura, R.1, Rodriguez, R.1, Palmer, J.2, Stein, A.1,
Chang, K.3, Slovak, M.L.3, Bhatia, R.1, Kirschbaum, M.1,
Forman, S.J.1, O’Donnell, M.R.1 1Division of Hematology/HSCT, City
of Hope National Medical Center, Duarte, CA; 2Department of Biosta-
tistics, City of Hope National Medical Center, Duarte, CA; 3Division of
Anatomic Pathology, City of Hope National Medical Center, Duarte,
CA.
We evaluated the outcome of reduced-intensity (RI) condition-
ing followed by allogeneic hematopoietic stem cell transplantation
(HSCT) in 31 patients with MDS who were not eligible for a
standard myeloablative-conditioning regimen. All 31 patients re-
ceived ﬂudarabine 125 mg/m2 plus melphalan 140 mg/m2 followed
by an allogeneic HSCT (blood stem cell: n  28, bone marrow:
n  3) from an HLA-identical sibling (SIB: n  15) or unrelated
donor (MUD: n  16). GVHD prophylaxis was cyclosporine
(CSP)  mycophenolate (MMF) (n  12) or FK-506  sirolimus
(n  2) or FK-506  methotrexate (MTX)  sirolimus (n  1) for
sibling donor transplants; and CSP  MMF  MTX (n  9), or
CSP  MMF (n  6) or FK-506  MMF  MTX (n  1), for
unrelated donor transplants. Median age was 53 years (range 32-
74). Ten patients had prior autologous HSCT. Diagnoses at time
of transplantation were RA (n 8), RARS (n 2), RAEB (n 15),
and RAEB-T (n  6). By IPSS criteria, 2 patients had low, 11 had
intermediate 1, 10 had intermediate 2, and 8 had high-risk MDS.
All patients engrafted with the median neutrophil recovery at day
15 (range: 9-24). After follow up of 20 months (median: range:
11-54 mo), 15 patients were alive. The 2-year actuarial overall
survival (OS), disease-free survival (DFS), relapse, and transplant-
related mortality (TRM) were 53.9% (CI: 43.8-63.0), 48.4% (CI:
38.8-57.3), 28.6% (CI: 16.2-47.4), and 24.7% (CI: 14.9-39.2) re-
spectively. Of 31 patients, grade II to IV acute GVHD occurred in
18 patients and grade III to IV in 11 patients. Twenty of 28
evaluable patients had chronic GVHD. There was no signiﬁcant
survival difference between related and unrelated donor HSCT
(SIB 42.7% vs. MUD 62.5%, P  .60). In univariate analysis,
higher IPSS or older age, or prior auto-SCT was not signiﬁcantly
associated with poor survival. Acute GVHD grade III-IV was
associated with higher TRM (HR  7.5; P  .01) and lower OS
(HR 3.3; P  .02). In summary, RI-HSCT was associated with
acceptable toxicity; and survival rate was comparable or superior to
full-intensity HSCT in this high-risk cohort.
Poster Session I
29BB&MT


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Treatment of myelodysplastic syndromes with allogeneic Hematopoietic Stem Cell Transplantation (HSCT)—impact of non-relapse mortality on outcomes

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