Clinical trial NCT01877837
Conditions: Sickle Cell Disease
Keywords: Stem cell transplant Sickle cell Stem cell transplantation Related Unrelated
Sponsor: Hackensack Meridian Health
Start date: 2011-06-01; Completion date: 2021-09-01
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This protocol will be investigating the use of stem cell transplantation, in related donors, to cure sickle cell disease. Sickle cell disease is a recessive disorder caused by a point mutation that results in the substitution of valine for glutamic acid at the sixth position in the B-chain of hemoglobin. This leads to sickling of the red blood cells under many conditions, such as hypoxia, dehydration, and hyperthermia. The sickling leads to vaso-occlusion, which causes irreversible damage in almost all systems in the body, including the central nervous system (CNS), lungs, heart, bones, eyes, liver, and kidneys.

Detailed description:
Primary objective:

1\) To determine disease free survival (DFS) at two years after matched sibling transplant using bone marrow (BM) after a conditioning regimen consisting of distal timed Alemtuzumab, Fludarabine, and Melphalan for patients 2-30 y/o

Secondary objectives:

1. Overall survival
2. Rate of neutrophil and platelet engraftment for BM
3. Incidence of graft failure
4. Incidence of grade II-IV and grade III-IV acute graft vs host disease (GVHD)
5. Incidence of chronic GVHD
6. Incidence of other transplant complications, such as veno-occlusive disease, central nervous system (CNS) toxicity, and idiopathic pneumonia syndrome (IPS)
7. Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus
8. Incidence of invasive fungal disease
9. Time to immune reconstitution via monitoring of lymphocyte subpopulations and immunoglobulin levels

Arms: arm 1: Matched sibling donors (9-10/10 marrow/PBSC or 5-6/6 UCB (single) with a total TNC dose of greater than 5 x 107/kg recipient weight), age 2-30 years after conditioning regimen Alemtuzumab , Fludarabine, and Melphalan.

1\) Patients will receive a conditioning regimen composed of Alemtuzumab, Fludarabine, and Melphalan as detailed in the table below.

Day Treatment

* -22 Alemtuzumab 3mg IV (test dose)
* -21 Alemtuzumab 10mg IV
* -20 Alemtuzumab 15mg IV
* -19 Alemtuzumab 20mg IV
* -8 Fludarabine 30mg/m2 IV
* -7 Fludarabine 30mg/m2 IV
* -6 Fludarabine 30mg/m2 IV
* -5 Fludarabine 30mg/m2 IV
* -4 Fludarabine 30mg/m2 IV
* -3 Melphalan 140mg/m2 IV
* -2 Rest Day
* -1 Rest Day
* 0 Stem Cell Infusion
Interventions: intervention 1: Alemtuzumab intervention 2: Fludarabine intervention 3: Melphalan intervention 4: Stem Cells
Intervention descriptions: intervention 1: Adjusted Ideal Body Weight Formula: AIBW = IBW + \[(0.4) x (ABW - IBW)\]

b) Medications

i.) Alemtuzumab I. Hb S% must be \< or = 45% within 7 days prior to initiation of Alemtuzumab II. Iron chelation and hydroxyurea must be discontinued \>48 hours before initiating therapy III. Alemtuzumab will be diluted in 100mL of 0.9% NS and infused at a rate as below intervention 2: I. Fludarabine should be diluted in 100 ml 0.9%NS and given over 30 minutes. II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Fludarabine intervention 3: I. Melphalan should be diluted in 0.9%NS to a concentration of 0.1 -0.45 mg/mL and given over 45 minutes. \*Entire dose must be infused within 60 minutes of reconstitution in Pharmacy.

II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Melphalan III. Patients should be encouraged to suck on a popsicle or something similar during the Melphalan infusion. intervention 4: Infusion of Hematopoietic Stem Cells

Protocol documents:
Prot_SAP_000.pdf: 
Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Reduced Intensity Matched Sibling
Bone Marrow Transplantation for
Sickle Cell Anemia in Patients 2-30
years old
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Table of Contents
I. Background
Page 3
II. Goal and Objectives
Page 7
III. Eligibility Criteria
Page 8
IV. Treatment Plan
Page 9
V. GVHD Prophylaxis
Page 11
VI. Supportive Care
Page 12
VII. Required Observations
Page 16
VIII. Drug Information
Page 19
IX. References
Page 40
Appendix A: Statistics
Page 47
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
I. Background/Rationale
Sickle Cell Disease
Sickle cell disease (SCD) affects approximately 72,000 individuals in the United States
and causes considerable morbidity and mortality1. It is a recessive disorder caused by a
point mutation that results in the substitution of valine for glutamic acid at the sixth
position in the Β-chain of hemoglobin.  This leads to sickling of the red blood cells under
many conditions, such as hypoxia, dehydration, and hyperthermia.  The sickling leads to
vaso-occlusion, which causes irreversible damage in almost all systems in the body,
including the central nervous system (CNS), lungs, heart, bones, eyes, liver, and kidneys.
The most devastating complication is cerebral infarction2, but other serious complications
include pulmonary disease due to recurrent acute chest syndrome (ACS), nephropathy,
retinopathy, vaso-occlusive pain crises (VOC), and avascular necrosis (AVN).  Organ
damage begins early in life and worsens over time; therefore, early treatment is a worthy
goal, even in patients who have not yet developed signs or symptoms of the disease.
Three prospective screening studies using echocardiography have shown that 20% of
adults with sickle cell disease have borderline or mild pulmonary hypertension, defined
by a pulmonary artery systolic pressure greater than 35 mm Hg; 10% of these adults have
moderate to severe pulmonary hypertension, defined by a pressure greater than 45 mm
Hg2,3.  Despite pulmonary artery systolic pressures that are much lower than those in
idiopathic or hereditary pulmonary hypertension, in sickle cell disease borderline or mild
pulmonary hypertension is associated with an extremely high risk of death3.  Because of
these many complications, the average life expectancy is decreased for sickle cell
patients, being 42 years for males and 48 years for females4.
Overt strokes occur in 9% of sickle cell patients before their 14th birthday5, and the
stroke-free survival decreases to 88.5% by 18 years of age6.  An additional 18% of
children with Hb SS disease will have silent cerebral infarcts by the age of 147.  Silent
infarcts are associated with an increased risk of overt stroke, low IQ, and poor academic
performance8-11.  Currently, the treatment for stroke is regular transfusions to keep the Hb
S% less than 30%.  However, in one study, 20% of the patients on a chronic transfusion
regimen had a second stroke12.  Known side effects of chronic transfusion include iron
overload and alloimmunization, which can both adversely affect the patient.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Hydroxyurea Use in Sickle Cell Disease
Hydroxyurea has emerged as an encouraging therapeutic agent in SCD.  Hb F is known
to be protective against clinical severity; a low Hb F% is associated with a higher risk of
developing VOC, organ damage, and early death4,13. Because hydroxyurea increases the
Hb F%, it may be beneficial in treating sickle cell patients.  Multiple studies have shown
that it reduces the number of painful events along with hospitalizations in both children
and adults14-17.  In addition, there is evidence that it may have clinical efficacy for
sickle-related organ damage, including proteinuria18, glomerular hyperfiltration19, splenic
dysfunction20-22, hypoxemia23, pulmonary hypertension24, neurocognitive delay25, silent
brain infarcts18, elevated Transcranial Doppler (TCD) velocities19,26,27, primary stroke
prevention27,28, and secondary stroke prevention29,30. Multiple large studies have also
showed that hydroxyurea is well tolerated with little short-term or long-term toxicity in
patients as young as six months20,31-34.  However, recent data from the prematurely closed
SWiTCH study, examining if patients with a history of CVA could be switched from
chronic transfusion therapy to hydroxyurea as treatment, showed an increased incidence
in second stroke in the patients receiving hydroxyurea35. This further demonstrates the
need for other therapy for sickle cell patients.
Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Hematopoietic stem cell transplantation (HSCT) is the only currently available cure for
patients with SCD.  The CIBMTR reported on 67 pediatric patients who received
HLA-matched sibling transplants after a myeloablative conditioning regimen36.  They
found that the overall survival (OS) and disease-free survival (DFS) were 97% and 85%,
respectively.  9 patients had graft failure, and the rates of acute and chronic GVHD were
10% and 22%, respectively.  The French group reported similar results in 87 patients who
received transplants from siblings who were either fully-matched or mismatched at 1
antigen after myeloablative conditioning37.  The OS was 93.1% and the event-free
survival (EFS) was 86.1%.  Graft failure occurred in 7% of the patients; however, after
the introduction of ATG as part of the conditioning regimen, this decreased to 2.9%.
Acute and chronic GVHD developed in 20% and 12.6%, respectively.  Both of these
studies demonstrate that matched sibling transplants after myeloablative conditioning
have acceptable results for the cure of sickle cell disease.
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Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
HSCT regimen: Myeloablative vs. Reduced-Intensity
Another limitation is the risk of mortality or treatment related toxicities associated with
myeloablative (MA) regimens.  Organ toxicities are more likely to occur and be more
severe in sickle cell patients who have impaired organ function or exposure to multiple
transfusions before HSCT38-40.  MA conditioning facilitates durable engraftment of donor
cells, but is limited by toxicities of the drugs as well as transplant-related
complications41,42.  In addition to prolonged myelosuppression, acute toxicities include
mucositis, anorexia, renal insufficiency, cardiac dysfunction, rash, seizures, GVHD, and
veno-occlusive disease (VOD)42.  Late toxicities include chronic GVHD, pulmonary
dysfunction, endocrine insufficiency, gonadal failure, and neurocognitive deficits43-47.
Because stable mixed chimerism is sufficient to cure sickle cell disease48, it is possible
that reduced intensity conditioning (RIC) might be effective even if it only results in
mixed chimerism.  Krishnamurti et al reported on stable donor engraftment after RIC
with Busulfan, Fludarabine, equine antithymocyte globulin, and total lymphoid
irradiation49.  6/7 patients demonstrated long term engraftment.  4/6 patients showed only
partial donor chimerism, but these patients still had an Hb >10 and alleviation of their
clinical sickle cell symptoms.
However, because of the risk of graft rejection, particularly in the heavily transfused
patients, a high level of immunoablation is important for successful donor engraftment.
The regimen of fludarabine and melphalan in combination with alemtuzumab would
provide a reduced intensity regimen while potentially preserving immunoablation.  This
regimen was used in 44 patients with malignant disorders50. Only 2 patients experienced
graft failure, the incidence of acute and chronic GVHD were 6.5% and 0%, respectively.
In this study, the alemtuzumab was given 4-8 days before HSCT, which may account for
the low GVHD risk, as it was likely still present in the recipient’s serum early
post-transplant.  However, in an immunocompetent host such as a sickle cell patient, this
could increase the risk of graft rejection.  Because of this, another study modified the
regimen to give alemtuzumab on days -21 to -19 prior to transplant in non-malignant
patients51,52.  So far, 60 patients between the ages of 2 and 20 have been treated with this
regimen, receiving either unrelated donors matched 8-10/10, HLA-identical sibling
donors, or UCB matched 4-6/6.  Graft failure has occurred in 5% of patients, although 2
of these patients had received a lower dose of melphalan in an attempt to further reduce
the intensity.  Acute and chronic GVHD occurred in 15% and 11 % of the patients,
respectively.  There were seven patients with SCD on this study.  The OS and DFS are
100% and 71%, respectively.  The reduced EFS is due to two patients that experienced
graft rejection, but they had received lower doses of Melphalan as discussed above.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Acute and chronic GVHD occurred in 0% and 14%, respectively.  This data supports the
use of this regimen in pediatric sickle cell patients.
HSCT for Sickle Cell Disease in Adults
All of the studies mentioned previously have mostly included patients <16, with a few
studies going up to the age of 27.  Because of this, there had been minimal evidence on
performing HSCT in young adult sickle cell patients.  However, a recently published
study examined this in 10 adult patients, ranging in age from 16 to 4553.  They received
alemtuzumab and TBI as a reduced intensity conditioning regimen prior to receiving a
fully matched sibling HSCT.  The OS and DFS were 100% and 90%, respectively, with
only one patient failing to engraft.  In addition, no patient experienced either acute or
chronic GVHD.  This small study demonstrates that young adult sickle cell patients may
also be able to tolerate a reduced intensity HSCT with minimal complications.
Organ Recovery Following HSCT
In addition to symptom alleviation, HSCT has also been shown to stabilize or reverse the
organ damage due to SCD.  In a long term follow-up study of patients who received
matched related HSCT, pulmonary function tests were stable in 22 of 26 patients, worse
in 2, and not studied in 254,55.  Linear growth measured by median height standard
deviation score improved from -0.7 before HSCT to -0.2 after HSCT54,55.  Radiologic
improvement of a patient with avascular necrosis of the humeral head has been
reported56, as well as correction of splenic reticuloendothelial dysfunction57,58.
The effect of HSCT on reversal of cerebral vasculopathy has been variable.  Many studies
have found that patients who successfully engraft do not experience any sickle-related
CNS complications and have evidence of stabilization of CNS disease on MRI55,59,60.  In
addition to stabilization, a few studies have found improvement in areas of previous
abnormality; however, this was in an extremely small subset of patients54,55,61.  One study
compared the vessel diameter on MRI of sickle cell patients treated with HSCT vs. those
treated with either chronic transfusion or hydroxyurea62. They found a 12% increase in
the lumen of 22 vessels in patients who underwent HSCT vs. an 8% increase in the lumen
of 42 vessels in the transfusion/hydroxyurea patients.  However, worsening of cerebral
large vessel disease and stroke has been reported after HSCT59.  Given this conflicting
data, this is an area that needs to be studied closer to determine the patient characteristics
that may contribute to improvement in the vessels after HSCT.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Results from previous patients enrolled on this clinical trial
We enrolled 23 patients so far on the original Pro1894 trial, 20 patients who underwent
matched sibling HSCT and three patients who underwent unrelated donor HSCT.  The
first three unrelated HSCT patients experienced only a 33% EFS, as one patient died
from GVHD related complications and one patient suffered early graft rejection with
autologous recovery.  Because of this, this trial was closed for unrelated HSCT, but
continued to enroll matched sibling HCST.  After 7 total patients had been enrolled on the
trial (5 sibling and 2 unrelated), the Alemtuzumab in the conditioning regimen was
moved up a week from d-22 to d-16 in an attempt to decrease GVHD while still
preserving engraftment.  Another 7 patients were enrolled (6 sibling & 1 unrelated), but
unfortunately 3 patients suffered graft rejection with autologous recovery without a
significant decrease in the GVHD incidence.  Because of this, the last 6 matched sibling
HSCT patients received the Alemtuzumab starting back at d-22.
In the 20 sibling HSCT patients, the overall survival rate is 94% with an EFS rate of
85%.  The one patient who passed away died from a non-transplant related infection at
more than 12 months post-BMT.  Two of the sibling HSCT recipients suffered secondary
rejection, both of whom received the intermediate timed Campath.  There has been no
graft rejection in patients whom received the distal timed Campath.
While these results are encouraging that matched sibling donor HCST using a reduced
intensity regimen is a safe and effective cure for all sickle cell patients regardless of
disease severity, the numbers are small.  Because of this, I would like to re-open this
study in order to continue to study the use of this regimen in any sickle cell patient with
sickle cell disease age 2-30 who has a matched sibling donor.
Primary objective:
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
1) To determine DFS at two years after matched sibling transplant using BM
after a conditioning regimen consisting of distal timed Alemtuzumab,
Fludarabine, and Melphalan for patients 2-30 y/o
Secondary objectives:
1) Overall survival
2) Rate of neutrophil and platelet engraftment for BM
3) Incidence of graft failure
4) Incidence of grade II-IV and grade III-IV acute GVHD
5) Incidence of chronic GVHD
6) Incidence of other transplant complications, such as veno-occlusive disease,
CNS toxicity, and idiopathic pneumonia syndrome
7) Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus
8) Incidence of invasive fungal disease
9) Time to immune reconstitution via monitoring of lymphocyte subpopulations
and immunoglobulin levels
III. Patient Eligibility
1) Matched sibling donors (10/10 marrow; can use stored sibling umbilical cord
blood to supplement bone marrow if available)
a.
Age 2-30
b. Hb SS, SΒthal0, SΒthal+, SC
c.
Evidence of ongoing hemolysis: Hb<10, retic >5%, LDH > 500, TB>2
(need at least 1 of 4 criteria)
d. Karnofsky/Lansky score ≥50
e.
LVSF>26% or LVEF>40%
f.
DLCO >40% or O2 sat >85% for those patients that can’t perform PFTs
g. GFR >70 and serum creatinine < 1.5 * ULN for age
h. ALT and AST < 5 x ULN, direct bilirubin <3 x ULN
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
i.
If the patient has been on chronic transfusion or has a ferritin >1000, liver
biopsy should be done and show no evidence of bridging fibrosis or
cirrhosis
2) Exclusion criteria
a.
Evidence of uncontrolled bacterial, viral, or fungal infection within one
month prior to initiation of the conditioning regimen
b. Pregnant or breastfeeding
c.
HIV positive
d. Written informed consent not obtained
IV. Treatment Plan
1) Patients will receive a conditioning regimen composed of Alemtuzumab,
Fludarabine, and Melphalan as detailed in the table below.
Day
Treatment
-22
Alemtuzumab 3mg IV (test dose)
-21
Alemtuzumab 10mg IV
-20
Alemtuzumab 15mg IV
-19
Alemtuzumab 20mg IV
-8
Fludarabine 30mg/m2 IV
-7
Fludarabine 30mg/m2 IV
-6
Fludarabine 30mg/m2 IV
-5
Fludarabine 30mg/m2 IV
-4
Fludarabine 30mg/m2 IV
-3
Melphalan 140mg/m2 IV
-2
Rest Day
-1
Rest Day
0
Stem Cell Infusion
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
For patients > 18 y/o, Fludarabine and Melphalan will be adjusted to the ideal
body weight (IBW) in patients weighing >125% IBW based on the following
formulas (ht in inches; IBW in kg):
For patients >60inches:
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.
Adjusted Ideal Body Weight Formula: AIBW = IBW + [(0.4) x (ABW – IBW)]
a) Medications
i.) Alemtuzumab
I. Hb S% must be < or = 45% within 7 days prior to initiation of
Alemtuzumab
II. Iron chelation and hydroxyurea must be discontinued >48
hours before initiating therapy
III. Alemtuzumab will be diluted in 100mL of 0.9% NS and
infused at a rate as below
a.
0 – 30 minutes:
10 mL/hr
b.
30 – 60 minutes:
20 mL/hr
c.
60 – 90 minutes:
40 mL/hr
d.
90 minutes – completion:
80 mL/hr
IV. Premedication
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
a.
Pre-medication with the following medications should
be given 30 minutes prior to the start of each infusion
of Alemtuzumab
i. Diphenhydramine 1mg/kg IV or PO
(maximum dose 50mg/dose)
ii. Acetaminophen 10-15mg/kg PO (maximum
dose 4g qday)
iii. Hydrocortisone 1-2mg/kg IV
iv. Meperidine 0.5g/kg IV q4-6 hr prn rigors (To
be kept at the bedside)
V. Test dose
a.
The dose should be administered in 75 mls of 0.9%
NS over 2 hours and not less than 24 hours prior to
administration to the first dose.
b. If not tolerated, please notify the study chair.
ii) Fludarabine
I.
Fludarabine should be diluted in 100 ml 0.9%NS and given
over 30 minutes.
II.
A daily dose of an antiemetic should be given 30 minutes
prior to administration of the Fludarabine
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
iii) Melphalan
I.
Melphalan should be diluted in 0.9%NS to a concentration
of 0.1 -0.45 mg/mL and given over 45 minutes. *Entire
dose must be infused within 60 minutes of reconstitution
in Pharmacy.
II.
A daily dose of an antiemetic should be given 30 minutes
prior to administration of the Melphalan
III.
Patients should be encouraged to suck on a popsicle or
something similar during the Melphalan infusion.
2) Infusion of Hematopoietic Stem Cells (See SOPs on intranet)
a.
Under no circumstance should the stem cell product be irradiated
b. A filter should be used as instructed in SOP.
c.
Vital signs should be monitored before beginning the infusion and every
15 minutes until the infusion has been completed.
d. Premedications should be given as below:
i.
Diphenhydramine 1mg/kg IV or po (maximum dose 50mg/dose)
ii.
Acetaminophen 10-15mg/kg po (maximum dose 4g qday)
iii.
Hydrocortisone 1-2mg/kg IV
iv.
Epinephrine 0.01mg/kg IM/IV (maximum dose 0.5mg) at
bedside prn anaphylactic reaction
e.
Oxygen via nasal canula or mask and ambu bag should be at bedside.
V. GVHD Prophylaxis
1) Patients will be given the regimen as described below:
Day
Regimen
-1
Tacrolimus dosed to
maintain appropriate levels.
Given through day 100 then
taper to day 180
Mycophenolate Mofetil
given through day +45 or 7
days after engraftment,
whichever is later
0
Stem Cell Infusion
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
i. Tacrolimus
1. Administration will begin on day -1 at a dose of
0.015mg/kg/day as a continuous drip, and dosing will
be adjusted to maintain a level of 10-20 ng/mL.
2. Once the patient can tolerate oral medications and has a
normal gastrointestinal transit time, Tacrolimus will be
converted to an oral form, at 3x the current IV dose
divided into two daily doses.
3. Patients will receive Tacrolimus until day 100, and then
it will be tapered between days 100 to 180 by 10% per
week as long as there is no evidence of GVHD.
ii. Mycophenolate Mofetil (MMF)
1. MMF will be given at a dose of 1gram IV q8 hours for
patients weighing >50kg or 15mg/kg IV q8 hrs for
patients weighing <50kg beginning the morning of day
-1.
2. Once the patient can tolerate oral medications and has a
normal gastrointestinal transit time, MMF will be
converted to oral at the same dose as the IV dose.
3. MMF will be stopped at day 45 or 7 days after
engraftment, whichever day is later, if there is no
evidence of acute GVHD.
4. If the patient has active acute GVHD requiring systemic
therapy, MMF may be stopped at the discretion of the
treating physician.
VI. Supportive Care Recommendation
1) Engraftment syndrome
a. This syndrome is a clinical diagnosis, with the most common
manifestations being transient fever, rash, and respiratory symptoms not
attributable to infection or GVHD.
b. Diagnostic criteria include fever >38.5 without an identifiable infectious
cause within 4 days of the start of neutrophil recovery AND any of the
symptoms below
i. An erythematous rash not attributable to GVHD or medications
ii. Capillary leak (i.e. weight gain, edema, ascites, effusions)
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
iii. Respiratory symptoms not attributable to idiopathic pneumonitis
syndrome (IPS)
c.
Mild symptoms may not require therapy; for progressive symptoms,
methylprednisolone at 2mg/kg/day is recommended for 5 days.
d. If symptoms are recurrent or prolonged, investigation for GVHD is
recommended.
2) Venous access
a. All recipients should have appropriate long-term central venous access
placed prior to beginning conditioning.
b. The placement of a triple lumen broviac is recommended.
3) Seizure prophylaxis
a. This is mandated in all recipients and should begin at the time
conditioning with Alemtuzumab starts.
b. The preferred drug is levetiracetam dosed as below:
i. For patients <16 years old, give 20mg/kg/day divided into two
doses (Maximum dose 500mg po BID)
ii. For patients 16 and older, give 500mg po BID
c.
Levels do not need to be monitored unless there is a clinical indication
(i.e. history of seizure, concern for CNS event)
d. Levetiracetam should be continued until day 180 or until Tacrolimus is
discontinued, whichever is later.
e.
Serum magnesium should be maintained >1.5 mg/dL while the patient is
receiving Tacrolimus to reduce the risk of seizures.
4) Hypertension
a. Hypertension should be strictly controlled to prevent CNS toxicity.  Blood
pressure should be followed closely and should be treated promptly to
maintain blood pressure at the patient’s pre-transplant baseline +/- 20%.
5) Growth Factor
a. GCSF will be given at a dose of 5mcg/kg/day SQ beginning on day 7 after
SCT.
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
b. It should be continued until the absolute neutrophil count (ANC) is
>1000/μL for 2 subsequent days post-nadir.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
6) Blood products
a. The hemoglobin should be maintained between 8 and 11 g/dL for at least
100 days after SCT.
b. Platelets should be maintained >50,000/μL after Alemtuzumab
administration and continuing after SCT to decrease the risk of
neurological events.
c.
All blood products should be irradiated and leukodepleted.  Only
recipients who are CMV negative need to receive CMV-negative products.
7) Treatment of fever/infections
a. Patients should be closely monitored for signs of infection closely and
treated as per institution guidelines with broad spectrum antibacterial,
antiviral, and antifungal agents.
b. Since patients will receive Alemtuzumab, they are all at high risk for
infections in the early post-transplant period.
8) Infection surveillance and prophylaxis
a. HSV
i. Acyclovir prophylaxis is recommended for 6 months post-SCT for
any patient who is HSV or VZV sero-positive.
ii. Acyclovir should be dosed 250mg/m2/dose PO or IV q8 hours
(maximum dose 800mg PO/IV q8)
b. PCP
i. Recipients should be started on trimetheprim-sulfamethoxazole or
an equivalent medication.
1. PCP prophylaxis should be started when Alemtuzumab is
begun.
2. Prophylaxis should be discontinued after the pm dose on
day -3, and not resumed until day 50 post-SCT unless
neutrophil recovery has not occurred.
a. If neutrophil recovery has not occurred by day 50,
PCP prophylaxis should be started with
Pentamidine 4mg/kg IV q4weeks.
c.
Fungal prophylaxis
i. Anti-fungal prophylaxis against Aspergillus sp. is recommended
with Voriconazole beginning w/ Alemtuzumab conditioning and
continuing until day 180 or until immunosuppression is
discontinued, whichever is later.
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
ii. The dose should be 4mg/kg/dose PO/IV q12 (maximum dose
600mg/day for patients >40kg or 300mg/day for patients <40kg)
iii. Because of the possibility of interactions between voriconazole and
Tacrolimus, Tacrolimus levels should be monitored at least weekly
to avoid toxicity.
d. Bacterial prophylaxis
i. Penicillin prophylaxis should begin when Alemtuzumab is started
and continue through day 180.
ii. The dose should be 250mg po BID for all patients.
e.
CMV
i. All patients must be screened with CMV PCR weekly until day
100 (If clinically stable and not requiring weekly visit CMV PCR
should be done at each visit).
ii. From day 100 to 180, screening with CMV PCR should occur at
least once a month.
iii. Antiviral treatment should be started if PCR reveals a viral load
>1000.  If this occurs before engraftment, foscarnet may be used to
prevent marrow suppression.
f.
Adenovirus
i. All patients should be screened with weekly adenovirus PCR from
serum until day 100 (If clinically stable and not requiring weekly
visit ADV PCR should be done at each visit).
ii. From day 100 to 180, screening with adenovirus PCR should occur
at least once a month.
iii. If the patients has clinical symptoms of a possible adenoviral
infection (i.e. diarrhea, hepatic dysfunction, respiratory distress),
adenovirus PCR should be sent from pertinent source (i.e. stool,
bronchoalveolar lavage).
iv. If an active systemic infection is diagnosed, cidofovir 5mg/kg q
week with Probenecid should be started.
g. EBV
i. All patients should be screened with EBV PCR weekly until day
100 (If clinically stable and not requiring weekly visit EBV PCR
should be done at each visit).
ii. From day 100 to 180, screening with EBV PCR should occur
monthly.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
iii. In the event of persistent EBV viremia or symptoms suggestive of
EBV PTLD (i.e. lymphadenopathy, fever, etc), therapy with
Rituximab 375mg/m2 q week for 4 doses is recommended.
VII. Required/Recommended Observations
1) Pre-Transplant
a.
History and physical examination: A complete history and physical
examination including accurate assessment and documentation of
hepatomegaly, splenomegaly; vital signs to include blood pressure,
oxygen saturation, weight, height, BSA.
b. Hematology (must be within one week prior to starting therapy):
CBC, differential, ABO and Rh typing, antibody screen, PT, PTT,
Fibrinogen.
c.
Microbiology studies on donor must be done within 30 days of day 0.
Microbiology studies on recipient must be done within 30 days of
starting therapy:
i. Antigen: Hepatitis Surface Antigen
ii. Antibody: Hepatitis A IgG/IgM, Hepatitis B Core
Antibody, Hepatitis B Surface Antibody, Hepatitis C
Antibody, CMV IgG/IgM, EBV IgG/IgM, VZV IgG/IgM,
HSV 1 & 2 IgG/IgM, HIV 1/2 antibody, Toxoplasmosis
IgG/IgM, HTLV I/II IgG, West Nile Virus IgG/IgM
iii. Trypanosoma cruzi
iv. RPR
d. Chemistry: Electrolytes, serum creatinine, BUN, total and direct
bilirubin, SGPT, SGOT, albumin, calcium, phosphorus, uric acid,
magnesium, LDH, glucose, alkaline phosphatase, cholesterol,
Triglycerides.
e.
HLA Typing
f.
STR: on donor and recipient
g. Cardiac Evaluation: Echocardiogram or MUGA scan with ejection
fraction (or fractional shortening) (within 45 days of starting therapy)
h. Pulmonary Evaluation: Chest x-ray (PA and lateral), PFTs (if age
appropriate, O2 saturation if unable to perform PFT) (within 45 days
of starting therapy)
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Version 0.05: Edit./Elig. Rev. Nov. 8,
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Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
i.
Renal Function: urinalysis, 12 or 24-hour creatinine clearance or
GFR (within 45 days of starting therapy)
j.
MRI/A of brain (within 45 days of starting therapy)
k.
l.
Performance Status: Karnofsky or Lansky score (age appropriate)
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Version 0.05: Edit./Elig. Rev. Nov. 8,
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Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
m. Pregnancy test for females of childbearing age (within 7 days of
starting therapy)
n. Consults: Dentistry, ophthalmology (within 60 days of starting
therapy)
2) Day +1 to +60 Post Allogeneic Donor Transplant
Required/ Recommended Observations
a.
History and Physical: An assessment to include graft-versus host disease
assessment, vital signs, and weight. Karnofsky or Lansky (age
appropriate) with history/physical at every visit.
b. Hematology:
i. Inpatient: Daily CBC with manual differential until the
absolute neutrophil count (ANC) reaches 500/mm3for three
consecutive days and the platelet count reaches >50,000/mm3
untransfused x 7 days, and then as clinically indicated
ii. Post-discharge: CBC at every visit
c.
Chemistry: Electrolytes, BUN, creatinine, glucose, total and direct
bilirubin, Ca++, Mg++, PO4, SGOT, SGPT, Albumin, and Alkaline
Phosphatase as clinically indicated. Cholesterol, Triglycerides, Uric Acid,
LDH, amylase, lipase, and GGT as clinically indicated
d. STR Studies and hemoglobin electropheresis at Days +30 and +60 (± 3
days)
e.
Tacrolimus levels at every visit.
f.
CMV DNA PCR, EBV PCR, and adenovirus DNA PCR q week
3) Required/ Recommended Observations Day +60 to +365
a.
History and Physical:  Assessment of graft vs. host disease, vital signs,
weight, with each clinic visit and as clinically indicated.
b. Hematology:  CBC with manual differential on Days +100, +180, and
+365 and as clinically indicated
c.
Cardiac Evaluation: Echocardiogram or MUGA scan with ejection
fraction (or fractional shortening) will be done on Day +365 (± 7 days)
d. Performance Evaluation:  Karnofsky or Lansky Score during clinic visit
on day +100 and +180 (± 7 days)
e.
STR Studies and hemoglobin electropheresis at Days +100, +180, and
+365 (± 7 days)
f.
Tacrolimus levels as clinically indicated.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
g. CMV DNA PCR, EBV DNA PCR, and adenovirus DNA PCR every visit
(not more than weekly) until Day+180 (± 7 days), then as clinically
indicated.
h. Immune reconstitution: Lymphocyte subset panel and
immunoglobulins at Day+100, Day+180, and Day+365 (± 7 days)
4) Required/Recommended Observations on or after Day +366
a.
History and Physical:  Assessment to include chronic graft vs. host disease
stage and grading), vital signs, weight, performance score on the following
post transplant dates:  15 months, 18 months, and 2 years
b. Hematology:  CBC with manual differential as clinically indicated.
c.
STR Studies and hemoglobin electropheresis: 2 years (± 10 days) post
allogeneic stem cell transplant
d. Tacrolimus levels as clinically indicated
e.
CMV DNA PCR every visit while receiving GVHD immunosuppressants
if clinically indicated.
f.
Immune reconstitution: Lymphocyte subset panel and
immunoglobulins at 18 months post HSCT (± 10 days)
g.
h. MRI/A of brain 2 years post allogeneic stem cell transplant (if initial
scan abnormal)
5) Required Late Effects Evaluation
a.
Development and Endocrine Follow up
i.
Yearly growth assessment (height, weight) with appropriate
growth work-up if <5th percentile or patient is falling off the
growth curve.
ii. Yearly pubertal assessment (if applicable) and appropriate
endocrine work-up if indicated.
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
VIII. Drug Information
Alemtuzumab
Source and Pharmacology:
Alemtuzumab binds to CD52, an antigen present on the surface of B and T lymphocytes,
a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. A
proportion of bone marrow cells, including some CD34+ cells, express variable levels of
CD52. The proposed mechanism of action is antibody-dependent cellular-mediated lysis
following cell surface binding of Campath to the leukemic cells.  In adult patients, the
mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6
days (range 1 to 14 days) after the last 30 mg dose.  Comparisons of AUC in patients ≥
65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are
necessary for age. Comparisons of AUC in female patients (n=4) versus male patients
(n=17) suggested that no dose adjustments are necessary for gender.  However, the
pharmacokinetics of Campath in pediatric patients have not been studied. The effects of
renal or hepatic impairment on the pharmacokinetics of Campath have not been studied.
Toxicity:
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Fever
●
Chills
●
Anemia due to
decreased number of
red cells
●
Infection due to
decreased number of
white blood cells
●
Bleeding due to
decreased numbers of
platelets
●
Weakened immune
system
●
Nausea
●
Vomiting
●
Diarrhea
●
Rash
●
Headache
●
Sweating
●
Back pain
●
Severe itching
●
Allergic reaction of
skin and blood vessels
●
Tiredness
●
Loss of appetite
●
Abdominal pain
●
Dizziness
●
High blood pressure
●
Blisters
●
Pain in the muscles
●
Herpes simplex infection
●
Inflammation of the
throat
24


Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Formulation and Stability:
Alemtuzumab is a sterile, clear, colorless, isotonic solution (pH 6.8-7.4) for injection.
Each single use vial contains 30 mg alemtuzumab, 8.0 mg sodium chloride, 1.44 mg
dibasic sodium phosphate, 0.2 mg potassium chloride, 0.2 mg monobasic potassium
phosphate, 0.1 mg polysorbate 80, and 0.0187 mg disodium edetate dihydrate. No
preservatives are added.
Guidelines for Administration:
Administer as an IV infusion over 2 hours. Do not administer as intravenous push or
bolus.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration. If particulate matter is present or the solution is
discolored, the vial should not be used. DO NOT SHAKE VIAL.
Use aseptic technique during the preparation and administration of Alemtuzumab.
Withdraw the necessary amount from the vial into a syringe.  Inject syringe contents into
100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert
the bag to mix the solution. Discard syringe.  The vial contains no preservatives and is
intended for single use only. DISCARD VIAL including any unused portion after
withdrawal of dose.
Use within 8 hours after dilution. Store diluted Alemtuzumab at room temperature
(15-30°C) or refrigerated (2-8°C). Protect from light.
Alemtuzumab is supplied in single-use clear glass vials containing 30 mg in 1 mL of
solution.  Store Alemtuzumab at 2-8°C (36-46°F). Do not freeze. If accidentally frozen,
thaw at 2-8°C before administration.  Protect from direct sunlight.
Supplier: Commercially available. See package insert for further information.
Fludarabine
Source and Pharmacology:
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then
phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate,
2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha,
ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The
mechanism of action of this antimetabolite is not completely characterized and may be
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
multi-faceted.  Limited pharmacokinetic data for Fludarabine are available from a
published study of children (ages 1-21 years) with refractory acute leukemias or solid
tumors (Children's Cancer Group Study 0971). When Fludarabine was administered as a
loading dose over 10 minutes immediately followed by a 5-day continuous infusion,
steady-state conditions were reached early.
Toxicity:
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to
occur in 20% or fewer
patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Anemia due to
decreased number of
red cells
●
Infection due to
decreased number of
white blood cells
●
Bleeding due to
decreased numbers of
platelets
●
Tiredness
●
Nausea
●
Vomiting
●
Weakened immune
system
●
Pneumonia
●
Diarrhea
●
Mouth sores
●
Skin rash
●
Fever
●
Swelling of hands and
feet
●
Numbness and tingling in
hands and/or feet related
to irritation of nerves of
the hand and/or feet
●
Changes in vision
●
Agitation/nervousness
●
Confusion
●
Cough
●
Difficulty breathing
●
Weakness
●
Severe brain injury and
death
Formulation and Stability:
Fludarabine is supplied as a white, lyophilized solid cake. Each vial contains 50 mg of
fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The
pH range for the final product is 7.2-8.2. Store under refrigeration, between 2º-8ºC
(36º-46ºF).
Fludarabine is supplied in a clear glass single dose vial (6mL capacity) and packaged in a
single dose vial carton in a shelf pack of five.
26


Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
27


Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Guidelines for Administration:
Administer by IV infusion through a peripheral or a central line.
Fludarabine should be prepared for parenteral use by aseptically adding Sterile Water for
Injection USP. When reconstituted with 2mL of Sterile Water for Injection, USP, the solid
cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will
contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to
adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. In clinical studies, the
product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection USP or 0.9%
Sodium Chloride USP.
Reconstituted Fludarabine contains no antimicrobial preservative and thus should be used
within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared
solutions. Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration.  Fludarabine should not be mixed with other drugs.
Supplier: Commercially available. See package insert for further information.
Melphalan
Source and Pharmacology:
Melphalan, a phenylalanine derivative of nitrogen mustard, is a bifunctional alkylating
agent. Melphalan forms covalent cross-links with DNA or DNA protein complexes
thereby resulting in cytotoxic, mutagenic, and carcinogenic effects. The end result of the
alkylation process results in the misreading of the DNA code and the inhibition of DNA,
RNA, and protein synthesis in rapidly proliferating tumor cells.  It is cell cycle
non-specific. After IV administration, melphalan plasma concentrations decline rapidly in
a
bi-exponential manner with distribution phase and terminal elimination phase half-lives
of approximately 10 and 75 minutes, respectively. Plasma melphalan levels are highly
variable after oral dosing, both with respect to the time of the first appearance of
melphalan in plasma (range approximately 0 to 6 hours) and to the peak plasma
concentration achieved. These results may be due to incomplete intestinal absorption,
a variable "first pass" hepatic metabolism, or to rapid hydrolysis. The oral dose averages
61% ± 26% of that following IV administration. The terminal elimination plasma
half-life of oral melphalan is 1.5 ± 0.83 hours. The steady-state volume of distribution of
melphalan is 0.5 L/kg. The extent of melphalan binding to plasma proteins ranges from
60-90%. Melphalan is eliminated from plasma primarily by chemical hydrolysis to
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Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
monohydroxymelphalan and dihydroxymelphalan. The 24-hour urinary excretion of
parent drug is approximately 10% suggesting that renal clearance is not a major route
of elimination of parent drug. Penetration into CSF is low. Despite the fact that the
contribution of renal elimination to melphalan clearance appears to be low, one
pharmacokinetic study suggests dosage may need to be reduced in patients with renal
impairment.
Toxicities:
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Loss of appetite
●
Nausea, vomiting
●
Skin breakdown if
drug leaks from vein
●
Anemia due to
decreased number of
red cells
●
Infection due to
decreased number of
white blood cells
●
Bleeding due to
decreased numbers of
platelets
●
Mouth sores
●
Temporary hair loss
●
Diarrhea
●
Inflammation of the
lung
●
Weakness
●
Weight loss
●
Low blood pressure
●
Excessive perspiration
●
Allergic reaction
●
Damage/ scarring of
lung tissue
●
Sterility
●
Seizure
Formulation and Stability:
Melphalan is available as a 2 mg scored tablet. Inactive ingredients include colloidal
silicon dioxide, crospovidone, hypromellose, macrogol/PEG 400, magnesium stearate,
microcrystalline cellulose, and titanium dioxide. Store in a refrigerator, 2°-8°C
(36°-46°F). Protect from light.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Melphalan for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each
single-use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20
mg povidone. Melphalan for Injection is reconstituted using the sterile diluent provided.
Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL,
ethanol (96%) 0.52 mL, and Water for Injection to a total of 10 mL. Store at controlled
room temperature 15°-30°C (59°-86°F) and protect from light.
1) Reconstitute to a concentration of 5 mg/mL by rapidly injecting 10 mL of
the supplied diluent directly into the vial of lyophilized powder using a
sterile needle (20-gauge or larger needle diameter) and syringe.
Immediately shake vial vigorously until a clear solution is obtained. Rapid
addition of the diluent followed by immediate vigorous shaking is
important for proper dissolution.
2) Immediately dilute the dose to be administered in NS to a final
concentration not to exceed 2 mg/mL for IV central line administration or
0.45 mg/mL for peripheral IV administration
3) A precipitate forms if the reconstituted solution is stored at 5°C. Do not
refrigerate the reconstituted product.
(The time between reconstitution/dilution and administration of melphalan should be kept
to a minimum because reconstituted and diluted solutions of melphalan are unstable.
Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in
reconstituted material from the reaction of melphalan with the sterile diluent for
melphalan. Upon further dilution with saline, nearly 1% label strength of melphalan
hydrolyzes every 10 minutes.)
Guidelines for Administration:
IV: Administer by IV infusion through a peripheral or a central line. Complete infusion
within 1 hour of product reconstitution.
PO: Give on empty stomach. Food decreases bioavailability. Melphalan is unstable in
solution and should not be mixed with fluids prior to administration. Tablets should not
be split or crushed in advance because humidity may lead to drug degradation.
Supplier: Commercially available. See package insert for further information.
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
G-CSF (Filgrastim)
Source and Pharmacology:
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli
bacteria into which has been inserted the human granulocyte colony stimulating factor
gene. It differs from the natural protein in that the N- amino acid is methionine and the
protein is not glycosylated. G-CSF is a lineage specific colony-stimulating factor which
regulates the production of neutrophils within the bone marrow and affects neutrophil
progenitor proliferation, differentiation, and selected end-cell functional activation
(including enhanced phagocytic ability, priming of the cellular metabolism associated
with respiratory burst, antibody dependent killing, and the increased expression of some
functions associated with cell surface antigens).The elimination half-life is similar for
subcutaneous and intravenous administration, approximately 3.5 hours. The time to peak
concentration when administered subcutaneously is 2-8 hours
Toxicity:
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Local irritation (skin)
at injection site
●
Ache or pain inside the
bones.  Increased
levels of liver enzymes
and uric acid in the
blood
●
Bleeding due to
decreased numbers of
platelets
●
Allergic reaction, low
fever
●
Enlargement or rupture
of the spleen
●
Worsening of
pre-existing skin rashes
●
Temporary hair loss
●
Inflammation of a blood
vessel in the skin
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Formulation and Stability:
Supplied as a clear solution in 300 mcg/mL 1 mL or 1.6 mL vials and prefilled syringes
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL. Vials are preservative free single use
vials. Discard unused portions of open vials. Store refrigerated at 2º-8ºC (36º-46ºF). Prior
to injection, filgrastim may be allowed to reach room temperature for a maximum of 24
hours. Avoid freezing and temperatures > 30ºC.
For IV use, dilute in D5W only to concentrations >15 mcg/mL. At concentrations
between 5 and 15 mcg/mL, human serum albumin should be added to make a final
albumin concentration of 0.2% (2 mg/mL) in order to minimize the adsorption of
filgrastim to infusion containers and equipment.
Dilutions of 5 mcg/mL or less are not recommended. Diluted filgrastim should be stored
at 2º-8ºC (36º-46ºF) and used within 24 hours. Do not shake.
Guidelines for Administration:
See Supportive Care section of the protocol.  Filgrastim should not be administered
within 24 hours of chemotherapy.
Supplier: Commercially available from various manufacturers. See package insert for
further information
TACROLIMUS (FK-506, Prograf®) NSC # 717865 (01/17/08)
Source and Pharmacology: Tacrolimus is a macrolide immunosuppressant produced by
Streptomyces tsukubaensis. Tacrolimus is a potent immunosuppressive agent which
prolongs the survival of the host and transplanted grafts in animal transplant models of
liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin,
cornea, and limb. Tacrolimus inhibits T-lymphocyte activation, although the exact
mechanism of action is not known. Experimental evidence suggests that tacrolimus binds
to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium,
calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin
inhibited. This effect may prevent the dephosphorylation and translocation of nuclear
factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene
transcription for the formation of lymphokines (such as interleukin-2, gamma interferon).
The net result is the inhibition of T-lymphocyte activation (immunosuppression).
Additionally, tacrolimus may inhibit cellular activities such as nitric oxide synthetase
activation and apoptosis, and may potentiate the action of corticosteroids in these
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Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
processes. Tacrolimus activity is primarily due to the parent drug. The plasma protein
binding of tacrolimus is approximately 99% and is independent of concentration over a
range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid
glycoprotein, and has a high level of association with erythrocytes. The t½ in adult
patients ranges from 11-19 hours. The pharmacokinetics of tacrolimus have been studied
in pediatric liver transplant patients (0.7 to 13.2 years of age). Following the IV
administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal
half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and
0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 pediatric patients,
the absolute bioavailability was 31 ± 21%. Whole blood trough concentrations from 31
patients less than 12 years old showed that pediatric patients needed higher doses than
adults to achieve similar tacrolimus trough concentrations. Tacrolimus is extensively
metabolized by the mixed-function oxidase system, primarily the cytochrome P-450
system (CYP3A) in the liver and to a lesser extent in the intestinal mucosa. The major
metabolite identified in incubations with human liver microsomes is 13-demethyl
tacrolimus. The main route of elimination is via the biliary tract and excretion in faeces.
The mean clearance in renal dysfunction and mild hepatic dysfunction is the same as
normal volunteers. Severe hepatic dysfunction (Pugh score >10) led to a substantially
decreased clearance. A retrospective comparison of Black and Caucasian kidney
transplant patients indicated that Black patients required higher tacrolimus doses to attain
similar trough concentrations; there were no gender-based differences.
The absorption of tacrolimus from the gastrointestinal tract is incomplete and variable
exhibiting large intra- and inter-patient variability. Administration with food significantly
decreases the rate and extent of absorption Drugs that stimulate or inhibit hepatic p-450
enzymes will alter clearance of tacrolimus and close attention to potential drug
interactions is crucial.
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Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
(Continued on next page)
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
•Headache
• Nausea and vomiting
• High blood pressure
• Loss of desire to eat or
appetite
• Reduced ability of the
body to fight infection
• Diarrhea or constipation
• Fever
• Tremor (shakiness usually
of the hands)
• Increases in the levels of
certain chemicals in the
blood because the kidney
is not working as well as
normal which may require
lowering the dose
• Fewer red blood cells in the
blood
• Difficulty sleeping or falling
asleep
• A feeling of weakness and/or
tiredness
• Pain which may be in the
abdomen (belly), back and/or
other parts of the body
• High levels of sugar in the
blood that may require
treatment
•Chest pain
• Hair loss
• Dizziness
• Elevation in the blood of
certain enzymes or bilirubin
found in the liver which may
mean the liver is not working
as well
• Bladder or kidney infection
• Fluid retention and build-up in
the tissues usually of the lower
legs leading to an increase in
weight
• Rash that may itch
• An increase in the levels of
lipids (fats) and cholesterol in the
blood which, if prolonged, could
lead to heart problems later in life
• Acid or upset stomach
(heartburn)
• Difficulty or discomfort on
swallowing
• Inflammation of the stomach or
esophagus
• Too much gas produced in the
intestines
• Shortness of breath and/or a
tight feeling in the chest with
wheezing and shortness of breath
• Increased cough
• Flu type symptoms with fever,
tiredness, aches and pains
• Severe allergic reaction which
can be life threatening with
shortness of breath, low blood
pressure, rapid heart rate chills
and fever (usually only with the IV
form)
• Allergic reactions
• Fluid build-up in the lungs
• Convulsions
• A fast heartbeat which may cause
pain in the chest
• Chest pain or discomfort that
occurs when heart muscle
does not get enough blood
• Severe damage to the brain which
may lead to difficulty carrying out
normal daily tasks and to coma
• Abnormal clotting of the blood
which could lead to bleeding in
the intestines or elsewhere
• Inflammation and clotting of
blood vessels which can lead to
pain and swelling in the area of the
clot
• Infections including those caused
by bacteria, virus, and fungus
which could be located in the skin,
blood, throat, sinuses, lungs or
abdomen
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
(Continued from previous page)
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
• Abnormal levels of
magnesium in the body
which may require that extra
magnesium by mouth or vein
• Low (or High) levels of
certain salts in the body
like potassium and
phosphate which may
require treatment
• Numbness and tingling in
the fingers and toes
• Changes in brain function such
that have difficulty in thinking
clearly, are sleepy, depressed,
anxious, have strange dreams, are
nervous, have changes in mood
which may include severe
depression, feelings of suicide,
feelings of
aggressiveness and violent
behavior or see or hear things that
are not there
• Fewer white blood cells and
platelets in the blood
• Greater than normal numbers of
white or red blood cells in the
blood
• Aches and Pains in the joints or
muscles
• Skin changes including pimples,
change in color, increased
tendency to sun burn and skin
sores
• Wounds may be slower to heal
• Excessive hair growth such as
on the face, eyebrows, arms and
legs
• Bleeding or tender gums,
overgrowth of gum tissue
• Changes in your vision or a
decrease in vision
• Ear pain or ringing in the ears
• Gallstones
• Severe rashes which can result in
loss of skin and damage to
mucous membranes
• Erosion (ulceration) of the lining
of the intestines which can result in
pain and/or bleeding or a hole in
the intestines which would cause
leakage into the abdomen with pain
and infection
• Damage to the liver which can
lead to inflammation and/or
scarring which could lead to a
yellow appearing skin, and fluid
collection in the abdomen which
makes it look larger
• Severe kidney damage (which
may be permanent)
• Diabetes mellitus - a condition
where the sugar in the blood is not
appropriately controlled and may
require treatment with insulin by
injection or drugs taken by mouth
• Damage to the heart muscle
• Excessive growth of white blood
cells that may lead to lymphoma a
cancer of the white blood cells
• Increased chance of skin cancers
35


Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Formulation and Stability:
IV formulation: Tacrolimus is available as a sterile solution (tacrolimus injection)
containing the equivalent of 5 mg anhydrous tacrolimus in 1 mL Each mL contains
polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP,
80% v/v. Store between 5°C and 25°C (41°F and 77°F).
Oral formulations:
Tacrolimus is available for oral administration as capsules containing the equivalent of
0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include lactose,
hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate.
The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg
capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains
gelatin, titanium dioxide and ferric oxide. Store at 25°C (77°F); excursions permitted to
15°-30°C (59°-86°F).
Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.
Tacrolimus Injection must be diluted with 0.9% Sodium Chloride Injection or 5%
Dextrose Injection before use to a concentration between 0.004 mg/mL and 0.02 mg/mL.
Diluted infusion solution should be stored in glass or polyethylene containers and should
be discarded after 24 hours. The polyoxyethylated castor oil contained in the concentrate
for intravenous infusion can cause phthalate stripping from PVC. It is strongly
recommended that glass bottles and non-PVC tubing be used to minimize patient
exposure to DEHP. Due to the chemical instability of tacrolimus in alkaline media,
Tacrolimus Injection should not be mixed or co-infused with solutions of pH 9 or greater
(e.g., ganciclovir or acyclovir). Monitor closely for an acute allergic reaction for the first
30 minutes and at frequent intervals thereafter.
Oral: Administer at a consistent time of day and at consistent intervals with regard to
meals. Tacrolimus may be given with food as long as it is given the same way each time;
however; administration with food significantly decreases the rate and extent of
absorption.
Supplier: Commercially available from various manufacturers. See package insert for
further information.
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Methylprednisolone or prednisone
Methylprednisolone is a corticosteroid and the methyl derivative of prednisolone.
Glucocorticoids produce widespread and diverse physiologic effects on carbohydrate,
protein, and lipid metabolism, electrolyte and water balance, functions of the
cardiovascular system, kidney, skeletal muscle, and the nervous systems. Glucocorticoids
reduce the concentration of thymus-dependent lymphocytes (T-lymphocytes), monocytes,
and eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human
lymphoid cells which are found in larger numbers on leukemic lymphoblasts. They also
decrease binding of immunoglobulin to cell surface receptors and inhibit the synthesis
and/or release of interleukins, thereby decreasing T-lymphocyte blastogenesis and
reducing expansion of the primary immune response. The specific cellular mechanisms
that act to halt DNA synthesis are thought to be related to inhibition of glucose transport
or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. At the
cellular level, corticosteroids appear to act by controlling the rate of protein synthesis.
The half-life of methylprednisolone is approximately 2.5 hours; however, the metabolic
effects at the tissue level persist for up to 20-30 hours. It is primarily metabolized in the
liver and excreted by the kidneys. Methylprednisolone 4 mg has equivalent potency to
prednisone 5mg.
Prednisone is a synthetic compound closely related to hydrocortisone. Glucocorticoids
produce widespread and diverse physiologic effects on carbohydrate, protein, and lipid
metabolism, electrolyte and water balance, functions of the cardiovascular system,
kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce the
concentration of thymus-dependent lymphocytes (T-lymphocytes), monocytes, and
eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human lymphoid
cells which are found in larger numbers on leukemic lymphoblasts. They also decrease
binding of immunoglobulin to cell surface receptors and inhibit the synthesis and/or
release of interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing
expansion of the primary immune response. The specific cellular mechanisms that act to
halt DNA synthesis are thought to be related to inhibition of glucose transport or
phosphorylation, retardation of mitosis, and inhibition of protein synthesis. Peak blood
levels occur within 2 hours of oral intake. Prednisone is approximately 75% protein
bound with a plasma t½ of 3.2 to 4 hours. (Biologic half-life is 12-36 hours.)
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2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Water retention
●
Overeating
●
Weakened immune
system
●
Temporary
personality changes
●
Abnormal hormone
production
●
High blood sugar
●
Slowed growth
●
Decreased bone
density
●
Headaches
●
Poor wound healing
●
Stomach swelling or
pain
●
Tissue swelling
●
High blood pressure
●
Stomach ulcer
●
Muscle weakness
●
Cataracts
●
Difficulty in falling
asleep
●
Worsening of diabetes
●
Inflammation of
pancreas
●
Personality disturbances
●
Bleeding in the stomach
and intestines
●
Increased pressure
within the eye
●
Disturbance of bone
calcium which can lead
to possible fractures or
permanent bone damage
Formulation and Stability:
Methylprednisolone:
Available for oral use in 2, 4, 8, 16, 24 and 32 mg tablets. Inactive ingredients vary
depending on manufacturer but tablet formulations may include: calcium stearate, corn
starch, erythrosine sodium, lactose, mineral oil, sorbic acid, sucrose, croscarmellose
sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polacrilin
potassium, sodium starch glycolate, and stearic acid.
Lyophilized Powder for Injection as methylprednisolone sodium succinate equivalent to
methylprednisolone is available as: Dual chamber vials of 40 mg (1 mL), 125 mg (2
mL), 500 mg (4 mL), 1000 mg (8 mL) also containing mono, dibasic sodium phosphate
and benzyl alcohol (diluent); Vials of 500 mg, 1 g, 2 g also containing monobasic and
dibasic sodium phosphate with or without separate vials of diluent containing benzyl
alcohol. Protect from light.
Store unreconstituted product at controlled room temperature 20°- 25°C (68°- 77°F).
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Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Prednisone:
Available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 50 mg tablets; liquid, 5 mg/5
mL or 5 mg/mL. Inactive ingredients vary depending on manufacturer but tablet
formulations may include: calcium or magnesium stearate, corn starch, lactose,
erythrosine sodium, mineral oil, sorbic acid, sucrose, talc and various dyes. Liquid
formulations may include: 5-30% alcohol, fructose, sucrose, saccharin, and sorbitol.
Guidelines for Administration: See Treatment section of the protocol.
Methylprednisolone:
Dilute lyophilized powder vials for injection with sufficient diluent to obtain a
concentration of 62.5 mg/mL. The manufacturer recommends the use of Bacteriostatic
sterile water for injection containing benzyl alcohol. Use sterile water for injection
without benzyl alcohol for neonates and infants < 2 years of age or patients with
hypersensitivity to benzyl alcohol.
Mix dual chamber vials as directed. Store solution at controlled room temperature
20°-25°C (68°-77°F).Use solution within 48 hours after mixing.
May be further diluted in Saline or Dextrose containing solutions for intravenous
administration.
Supplier: Both commercially available from various sources. See package insert for
further information
Mycophenolate Mofetil: This drug will be used as part of GVHD prophylaxis for cord
blood recipients.
Source and Pharmacology:
Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed
to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive,
and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and
therefore inhibits the de novo pathway of guanosine nucleotide synthesis without
incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their
proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage
pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative
responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation.
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Version 11 – Campath Dosing Change:  November 25, 2015
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Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on
lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents
the glycosylation of lymphocyte and monocyte glycoproteins that are involved in
intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into
sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early
events in the activation of human peripheral blood mononuclear cells, such as the
production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of
these events to DNA synthesis and proliferation.
Following oral and intravenous administration, mycophenolate mofetil undergoes rapid
and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is
rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of
MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate
mofetil, can be measured systemically during the intravenous infusion; however, shortly
(about 5 minutes) after the infusion is stopped or after oral administration, MMF
concentration is below the limit of quantitation (0.4 µg/mL).
Following oral and intravenous dosing, mycophenolate mofetil undergoes complete
metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically
after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the
phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo,
MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of
the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral
administration of mycophenolate mofetil to healthy subjects:
N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of
N-(2-hydroxyethyl)-morpholine.
Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to
12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in
approximately a 40% decrease in the MPA AUC (largely as a consequence of lower
concentrations in the terminal portion of the profile). These observations suggest that
enterohepatic recirculation contributes to MPA plasma concentrations.
Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50%
increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal
insufficiency.
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Version 8 – Editorial Changes:  June 30, 2014
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Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Orally
administered radiolabeled mycophenolate mofetil resulted in complete recovery of the
administered dose, with 93% of the administered dose recovered in the urine and 6%
recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as
MPAG. At clinically encountered concentrations, MPA and MPAG are usually not
removed by hemodialysis. However, at high MPAG plasma concentrations (> 100
ug/mL), small amounts of MPAG are removed. Mean (±SD) apparent half-life and
plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral
administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous
administration, respectively.
The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric
patients (ranging from 1 year to 18 years of age) receiving CellCept oral suspension at a
dose of 600 mg/m2 bid (up to a maximum of 1 g bid) after allogeneic renal
transplantation.
The CellCept oral suspension dose of 600 mg/m2 bid (up to a maximum of 1 g bid)
achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal
transplant patients receiving CellCept capsules at a dose of 1 g bid in the early
posttransplant period. There was wide variability in the data. As observed in adults, early
posttransplant MPA AUC values were approximately 45% to 53% lower than those
observed in the later post transplant period (> 3 months). MPA AUC values were similar
in the early and late posttransplant period across the 1 year to 18 year age range.
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Toxicity:
Likely
(“Likely” refers to a side
effect that is expected to
occur in more than 20% of
patients.)
Less Likely
(“Less likely” refers to a side
effect that is expected to occur
in 20% or fewer patients.)
Rare, but Serious
(These possible risks have been
reported in rare occurrences,
typically less than 2% of
patients.  They may be serious if
they occur.)
●
Diarrhea
●
Stomach pain
●
Upset stomach
●
Vomiting
●
Difficulty falling
asleep or staying
asleep
●
Pain, especially in the
back, muscles, or
joints
●
Constipation
●
Swelling of the hands,
feet, ankles, or lower
legs
●
Difficulty breathing
●
Shaking hands that you
cannot control
●
Unusual bruising or
bleeding
●
Headache
●
Fast heartbeat
●
Excessive tiredness
●
Dizziness
●
Pale skin
●
Weakness
●
Blood in stools
●
Bloody vomit
●
Loose, floppy muscles
●
White patches in mouth
or throat
●
Swelling of gums
●
Vision changes
●
Rash
●
Low blood counts
●
Damage to unborn baby
●
Limited effectiveness of
birth control
●
Progressive Multifocal
Leukoencephalopathy
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Formulation and Stability:
Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in
water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH
3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol.
The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The
pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the
phenolic group.
Mycophenolate mofetil hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose
Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.
CellCept is available for oral administration as capsules containing 250 mg of
mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a
powder for oral suspension, which when constituted contains 200 mg/mL mycophenolate
mofetil.
Inactive ingredients in CellCept 250 mg capsules include croscarmellose sodium,
magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells
contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium
lauryl sulfate, titanium dioxide, and yellow iron oxide.
Inactive ingredients in CellCept 500 mg tablets include black iron oxide, croscarmellose
sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400,
povidone (K-90), red iron oxide, talc, and titanium dioxide; may also contain ammonium
hydroxide, ethyl alcohol, methyl alcohol, n-butyl alcohol, propylene glycol, and shellac.
Inactive ingredients in CellCept Oral Suspension include aspartame, citric acid
anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate
dihydrate, sorbitol, soybean lecithin, and xanthan gum.
CellCept Intravenous is the hydrochloride salt of mycophenolate mofetil. The chemical
name for the hydrochloride salt of mycophenolate mofetil is 2-morpholinoethyl
(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4
-hexenoate hydrochloride. It has an empirical formula of C23H31NO7 HCl and a molecular
weight of 469.96.
CellCept Intravenous is available as a sterile white to off-white lyophilized powder in
vials containing mycophenolate mofetil hydrochloride for administration by intravenous
infusion only. Each vial of CellCept Intravenous contains the equivalent of 500 mg
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mycophenolate mofetil as the hydrochloride salt. The inactive ingredients are polysorbate
80, 25 mg, and citric acid, 5 mg. Sodium hydroxide may have been used in the
manufacture of CellCept Intravenous to adjust the pH. Reconstitution and dilution with
5% Dextrose Injection USP yields a slightly yellow solution of mycophenolate mofetil, 6
mg/mL.
Guidelines for Administration: See Treatment section of protocol.
For IM/IV use: Caution should be exercised in the handling and preparation of solutions
of mycophenolate Intravenous. Avoid direct contact of the prepared solution of
mycophenolate Intravenous with skin or mucous membranes. Mycophenolate
Intravenous does not contain an antibacterial preservative; therefore, reconstitution and
dilution of the product must be performed under aseptic conditions.
Additionally, this product is sealed under vacuum and should retain a vacuum throughout
its shelf life. If a lack of vacuum in the vial is noted while adding diluent, the vial should
not be used.
Mycophenolate Intravenous infusion solution must be prepared in two steps: the first step
is a reconstitution step with 5% Dextrose Injection USP, and the second step is a dilution
step with 5% Dextrose Injection USP. A detailed description of the preparation is given
below:
Step 1
a.
Two (2) vials of Mycophenolate Intravenous are used for preparing each 1 g dose,
whereas three (3) vials are needed for each 1.5 g dose. Reconstitute the contents
of each vial by injecting 14 mL of 5% Dextrose Injection USP.
b. Gently shake the vial to dissolve the drug.
c.
Inspect the resulting slightly yellow solution for particulate matter and
discoloration prior to further dilution. Discard the vials if particulate matter or
discoloration is observed.
Step 2
a.
To prepare a 1 g dose, further dilute the contents of the two reconstituted vials
(approx. 2 x 15 mL) into 140 mL of 5% Dextrose Injection USP. To prepare a 1.5
g dose, further dilute the contents of the three reconstituted vials (approx. 3 x 15
mL) into 210 mL of 5% Dextrose Injection USP. The final concentration of both
solutions is 6 mg mycophenolate mofetil per mL.
b. Inspect the infusion solution for particulate matter or discoloration. Discard the
infusion solution if particulate matter or discoloration is observed.
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If the infusion solution is not prepared immediately prior to administration, the
commencement of administration of the infusion solution should be within 4 hours from
reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions
permitted to 15° to 30°C (59° to 86°F).
Mycophenolate Intravenous should not be mixed or administered concurrently via the
same infusion catheter with other intravenous drugs or infusion admixtures.
For oral use: It is recommended that Mycophenolate oral suspension be constituted by
the pharmacist prior to dispensing to the patient.
Mycophenolate oral suspension should not be mixed with any other medication.
Supplier: Commercially available from various manufacturers. See package insert for
further information.
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References
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Version 8 – Editorial Changes:  June 30, 2014
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Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
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63. Laver, J., Hulsey, T., Jones, J. & et al Assessment of barriers to bone marrow
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Ref Type: Abstract
67. Wagner, J., Barker, J., DeFor, T., Baker, K. & et al Transplantation of unrelated
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disease: influence of CD34 cell dose and HLA disparity on treatment-related
mortality and survival. Blood 100, 1611-1618 (2002).
68. Wall, D., Carter, S., Kernan, N. & et al Busulphan/melphalan/antithymocyte
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infant leukemia in young children: the Cord Blood Transplantation study (COBLT)
experience. Biology of Blood and Marrow Transplantation 11, 637-646 (2005).
69. Locatelli, F. et al. Related umbilical cord blood transplantation in patients with
thalassemia and sickle cell disease. Blood 101, 2137-2143 (2003).
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1.
2.
3.
4.
5.
6.
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Appendix A: Statistics
Study Design
The single center study is Phase III trial, consisting of one arms: sickle cell disease
patients 2-30 years old receiving related transplant using bone marrow after a
conditioning regimen consisting of Alemtuzumab, Fludarabine, and Melphalan.  The
anticipated trial will enroll 20 additional patients.
Accrual
It is anticipated that 7 years will be needed to enroll the additional patients.
Study Duration
Patients will be followed for at least 2 years post transplant.
Randomization
This is a nonrandomized trial; there will be no randomization considerations in this trial.
Primary Objective:
1)
To determine DFS at two years after matched sibling transplant using BM after a
conditioning regimen consisting of distal timed Alemtuzumab, Fludarabine, and
Melphalan for patients 2-30 y/o
The composite endpoint consists of death and graft rejection.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Secondary objectives:
10) Overall survival
11) Rate of neutrophil and platelet engraftment for BM vs. UCB
12) Incidence of graft failure
13) Incidence of grade II-IV and grade III-IV acute GVHD
14) Incidence of chronic GVHD
15) Incidence of other transplant complications, such as veno-occlusive disease,
CNS toxicity, and idiopathic pneumonia syndrome
16) Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus
17) Incidence of invasive fungal disease
18) Time to immune reconstitution via monitoring of lymphocyte subpopulations
and immunoglobulin levels
Sample Size and power calculations.
This study will enroll 20 patients. Sample size calculation was not performed as this
study is exploratory in nature.  Given the small size of the study, we do not expect to be
able to obtain appropriate power, which is appropriate as this is a pilot study.
Demographic and Baseline Characteristics
All demographics and characteristics that are continuous will be summarized by means
(SD) or median (interquartile range) depending on whether or not the data demonstrate
evidence of having come from a normal distribution, as validated by the Shapiro-Wilk
test. All categorical data will be presented as a frequency (%). The variables will include
age, gender, performance status, disease symptoms, serum bilirubin level, serum
creatinine level, pulmonary function test, cardiac function test, donor age, donor gender,
cerebral MRI, serum ferritin, and immune reconstitution baseline characteristics.
Analysis of the Primary Endpoint:
The DFS at the 2 year endpoint will be estimated using the Kaplan Meier product limit
estimator.  The frequencies of the events, i.e. graft failure, will be enumerated and
presented.
Analysis of Secondary endpoints:
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Overall survival: The distribution of time to death from any cause will be estimated by
Kaplan- Meier product limit function and plotted. The overall survival will be measured
from the time of transplant to any death and patients will be followed for 2 years.
Rate of neutrophil and platelet engraftment for BM: To assess the incidence and rate
of each type of engraftment for bone marrow, cumulative incidences curve will be
plotted.  Any death occurring before each type of engraftment will be considered a
competing risk.
Incidence of graft failure: The incidence of graft failure will be assessed by cumulative
incidence function and the corresponding curve will be plotted. Any death occurring
before the onset of graft failure will be considered as a competing risk.
Incidence of grade II-IV and grade III-IV acute GVHD: The incidence of grade II-IV
or grade III-IV acute GVHD will be assessed from the day of transplant to the first acute
GVHD onset using cumulative incidence function and corresponding curve will be
plotted. Any death occurring before each type of GVHD will be considered a competing
risk.
Incidence of chronic GVHD: The incidence of chronic GVHD from day of transplant
will be assessed by a cumulative incidence curved estimated by cumulative incidence
function. Any death occurring before the onset of chronic GVHD will be considered as a
competing risk.
Incidence of other transplant complications, such as veno-occlusive disease, CNS
toxicity, and idiopathic pneumonia syndrome
The incidence of other transplant complications (veno-occlusive disease, CNS toxicity,
and idiopathic pneumonia syndrome) from day of transplant will be evaluated by a
cumulative incidence curve estimated from the cumulative incidence function. Any death
occurring before onset of each of these complications will be considered a competing
risk.
Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus
To assess the incidence of reactivation of CMV, EBV, adenovirus and BK/JC virus,
cumulative incidence function will be estimated and plotted. Any death occurring before
onset of each of these reactivations will be considered a competing risk.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
Incidence of invasive fungal disease: To assess the incidence of reactivation of fungal
disease, cumulative incidence function will be estimated and plotted. Any death
occurring before onset of each of these reactivations will be considered a competing risk.
Time to immune reconstitution via monitoring of lymphocyte subpopulations and
immunoglobulin levels: To assess time to  immune reconstitution, lymphocytes subsets
B and T cells) and immunoglobulin levels measured at the five time points
(Pre-transplantation, Day +100, Day +180, Day +365 and Day 366+)  will be presented
using boxplots for each treatment group.
Stopping Guidelines and interim analysis
In order to formulate the stopping guidelines, assumptions are based on acceptable rates
of the overall mortality by Day 100 and graft rejection by Day 100
2.1 Overall Mortality
The overall mortality at 100 days is anticipated to be ≤10%. When the 100 day an overall
mortality rate exceeds 10% based on a truncated SPRT, the stopping rule will be triggered
in arm with 10 patients. The stopping rule is summarized in the Table 2.1.2
Table 2.1.2 Stopping Rule for Overall Mortality By Day 100 in Related
Donor Matched Patients
Stage k
Number  of  Evaluable1
Patients Accrued in kth
Stage
Number of Deaths
1
{1-10}
2
1 Evaluable patients are those who proceed to transplant.
If the number of deaths out of patients accrued at any stage is equal to the corresponding value in the 3
rd column, then the trial will be halted.
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Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
2.2 Graft Rejection
We will describe the stopping guideline for failure to engraft donor cells by Day 100. It is
assumed that the rate of occurrence of this toxicity marker is < 20% in both unrelated and
related donor matched patients.
When the 100 day graft rejection rate exceeds 20% based on a truncated SPRT, the
stopping rule will be triggered in the10 patient arm. The stopping rule is summarized in
the Table 2.2.
Table 2.2 Stopping Rule for Graft Rejection By Day 100 in Related BMT Patients
Stage k
Number  of Evaluable1
Patients Accrued in kth
Stage
Number of Graft
Rejections
1
{1-10}
3
1 Evaluable patients are those who proceed to transplant.
If the number of deaths out of patients accrued at any stage is equal to the corresponding value in the 3 rd
column, then the trial will be halted.
58


Version 0.05: Edit./Elig. Rev. Nov. 8,
2012
Version 6 – PI Changes and Editorial Changes – March 26, 2013
Version 7 – Treatment Schedule Change:  September 30, 2013
Version 8 – Editorial Changes:  June 30, 2014
Version 9 – Removal of unrelated arm and editorial changes:  March 26, 2015
Version 10 - Editorial Changes (Patient Eligibility):  May 27, 2015
Version 11 – Campath Dosing Change:  November 25, 2015
Version 12:  April 11, 2019
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