Pulsipher, M.A.

Wall, D.

Grimley, M.

Goyal, R.

Grupp, S.

Bunin, N.

M.A. Pulsipher

D. Wall

M. Grimley

R. Goyal

S. Grupp

N. Bunin

Crossref

Sirolimus (SRL)-Based GVHD Prophylaxis After Allogeneic HSCT in Pediatric All Patients: Low NRM, Low Incidence of VOD, and Higher Than Expected EFS: Results of a Multi-Institutional Pilot Study

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Sirolimus (SRL)-Based GVHD Prophylaxis After Allogeneic HSCT in Pediatric All Patients: Low NRM, Low Incidence of VOD, and Higher Than Expected EFS: Results of a Multi-Institutional Pilot Study 

Poster Session-I 57for the CD19 molecule (CD19.CAR) present on most B-ALL blasts.
Six multivirus-specific CTL lines were generated from mononuclear
cells (MNCs) obtained from the peripheral blood (PB) of healthy do-
nors and umbilical cord blood (UCB). MNC were stimulated weekly
with dendritic cells and EBV-lymphoblastoid cell lines transduced
with an adenovector encoding the CMV pp65 protein (Ad5/
f35pp65). After the 3rd stimulation, CTLs were transduced with a ret-
rovirus encoding the CD19.CAR, and then further expanded. Growth
kinetics was unchanged from control multivirus CTLs (NT-CTLs).
CD19.CAR expression was 65 6 14% for UCB-CTLs and 62 6
16% for PB-CTLs and co-expression was seen in virus specific CTL
populations visualized using pp65, hexon and EBVMHCmultimers.
CAR-modified CTLs retained native receptor function against viral
targets as assessed by 51Cr release and IFNg Elispot assays; producing
the same level of cytotoxic activity against autologous PHA-blasts
loaded with pp65 pepmix (PB-CTLs-69%634% and UCB-
CTLs-39%.617%) as NT-CTLs (PB-CTLs-74%68% and UCB-
CTLs-38%615%). CD19.CAR1 and control PB-CTLs produced
IFNg in response topp65 (8326 53vs869657SFC/105 cells, respec-
tively), hexon (285629vs1256 4) andEBVantigens (323614vs309
6 46). CD19.CAR1 andNT-UCB-CTLs responded to pp65 (1006
14 vs 1806 19 SFC/105 cells, respectively) and hexon (1306 28 vs 52
6 20) pepmix. CD19.CAR1 PB-CTLs and UCB-CTLs lysed
CD191 target cells including Raji (73%610% and 63%612%, re-
spectively, at a 40:1 E:T ratio), and primary B-ALL cells (68%61%
and 68%66%, respectively), but not the CD19- target HDLM-2
(10%64% and 8%64, respectively). In contrast \10% cytotoxic
activity against CD191 targets was observed for control CTLs.
CD191 targets were completely eliminated on co-culture
withCD19.CAR1CTLs.HenceCD19.CARcan be effectively trans-
ferred tomultivirus-specific CTLs generated fromboth PB andUCB,
potentially providing transplant recipients with a single T cell product
that possesses both anti-viral and anti-leukemic properties.151
OUTCOMES OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLAN-
TATION (HSCT) FOR ADVANCED PHASES OF CHRONIC MYELOID
LEUKEMIA (CML) IN THE EARLY IMATINIB MESYLATE (IM) ERA
Khoury, H.J., Kukreja, M., Wang, T., Woolfrey, A., Szer, J., Cortes, J.,
Horowitz, M.M., Lee, S. CIBMTR, Milwaukee, WI
Despite advances in supportive care, allografting patients in ad-
vanced phases of CML remains associated with poor outcomes.
We analyzed CIBMTR data of these patients transplanted between
1999–2004, to assess the impact of pre-transplant IM on outcomes
and identify prognostic factors. The cohort included 449 patients
in second chronic phase (CP2, n 5 184), accelerated (AP, n 5
185), and blast phase (BP, n5 80) CMLwho receivedHLA-identical
sibling (27%), related (3%), and matched or mismatched unrelated
donor (70%), peripheral blood (47%) or bone marrow (53%)
HSCT after myeloablative (78%) or non-myeloablative (22%) con-
ditioning. GVHD prophylaxis consisted of CSA/MTX (52%),
FK506/MTX (23%) or other (25%). 52% (96/184) of patients in
CP2, 49% (91/185) in AP, and 46% (37/80) received IM for median
of 7 (1–60), 11 (1–54), and 8 (1–36) months, respectively, prior to
a planned transplant (43%) or transplantation for IM intolerance
(6%), or failure (51%). Last dose of IM was administered within
15 days of the start of conditioning in 117 (52%), 15–30 days in 17
(8%), 30–90 days in 37 (16%) and .90 days in 53 patients (24%).
The table below summarizes outcomes at 3 years
CP2 AP BPProbability (95%CI) Probability (95%CI) Probability (95%CI)OS 36 (29–43) 43 (35–50) 14 ( 8–23)
Relapse 34 (27–41) 26 (20–33) 36 (26–48)
LFS 27 (20–34) 37 (30–44) 10 ( 4–17)Cox proportional hazards regression models were constructed to
assess factors that affected overall survival (OS), leukemia-free sur-
vival (LFS), TRM, relapse, acute and chronic GVHD. Time from
diagnosis to transplant, KPS, and degree of HLAmatching indepen-dently predicted OS, relapse and LFS; while GVHD prophylaxis,
CMV serostatus, sex mismatch, conditioning regimen, and degree
of HLA matching affected GVHD and TRM. Pre-transplant IM
had neither a positive nor a negative impact on transplant outcomes.
Reported reason to proceed with allografting (IM resistance, or
planned transplant) and duration of IM therapy prior to transplanta-
tion did not impact on any outcomes. Causes of death included
disease recurrence (CP2 33%, AP 26%, BP 43%) and complications
ofGVHD(CP248%,AP54%,BP35%).The retrospective nature of
this study, absence of information on disease status at time of initia-
tion of IM, and changes in disease status while on IMwere limitations
of this study. We conclude that conventional prognostic indicators
remain the major determinants of transplant outcomes in advanced
phasesofCML.CP2andAPpatients appear tohave similar outcomes
while BP patients do very poorly. The administration of imatinib
prior to HSCT was not associated with improved outcomes.152
SIROLIMUS (SRL)-BASED GVHD PROPHYLAXIS AFTER ALLOGENEIC
HSCT IN PEDIATRIC ALL PATIENTS: LOW NRM, LOW INCIDENCE OF
VOD, AND HIGHER THAN EXPECTED EFS: RESULTS OF A MULTI-INSTITU-
TIONAL PILOT STUDY
Pulsipher, M.A.1, Wall, D.2, Grimley, M.3, Goyal, R.4, Grupp, S.5,
Bunin, N.5 1University of Utah/Primary Children’s Medical Center,
Salt Lake City, UT; 2CancerCare Manitoba, Winnepeg, MB, Canada;
3Methodist Children’s Hospital, San Antonio, TX; 4Children’s Hospital
of Pittsburgh, Pittsburgh, PA; 5Children’s Hospital of Philadelphia, Phil-
adelphia, PA
Relapse and NRM after allogeneic HSCT remain significant bar-
riers to success in treating very high-risk ALL. Sirolimus (SRL) has
been shown to have cytotoxic activity against human ALL at serum
levels used for immune suppression. We hypothesized that the addi-
tion of SRL to a tacrolimus (TAC)/methotrexate (MTX)GVHDpro-
phylaxis regimen would decrease relapse after HSCT for ALL. This
multi-institutional pilot trial included a preparative regimen of TBI
(1200cGy), thiotepa (5mg/kg/dx2) and cyclophosphamide (60mg/kg
 2). Pts received IV TAC (start d-2, target 5–10ng/mL), PO SRL
(start d0, target 3–12ng/mL), and IV MTX (5mg/m2, d1, 3, and 6
plus d11 for UD BM/PBSC). TAC was tapered between d142–96
for MRD and d1100–180 for others. SRL was tapered over 4 wks
starting 6m after transplant. The study enrolled 58 pediatric pts
(med age 9 (1–22)) with a med f/u of 22m (2–63m). Immunopheno-
types included 47 B-lineage and 11 T-lineage. Risk groups included
17 pts in high risk (HR) CR1, 14 in HR CR2 (BM relapse\36m
from dx), 16 in intermediate risk (IR) CR2 (5 isolated extramedullary
(IEM) relapse, 11 late BM relapse $36m), and 11 in CR3. Stem cell
sources included 25 MRD, 28 UCB, and 5 UD. Results: 2yr EFS
was 71% (SE 6.4) and did not differ by stem cell source. 2yr EFS by
risk groups is outlined in the table. CIBMTR anticipated OS for pe-
diatric ALL in early phase (CR1) is 48–60% (UD vsMRD), interme-
diate phase (CR2) 39–52%, and late phase 17–29%; by comparison
our EFS outcomes exceed these projections by 20–30%. Toxicity
with the regimenwas low.One recipient ofCB failed to engraft, a sec-
ond relapsed prior to engraftment, and remaining pts engrafted at
a median of 20d (13–31) and 29d (16–62) for MSD/UD and CB, re-
spectively. Acute GVHD grade II-IV and III-IV occurred in 41 and
21% of patients, respectively, while cGVHD occurred in 8 and
37% of RD and UD recipients. NRM occurred in 6 pts (10%: 5
CB, 1 MSD). Significant toxicities included VOD (5pts (8%), fatal
in2 cases), non-fatalHUS(2pts), andnon-fatal IPS (1pt). In summary,
SRL-based GVHD prophylaxis after TBI/TT/Cy allogeneic HSCT
results in high rates of engraftment, lowNRM, and improved 2yrEFS
in all risk groups.Though numbers are small, as opposed to recent re-
ports in adult trials, sirolimus/mtx does not appear to increase the risk
of VOD in children (anticipated rates 11–20%). A phase 3 trial in the
COG for ALL patients comparing TAC/MTX with TAC/MTX/
SRL after TBI/TT/Cy allogeneic HSCT is ongoing.Two Year EFS after Sirolimus-Based HSCT
ALL Risk Group ALL HR CR1 ALL HR CR2 ALL IR CR2 ALL CR32yr EFS (6SE) 85% (610) 57% (613) 85% (610) 48% (617)


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Sirolimus (SRL)-Based GVHD Prophylaxis After Allogeneic HSCT in Pediatric All Patients: Low NRM, Low Incidence of VOD, and Higher Than Expected EFS: Results of a Multi-Institutional Pilot Study

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