Allogeneic Bone Marrow Transplantation From HLA Identical Related Donors for Patients With Hemoglobinopathies: Hemoglobin SS, Hemoglobin SC, or Hemoglobin SB0/+ Thalassemia
Phase: NA
Conditions: Sickle Cell Disease, Hemoglobin SC
Sponsor: Tami D. John

SCALLOP - 1
October 1, 2004 Version 1.0
3-4-05 Version 1.1
3-8-06 Version 2.0
10-11-06 Version 3.0
4-17-07 Version 4.0
11-26-08 Version 5.0
10-29-09Version 6.0
7-16-13Version 7.0
10-04-13Version 8.0
ALLOGENEIC BONE MARROW TRANSPLANTATION
FROM HLA IDENTICAL RELATED DONORS
FOR PATIENTS WITH HEMOGLOBINOPATHIES: HEMOGLOBIN SS,
HEMOGLOBIN SC, OR HEMOGLOBIN Sf30/+ THALASSEMIA
PRINCIPAL INVESTIGATOR
Kathryn S. Leung, MD
CO-INVESTIGATORS
Robert Krance, MD
Malcolm K. Brenner, PhD, FRCP, MRC Path
George Carrum, MD
Adrian Gee, MI Biol PhD
Helen E. Heslop, MD, FRACP, FRCPA
Stephen Gottschalk, MD
Donald Mahoney, MD
Bambi Grilley, RPh
Caridad Martinez, MD
Texas Children’s Hospital
6621 Fannin Street
Houston, TX 77030-2399
Houston Methodist Hospital
6565 Fannin Street
Houston, TX 77030-2707

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TABLE OF CONTENTS
ELIGIBILITY CHECKLIST ..........................................................................................................
3
1.0 OBJECTIVES'........................................................................................................................
5
2.0 BACKGROUND.....................................................................................................................
5
3.0 DRUG INFORMATION..........................................................................................................................
10
4.0 PATIENT ELIGIBILITY ........................................................................................................................
17
5.0 STUDY DESIGN ....................................................................................................................
19
6.0 TREATMENT PLAN.............................................................................................................
19
8.0 LABORATORY EVALUATION ..........................................................................................................
22
9.0 EVALUATION CRITERIA....................................................................................................................
24
10.0
CRITERIA FOR TAKING PATIENT OFF STUDY....................................................................
25
11.0
REPORTING REQUIREMENTS.....................................................................................................
25
12.0
STATISTICAL CONSIDERATIONS...............................................................................................
26
13.0
INVESTIGATOR'S BROCHURE WAIVER.................................................................................
27
14.0
REFERENCES....................................................................................................................
28
15.0
APPENDICES .....................................................................................................................
34
APPENDIX 1: SICKLE CHRONIC LUNG DISEASE STAGING CRITERIA ..................
34
APPENDIX 2: COMMON TOXICITY CRITERIA.................................................................
36

S C A L L O P - 3
E LI GI BI LI T Y C H E C K LI S T
P A TI E N T I D
P A TI E N T N A M E
Y E S
N O
V A L U E
T h e p atie nt m ust ha ve h o m oz y g o us he m o gl o bi n S, or he m o gl o bi n S C, or he m o gl o bi n
S 0 t h al ass e mia.
P atie nts wit h S C D or its varia nts m ust ha ve se vere he m o gl o bi n o pat h y defi ne d as:

Pre vi o us ce ntral ner v o us s yste m vas o- occl usi ve e pis o de wit h or wit h o ut resi d ual
ne ur ol o gic fi n di n gs or

Fre q ue nt pai nf ul vas o- occl usi ve e pis o des w hic h si g nifica ntl y i nterfere wit h
n or mal lif e acti vities a n d necessit ate c hr o nic tra nsf usi o n t hera p y or

Rec urre nt S C D c hest s y n dr o me e pis o des w hic h necessitate c hr o nic tra nsf usi o n
t h era p y or

Se vere a ne mia w hic h pre ve nts acce pta ble q ualit y of life a n d necessitates c hr o nic
tra nsf usi o n t her a p y
O R h a ve t he f oll o wi n g criteria defi ne d as:

A n y of t he a b o ve s y m pt o ms i n w hic h t he patie nt is n ot u n der g oi n g c hr o nic
tra nsf usi o n t her a p y

T he p atie nt is u n der g oi n g c hr o nic tra nsf usi o n t her a p y f or s y m pt o ms ot her t ha n
t h at liste d a b o ve a n d w hic h si g nifica ntl y i nt erfer es wit h n or mal life acti vities

Faile d h y dr o x y urea t hera p y

A b n or mal tr a nscra nial D o p pl er ultras o u n d

A b n or mal
M RI/ M R A of t he brai n

I n dicati o n of p ul m o nar y h y perte nsi o n o n 2 se parate ec h ocar di o gra m
e xa mi n ati o ns

Patie nts w h o pla n t o ret ur n t o res o urce p o or areas or c o u ntries
T he p atie nt m ust ha ve a n H L A ge n ot y pe i de ntical d o n or or 5/ 6 H L A matc he d relate d
d o n or
Bet w ee n t h e a ges of birt h a n d 4 0 ye ars.
W o me n of c hil d b eari n g p ote nti al m ust ha ve a ne gati ve pre g na nc y t est.
Bi o ps y pr o ve n c hr o nic acti ve he patitis or cirr h osis.
S C D c hr o ni c l u n g disease > sta ge 3 (s ee A p pe n di x 1)
Creati ni n e cleara nce < 4 0 ml/ mi n/ 1. 7 3
M 2
Se vere car diac d ysf u ncti o n defi ne d as s h orte ni n g fracti o n < 2 5 % or N Y H A class III or
gr eater
HI V i nfecti o n
Se vere b ut u ns pecifie d c hr o nic or ga n t o xicit y w hic h is li kel y t o di mi nis h t he patie nt's
ca p acit y t o s ur vi ve t he i m m e diate p ost B M T p hase
I na de q uate i ntellect ual ca pacit y t o gi ve i nf or me d c o nse nt (i n t he case of mi n ors, t his
criteria m ust b e f ulfille d b y t he l e gal g uar di a n)
Be pr e g n a nt, l actati n g or u n willi n g t o us e a p pr o priat e birt h c o ntr ol
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
T he patie nt m ust n ot
ha ve:
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _

SCALLOP - 4
To check eligibility call Dr. Leung or Dr Krance at 832-824-4219. For patient registration, contact the research
coordinator at 832-824-4881.
Signature ofM.D.
NOTE: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at
the investigator’s discretion after approval from the CCGT Protocol Review Committee and the FDA Reviewer.

SCAL
LOP - 5
1.0 OBJECTIVES
1.1
To evaluate recovery of organ function known to be compromised in
patients with sickle cell disease (SCD) or sickle hemoglobin variants
(hemoglobin SC or hemoglobin SJ30/+) after undergoing allogeneic SCT
from HLA genotype identical donors. Specifically, to determine whether
organ dysfunction (brain, heart, lung, kidney, liver, spleen, etc.) secondary
to these severe hemoglobinopathies can be improved or reversed following
allogeneic BMT.
1.2
To evaluate the use of PET scan examination in assessing metabolic
function of organs known to be compromised in patients with SCD,
hemoglobinSC, or hemoglobin SJ30/+ after undergoing allogeneic SCT
from HLA genotype identical donors. Specific organs for evaluation
include brain, spleen, kidney, and bone.
1.3
To evaluate response to immunization after BMT in patients with SCD,
hemoglobin SC, or hemoglobin SJ30/+.
2.0 BACKGROUND
Allogeneic SCT for severe hemoglobinopathies
Data from the Cooperative Study of Sickle Cell Disease (CSSCD) indicates that
85% of children with SCD are likely to survive to their twentieth birthday.1 This is
an improvement over the 50% probability of survival noted during the 1960s.2
This improvement is largely attributed to better overall medical management of
sickle cell disease, patient education, vaccination against Streptococcus
pneumoniae and Hemophilus influenza B, and possibly to prophylactic
administration of penicillin.1 Nevertheless, the life expectancy and mortality rate
remain unacceptable. Table 1 presents the cause of death among 2,824 children
with sickle hemoglobinopathies as reported by the CSSCD.1
Table 1
CAUSE OF DEATH
NUMBER OF PATIENTS (%)
Bacterial infection
28 (38.4%)
Cerebrovascular accident
9 (12.3%)
Other

Sickle cell disease related
8(11.0%)

Non-sickle cell disease related
5(6 8%)
-
Trauma
-
Other
4(5.5%)
Unknown

Died outside CSSCD center
14(19.2%)

Died at CSSCD center
-
Autopsy not performed
3(4.1%)
-
Autopsy performed
2(2.7%)

S C A L L O P -
T he hi g h m ortalit y r at e is m ai nt ai ne d after a ge 2 0. As S C D pati e nts a ge, e n d
or ga n fail ure of l u n g, ki d ne y, a n d brai n res ults i n pre mat ure deat h. At prese nt, t he
me dia n s ur vi val f or me n wit h S C D is 4 2 years a n d f or w o me n 4 8 years. 3
C o m pare d t o t he e ntire Afr o- A meri ca n p o p ulati o n, life e x pecta nc y f or S C D
patie nts is decrease d 2 5- 3 0 years.
Be y o n d t he hi g h m ortalit y rate, S C D patie nts e nc o u nter m or bi dit y t hat se verel y
de mea ns t heir q ualit y of life. Pai n crisis, ac ute c hest s y n dr o me, a n d ha n d-f o ot
s y n dr o me ma y re q uire fre q ue nt h os pitalizati o n.
M ore f ore b o di n g se q uelae are
t h ose t hat per ma ne ntl y disa ble, i ncl u di n g re nal fail ure, c hr o nic le g ulcers,
reti n o pat h y, pria pis m, a n d oste o necr osis. Fi nall y, t here are t h ose e ve nts, s uc h as
str o ke, t hat n ot o nl y per ma ne ntl y disa ble b ut als o place t he patie nt at i m mi ne nt
ris k of deat h.
C hr o nic bl o o d tra nsf usi o n is o ne f or m of t hera p y t o pre ve nt sic kli n g. Dil uti o n of
t he S C D patie nt's re d cells b y tra nsf use d re d cells i n hi bits t he i n viv o d y na mics
t hat pr o m ote sic kli n g. He m o gl o bi n S c o nce ntrati o n m ust be mai ntai ne d bel o w
3 0 % f or t his t hera p y t o be effecti ve. 5 H o we ver, c hr o nic tra nsf usi o n is n ot wit h o ut
ris ks. I nfecti o n, re d cell se nsitizati o n, a n d tr a nsf usi o n reacti o n are p ote ntial
hazar ds; a n d l et hal ir o n acc u m ulati o n is a n i ne vit a ble c o nse q ue nce u nless
c hel ati o n is pr o vi de d. Effecti ve ir o n c helati o n re q uires Def er o xa mi ne
a d mi nistrati o n, i ntra ve n o us or s u bc uta ne o us, 5- 7 da ys per wee k, u p t o 1 0 h o urs
per da y. T he a n n ual e x pe nse of t his treat me nt is esti mate d t o ra n ge bet wee n
$ 1 0, 0 0 0 a n d $ 3 0, 0 0 0. E ve n f or patie nts wit h a de q uate res o urces, t his t hera p y is
de ma n di n g. A n d f or t h ose li vi n g i n u nacce pta bl e s ocial circ u msta nces, t he
de ma n ds ma y be i ns ur m o u nta ble.
O nce i nitiate d, t here is n o rec o urse; tra nsf usi o n t hera p y m ust be c o nti n ue d
i n defi nitel y. T he c o nse q ue nces of lifel o n g treat me nt are lar gel y u n k n o w n. Patie nt
c o m plia nce will u n d o u bte dl y di mi nis h as t he d urati o n of treat me nt is e xte n de d.
Re d cell se nsitizati o n a n d t o xi cit y fr o m Defer o xa mi ne t hera p y are als o m or e
li kel y t o occ ur. A n d if t he e x perie nce of t halasse mic patie nts is rele va nt, 1 0 t o 1 5
years of c hr o nic tra nsf usi o n a n d c helati o n is li kel y t o res ult i n he m osi der osis a n d
dia betes. 2 6 It is f or all t hese reas o ns t hat tra nsf usi o n t hera p y is c o nsi dere d o nl y f or
t h ose patie nts w h ose life is clearl y e n da n gere d. F or S C D patie nts w h ose s ur vi val
is n ot i m me diatel y t hreate ne d, li vi n g wit h se vere m or bi dit y is t heir o nl y o pti o n.
C urre ntl y, a n acce pte d alter nati ve t hera p y is H y dr o x y urea ( H U), a
c he m ot hera pe utic a ge nt t hat is k n o w n t o i ncrease fetal he m o gl o bi n pr o d ucti o n.
T his a ge nt i nterr u pts D N A s y nt hesis b y i n hi biti n g ri b o n ucle osi de di p h os p hate
re d u ct as e. It is t h o u g ht t hat H U pr o d uc es a t o xi c eff e ct o n l at e er yt hr oi d
pr o ge nit or cells w he n it i nterr u pts D N A s y nt hesis i n t hese ra pi dl y di vi di n g cells.
T his t he n lea ds t o stress er yt hr o p oiesis, w hic h i ncreases t he n u m ber of “ F cells,”
res ulti n g i n fetal he m o gl o bi n pr o d ucti o n.6 4 I ncreasi n g fetal he m o gl o bi n als o
lea ds t o i n hi biti o n of H b S p ol y merizati o n wit h t he i ncrease d i n s ol u bilit y of c 2f 3S 
h y bri d m olec ules. 6 5

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Multiple reports looking at HU therapy have shown a significant decrease in
hospitalization due to recurrent vasoocclusive crisis (VOC). In addition Ferster et
al showed a significant decrease in the number of transfusion per patient-year
from 1.83 before HU therapy to 0.2 after HU therapy. However, to date, there is
no evidence for HU therapy to be beneficial to patients with a history of stroke(s).
It is also not known what the long-term side effects would be in a population who
will require life long therapy. Of concern is the leukemogenic property of this
chemotherapeutic agent. Other side effects that are common include dose
dependent transient myelosuppression, nausea, vomiting, and skin rash. These
side effects tend to occur in the acute phase of treatment.65
Other medical treatments are available, but are currently in ongoing studies with
little data. Theses studies include nitric oxide, magnesium supplementation, and
short chain fatty acid such as butyrate therapy. However, none of the above
mentioned therapies offer a potential cure for patients with SCD.
Given the current dilemma, allogeneic BMT is now being utilized as an
alternative therapy for patients with severe SCD.6 The interest has been prompted
by the successful use of BMT for patients with homozygous j3+/0 thalassemia.7
These patients encounter problems similar to those of SCD patients, including
disturbances in growth and sexual maturation, episodic bacteremia, and end organ
failure. Likewise, management with chronic transfusion and chelation therapy has
been used to ameliorate the disease process.8 With alloBMT, the defect that
underlies the pathophysiologic basis for the disease, namely absence of j3 chain
synthesis, is corrected once donor hematopoiesis is established. A recent report
details the outcome for 222 patients with thalassemia following alloBMT.9
Among patients with adequate iron chelation and without hepatomegaly or portal
fibrosis, the probability of survival and event-free survival are 97% and 94%
respectively. This rivals if not surpasses the survival of patients maintained on
chronic transfusion and chelation.26 Even for patients with some degree of
hepatomegaly, less optimal iron chelation, or portal fibrosis, disease free survival
is 85%. Only for patients with abnormal findings for all these does disease free
survival fall to 64%57,58. At present, hematopoietic stem cell transplantation must be
considered the optimal therapy for patients with severe j3 thalassemia who have an
HLA identical related donor. Such patients are eligible for treatment on this study
as in keeping with best clinical practice.
The first BMT for a patient with SCD was performed at St. Jude Children’s
Research Hospital (SJCRH). 10 The indication for transplantation was to treat this
patient's acute myeloid leukemia and not to cure sickle cell anemia. The donor
was an HLA genotype identical brother with sickle cell trait. The BMT
preparatory regimen included single fraction total body irradiation (TBI) and
cyclophosphamide; methotrexate and prednisone were used to prevent graft-
versus-host disease (GVHD). White cell engraftment occurred at day 12, and
platelet engraftment at day 20. Acute GVHD grade III involving the skin and

SCALLOP -
Currently, very little has been reported about organ function after BMT in patients
with sickle cell anemia. Evaluation of splenic function with nuclear scintigraphy
gastrointestinal tract developed 6 weeks post transplant and evolved into chronic

SCALLOP -
9
skin GVHD. Although the patient endured a complicated post transplant course,
hematologic remission with full chimerism persists to this date.
Subsequently a number of centers here and in Europe undertook allogeneic SCT for
patients with SCD. European investigators advocated SCT for any SCD patient for
whom an HLA matched related donor was identified; their SCD patients were
temporary resident African children destined to return to medically poorly served
areas.10-12 More recently indications for SCT follow the eligibility criteria as
proposed by the consensus conference.52 Vermylen reported the results of SCT for 50
patients, 36 of whom met the consensus criteria.53 All patients received
myeloablative conditioning and cyclosporine combinations for GHVD prevention.
Event-free survival remained at 82% overall and 76% for patients transplanted for
significant sickle cell disease-related morbidity. Overall survival stood at 93% but
88% for the more severely affected cohort. Three patients never engrafted, and 2
patients developed delayed graft rejection. Two patients died--one from
complications of GVHD and the other from sudden death 6 years post transplant.
Only 1 patient developed acute GVHD grade III.
Additionally, Walters et al looked at 50 children from the US and Europe who
were less than 16 years of age with symptomatic disease and who had an HLA
matched related allogeneic donor. Indications for SCT included a history of
stroke, recurrent acute chest syndrome or sickle pulmonary disease, and recurrent
vaso-occlusive crises. Forty-seven of the 50 patients survived with a median
follow-up of 38.6 months. Forty-five patients demonstrated stable engraftment of
donor hematopoietic cells. Graft rejection or recurrence of sickle cell disease
occurred in five patients, and three patients died of intracranial hemorrhage or
GVHD.62 Overall survival was 94% and EFS 84%.
Our experience includes 7 patients with SCD (meeting the consensus criteria for
eligibility) with median follow-up of 24.5 months (range 1yr-6yr). All patients
received stem cells from sibling donors of which five were fully matched and 1
was 5/6 HLA matched donor; all engrafted. Two patients had stable mixed
chimerism, but without evidence of disease. GVHD either did not develop or was
grade I, and all patients are alive. To date, overall survival is 100% with EFS
100%.
In summary the experience of SCT in SCD and thalassemia affirms the feasibility
of this undertaking. With alloSCT patient hematopoiesis can be ablated, and
donor hematopoiesis established. Data also indicate that SCT can be
accomplished without adversely impacting survival and without causing lasting
procedure- related morbidity. What remains uncertain is whether SCT will
prevent progressive organ damage and improve the quality of life. The next goal
is to assess organ functions in SCD patients after SCT. We plan to evaluate post
SCT organ functions by using Positron Emission Tomography (PET) technology,
a novel approach in the SCD patient population.
Organ function evaluation in patients with sickle cell disease

SCALLOP - 10
has shown recovery of function after BMT in 3 patients when splenic function
was investigated.67 Walters et al showed pulmonary function to be stable or
improved in a series of 26 patients with sickle cell anemia after BMT.
Additionally, CNS abnormalities have been shown to be stabilized after BMT
using follow up MRI studies. In one case report osteonecrosis was seen to be
improved after allogeneic BMT in a teenage boy with sickle cell disease.68
Currently, data that have been reported on organ evaluation in patients with SCD
post BMT involve use of conventional radiographic techniques. A powerful and
promising scanning technique, positron emission tomography (PET) has been
used to look at CNS abnormalities in patients with sickle cell anemia.
Information about vascular blood flow using [15 O]-H2O and tissue metabolism
using [18F]-fluoro-D-deoxy-glucose (FDG) can be deduced from PET scan. An
advantage of PET is its ability to objectively quantify FDG uptake using
standardized ratios for various organs. In SCD patients multiple reports have
shown larger areas of abnormalities in the brain with regards to vascular flow and
metabolic uptake on PET evaluation when compared to MRI findings in patients
with sickle cell anemia.69-70 Additionally, there have been abnormal findings on
PET evaluation of the brain despite normal MRI results in patients with sickle
cell.
PET scan has also been useful in evaluating other organs beside the CNS under
various medical conditions. These medical conditions include malignancies,
infections, and areas of inflammation that involve the bone, kidneys, and lungs.
These organs are known to be compromised in patients with sickle cell anemia.
Selection of sickle cell patients eligible for SCT
Increased blood flow velocity in the distal internal carotid artery and middle
cerebral artery on transcranial doppler evaluation has been shown to be a predictor
of future cerbrovascular event (CVA) in patients with SCD.71 This has been
further confirmed by the recent STOP trial looking at prevention of stroke using
chronic transfusion therapy in patients who are high risk for CVA based on an
abnormal transcranial doppler. Following a cerebrovascular event, SCD patients
are at excessive risk of subsequent stroke. In one report, two-thirds of the patients
experienced a second event, usually within 12 to 24 months.5
As detailed above, chronic transfusion therapy with chelation is the only
acceptable therapy. Unfortunately, transfusion therapy once initiated must be
continued lifelong. Discontinuing transfusion therapy even after 12 years has
precipitated a subsequent stroke19, but a lifelong transfusion and chelation
program is unlikely to be successful for all the reasons mentioned. For patients in
this quandary, BMT may be an acceptable alternative.
Sickle cell chronic lung disease (SCCLD) is an unremitting, progressive, and
invariably fatal complication of SCD.20 Typically, symptoms and signs become
evident in the second decade. Recurrent episodes of acute chest syndrome often
herald its onset. Diagnosis and staging of SCCLD utilizes a constellation of

SCALLOP - 11
clinical symptoms, chest x-ray changes, and alteration in pulmonary function

SCALLOP - 12
tests.20 Although sudden death from myocardial hypoxia can be a terminal event,
most patients die from pulmonary failure. On average, patients with stage I
SCCLD survive 7.1 years.20 There is no treatment, and the palliating role of
transfusion and chelation is not established. The implacable threat of SCCLD
justifies the risk of BMT as an alternative to transfusion.
Frequent pain crisis can have mortal consequences for SCD patients and BMT
may be justified therapy for such patients. Data from the CSSCD unequivocally
establish that after age 20 years, patients having 3 or more pain crises per year die
prematurely. Median survival is reached 10 years earlier for these patients
compared to that for patients having fewer crises.21 Until the CSSCD data became
available, pain crisis was generally considered a universal feature of SCD. In
reality, individual patients tend to maintain a characteristic pain rate (the number
of pain crises per year) that is constant over time. This pain rate may be quite
low; according to the CSSCD data; over a 5-year period 40% of patients did not
seek medical attention for pain. Yet for other patients, the frequency of pain crises
is devastatingly high; in this study of over 3000 patients, 5% of patients accounted
for one-third of these events. Not clear from the CSSCD data is whether there is a
significant correlation between pain rate and mortality for adolescent patients.
The fact that few deaths occurred among this age group may have precluded
making the association. However, if adolescents with high pain rate maintain this
rate as they age, then presumably these patients will become the group that suffers
premature mortality. Data from the CSSCD and elsewhere support the constancy
of pain rates over time.22 Further observation of the CSSCD population will
clarify the association of adolescent pain rate and premature mortality. For now,
patients with pain crises frequent enough to require chronic transfusion will be
eligible for BMT.
The risk/benefit relationship for patients treated on this protocol is encouraging;
BMT for younger patients with SCD has not been associated with an unacceptable
risk of death or severe morbidity. Several series have shown that eradication of
patient hematopoiesis (i.e. engraftment) has been followed by excellent quality of
life and relief from some manifestations of chronic SCD.60,61
3.0 DRUG INFORMATION
3.1 BUSULFAN
Therapeutic Classification: Bifunctional alkylating agent
Pharmaceutical Data: Busulfan (Busulfex Injection® Orphan Medical) is
supplied as a sterile solution in single-use ampules containing 60 mg at a
concentration of 6mg/ml. It is provided as a mixture of demethylacetamide
(DMA) and polyethylene glycol 400 (PEG400).
Solution Preparation: Busulfan solution for injection must be diluted with
either 0.9% Sodium Chloride Injection (NS) or 5% Dextrose Injection (D5W)

Mechanism of Action: Busulfan is a bifunctional alkylating agent in which two
labile methanesulfonate groups are attached to opposite ends of a four-carbon
SCALLOP - 13
prior to administration. The diluent quantity must be 10 times the volume of
busulfan, ensuring that the final concentration is > 0.5 mg/ml. Sample calculation

SCALLOP - 14
for a 50 kg patient: (50 kg) x (0.8 mg/kg of busulfan) = 40 mg = 6.7 ml. 6.7 ml
of busulfan + 67 ml of NS = 74 ml total volume. Final concentration: 0.54
mg/ml.
Stability and Storage Requirements: After dilution with NS or D5W, busulfan
is stable at room temperature (25 degrees Celsius) for 8 hours. The infusion must
be completed within that time. Prior to mixing: Store under refrigeration (2 to 8
degrees Celsius). Busulfan for injection is stable at 4 0 for at least 12 months.
Route of Administration: Busulfan should be administered intravenously via a
central venous catheter as a two-hour infusion.
Usual Dosage Range: 0.8-1 mg/kg/dose given every 6 hours for a total of 16
doses. For patients less than 4 years of age a dose of 1 mg/kg/dose will be used
and for patients > 4 years the starting dose will be 0.8 mg/kg/dose. Doses are
based on actual body weight, unless the patient’s weight is greater than 30% of
ideal body weight, then dosing will be based on adjusted weight of ideal plus
25%. Busulfan pharmacokinetics will be performed on all patients with dose
adjustment as appropriate.
Pharmacokinetics: Doses will be adjusted to achieve the desired plasma area
under the curve (AUC) of 900 – 1200.imol-min/L. Doses will be adjusted as
necessary pending the results of the first dose pharmacokinetics. For patients
whose AUC values are greater than 5% outside the acceptable AUC range, the
dose will be adjusted to achieve a target AUC of 1125.imol-min/L (midpoint of
acceptable range) not to exceed a maximum dose of 1.6 mg/kg per dose of
busulfan.
Side effects: Myelosuppression, neurotoxicity (manifesting as seizures), mild to
moderate nausea and vomiting, mild to moderate tachycardia, skin
hyperpigmentation, sterility, and rarely hepatotoxicity (hepatic veno-occlusive
disease) and pulmonary toxicity (interstitial fibrosis).
Special Precautions: Increased toxicity in obese patients unless dose is adjusted
appropriately. Generalized seizures have been reported after use of high dose
busulfan. All patients will be treated with phenytoin 5 mg/kg/dose (IV or PO) q 6
hr beginning on day -10 for 24 hr until completion of busulfan. A trough
phenytoin level should be obtained 6 hours after the fourth dose. The therapeutic
range for this drug is 10-20.ig/ml. If the level is below 10.ig/ml, two additional
doses of 5 mg/kg/dose should be administered q 6 hours. If the level is below 5
.ig/ml, an additional four doses of phenytoin should be administered q 6 hours
over the next 24 hours. If the phenytoin level is within the therapeutic range,
maintenance therapy should begin at a dose of 5 mg/kg/day (IV or p.o.) in two
divided doses until day -4. Patients experiencing seizure activity should be
evaluated neurologically and treated as clinically indicated.

SCALLOP - 15
alkyl chain. In aqueous media, busulfan hydrolyzes to release the
methanesulfonate groups. This produces reactive carbonium ions that can alkylate
DNA. DNA damage is thought to be responsible for much of the cytotoxicity of
busulfan.
Human Pharmacology: Busulfan can be administered orally or intravenously.
Busulfan achieves levels in cerebrospinal fluid similar to plasma levels. Busulfan
is predominantly metabolized by conjugation with glutathione, both
spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate
undergoes further extensive oxidative metabolism in the liver. Approximately
30% of busulfan and metabolites can be recovered in the urine within 48 hours
after administration.
3.2 CYCLOPHOSPHAMIDE (CYTOXAN, CTX) NSC# 26271
Source and Pharmacology: An alkylating agent, related to nitrogen mustard,
biochemically inert but metabolized by liver phosphamidases to active
components, e.g. 4-hydroxycyclophosphamide, which are excreted exclusively by
the kidney. CTX is non-phase-specific. The plasma half-life ranges from 4 to 6.5
hours. When taken orally, 25% may be passed in the stool unchanged.
Formulation and Stability: Injectable form is available as white crystals with
sodium chloride added, in vials containing 100 mg, 200 mg and 500 mg. All
preparations are stable at room temperature (not to exceed 30oC). Reconstitute
with 5 ml sterile water for 100 mg vials, 10 ml for 200 mg vials and 25 ml for 500
mg vials. Also available in 1 g and 2 g vials; reconstitute with 50 ml and 100 ml
sterile water, respectively. Discard solution after 24 hours at room temperature;
stable up to 6 days if refrigerated (2o-8oC). CTX is also available in 25 and 50 mg
tablets.
Supplier: Commercially available.
Toxicity:
Acute dose-limiting toxicity - myelosuppression, primarily leukopenia, with a
nadir at 8-14 days. Therapy must be withheld if acute hemorrhagic cystitis occurs.
Therapy may be started once hematuria clears and there is no evidence of a
contracted bladder. Very high doses over a short period of time may be associated
with myocardial necrosis, transiently blurred vision, and cardiac toxicity with
arrhythmias. Other adverse reactions include anorexia, nausea and vomiting,
alopecia, SIADH, immunosuppression, and gonadal suppression with associated
sterility. Pulmonary fibrosis is rare. Hemorrhagic cystitis: Hematuria is not
uncommon at this dose level, but is usually not symptomatic or severe. Adequate
urine flow is essential to avoid cystitis. All patients will be treated with MESNA
coincident with each dose of CTX (see below). Pyridium will be given for
symptomatic relief. Alopecia: Usually reversible.
Skin rash: Ten to 20% of patients develop a diffuse maculopapular rash 24-72

SCALLOP - 16
hours following CTX. The rash usually clears in 24-48 hours. Diarrhea: treated
symptomatically. Fluid retention: CTX has an anti-diuretic effect usually

SCALLOP - 17
counteracted by furosemide administration. Careful physical examination should
be made and daily weights and electrolytes determined to detect fluid overload
early. Anemia: Hemoglobin drops can occur at this dose, presumably due to
hemolysis.
Chronic toxicity - gonadal dysfunction is dose-related. The prepubertal gonad is
less susceptible. Hormonal function is generally preserved, especially in the male;
fertility is mainly affected (spermatogenesis in the male, follicle formation in the
female). Sterility may be partially reversible. Gonadal effects of administration
during puberty are uncertain; the risk of sterility may be increased.
Secondary neoplasms have occurred in a small number of patients receiving this
drug. Cardiomyopathy: At doses greater than 200 mg/kg, CTX can cause fatal
cardiac necrosis with heart failure. Patients are monitored by daily EKGs to
detect decrease in voltage. Non-specific ST changes are not unusual but a
decrease in voltage is significant and ominous. CTX is contra-indicated in
patients with existing cardiac disease. The EKG must be checked before each
dose of CTX; patients developing significant reduction in cardiac voltage will
have all subsequent doses discontinued. Reproduction: The long term effects are
unknown but sterility is probable.
Dose adjustments: CTX in the study will be given at a dose of 50 mg/kg IV ideal
body weight or actual body weight, whichever is lowest on each of four
successive days. CTX is dissolved in 100-250 cc of D5W and administered over a
30-60 min period followed by IV hydration for 12 hr with 2.4 L/m2.
Diuresis and hydration: The urine flow during and for 12 hours after CTX
administration is to be kept at a minimum of 2.5 cc/kg/hr. If the urine output
decreases below these numbers, Furosemide 10-20 mg/m2 IV may be given. IV
fluids at 2.4 L/m2/12 hr post CTX will be routinely employed. A Foley catheter
may be placed in young children if difficulty is measuring urine output occurs.
Route of Administration: Intravenous
3.3
MESNA (Sodium 2-Mercaptoethane Sulfonate, Mesnex, Urimetexan)
Source and Pharmacology: MESNA is a thiol compound with the capacity of
inhibiting the urotoxicity of the oxazaphosphorines, ifosfamide and
cyclophosphamide. Within 1 hour of administration, MESNA is completely
oxidized to DiMESNA, a totally inert compound. There is little or no tissue
penetration. Following glomerular filtration DiMESNA is rapidly reduced in the
renal tubules back to MESNA which inactivates the oxazaphosphamides, thus
preventing bladder toxicity. After 3 hours, negligible amounts of MESNA were
present in the urine of rats given 100 mg/kg by IV push.
Formulation and Stability: Available in ampules containing 100 mg/ml of
solution containing disodium edentate 0.25 mg and sodium hydroxide to adjust
pH 6.5 to 8.5 in water for injection. Supplied on 200, 400 and 1000 mg ampules.

SCALLOP - 18
light-sensitive, and intact ampules are stable for five years from manufacture.
MESNA can be mixed in the following intravenous infusion solutions with less
than 5% decomposition over 24 hours: 5% dextrose, 5% dextrose in 0.45 sodium
chloride, 0.9% sodium chloride and lactated Ringer's. MESNA may be mixed with
ifosfamide, but is incompatible with cisplatin.
Supplier: Commercially available.
Toxicity: May cause nausea and vomiting, and a bitter taste during IV
administration. At 60-70 mg/kg IV daily x 4, abdominal pain, headache, limb and
joint pain, lethargy, diarrhea, and transient hypotension have been encountered.
Route of administration: (To be supplied by PI)
3.4 CYCLOSPORIN: (SANDIMMUNE)
Source and Pharmacology: Cyclosporin is an immunosuppressive agent produced
by Tolypocladium inflatum Gams or Cylindrocarpon lucidum Booth. Cyclosporin is a
nonpolar, cyclic polypeptide antibiotic consisting of 11 amino acids. It is thought that
cytotoxic T-lymphocytes (CTLs) together with helper T-cells, natural killer cells
and the release of lymphokines, including interleukin-2 (IL-2), play a major role in
graft rejection and graft versus host disease. The exact
mechanism(s) of the immunosuppressive action of CsA has not been fully elucidated.
Experimental studies suggest that the primary actions of CsA in preventing graft
rejection and in establishing immunologic unresponsiveness to allografts are (1) the
prevention of precursor CTL from acquiring responsiveness
to IL-2, and thereby inhibiting the activation of CTLs; (2) the inhibition of
production of IL-2 and other cytokines, the signals that lead to proliferation and
activation of effector cells. In contrast, CsA apparently leaves B cells and
macrophage function essentially unimpaired.
The selective effect of CsA on the immune system is largely unexplained. Studies
seem to indicate that at the intracellular level CsA interferes with the calcium-
dependent activation of various enzymes systems including the enzymatic
cascades accounting for IL-2 production and IL-2 receptor formation.
Formulation and Stability: Cyclosporine (CsA) oral solution is supplied in 50
ml bottles. It has a clear, yellow, oily appearance. Each ml contains 100 mg of
CsA and ethanol 12.5% by volume dissolved in an olive oil compound, Labrafil
M 1944CS (polyoxethylated oleic glycerides) as the vehicle. Prior to oral
administration, the appropriate dose of the CsA solution must be further diluted
with milk, chocolate milk, or orange juice, stirred well, and taken by the patient at
once. To ensure adequate dose administration, the glass should be rinsed with more
milk or orange juice and given to the patient. It should not be allowed to stand for
any length of time.
Cyclosporin is also supplied as soft gelatin capsules in a 25 mg and 100 mg
strength. Both capsules contain a maximum of 12.7% ethanol, USP dehydrated.
Intravenous CsA is supplied in a 5 ml sterile ampule for intravenous
administration. Each ml contains 50 mg of CsA, 650 Cremophor IL

SCALLOP - 19
(polyoxethylated castor oil) and ethanol 32.9% by volume. Cyclosporin
concentrate for injection diluted to a final volume of 2 mg/ml is stable for 24
hours in 5% dextrose or 0.9% sodium chloride. Dilutions of the drug in dextrose
or sodium chloride should not require protection from light. The solution should
be checked for particulate matter and discoloration. The solution may be
administered as a continuous infusion over 24 hours, or divided as short-term
infusions (2-6 hours) every 12 hours.
Supplier: Commercially available (Sandoz).
Toxicity: The most frequent and clinically important adverse effect of
cyclosporin is nephrotoxicity. Elevation of BUN and serum creatinine
concentrations resulting from cyclosporin therapy appear to be dose-related, may
be associated with high trough concentrations of the drug, and are usually
reversible with discontinuation of the drug. Clinical manifestations may include
fluid retention, edema, and in some cases, hyperchloremic, hyperkalemic
metabolic acidosis. The risk of renal toxicity increases with administration of
other potentially nephrotoxic agents. Hypertension may develop, generally within
the first few weeks of therapy and affects both systolic and diastolic blood
pressure. Some evidence suggests that hypertension results from the renal
vasoconstrictive effects of the drug. Hypertension may respond to dosage
reduction and/or antihypertensive therapy. Adverse nervous system effects occur
frequently, with tremor occurring in a large percentage of patients. Tremor may
be manifested as fine hand tremor, usually is mild in severity, may improve
despite continued therapy, and/or may be alleviated with dosage reduction.
Seizures, headache, paresthesia, hyperasthesia, flushing and confusion have also
been reported occasionally. Other adverse effects include hirsutism, gingival
hyperplasia, and hepatotoxicity. Adverse GI effects occur frequently during
cyclosporin therapy, including diarrhea, nausea, vomiting, anorexia and
abdominal discomfort. Infectious complications have occurred frequently.
Adverse hematologic effects have occurred occasionally during cyclosporin
therapy.
Route of Administration: Intravenous and by mouth.
3.5 METHOTREXATE: (MTX, AMETHOPTERIN)
Source and Pharmacology: A folate analogue which inhibits the enzyme
dihydrofolate reductase, which halts DNA, RNA and protein synthesis. Initial IV
half-life is about 1.2 hours with a second phase of 10.4 hours. Orally
administered MTX undergoes dose-dependent absorption (average of 35% at
doses of 15-75 mg/m2), with the average time of peak concentration at 2 hours.
MTX is excreted unchanged in the urine, and at high doses given over 24 hours, it
is partially metabolized (40%) to hydroxy MTX and excreted. After IT
administration, the drug is rapidly distributed in the CSF with initial half-life of
4.5 hours and a second phase of 14 hours. High-dose methotrexate should not be
given to patients with severe renal dysfunction, significant pleural effusions or
ileus. Leucovorin rescue should be started within 48 hours of starting high-dose
methotrexate; it may be necessary after IT administration, particularly if IT
therapy is given to patients with renal dysfunction.

SCALLOP - 20
Formulation and Stability: Commercially available as 12, 25, 50, 100, 200 mg
vials as solution and 500 and 1000 mg vials of powder. Tablets are available at
2.5 mg. Intact vials and bottles of tablets bear an expiration date.
Supplier: Commercially available.
Toxicity: Acute dose-limiting toxicity consists of marrow suppression with the
nadir for anemia at 6-13 days, leukopenia at 4-7 days and thrombocytopenia at 5-
12 days. Other factors which may limit or delay therapy include ulcerative
stomatitis, severe diarrhea or acute nephrotoxicity. Most patients experience a
transient decrease in glomerular filtration rate during high-dose methotrexate.
Other adverse effects include nausea, vomiting, anorexia, gingivitis, glossitis,
stomatitis, immunosuppression, hepatic toxicity, rash, pleuritis, pruritus,
vasculitis, photosensitivity, depigmentation or hyperpigmentation, alopecia,
dizziness, malaise, blurred vision, and increased skin sensitivity to sunlight.
Patients with Down Syndrome have a tendency to have delayed MTX clearance
and greater risk of toxicity, despite increased leucovorin rescue, so that caution is
advised.
NOTE: Renal dysfunction will enhance toxicity.
IT administration has been associated with increased CSF pressure, headache,
pleocytosis, fever, vomiting, nuchal rigidity, convulsions, paresis, Guillain-Barre
syndrome, leukoencephalopathy and death.
Route of Administration: Intravenous.
3.6 CAMPATH-1H
Source and Pharmacology: CAMPATH-1H is a humanized antilymphocyte
monoclonal antibody. The Campath-1 antigen in humans (CD52) is
predominantly expressed on peripheral blood lymphocytes, monocytes, and
macrophages. CAMPATH-1H causes lysis of lymphocytes by fixing to CD52, a
highly expressed, non-modulating antigen on the surface of lymphocytes. It
mediates the lysis of lymphocytes via complement and antibody dependent cell
mediated cytotoxicity mechanisms. CAMPATH-1H rapidly reaches a peak
concentration after IV administration. The half-life has been thought to be
approximately 60 hours, although recent data suggest a more prolonged
persistence. The route of elimination is not known, but is probably via uptake and
metabolism by the reticulo-endothelial system of the liver and spleen.
Formulation and Stability: CAMPATH-1H is supplied as a purified preparation
diluted in phosphate buffered saline (PBS) with 0.05 mmol EDTA. Tween 80 is
added to a concentration of 0.01%. The final product is a clear, colorless isotonic
solution free of visible particulate matter. The glass ampules will contain 30mg of
antibody in 3 mL of sterile PBS at a concentration of 10 mg/ml. . It should be
stored, protected from light, in a refrigerator at between 2° and 8° C. .
After dilution in D5W or NS, the resulting solution is stable for 24 hours at 2-80C
(36-460F). However, the product contains no preservative and must therefore be

SCALLOP - 21
used within 8 hours. Intravenous CAMPATH-1H will be diluted in 100cc of
0.9% normal saline or 5% Dextrose and administered intravenously over 2 hours.
CAMPATH-1H must be filtered with a sterile, low-protein binding, 5 m filter
prior to dilution.
Dose: A dose of 10 mg/patient has been chosen based on the plasma
concentrations required for activity, and on the previous extensive published
human experience using the dose for lymphocyte depletion.
Supplier: Investigational. L&I Partners, LP
Toxicity: CAMPATH-1H is a potent lymphocyte-depleting agent. WHO Grade 3
and 4 neutropenia and thrombocytopenia emerge on treatment in approximately
10-20% of patients. Infections resulting from CAMPATH-1H induced
immunosuppression is the major type of adverse event occurring outside the
CAMPATH-1H administration period, with the most common infections being
mucocutaneous herpes simplex and candidiasis.
The majority of other adverse events seen in CAMPATH-1H trials can be
categorized as being administration-related and of short duration. There is usually
a first dose effect consisting of cytokine release type phenomena including
hypotension, rigors, fever, shortness of breath, chills, rashes, etc. These side
effects can be significantly ameliorated or avoided by premedicating the patients
with methylprednisolone or hydrocortisone.
Route of Administration: Intravenous.
4.0 PATIENT ELIGIBILITY
4.1 Patients with an HLA genotype identical sibling/related donor and hemoglobin
SS, hemoglobin SC, or hemoglobin SJ30/+ and at least one of the following
conditions:
4.1.1 previous central nervous system vaso-occlusive episode with or
without residual neurologic findings, or has an abnormal
transcranial doppler exam without neurologic findings, or
abnormal MRI/MRA of the brain with or without neurologic
findings;
4.1.2 frequent painful vaso-occlusive episodes which significantly
interfere with normal life activities and which necessitate chronic
transfusion therapy;
4.1.3 recurrent SCD chest syndrome events, which necessitate chronic
transfusion therapy;
4.1.4 severe anemia which prevents acceptable quality of life and
necessitates chronic transfusion therapy;

SCALLOP - 22
4.1.5 Any of the above symptoms in which the patient is not undergoing
chronic transfusion therapy;
4.1.6 The patient is undergoing chronic transfusion therapy for
symptoms other than those listed and which significantly interferes
with normal life activities;
4.1.7 Failed hydroxyurea therapy;
4.1.8 Indication of pulmonary hypertension on 2 separate
echocardiogram examinations;
4.1.9 Patients who plan to return to resource poor areas/countries.
4.2 Between the ages of birth and 40 years.
4.3 Women of childbearing potential must have a negative pregnancy test.
4.4
The following patients who otherwise satisfy eligibility requirements will
be ineligible:
4.4.1 Patient with biopsy proven chronic active hepatitis or fibrosis with
portal bridging.
4.4.2 Patient with stage 4 SCD chronic lung disease (see Appendix 1).
4.4.3 Patient with severe renal dysfunction defined as creatinine
clearance < 40 ml/min/1.73M2.
4.4.4 Patient with severe cardiac dysfunction defined as echocardiogram
shortening fraction < 25% or NYHA class III or IV.
4.4.5 Patient with HIV infection.
4.4.6 Patient with unspecified chronic toxicity serious enough to
detrimentally affect the patient’s capacity to tolerate bone marrow
transplantation.
4.4.7 Patient or patient's guardian(s) unable to understand the nature and
risks inherent in the BMT process.
4.4.8 Pregnant/lactating women and those unwilling to use acceptable
contraception will be excluded.
4.4.9 Patient or patient’s guardian who have not signed an informed
consent.
NOTE: Patients who would be excluded from the protocol strictly for
laboratory abnormalities can be included at the investigator’s discretion

SCALLOP - 23
after approval by the CCGT Protocol Review Committee and the FDA
reviewer.
5.0 STUDY DESIGN
This is a nonrandomized study looking at organ function improvement after BMT
in SCD patients. We plan to enroll 15 patients over a period of 3-4 years. (See
section 1 for objectives of this study).
6.0 TREATMENT PLAN
6.1 BONE MARROW PREPARATORY REGIMEN
6.1.1 Prior to initiating the BMT preparatory regimen patients will

have placement of a double lumen Hickman catheter

have a percutaneous liver biopsy.
6.1.2 Prior to initiating the BMT preparatory regimen, the patient's
hemoglobin SS concentration must be < 30%. This may
necessitate the patient undergoing partial exchange transfusion.
6.1.3 Treatment schedule
Protocol day
Treatment
10
Begin Dilantin or Lorazepan
-9
Busulfan 4.0 mg/kg/day IV divided into four
doses daily for four days; total dose = 16
mg/kg
-8
BU X 4 (Based on AUC < or = 1200 tMol-
min/L)
-7
BU X 4 (Based on AUC < or = 1200 tMol-
min/L)
-6
BU X 4 (Based on AUC < or = 1200 tMol-
min/L)
-5
Campath 1H 10mg/IV
CTX 50mg/kg +MESNA
-4
Campath 1H 10mg/IV
CTX 50mg/kg+MESNA
-3
Campath 1H 10mg/IV + CTX 50 mg/kg +
MESNA
-2
CTX 50mg/kg +MESNA + Campath 1H
10mg/IV
-1
REST
0
bone marrow infusion with premeds as per
CAGT SOPs.

SCALLOP - 24
BU (busulfan) = 4.0 mg/kg/day (total 16 mg/kg), dosage adjusted
to age (see section 3.1). Daily dose divided into every 6 hour IV.
The dose of busulfan and cyclophosphamide is based upon the
ideal body weight. The dose of BU will be further adjusted to
achieve the desired plasma area under the curve (AUC) of 1100
–
1200.imol-min/L. Doses will be adjusted as necessary pending the
results of the first dose pharmacokinetics. For patients whose
AUC values are greater than 5% outside the acceptable AUC
range, the dose will be adjusted to achieve a target AUC of 1125
.imol-min/L (midpoint of acceptable range) not to exceed a
maximum dose of 1.6 mg/kg per dose of busulfan.
Anticonvulsant therapy: All patients require anticonvulsant therapy
while receiving busulfan. Dilantin or lorazepam are the two agents
most frequently used in this regard. The clinical pharmacist must
review orders for anticonvulsants. Dosing should be dictated by
blood anticonvulsant levels whenever possible. Anticonvulsant
therapy will be continued through day +100 at a minimum.
CTX (cyclophosphamide) = 50 mg/kg IV on each of four
successive days. Hematuria is not uncommon at this dose level of
cyclophosphamide. Adequate urine flow is essential and the exact
hydration and MESNA doses should be followed. Please see agent
information section 3.0 and preprinted order sheets.
Campath 1H on four successive days. Prior to Campath patients
will receive a premedication as appropriate to prevent allergic
reaction. The dosage is as follows:
Children
Adolescents & Adults
5-15 kg: 3 mg IV in 30 ml NS
15.1 kg: 5 mg IV in 50 ml NS
>30 kg: 10 mg IV in 100 ml NS
10 mg IV in 100 ml NS
6.1.4 Bone marrow dose: To ensure the probability for bone marrow
engraftment, 4 x 108 nucleated cells/kg patient weight will be the
target at donor bone marrow harvest.
6.1.5 After transplantation, G-CSF will be administered as medically
indicated.
6.2 GRAFT VERSUS HOST DISEASE PROPHYLAXIS
6.2.1 Cyclosporin will be administered beginning day -2. Initial dose
will 5 mg/kg infused over 24 hours. Modifications in cyclosporin
dose will be determined by the measured blood concentration

SCALLOP - 25
(cyclosporin levels will be maintained within the acceptable
therapeutic range). For patients without GVHD, cyclosporin will
be tapered over 6 months.
6.2.2 Experience in performing stem cell transplantation for patients
with SCD indicates that hypertension may precipitate seizures. It is
important to measure and maintain blood magnesium levels in the
normal range and to provide effective antihypertensive therapy to
patients developing hypertension.
6.2.3 Because Campath IH infusions will provide a persisting level of
antibody over the transplant period, it will contribute to anti-GvHD
activity. Additional Graft versus Host disease prophylaxis will
consist of Methotrexate, administered on day +1, at a dose of 15
mg/m2 IV , and on day +3, +6, and +11 at 10 mg/m2 IV.
6.2.4 For patients who develop GVHD, methylprednisolone will be
added at an initial dose of 1 mg/kg. Dose will be increased for
persistent or progressive GVHD.
6.3 CONCURRENT TREATMENT AND SUPPORTIVE CARE (Note these
treatment and supportive care measures may be altered or supplemented by
any current IRB approved treatment protocol or by substitution of
Standard Operating Procedure guidelines)
6.3.1 Irradiate all blood products (except the bone marrow) with 1500-
3500 cGy.
6.3.2 Leukocyte filtered RBCs and platelet components will be used to
minimize transmission of CMV. Patients who are CMV negative
with CMV negative donors will receive CMV negative blood
products.
6.3.3 Platelets: Irradiated leukocyte poor platelet concentrates are
transfused to prevent bleeding, especially CNS bleeding, and the
circulating platelet count should be maintained at or greater than
50,000/mm3 for the first 5 weeks post-BMT. Thereafter
transfusion will be guided by patient’s clinical state.
6.3.4 Red cells: PRBCs (irradiated, leukocyte poor) 10-15 cc/kg/dose
will be administered to keep the hemoglobin level >10 g/dl. Higher
hemoglobin concentrations might be considered for patients with
pulmonary insufficiency.
6.3.5 Hyperalimentation: Adequate alimentation appears to be an
essential for successful transplantation. Parenteral hyperalimen-

SCALLOP - 26
tation is maintained until normal enteral alimentation can be
resumed as judged by the clinical situation.
6.3.6 Prophylaxis and management of infections:
6.3.6.1
Prophylaxis and management of infections according to
CAGT Clinical SOPs for infectious prophylaxis.
6.3.7 Monitoring of Post Transplant Sickle Cell Symptoms: Patients
will be requested to report all symptoms of sickle cell disease, and
these will be assessed formally at each clinic visit. In particular,
they will be asked to report episodes of pain. Acute chest
syndrome, CNS disturbances and priapism.
7.0 LABORATORY EVALUATION
7.1
Prestudy Evaluation
7.1.1 History
A complete history will be obtained to document clinical course of
symptoms related to the patient’s hemoglobinopathy
7.1.2 Physical Exam:
A complete physical exam
7.1.3 Laboratory Evaluation: Pre-BMT
CBC, reticulocyte count
Hemoglobin profile or electrophoresis, quantitate F, A2, S for both
patient and sibling donor
STRs (Serial Tandem Repeats) for patient and donor
Electrolytes, calcium, magnesium, phosphorus, uric acid, BUN,
creatinine, albumin, prealbumin, total bilirubin, SGOT, SGPT,
alkaline phosphatase, LDH, triglycerides
Ferritin, iron if not done in the last year
FSH, LH, testosterone or estrogen, thyroid battery
Echocardiogram; EKG; CPK; 24 hour Holter monitor if clinically
indicated

SCALLOP - 23
Pulmonary function tests (FVC, FEV1, arterial blood gas)
Chest x-ray
Brain MRI & MRA (contrast injection optional)
PET scan of head and body
Ophthalmology consultation as clinically indicated
Dental consultation as clinically indicated
Gulf Coast Donor Panel
Patient and donor immunization with Prevnar 7 at least 2 weeks
before BMT
Neuropsychiatric evaluation
24 hr urine protein and creatinine clearance; Tc99m DPTA plasma
clearance (GFR)
Liver biopsy
7.2
Laboratory evaluation: During in-patient and up to day +120 and
thereafter
7.2.1 CBC with WBC differential and platelet count at a minimum
weekly or as clinically indicated beginning with the BMT
preparatory regimen continuing until the patient is no longer red
cell and platelet transfusion dependent.
7.2.2 Electrolytes, BUN, creatinine, magnesium, calcium, phosphorus,
glucose at a minimum weekly during bone marrow transplant
preparatory regimen; thereafter daily until discharge or
reestablishment of enteral nutrition.
7.2.3 Albumin, SGOT, SGPT, GGT, alkaline phosphatase, and total
bilirubin, and uric acid at a minimum two times/week beginning
with BMT preparatory regimen continuing until discharge.
7.2.4 Urinalysis during hospitalization as clinically indicated.
7.2.5 Weekly CMV antigen or as clinically indicated until day +120;
thereafter at the discretion of MD.
7.2.6 Bone marrow aspirate at approximately day +28 and at day +120.

S C A L L O P - 2 8
7. 2. 7 B o ne marr o w f or S T Rs at a p pr o xi matel y da y + 2 8 a n d da y + 1 2 0.
Peri p heral bl o o d f or S T Rs at a p pr o xi matel y da y of e n graft me nt a n d
at D + 1 0 0.
7. 2. 8 He m o gl o bi n pr ofile or electr o p h oresis wit h he m o gl o bi n F
q ua ntificati o n if S T R st u dies s h o w mi xe d c hi meris m.
7. 2. 9 Ferriti n a n d ir o n e ver y t hree m o nt hs as cli ni call y i n dicate d
7. 2. 1 0 P E T sca n of brai n a n d b o d y at 6 m o nt hs a n d 1 year p ost S C T
7. 2. 1 1 E C H O a n d E K G as cli nicall y i n dicate d
7. 2. 1 2 P ul m o nar y f u ncti o n st u dies as cli nicall y i n dicate d
8. 0 E V A L U A TI O N C RI T E RI A
T he maj or g oal of t his st u d y is t o deter mi ne t he be nefits of all o ge neic B M T i n
relati o n t o or ga n f u ncti o n rec o ver y p ost tra ns pla nt i n patie nts wit h se vere S C D, its
varia nts, a n d h o m oz y g o us
0/ + t halasse mia. I m pr o ve me nt i n F D G u pta ke o n P E T
s h o wi n g re versal of or ga n d ysf u ncti o n a n d i ncrease i n a nti b o d y titers p ost
p ne u m o c oc cal i m m u ni z ati o n will be pri m ar y e n d p oi nts. B M T-r el at e d
m or bi dit y/ m ortalit y, s pecificall y G V H D a n d i nfecti o ns will be cl osel y m o nit ore d
a n d t heir i m pact o n s ur vi val will be m o nit ore d i n t he statistical desi g n. I n
a d diti o n, t he effect of B M T o n t he c o urse of S C D f oll o wi n g B M T will be
assesse d b yla b orat or ytests a n d dia g n ostici ma gi n g as o utli ne d i nt he pre vi o us
secti o n. S ur vi val a n d disease free s ur vi val will be deter mi ne d.
8.1 
E n graft me nt: he mat ol o gic rec o ver y p ost B M T will be sc ore d base d o n t he
Dart m o ut h Tra ns pla nt Criteria:
Sc ore
0 P ol ys n e v er < 5 0 0/
l, pl at el ets n e v er < 1 0, 0 0 0/l
1 P ol ys > 5 0 0/
l, pl at el ets > 1 0, 0 0 0/l wit hi n 4 we e ks of B M T
2 P ol ys > 5 0 0/
l, pl at el ets > 1 0, 0 0 0/l 4- 8 we e ks p ost B M T
3 P ol ys < 5 0 0/
l, pl at el ets < 1 0, 0 0 0/l be y o n d 8 we e ks
4 Deat h d ue t o bact erial or f u n gal i nfecti o ns, or he m orr ha ge
ass ociat e d wit h p ol ys < 5 0 0/ l, plat el ets < 1 0, 0 0 0/l m ore
t ha n 8 wee ks p ost B M T
8.2  
Graft vers us h ost disease ( Seattle criteri o n)
F or s ki n: Sta ge 
S ki n I n v ol ve me nt
0 
0

SCALLOP - 29
1
greater than 0, less than 25%
2
greater than or equal to 25%, less than or equal to
50%
3
greater than 50%
4
greater than 50% with blisters
For gut: Stage
Stool Volume
0
less than 7 cc/kg
1
greater than or equal to 7 cc/kg, less than 14 cc/kg
2
greater than or equal to 14 cc/kg, less than 21 cc/kg
3
greater than or equal to 21 cc/kg, less than 28 cc/kg
4
greater than or equal to 28 cc/kg
For liver: Stage
Bilirubin (mg/dL)
0
less than 2
1
greater than or equal to 2, less than 3
2
greater than or equal to 3, less than 6
3
greater than or equal to 6, less than 15
4
greater than or equal to 15
Overall: Grade
Organ Stage
0
0
1
skin = 1 or 2
2
skin = 3, or skin less than or equal to 3 and gut or
liver equal to 1
3
skin greater than or equal to 3 and gut or liver equal
to 2 or 3
4
skin, gut or liver equal to 4
8.3
Common toxicity criteria (see Appendix 2)
9.0 CRITERIA FOR TAKING PATIENT OFF STUDY
Death and patient withdrawal will be the only reasons a patient can be withdrawn
from study.
10.0 REPORTING REQUIREMENTS
10.1 To register patients contact the research coordinator at 832-824-4881. A
copy of the consent form should be sent to her.
10.2 The data to be collected will be all data relevant to the objectives of the
protocol.
10.3 Forms to be completed:

Eligibility checklist

On study form

SCALLOP - 30

Adverse event record

Response

Follow up forms

Off study forms
10.4 Drug toxicity and/or adverse reactions
Adverse events will be collected according to SOP J02.05.XX, J02.06.XX
and J02.78.XX.
10.5 Relapse and survival data will be collected until 2 years after transplant.
11.0 STATISTICAL CONSIDERATIONS
This is a nonrandomized investigational study looking at potential organ function
recovery after allogeneic BMT using a preparatory regimen of busulfan,
cyclophosphamide, and MESNA and Campath IH, in patients with SCD. We
expect to enroll 15 patients over a period of 3 to 4 years. Safety monitoring will
be conducted using Wald's sequential probability ratio test (SPRT)25 to monitor
the rate of engraftment. The primary endpoint, organ function recovery, will be
assessed for each patient at 3 months, 6 months, 1 year, and 2 years post transplant
using MRI and PET scans. Also, immune response to pneumococcal vaccine will
be evaluated using pneumococcal antibody titers.
We expect abnormalities in organ function to be stabilized or improved after
BMT and antibody titers to rise after immunization.
Also, we expect 90% of the patients to engraft with an incidence of AGVDH of
15%-20% stage I and 5%-10% stage II or greater. No data for CGVHD exists for
high-risk SCD patients.
The table, below, lists the total number of engraftment failures (including deaths
or lost grafts prior to day +120) observed on day +120 necessary to trigger a
suspension of accrual until a thorough reevaluation of the protocol has been
completed. Additionally, if at any time two deaths prior to day +120 are observed
accrual will be suspended and a thorough analysis conducted. These estimates
provide a 10% chance of erroneously concluding that the true rate of engraftment
is 90% or greater when in fact it is less than 80%. They also allow for a 10%
chance of mistakenly concluding that the true engraftment rate is less than 80%
when in fact it is at least 90%.
Engraftment Failure
Safety
Monitoring Guidelines
Patients Entered (n)
Engraftment Failures
1
-

SCALLOP - 31
Patients Entered (n)
Engraftment Failures
2
-
3
-
4
4
5
4
6
4
7
4
8
4
9
5
10
5
11
5
12
5
13
5
14
5
15
5
Kaplan-Meier estimates and associated confidence intervals of disease free
survival, time to engraftment failure, survival, and organ function recovery will be
developed for all patients registered on the study.
Risk/benefit of this therapy (5.3) can be made only by subjective comparison to
the risk/benefit of other available therapy for SCD. No statistical analyses will
accompany this objective.
12.0 INVESTIGATOR’S BROCHURE WAIVER
12.1An investigator’s brochure is not required as Houston Methodist Hospital and
Texas Children’s Hospital Stem Cell Transplant Units function as one
single and fully integrated administrative unit. The physicians involved
in the Campath studies will be identical at both sites and will be closely
involved in the drug administration process and patient evaluation.

SCALLOP - 32
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46.
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SCALLOP - 38
Pulmonaryfunction
tests*
Decreased FVC, TLC,
FEV1, and FEV1/FVC
ratio (mild, 80% of
predicted normal, or 1
S.D. below normal)
ECGandECHO
Left ventricular
preponderance persists
15.0 APPENDICES
APPENDIX 1
Sickle Chronic Lung Disease: Staging Criteria
ClinicalMarkers
Stage1
Stage2
Stage3
Stage 4
Chestpain
Recurrent substernal
pain and chronic cough
Bloodgases
Normal oxygen
saturation
X-ray
Decreased distal
pulmonary vascularity,
hyperexpansion,
evidence suggestive of
increased interstitial
markings
Increased pain
over Stage 1
Normaloxygen
saturation
Diffuse, fine
interstitial
fibrosis involving
all lobes of the
lung
Severe midline
crushing chest
pain
Hypoxia with
partial pressure
oxygen (70 mm
Hg) during stable
periods
Severe and
prolonged pain
with dyspnea at
rest
Partial pressure
oxygen (60 mm
Hg) during
stable periods
Decreased FVC,
FEV1, TLC,
DCD and
FEV1/FVC ratio
(monderat 60%
of predicted, or
2 S.D. below
normal)
Balanced
ventricular
hypertrophy
Decreased FVC,
FEV1, TLC,
DCO, and
FEV1/FVC ratio
(severe, 40% of
predicted, or 3
S.D. below
normal)
Rightventricular
hypertrophy and
right atrial
enlargement.
Progressive
increase in heart
size
Pulmonaryfibrosis
Severe pulmonary
fibrosis
Normal
Normal
Borderline
elevation or
normal
Pulmonaryartery
pressure

Patient frequently
unable to
complete testing
due to degree of
hypoxia
Severe right
ventricular and
right atrial
hypertrophy.
IschemicTwaves
in V1 and V2
and p pulmonale
Markedlyelevated
with pulmonary
hypertension

SCALLOP - 40
The stage of sickle cell chronic lung disease will be determined by the clinical feature representing the highest (i.e.
the most severe) stage. In practice, clinical features tend to move in tandem. Marked disparity between these
features as related to stage of lung disease must be satisfactorily addressed by the pulmonologist.

SCALLOP - 41
APPENDIX 2
COMMON TOXICITY CRITERIA
GRADE
TOXICITY
0
1
2
3
4
Blood/Bone Marrow
WBC
4.0
3.0-3.9
2.0-2.9
1.0-1.9
<1.0
PLT
WNL
75.0-normal
50.0-74.9
25.0-49.9
<25.0
Hgb
WNL
10.0-normal
8.0-10.0
6.5-7.9
<6.5
Granulocyte
s/
Bands
2.0
1.5-1.9
1.0-1.4
0.5-0.9
<0.5
Lymphocytes
2.0
1.5-1.9
1.0-1.4
0.5-0.9
<0.5
Hemorrhage
(clinical)
none
mild, no
transfusion
gross,
1-2 units
transfusion per
episode
gross,
3-4 units
transfusion per
episode
massive, >4 units
transfusion per
episode
Infection
none
mild
moderate
severe
life-threatening
Gastrointestinal
Nausea
none
able to eat
reasonable intake
intake
significantly
decreased
but
can eat
no significant
intake
--
Vomiting
none
1 episode in 24
hrs
2-5 episodes in
24 hrs
6-10 episodes in
24 hrs
>10 episodes in
24 hrs,
or
requiring
parenteral support
Diarrhea
none
increase of 2-3
stools/day
over
pre-Rx
increase of 4-6
stools/day,
or
nocturnal stools,
or moderate
cramping
increase of 7-9
stools/day,
or
incontinence, or
severe cramping
increase of
10
stools/day or
grossly bloody
diarrhea, or need
for parenteral
support
Stomatitis
none
painlesss
ulcers,
erythema, or mild
soreness
painful
erythema,
edema, or ulcers,
but can eat
painful
erythema,
edema, or ulcers,
and cannot eat
requires
parenteral or
enteral support
Liver
Bilirubin
WNL
--
<1.5
× N
1.5-3.0
× N
>3.0
× N
Transaminas
e
(SGOT,
SGPT)
WNL
2.5
× N
2.6-5.0
× N
5.1-20.0 x N
>20.0
× N

Alk Phos or
5'nucleotid
ase
WNL
2.5
Liver
(clinical)
no change
from
baseline
--
Creatinine
WNL
<1.5
Proteinuria
no change
1+
<0.3
<3 g
Hematuria
neg
micr
Alopecia
no loss
mild
Pulmonary
none or
no change
asymp
abno
PFTs
Cardiac
dysrhythmia
s
none
asymp
tran
requi
ther
Cardiac
function
none
asym
decli
ejec
by l
of b
Cardiac
—
ischemia
none
nonsp
flat
Cardiac
—
pericardial
none
asymp
effus
inter
requ
Hypertensio
n
none or
no change
asym
trans
by gr
mmHg
>150
previ
treat
Hypotension
none or
no change
chang
no t
(inc
tran
orth
hypo
Kidney,Bladder
Heart
BloodPressure
× N
2.6-5.0
× N
5.1-20.0
-
--
precoma
× N
1.5-3.0
× N
3.1-6.0
×
or
g% or
g/L
2-3+ or
0.3-1.0 g%
or
3-10 g/L
4+ or
>1.0 g% o
>10 g/L
ro only
gross,
no clots
gross + cl
hair loss
pronounced or
total hair loss
--
ptomatic, with
rmality in
dyspnea
on
significant
exertion
dyspnea at
normal lev
of activit
ptomatic,
sient,
iring no
rapy
recurrent or
persistent, no
therapy required
requires t
mptomatic,
ine of resting
tion fraction
less than 20%
aseline value
asymptomatic,
decline of resting
ejection fraction
by more than 20%
of
baseline value
mild CHF,
responsive
therapy
pecific T-wave
ttening
asymptomatic, ST
and T wave changes
suggesting
ischemia
angina with
evidence f
infarction
ptomatic
sion, no
rvention
uired
pericarditis
(rub,
chest pain, ECG
changes)
symptomati
effusion;
required
mptomatic
sient increase
reater than 20
(0)
or to
/100 if
iously WNL; no
tment required
recurrent or
persistent
increase
by greater than 20
mmHg
(0)
or to
>150/100 if
previously WNL; no
treatment required
requires
therapy
ges requiring
therapy
cluding
nsient
hostatic
tension)
requires fluid
replacement or
other therapy but
not
hospitalization
requires t
and hospit
ization;re
within 48
stopping t
SCALLOP - 42
× N
>20.0
× N
hepatic coma
N
>6.0
× N
r
Nephrotic syndrome
lots
requires
transfusion
--
t
el
ty
dyspnea at rest
treatment
requires
monitoring; or
hypotension, or
ventricular
tachycardia, or
fibrillation
to
severe or
refractory CHF
hout
for
n
acute myocardial
infarction
ic
drainage
tamponade;
drainage
urgently required
hypertensive
crisis
therapy
tal-
esolves
hrs of
he agent
requires
therapy
and
hospitaliz-
ation for >48hrs
after
stopping
the agent

Neuro
—
sensory
none or
no change
mild p
loss o
tendon
Neu
paresthesias,
of deep
mild or moderate
objective sensory
severe objec
sensory los
n reflexes
loss; moderate
paresthesia
paresthesias
that interfe
with functi
SCALLOP - 43
ctive
s or
-
-
as
ere
ion

SCALLOP - 44
Neuro
—
headache
none
mild
moderate or severe
but transient
unrelenting and
severe
--
Neuro
—
constipatio
n
none or
no change
mild
moderate
severe
ileus >96 hrs
Neuro
—
hearing
none or
no change
asymptomatic
hearing loss on
audiometry only
tinnitus
hearing loss
interfering with
function but
correctable with
hearing aid
deafness not
correctable
Neuro
—
vision
none or
no change
--
--
Symptomatic
subtotal loss
of vision
blindness
Skin
none or
no change
scattered macular
or papular eruption
or erythema that is
asymptomatic
scattered macular
or papular eruption
or erythema with
pruritus or other
associated symptoms
generalized
symptomatic
macular, papular,
or vesicular
eruption
exfoliative
dermatitis or
ulcerating
dermatitis
Allergy
none
transient rash,
drug fever <38 C,
100.4
F
urticaria, drug
fever >38 C,
100 F,
mild bronchospasm
serum sickness,
bronchospasm, req
parenteral meds
anaphylaxis
Fever in
absence of
infection
none
37.1-38.0
C
98.7-100.4
F
38.1-40.0
C
100.5-104.0
F
>40.0
C, >104.0
F
for less than 24
hours
>40.0
C (104.0
F)
for more than 24
hrs or fever
accompanied by
hypotension
Local
none
pain
pain and swelling,
with
inflammation
or phlebitis
ulceration
plastic surgery
indicated
Weight
gain/loss
<5.0%
5.0-9.9%
10.0-19.9%
20.0%
--
Hyperglycem
ia
<116
116-160
161-250
251-500
>500 or keto-
acidosis
Hypoglycemi
a
>64
55-64
40-54
30-39
<30
Metabolic
Amylase
WNL
<1.5
× N
1.5-2.0
× N
2.1-5.0
× N
>5.1
× N
Hypercalc
emia
<10.6
10.6-11.5
11.6-12.5
12.6-13.5
13.5
Hypocalce
mia
>8.4
8.4-7.8
7.7-7.0
6.9-6.1
6.0

SCALLOP - 45
Hypomagne
semia
>1.4
1.4-1.2
1.1-0.9
0.8-0.6
0.5
Fibrinoge
n
WNL
0.99-0.75 x N
0.74-0.50 x N
0.49-0.25 x N
0.24 x N
Prothromb
in
time
WNL
1.01-1.25 x N
1.26-1.50 x N
1.51-2.00 x N
>2.00 x N
Coagulation
Partial
thrombopl
astin
time
WNL
1.01-1.66 x N
1.67-2.33 x N
2.34-3.00 x N
>3.00 x N