Chao, N.

Chute, J.

Gasparetto, C.

Horwitz, M.

Long, G.

Morris, A.

Rizzieri, D.

Spasojevic, I.

Sullivan, K.

Telen, M.

Elsevier - Publisher Connector 

244
FLUDARABINE-BASED NON-MYELOABLATIVE STEM CELL TRANSPLAN-
TATION IN A PATIENT WITH SICKLE CELL DISEASE AND RENAL FAIL-
URE: CLINICAL OUTCOME AND PHARMACOKINETIC COMPARISON TO
PATIENTS WITH NORMAL RENAL FUNCTION
Spasojevic, I.1, Morris, A.3, Long, G.3, Gasparetto, C.3, Sullivan, K.3,
Chute, J.3, Telen, M.2, Chao, N.3, Rizzieri, D.3, Horwitz, M.3 1De-
partment of Medicine; 2Division of Hematology; 3Division of Cellular
Therapy, Duke University School of Medicine, Durham, NC.
End-organ damage is common in adult patients with Sickle Cell
Disease (SCD), therefore an effective non-myeloablative approach
to allogeneic stem cell transplantation (SCT) would be ideal. Flu-
darabine is a component of most non-myeloablative conditioning
regimens. Since 40% of the active metabolite, 2-ﬂuoro-ara-A (F-
Ara-A), is cleared by the kidneys, use in patients with renal insuf-
ﬁciency or renal failure is hazardous. We report the outcome of
two adult SCD patients who underwent non-myeloablative SCT
from their HLA-identical matched siblings on an NHLBI-spon-
sored clinical trial. Patient #1 is a 21 year-old male with normal
renal function and patient #2 a 27 year old with dialysis-dependent
end-stage renal disease. Conditioning consisted of Total Body
Irradiation 200cGy followed by Fludarabine (Pt #1: 30 mg/m2, Pt
#2: 24 mg/m2) Cyclophosphamide 500mg/m2, both given over four
days and Campath 1-H 100mg over 5 days. Mycophenolate
Mofetil 2 grams/day was given for 100 days. Patient #1 and #2
received peripheral blood stem cell grafts containing 21106 and
19106 CD34 cells/kg, respectively. Patient #2 underwent 6
hours of conventional hemodialysis using an F200 dialyzer, 12
hours after each Fludarabine dose. Plasma samples from patient #2
and two additional non-SCD patients with normal renal function
undergoing stem cell transplantation using the same chemotherapy
preparative regimen were collected over 24 hours after doses 1 and
4 of Fludarabine. F-Ara-A was measured by a validated LC/
MS/MS assay. Both SCD patients achieved full donor erythroid
chimerism and stable mixed lymphoid and myeloid chimerism
(donor CD15/CD3; Pt #1 89%/87% 14 months post-transplant,
Pt #2 86%/45% 6 months post transplant). Neither patient devel-
oped graft vs host disease, neurological complications or any other
SCD-related complications following transplantation. Both have
normal blood counts and are on no immunosuppressive medica-
tions. F-Ara-A pharmacokinetic parameters obtained using non-
compartmental analysis are given in the table. With a 20% dose
reduction followed by intensive daily dialysis, we achieved Fludara-
bine levels that are nearly identical to that achieved in patients with
normal renal function. This allowed for robust donor stem cell
engraftment without Fludarabine-related toxicity. We conclude
that non-myeloablative allogeneic SCT for adult patients with
SCD is feasible, even in the setting of end-stage renal disease.
First Dose Fludarabine Pharmacokinetic Parameters
Patient with:
Cmax
(/L)
t1/2
(h)
CL
(L/h)
Vss
(L)
AUClast
(mgh/L)
Renal Failure and SCD 549 5.9 5.3* 52 4093
Normal Renal Function-1 788 10.5 6.4 72.6 3972
Normal Renal Function-2 1170 9.2 6.4 59.6 4049
*calculated from dialysis phase slope; Cmax Maximum Concentra-
tion, t1/2 half life, CL clearance, Vss Steady State Volume of
Distribution, AUC Area under curve
245
DONOR KILLER IG-LIKE RECEPTOR HAPLOTYPE IS ASSOCIATED WITH
LOWER RELAPSE IN CHRONIC MYELOGENOUS LEUKEMIA PATIENTS
UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTA-
TION
Abarghoui, F.1, Pinto-Agnello, C.2, Gooley, T.3, Senitzer, D.4,
Malkki, M.3, Dupont, B.2, Petersdorf, E.3, Hsu, K.1, International
Histocompatibility Working Group.5 1Memorial Sloan-Kettering Cancer
Center, New York, NY; 2Sloan-Kettering Institute for Cancer Research,
New York, NY; 3Fred Hutchinson Cancer Research Center, Seattle, WA;
4City of Hope Cancer Center, Duarte, CA; 5International Histocompat-
ibility Working Group.
In allogeneic hematopoietic cell transplantation (HCT), do-
nor natural killer (NK) cells can prevent leukemia relapse and
prolong survival. NK alloreactivity has been shown to be inﬂu-
enced by the killer Ig-like receptor (KIR) repertoire of the
donor and the HLA class I KIR ligand phenotype of the recip-
ient. We sought to determine if more activating receptors in the
donor KIR repertoire would inﬂuence the outcome of alloge-
neic transplant for hematologic malignancies. Comprising 50%
of all haplotypes in the Caucasian population, KIR haplotype-A
is a conserved haplotype with nearly no activating KIR. In
contrast, haplotype-B comprises a variety of different haplo-
types, most of which contain several activating KIR. Using data
provided from the International Histocompatibility Working
Group, we studied the donor KIR genotypes from 541 unrelated
donor transplants and examined the impact of donor KIR hap-
lotype on overall surivival (OS) and relapse, by segregating
donor-recipient pairs into those in which the donor was ho-
mozygous for KIR haplotype A (AA) versus those in which the
donor was heterozygous or homozygous for the B-haplotype.
Models were adjusted for disease severity, HLA-mismatch, and
patient age. There was no survival advantage to having a donor
with a B haplotype compared to AA donors (HR 1.05, 95% CI
0.80-1.37, p0.73). However, there was a signiﬁcant effect of
donor B haplotype on relapse, where the presence of a donor B
haplotype (n330) compared to donor AA (n162) was associ-
ated with signiﬁcantly lower hazard of relapse (HR0.41, 95%
CI 0.33-0.67, p0.0001). The haplotype B effect on relapse was
overwhelming strong in transplants for CML (n189,
HR0.15, 95% CI 0.08-0.27, p0.0001). There was no signif-
icant donor B-haplotype effect on relapse in AML (n104, HR
0.80, 95% CI 0.40-1.63, p0.54) or ALL (n96, HR 0.76, 95%
CI 0.30-1.95, p0.57). There was no clear association between
any speciﬁc activating KIR and decreased relapse, nor was there
was an association between cumulative numbers of activating
KIRs and decreased relapse. These results suggest that the
association between haplotype B and decreased relapse in CML
may be related to factors other than activating KIR present or
associated with the B-haplotypes and absent in the A-haplotype.
These results have implications for donor selection in patients
with CML who are referred for allogeneic transplantation.
246
ALLOGENEIC BLOOD AND MARROW TRANSPLANTATION IN THALAS-
SEMIA MAJOR CLASS 3: AN EXPERIENCE OF IRAN
Iravani, M.1, Ali Mogaddam, K.1, Nedaeifard, L.1, Khatami, F.1,
Gavamzadeh, A.1, Golibeygian, S.1, Bab Hadiashar, N.1, Jalili, M.1,
Tagipur, R.1, Gaffari, F.1, Mousavi, A.1 1Hematology-Oncology and
BMT Research Center, Tehran University of Medical Sciences, Tehran,
Islamic Republic of Iran.
Objective:Our aim for this study was to describe the outcome of
blood and marrow transplantation in patients with class 3 Thalas-
semia major.
Methods: Since December 1992 till september 2006, ﬁfty-two
patients with Thalassemia class 3 received blood and marrow
transplantation from their Human Leukocyte Antigen(HLA)-iden-
tical siblings. Thirty-two patients received bone marrow and
twenty patients received peripheral blood stem cell transplantation.
Conditioning regimen in 47 patients was Cyclophosphamide 40
mg/kg/day (from day–5 to -2) and Busulfan 3.5 mg/kg/day (from
day –9 to -6) and in these patients Graft Versus Host Disease
(GVHD) prophylaxis regimen was Cyclosporine.A (CY.A)
1.5mg/kg /day/IV (day–3), then 3mg/kg/day IV (days 7, 11),
then 12.5 mg/kg/day/PO and Methotrexate 10mg/m2 (day 1),
6mg/m
2
(days 3, 6). Conditioning regimen in 5 patients was
Fludarabin 40 mg/m2 (from –6 to –2) and Busulfan 4 mg/kg (from
–5 to –2) and in this patients GVHD prophylaxis regimen was
(CY.A) 3 mg/kg/day IV (days –3 and 7), then 12.5 mg/kg/day
PO.
Results: Median age at time of transplantation was 8.5 years
(age range: 1-26), Male/Female: 21/31.Median time of absolute
Poster Session II90


244: Fludarabine-based non-myeloablative stem cell transplantation in a patient with sickle cell disease and renal failure Clinical outcome and pharmacokinetic comparison to patients with normal renal function

file:///data/core-remote/dit/data/elsevier/pdf/8f6/aHR0cDovL2FwaS5lbHNldmllci5jb20vY29udGVudC9hcnRpY2xlL3BpaS9zMTA4Mzg3OTEwNjAxMTAxMw==.pdf

244: Fludarabine-based non-myeloablative stem cell transplantation in a patient with sickle cell disease and renal failure Clinical outcome and pharmacokinetic comparison to patients with normal renal function

Abstract

Similar works

Full text

Available Versions

Elsevier - Publisher Connector

Elsevier - Publisher Connector