Baker, S.

Blazar, B.R.

Burke, M.

Cao, Q.

Gulbahce, E.

MacMillan, M.L.

Orchard, P.

Tolar, J.

Verneris, M.R.

Wagner, J.E.

Elsevier - Publisher Connector 

Poster Session I 81iron overload pre-HSCT who required aggressive iron manage-
ment post-HSCT. Liver iron concentration (LIC), a surrogate of
total body iron burden, was assessed by liver biopsy and/ormagnetic
reasonance imaging (T2* or R2 MRI). Abnormal LIC was defined
as .1.5 mg iron/g dry liver tissue. Results: Patient characteristics
are presented in Table 1. 7 out of the 11 patients identified were
not previously known to have iron overload. The majority of these
patients presented with elevations in liver transaminases as the pri-
mary sign of excess iron. Liver biopsy and/or MRI were used to di-
agnose iron overload, and in all cases MRI was the method used to
assess the change in iron burden while patients were receiving ther-
apy. Most patients were managed with phlebotomy (range: 4–10 cc/
kg of blood removed every 2–4 weeks). Phlebotomy was effective in
reducing iron burden as evidenced by normalization of transami-
nases and decrease in LIC and ferritin. One patient, managed
with an oral iron chelator, did not have a reduction of overall iron
burden. Conclusions: . Iron overload should be considered in
HSCTpatients presenting with abnormal transaminases and/or hy-
perferritinemia after transplant. MRI is a useful diagnostic tool and
may obviate the need for invasive liver biopsy. Phlebotomy appears
to be effective in reducing iron burden, however the safety and effi-
cacy of chelators is not yet established. There is a need for prospec-
tive studies to define the prevalence of iron overload, establish
guidelines for screening, and develop safe and effective therapies.
As a result, we have initiated a prospective study using R2 MRI to
determine the incidence and morbidity associated with iron over-
load in this patient population.
Characteristics of Patients With Iron Overload
Condition LIC pre/postNumber Diagnosis, Age
Type of
HSCT
tLeading
o Iron Overload
Diagnosis oManagment
f Iron Overloadtreatment
(mg iron/g
liver)
mALT
ax/min
(u/L)Ferritin
max/min
(ng/mL)1 Relapsed
ALL, 1 yoMURD Abnormal LFT’s Phlebotomy 7.3/4.0 254/38 2,896/4492 PNH, 18 yo MURD Abnormal LFT’s Desferasirox 10.7/13.6 910/56 5,127/2,5273 Relapsed
ALL, 6 yoMURD Abnormal LFT’s Phlebotomy 5.1/1.9 404/57 4,071/7964 Relapsed
ALL, 10 yoMURD Abnormal LFT’s Phlebotomy 16.0/– 314/53 5,586/2,3505 Sickle
Cell Anemia, 9 yoMRD Abnormal LFT’s Phlebotomy
planned4.9/– 313/– 1,810/–6 AML, 4 yo MRD Hyperferritinemia Phlebotomy
planned5.1/– 70/– 1,938/–7 ALL, 12 yo 4/6 Cord Abnormal LFT’s Phlebotomy
planned13.0/– 209/– 3,645/–8 Diamond-
Blackfan
Anemia, 9 yoMRD Chronic
transfusion
historyPhlebotomy 17.5/0.9 13/4 1,029/1199 Aplastic
Anemia, 6 yoMRD Chronic
transfusion
historyPhlebotomy 22.5/– 35/20 4,574/2,82410 Beta-
thalassemia,
8 yoMRD Chronic
transfusion
historyPhlebotomy 7.0/– 38/31 3,900/65811 Beta-
thalassemia,
7 yoMRD Chronic
transfusion
historyPhlebotomy
planned8.6/– 94/41 1,888/–Abbreviations: PNH 5 Paroxysmal Nocturnal Hemoglobinuria,
ALL5Acute Lymphoblastic Leukemia, AML5AcuteMyeloid
Leukemia, MURD 5 Matched Unrelated Donor, MRD 5
Matched Related Donor, ALT 5 Alanine Aminotransferase.
217
CHALLENGES IN THE USE OF HEMATOPOIETIC STEM CELL TRANSPLAN-
TATION FOR ECTODERMAL DYSPLASIA WITH IMMUNE DEFICIENCY
Fish, J.D.1, Duerst, R.E.2, Gelfand, E.W.3, Orange, J.4, Bunin, N.1.
1The Children’s Hospital of Philadelphia, Philadelphia, PA; 2Children’s
Memorial Hospital, Chicago, IL; 3National Jewish Medical and ResearchCenter, Denver, CO; 4The Children’s Hospital of Philadelphia, Philadel-
phia, PA.
Genetic mutations affecting regulatory proteins of NF-kB result
in heritable diseases of development and immunity. Hypomorphic,
X-linked mutations in the IKBKG gene (NEMO protein), and hy-
permorphic, autosomal dominant mutations in the IKBA gene
(IkBa protein), are associated with a phenotype of ectodermal dys-
plasia with immune deficiency (ED-ID). ED-ID predisposes pa-
tients to bacterial and mycobacterial infections, and is typically
fatal. Allogeneic HSCT may correct the immune deficiency associ-
ated with NEMO or IkBamutations, but there are few reports. We
report 3 patients with ED-ID who underwent HSCT. All patients
experienced engraftment difficulties. Patient 1 presented with fe-
vers, diarrhea, diffuse erythema and desquamation. Hypogamma-
globulinemia with normal B- and T- cell numbers and subsets
were noted, and genetic analysis revealed a hypomorphic NEMO
mutation. He received matched sibling donor peripheral blood
stem cells (PBSC) at 6 months following reduced-intensity condi-
tioning with fludarabine, busulfan and ALG. Neutrophil engraft-
ment was achieved at day 117, and maximal donor T-cell
chimerism of 53% at day 177, which then declined. A second
PBSCT from the same donor was undertaken after conditioning
with alemtuzumab, fludarabine and melphalan, with stable donor
chimerism through day1310. Patient 2 developed diarrhea, failure
to thrive and recurrent infections including MAI. Inadequate anti-
body responses, but normal B- and T- cell numbers and subsets
were noted. Genetic analysis demonstrated a hypomorphic
NEMO mutation. A MUD BMT was performed at 3 years of age
following myeloablative conditioning with busulfan, cyclophospha-
mide and ALG. Poor engraftment was noted, with persistent neu-
tropenia despite chimerism of 95% donor at day 138. The
patient was re-conditioned with fludarabine, and a CD34-selected
PBSC boost from the same donor. Although complete chimerism
was achieved, the patient remained pancytopenic and died at day
1314 of gram-negative infection. Patient 3 presented with recur-
rent bacterial infections, p.carinii, and chronic diarrhea. Genetic
analysis confirmed an IkBa mutation. The patient underwent
a MUD cord blood transplant following myeloablative condition-
ing with busulfan and cyclophosphamide, but expired from sepsis
prior to engraftment. These cases suggest that patients with im-
mune deficiencies caused by NEMO or IkBa mutations may have
intrinsic barriers to successful engraftment, which require further
investigation.
218
LOWER LEUKEMIA RELAPSE IN PATIENTS WITH PULMONARY CYTO-
LYTIC THROMBI AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANS-
PLANT
Verneris, M.R.1, Gulbahce, E.2, Burke, M.1, Cao, Q.1,
MacMillan, M.L.1, Tolar, J.1, Orchard, P.1, Blazar, B.R.1, Baker, S.1,
Wagner, J.E.1. 1University of Minnesota, Minneapolis, MN; 2Univer-
sity of Minnesota, Minneapolis, MN.
Pulmonary cytolytic thrombi (PCT) is an uncommon post-trans-
plant complication, which is more commonly reported in children
than adults. PCT typically presents with low grade fever, cough,
shortness of breath and/or hypoxia. Lung CT findings range from
small, peripheral nodules to large diffuse infiltrates. The diagnosis
is established by lung biopsy, which reveals areas of the pulmonary
vasculature which are occluded with cellular debris. Bronchoscopy
and lung biopsy are negative for infectious organisms by both im-
muno-stains and culture.While the pathogenesis of PCT is not cur-
rently known, it has been previously shown that patients with PCT
frequently have concurrent aGVHD and that PCT responds to sys-
temic corticosteroid treatment. Considering that such treatment
may impair graft vs. leukemia (GVL) reactions, we investigated
the outcome of patients who developed PCT after transplantation
for hematological malignancy. From 1993–2006, we identified 14
pediatric patients with biopsy proven PCT and a hematological ma-
lignancy (9 ALL, 3 AML and 2 CML). PCTwas diagnosed at an av-
erage of 901/-38 days (range 38–342) after transplant. We
compared outcomes to a cohort of pediatric leukemia patients
that not develop PCT, but were transplanted during the same
time interval (n 5 323). There were no significant differences
82 Poster Session Ibetween the two groups with respect to age, gender, disease type, or
CMVstatus. Likewise, therewere no significant differences between
thePCTand control groupswith respect to donor source (related vs.
unrelated), progenitor cell source (BM vs. UCB) or HLA disparity.
In this cohort, PCT patients were more likely to have grade II-IV
aGVHD (86 vs. 35%, p 5 0.01) and grade III-IV aGVHD (35 vs.
15%, p 5 0.03). Similarly, PCT patients were more likely to have
cGVHD (36% vs. 13%, p 5 0.01). The cumulative incidence of
non-relapsemortality and overall survival at 5 yrs, however,was sim-
ilar in both groups (p5 0.29 and p5 0.12, respectively). In univar-
iate analysis, a significantly lower risk of relapse at 3 years was noted
in patients with PCT (0% vs. 30% [25–36%], p5 0.02). In Cox re-
gression, aGVHD (p5 0.05), cGVHD (p5 0.01) and development
of PCT (p\0.01) were associated with protection form relapse. Of
the 6 deaths in the PCT group, 5 patients had pulmonary complica-
tions at the time of death. Collectively these data suggest that pa-
tients with PCT are at high risk for cGVHD and pulmonary
associated toxicity, but lower risk of relapse.
219
HYPERCALCEMIA AFTER HEMATOPOIETIC STEM CELL TRANSPLANTA-
TION FOR OSTEOPETROSIS
Martinez, C.1, Orchard, P.J.1, Wagner, J.E.1, Petryk, A.2, Tolar, J.1.
1University of Minnesota, Minneapolis, MN; 2University of Minnesota,
Minneapolis, MN.
Osteopetrosis (OP) is a clinical syndrome characterized by insuf-
ficient osteoclastic activity resulting in defective bone resorption
and marked increase in bone density. The recessive form of osteo-
petrosis (‘‘malignant osteopetrosis’’) has been successfully treated
with allogeneic hematopoietic cell transplantation (HCT), second-
ary to engraftment of donor-derived functioning osteoclasts result-
ing in bony remodeling and establishment of normal hematopoiesis.
While hypocalcemia is a common presenting feature of recessive os-
teopetrosis, hypercalcemia may be observed following HCT due to
rapid engraftment of osteoclasts differentiated from the hematopoi-
etic precursors. To investigate the incidence of hypercalcemia after
HCT, we have evaluated nine patients with osteopetrosis (a median
age of 2 years, range 0.5 – 28 yrs) treated at the University of Min-
nesota during a 7 year period (2000–2007). Eight patients were re-
ceiving their initial transplant, and one patient received a second
HCT, following graft failure. The conditioning regimen consisted
of busulfan, fludarabine, equine ATG and total lymphoid irradia-
tion. Donor grafts consisted of URD BM (2), URD UCB (3),
REL PBSC (2), and URD PBSC (2). All patients that received
a BM or PBSC graft engrafted with donor grafts, while recipients
of UCB had a transient partial engraftment followed by autologous
recovery. The median day of myeloid recovery (defined as an abso-
lute neutrophil count of 500 or above for 3 consecutive days) was
day 20 (range 14–42 days). Elevated calcium levels were found in
three of the nine patients. The elevation of calcium levels was ob-
served at a median day 12 (range 10–15) which correlated with ini-
tial count recovery. The median day of highest calcium levels in
these three patients was day 21 with a mean calcium level of 12.9
mg/dL (SD 1.18). Clinically, hypercalcemia was managed with in-
travenous fluids, furosemide diuresis and calcitonin. The median
age of the group of patients with hypercalcemia was 24 years. In
contrast the median age of the patients that didn’t experience hyper-
calcemia was 1 year of age. No correlation was found between hy-
percalcemia and type of donor graft, HLA match, or CD341 cell
dose. The implications of the current study are that hypercalcemia
occurs after HCT in approximately one third of theOP patients and
that it may be more common in older patients, perhaps due to age
dependent increase in bone mass.
220
TOLERABILITY OF DAPSONE IN PEDIATRIC HEMATOPOIETIC STEM
CELL TRANSPLANT
O’Connor, M.R., Duncan, C., Myers, K., Lehmann, L. Dana-Farber
Cancer Institue, Boston, MA.
Dapsone is a commonly used drug for pneumocystis carinii pneu-
monia (PCP) prophylaxis in pediatric Hematopoietic Stem CellTransplant (HSCT) patients. However, its use is frequently limited
by toxicities such as hemolysis and methemoglobinemia. We per-
formed a retrospective medical record review of all pediatric
HSCT patients at our institution between January 1, 2001 and
June 8, 2007. We identified all patients that received dapsone as
PCP prophylaxis and documented course limiting adverse effects.
402 patients received 447 transplants during the study period. Dap-
sone was prescribed as PCP prophylaxis in 111 instances (24.8%). In
27.9% of these instances patients completed the recommended
course without incident. 72.1% of the time patients were changed
to an alternative prophylactic agent due to dapsone-associated ad-
verse events.Hemolysis was themost common reason for discontin-
uation of dapsone and it occurred in 41(36.9%) cases.
Methemoglobinemia was the second most common adverse effect
and it occurred in 27 (24.3%) instances. The mean methemoglobin
level for this group was 4.4% with a range of 2.2–16% (upper limit
of normal at our institution is 1.5%). Dapsone was discontinued in
the remaining patients because of rash (7), increased liver function
tests (1), and tachycardia and vertigo (1). Three patients were lost
to follow-up. In patients who received dapsone there were no docu-
mented cases of PCP.Dapsonewas an effective, yet poorly tolerated
agent in this group of pediatric stem cell transplant patients. Pro-
viders should maintain a high level of awareness for toxicities
when utilizing dapsone in pediatric stem cell transplant patients.221
PRELIMINARY RESULTS OF NON-ABLATIVE CONDITIONING (NAC)
WITH BUSULFAN (Bu), FLUDARABINE (Flu) AND ALEMTUZUMAB FOL-
LOWED BY ALLOGENEIC STEM CELL TRANSPLANTATION (AlloSCT) TO
INDUCE MIXED DONOR CHIMERISM IN PATIENTS WITH SICKLE CELL
DISEASE (SCD)
Bhatia, M.1, Baldinger, L.1, Billote, G.1, Morris, E.1, Bradley, M.B.1,
George, D.1, Garvin, J.1, Satwani, P.1, Schwartz, J.1, Wolownik, K.1,
Foley, S.1, Hawks, R.1, Baxter-Lowe, L.A.2, Cairo, M.S.1. 1Columbia
University, New York, NY; 2UCSF, San Francisco, CA.
SCD is associated with a decrease in lifespan and quality of life in
children. The only known cure is AlloSCT from a matched family
donor with only 15% of patients having an unaffected, HLA-
matched identical sibling. Patients undergoing myeloablative Al-
loSCT are at risk for numerous complications post SCT including
death, graft versus host disease (GVHD), and infections. Full donor
chimerism is not necessary to correct the underlying genetic defect
and eliminate symptoms in patients with SCD. In this study, we re-
port the preliminary results of NAC and AlloSCT from related
matched family and unrelated umbilical cord blood (UCB) donors
in 7 patients (7M:0F) with high risk SCD (HbSS 5 4, HbSC 5 2,
HbSßThal 5 1). Conditioning was Bu (4 mg/kg  4 d # 4 yrs
and 12.8 mg/kg  4 d . 4 yrs), Flu (30 mg/m2  6 d), and Alemtu-
zumab (2 mg/m2 1 d, 6 mg/m2 2 d, and 25 mg/m2 2 d). UCB
recipients also received rabbit antithymocyte globulin (2 mg/kg 4
d). Mean age was 5.8 years 1/-4.03 (1.4–13.75 years). Donor sour-
ces were: 2 6/6 HLA-matched sibling bone marrow (BM), 2 6/6
HLA-matched UCB, and 3 4/6 unrelated UCB. Mean cell dose
was 12.021/-13.0  107 TNC/kg and 1.031/-1.66  106 CD34/
kg. Patients received tacrolimus and mycophenolate mofetil as
GVHD prophylaxis and phenytoin as seizure prophylaxis for 180
days post SCT. Of 5 patients evaluable for myeloid recovery (1
did not nadir, 1 too early), mean neutrophil and platelet recovery
was on day1306 7(n5 5) and day1606 18(n5 5), respectively.
One patient had primary graft failure at day 160 post SCT (Bu
steady state concentration (Css) 552 ng/ml). Busulfan pharmakoki-
netics were then changed to maintain Css between 600–900 ng/ml.
Mean whole blood donor chimerism on days 130, 160, and 1100
was 49%633(n5 6), 61%632(n5 5), and 82%613(n5 4), respec-
tively. More recently, erythroid engraftment (CD71) is being deter-
mined. Mean CD71 chimerism on days 130 and 160 was
55.3%641(n 5 3) and 61.1%617.5(n 5 3), respectively. Hb elec-
trophoresis was done on all patients with mean %HbS levels of
1.80 6 1.02(n 5 5) and 7.46 6 9.88(n 5 5) on days 130 and
1100, respectively. Grades II-IV acute GVHD was seen in 3/7 pa-
tients(42%). Chronic extensive GVHD was seen in 1/5(20%) pa-
tients. All patients are alive with the longest follow up being 1120


218: Lower Leukemia Relapse in Patients with Pulmonary Cytolytic Thrombi after Allogeneic Hematopoietic Cell Transplant 

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218: Lower Leukemia Relapse in Patients with Pulmonary Cytolytic Thrombi after Allogeneic Hematopoietic Cell Transplant

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