A Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Disease and Other Hemoglobinopathies
Phase: NA
Conditions: Sickle Cell Disease, Hemoglobinopathies
Sponsor: Vanderbilt-Ingram Cancer Center

Version dated December 04, 2017 
Page 1 of 46 
VICCNCCTT12108:  A Non-Myeloablative Conditioning and Transplantation of 
Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients with Sickle 
Cell Disease and Other Hemoglobinopathies                        NCT01850108
Amendment Number: 5 
 
Amendment Date: December 04, 2017 
Summary of Changes
Revised/Added Section 
Revision Location 
in Tracked 
Change Protocol 
(PDF page numbers) 
Description of Revision 
Entire Protocol 
Throughout 
protocol 
Minor formatting and grammatical revisions, headers and 
page numbers updated 
Cover pages 
Pages 1-3 
•
Amendment 4 Summary of changes deleted
•
Amendment number and date updated
•
Co-Investigators updated
•
Table of Contents updated
Treatment Schema 
Pages 5-6 
•
Thiotepa dosing clarified
•
Gonadal shielding added to TBI
•
Cyclophosphamide (CTX) dose timing clarified
•
Day 100 visit added
Secondary Objective 1.2 
Page 7 
•
Day 100 visit added
Section 3.4 
Page 13 
•
Thiotepa dosing clarified
Section 3.9 
Page 16 
•
Information about corticosteroid use added
Section 3.10 
Page 17 
•
Information about Total Body Irradiation added
Section 4.3 
Pages 19-20 
•
Criteria for HLA-haploidentical first-degree relatives
added to donor eligibility
•
Donor exclusion criterion added for donors with
clinically significant hemoglobinopathy (sickle trait is
acceptable)
Section 5.3 
Page 21 
•
Thiotepa dosing clarified
Section 5.5 
Page 22 
•
Cyclophosphamide (CTX) dose timing clarified
Section 5.10 
Pages 25 
•
Updated from “Anti-seizure prophylaxis” to
“Prevention of post-BMT Neurological Events and
Posterior Reversible Encephalopathy Syndrome
(PRES)”
•
Hypertension management for the prevention of CNS
toxicity guidance provided
Section 5.13 
Page 25-26 
•
Contraception guidance added

Version dated December 04, 2017 
Page 2 of 46 
Revised/Added Section 
Revision Location 
in Tracked 
Change Protocol 
(PDF page numbers) 
Description of Revision 
Section 5.14 
Page 26 
•
Guidance for the management of slow engraftment
and graft failure added
Section 6.0 
Pages 27-28 
•
Schedule of assessments table updated
o
Formatting updated
o
Timing of informed consent
o
Day 100 visit added
o
Day 180 visit added
o
Timing of tests pre-enrollment clarified
o
Window for annual visits added
•
Additional footnotes added to clarify assessments
Section 6.1.2 
Page 29 
•
Echo/MUGA updated to include estimation of TRJ
velocity and BNP
Section 6.2 
Pages 30-31 
•
Updated to include Day 100 and Day 180 visits
Section 7.4 
Page 34 
•
Updated to include Day 100 visit
Section 8.3 
Page 34-35 
•
Updated to include Day 100 visit
Section 8.4 
Page 35 
•
Updated to include Day 100 visit
Section 9.1 
Pages 37-39 
•
Updated SAE reporting criteria and procedures
•
Updated Data Monitoring and Auditing language
Section 13.0 
Page 42 
•
Updated to include Day 100 visit

BMT12108 Protocol v5: December 04, 2017 
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TREATMENT SCHEMA………………………………………………… 5-6 
1.0 
OBJECTIVES…………………………………………………… 7 
2.0 
BACKGROUND AND RATIONALE………………………....  7-10 
3.0 
DRUG INFORMATION………………………………………... 11-17 
4.0 
PATIENT SELECTION/REGISTRATION…….…………….. 17-20 
5.0 
TREATMENT PLAN…………………………………………..  20-26 
6.0 
PATIENT MONITORING…………………………………….. 26-31 
7.0 
POST-BMT EVALUATION…………………………………... 32-34 
8.0 
STUDY PARAMETERS……………………………………… 34-36 
9.0 
DATA MANAGEMENT………………………………………. 36-39 
10.0 
STATISTICAL CONSIDERATIONS………………………... 39-41 
11.0 
RECORDS…………………………………………………….. 41-42 
12.0 
ON-STUDY DATE…………………………………………….. 42 
13.0 
OFF-STUDY DATE…………………………………………… 42 
REFERENCES………………………………………………… 43-44 
APPENDICES…………………………………………………. 45-46 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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TREATMENT SCHEMA 
 
DAY  
DRUG 
 
 
DOSE 
 
-9 
 
Thymoglobulin  
 
0.5 mg/kg IV with pre-meds 
 
 
 
 
 
 
Start steroid taper 
 
 
 
 
 
 
 
Start anti-seizure prophylaxis  
 
-8 
 
Thymoglobulin  
 
2 mg/kg IV daily with pre-meds 
 
-7 
 
Thymoglobulin  
 
2 mg/kg IV daily with pre-meds 
Thiotepa 
Thiotepa 5 mg/kg IV q 12h (10 mg/kg 
total) 
 
-6 
 
Fludarabine   
 
30 mg/M2 IV daily  
Cyclophosphamide (CTX)  
14.5 mg/kg IV daily* 
 
-5 
 
Fludarabine   
 
30 mg/M2 IV daily  
Cyclophosphamide (CTX)  
14.5 mg/kg IV daily* 
Donor starts G-CSF on day -5 
 
-4 
 
Fludarabine   
 
30 mg/M2 IV daily  
 
-3 
 
Fludarabine   
 
30 mg/M2 IV daily  
 
-2  
 
Fludarabine   
 
30 mg/M2 IV daily  
 
-1  
 
TBI  
 
 
 
200 cGy with gonadal shielding 
 
0 
Infuse G-CSF primed bone marrow                                                   
(start antimicrobial prophylaxis**) 
 
+3 
 
Cyclophosphamide (CTX) 
50 mg/kg IV daily 
Mesna  
 
 
40 mg/kg IV daily** 
(First dose of CTX must be administered 60-72 hour after infusion 
of marrow) 
 
+4  
 
Cyclophosphamide (CTX) 
50 mg/kg IV daily 
Mesna  
 
 
40 mg/kg IV daily** 
 
+5  
 
Begin Sirolimus  
 
(section 5.6) ** and 
MMF  
15 mg/kg PO TID with maximum 
daily dose 3 gm/day 
 
+30 
 
Assess Chimerism in peripheral blood 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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+35 
 
Discontinue MMF 
 
+60 
 
Assess Chimerism in peripheral blood 
 
+100  
Assess Chimerism in peripheral blood 
 
+180  
Evaluate disease 
Assess Chimerism in peripheral blood 
 
+365  
Discontinue sirolimus 
Evaluate disease 
Assess Chimerism in peripheral blood 
 
+1yr, 2 yrs 
Evaluate disease 
Assess Chimerism in peripheral blood 
 
* Refer to Section 5.0 (Treatment plan) for complete dosing instructions. 
** Or as per institutional standards. 
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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1.0 Objectives 
 
Primary Objectives 
1.1 Obtain estimates of transplant-related mortality (TRM) and progression-free 
survival in patients with severe hemoglobinopathies receiving non-
myeloablative conditioning and transplantation of partially human leukocyte 
antigen (HLA)-mismatched bone marrow from first-degree relatives (“mini-
haploBMT”) as well as HLA-matched donors. 
 
Secondary Objectives 
1.2 Characterize donor hematopoietic chimerism in peripheral blood at days 
~30, ~60, ~100 and ~180 after mini-haploBMT. 
1.3 Characterize hematologic and non-hematologic toxicities of mini-haploBMT. 
1.4 Evaluate the impact of Haplo-identical Bone Marrow Transplant (BMT) in 
attenuating the progression of stroke, silent infarct or abnormal TCD with 
progressive vasculopathy in children with sickle cell disease (SCD) 
performed by MRA.  
1.5 Attenuation of progressive disease (adults): including severe and debilitating 
vaso-occlusive pain (despite hydroxyurea or chronic blood transfusion 
therapy), stroke and silent infarct, chronic kidney and chronic lung diseases. 
 
 
2.0 Background 
  
Allogeneic blood or marrow transplantation (alloBMT) is a curative therapy for a 
variety of hematologic disorders, including sickle cell disease and other 
hemoglobinopathies such as thalassemia. Even when it is clear that alloBMT can 
give to these patients an improvement in their disease1, myeloablative transplants 
have important toxicities and mortalities associated. Substantial progress has 
been made recently in the development of reduced intensity conditioning 
regimens that facilitate the sustained engraftment of donor marrow with reduced 
toxicity.  Most of these regimens incorporate highly immunosuppressive purine 
analogues, such as fludarabine, which allow the reduction or elimination of 
myeloablative agents such as busulfan or total body irradiation without 
endangering the sustained engraftment of HLA-identical allogeneic stem cells.  
Preliminary results of non-myeloablative allogeneic stem cell transplantation, or 
NST, suggest that the procedure can be performed in patients who are ineligible 
for myeloablative alloBMT, and that sustained remissions of several hematologic 
malignancies can be obtained. 
 
Despite the encouraging results in hematologic malignancies, the results of 
nonmyeloablative alloBMT in patients with hemoglobinopathies are less 
encouraging. Recently, Jacobsohn et al reported on 13 patients with non-
malignant conditions undergoing nonmyeloablative alloBMT2.  Engraftment was 
poor in patients with hemoglobinopathies as only one patient engrafted out of 4 
patients. These findings have been duplicated in other small studies3,4.  Also, the 
lack of suitable donors continues to be a limit to access to transplantation. 
Therefore, developing novel strategies that address the issue of expanding donor 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 8 of 46 
pool and have different immune suppression are of paramount relevance for the 
therapy of sickle cell disease. 
 
In the past five years, investigators at Johns Hopkins have developed a non-
myeloablative conditioning regimen for transplantation of marrow from partially 
HLA-mismatched, or haploidentical, bone marrow from first-degree relatives.  The 
regimen’s main goal, J9966 (RPN 99-11-05-01), was to titrate the dose of pre- 
and post-transplantation cyclophosphamide (CTX), a potent immunosuppressive 
drug, given in conjunction with pre-transplantation fludarabine and total body 
irradiation (TBI), to achieve a regimen that had an acceptably low risk of graft 
rejection and GVHD, the two major complications of haploidentical BMT.  All 
patients received mycophenolate mofetil (MMF) and tacrolimus (FK), beginning on 
day 4 or 5 and terminating on days 35 and 50-180, respectively, to reduce the 
incidence and severity of GVHD.  The first cohort of three patients received no 
pre-transplantation CTX and 50 mg/kg CTX IV on day 3, and two of the patients 
rejected their grafts.  A second cohort of 20 patients received 14.5 mg/kg CTX IV 
on days –6 and –5 in addition to 50 mg/kg IV on day 3.  Of 18 evaluable patients, 
13 patients had donor engraftment on day 60, but accrual of patients to this dose 
level was stopped because 8/13 patients developed severe GVHD, an incidence 
convincingly in excess of the stopping criterion of 20%.  To reduce the incidence 
of GVHD, a third cohort of patients received an additional dose of CTX 50 mg/kg 
IV on day 4, and MMF dosing was increased from bid to tid, based upon 
pharmacokinetic data suggesting the need for more frequent dosing.  Of 
seventeen evaluable patients so far, two patients have had non-fatal graft 
rejection, and only one patient treated according to the protocol has had severe 
GVHD (an additional patient developed severe GVHD after withdrawal of 
immunosuppression to treat relapse).  Two patients died of causes other than 
relapse: one from GVHD, and the other from disseminated fungal infection.  Of the 
sixteen patients who have been followed up to 100 days for relapse, eight have 
relapsed at a median of 64 days (range 24-~100) after transplantation, and six 
patients are alive and disease free at a median of 206 days (range, 100-429 days 
[as of Feb 8, 2004]) following BMT.  
 
In order to better judge the safety and efficacy of the non-myeloablative BMT 
protocol, the tables below compare the results of J9966, dose level 3, to the 
results of the four largest published trials of HLA-identical sibling peripheral blood 
versus bone marrow transplantation for early stage leukemia. 
 
Engraftment Data 
 
Author 
N (PB/BM) 
Median age 
ANC 500/mm3† 
Plt 20K† 
Plt 50K† 
Blaise5 
48/52* 
37/36 
15/21 
13/21 
15/26 
Bensinger6 
81/91 
42/42 
16/21 
13/19 
NA 
Schmitz7 
163/166 
39/37 
12/15 
15/20 
20/26 
Couban8 
109/118 
45/44 
19/23 
16/22 
NA 
J9966 
17 
31 
16 
24 
31 
*Numbers represent: recipients of peripheral blood/recipients of bone marrow 
†Time from transplantation to designated count, sustained without transfusion 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Outcomes data 
 
Author 
aGVHD II-IV 
(%) 
aGVHD III-IV 
(%) 
cGVHD (%) 
TRM (%) 
Relapse 
(%) 
Blaise 
45/42* 
17/28 
55/30 
23/21† 
6/11 
Bensinger 
64/57 
15/12 
46/35 
21/30† 
14/25 
Schmitz 
52/39 
28/16 
66/50 
24/24* 
12/7 
Couban 
44/44 
26/18 
40/30 
7/16† 
15/20 
J9966 
47 
13 
NA 
13 
50 
*Numbers represent: recipients of peripheral blood/recipients of bone marrow 
†Transplant-related mortality (TRM) or relapse over entire study (median f/u ~ 2 
years) 
†100 day mortality 
 
Compared to the patients receiving HLA-identical sibling bone marrow following 
myeloablative conditioning, patients on J9966 were younger, took longer to 
engraft platelets, and had a substantially higher rate of relapse, but were similar in 
the time to neutrophil recovery, the incidence of GVHD, and transplant-related 
mortality (TRM).  The higher rate of relapse for patients on J9966 may be 
attributable to a benefit of myeloablative conditioning in reducing the risk of 
relapse, or that patients on J9966 had advanced, poor prognosis hematologic 
malignancies, which relapse more frequently than early leukemia after alloBMT. 
Relapse will not be an issue with hemoglobinopathies. 
 
Since the toxicities of non-myeloablative haploidentical BMT (haploBMT) were not 
known when the trial was written, eligibility for J9966 was restricted to patients 
with advanced, poor-risk hematologic malignancies, such as chronic myeloid 
leukemia in 2nd chronic phase, advanced myelodysplasia, acute leukemia in 2nd 
remission, and lymphoma in relapse after autologous BMT.  Eligibility on the 
protocol has been expanded to ‘standard risk’ hematologic malignancies in trial 
J0457, which is still ongoing. 
 
Between J9966 and J0457, 56 patients with hematologic malignancies received 
cyclophosphamide 50 mg/kg IV, either once (on day 3) or twice (on days 3 and 4) 
after non-myeloablative conditioning and haploidentical bone marrow transplant. 
Most of these patients had advanced disease or failed a previous autologous 
transplant. All were conditioned as outpatients with fludarabine, 
cyclophosphamide, and total body irradiation, transplanted with non-T cell-
depleted marrow, and treated with tacrolimus and mycophenolate mofetil 
beginning the day after the last dose of cyclophosphamide. The most interesting 
finding was that compared to patients receiving a single dose of post-transplant 
cyclophosphamide, those receiving two doses had significantly less grade II-IV 
aGVHD (43% vs. 78%; p=.01) and grade III-IV aGVHD (20% vs. 53%; p=.006) by 
day 200 after transplant. Death from GVHD occurred in 5/13 assessable patients 
receiving one dose versus 2/28 assessable patients receiving 2 doses of 
cyclophosphamide.  
 
Since the data to date suggest that this treatment regimen may be as safe as 
HLA-identical sibling BMT after myeloablative conditioning, non-myeloablative 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 10 of 46 
haploidentical BMT may be considered a reasonable treatment option for patients 
who have hemoglobinopathies. Also, the novel use of post-transplant 
cyclophosphamide on top of the nonmyeloablative conditioning emerges as an 
interesting option of immunotherapy to prevent graft rejection. Moreover, as 
cancer relapse is not a concern in the setting of hemoglobinopathies engraftment 
with NST should be curative. 
 
In clinical transplantation, antithymocyte globulin (ATG) has been used 
extensively in conventional myeloablative and non-myeloablative conditioning 
regimens to facilitate engraftment in patients with sickle cell disease14. This effect 
is largely mediated by in vivo T-cell depletion produced by the ATG, similar to the 
effect of monoclonal T-cell antibodies in the murine model. 
 
Given that sirolimus (as opposed to calcineurin inhibitors) has not been commonly 
associated with the posterior reversible encephalopathy syndrome (PRES), 
sirolimus was preferred.   
 
Based on preliminary data, as of July 2012, 19 patients with SCD were referred 
for BMT (17 adults), using the haploBMT approach. Due to donor specific 
antibodies, 2 donors were medically ineligible. Thus 17 (89%) received a 
haploBMT, 3 matched sibling donors and 14 haploidentical donors. Median age 
was 30 years (range, 15‐46). There has been no mortality or GVHD requiring 
treatment. 11 of 17 (65%) engrafted at levels sufficient to reverse their sickle cell 
phenotype. 1 patient had primary graft failure (GF) and 5 late GF. Six patients (all 
haploBMT) had full donor chimeras and off immunosuppressive therapy. 5 mixed 
chimeras.  One patient had acute grade II skin GVHD, 3 patients experienced 
PRES, none since using sirolimus. There were 3 cases of CMV reactivation, but 
no CMV disease. Hemolytic anemia due to SCD was completely eliminated in all 
patients. Thus, haploBMT from related haploidentical donors is relatively safe and 
feasible for children and adults with SCD. By expanding the donor pool to include 
haploidentical donors most patients with SCD will be eligible for BMT.  
 
While these results are actually very good considering the fact that most of these 
patients have been haploidentical, there is a clear need for improvement. 
Experimental data using high dose cyclophosphamide has clearly shown that in 
order to increase engraftment efficiency there are 2 clear strategies to follow: 
increase the intensity of the conditioning (such as increasing the dose of TBI) or 
increase the cell dose of the graft 9, 10. Increasing the intensity of the conditioning 
can translate into increasing toxicities, therefore, it was decided to increase the 
cell count in the graft. As with standard bone marrow harvest there may be a limit 
on the number of cells that can be harvested, “priming the marrow” with filgrastim 
comes as an attractive option11-13. Studies using bone marrow priming with 
filgrastim show that it is possible to double the number of nucleated cells from the 
marrow, and interestingly, high cell doses have not been associated with 
increased risk of GvHD or severe toxicities to the donor12, 13.  
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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3.0   DRUG INFORMATION 
 
3.1 Fludarabine 
 
Fludarabine phosphate is commercially available. 
 
Fludarabine phosphate is purine antimetabolite, that, after administration, 
undergoes rapid conversion in plasma to the nucleoside 2-fluoro ara-A (F-araA). 
F-araA subsequently enters cells where it is phosphorylated to F-araATP and the 
monophosphate F-araAMP.  Once activated, F-araATP inhibits DNA polymerase 
and ribonucleotide reductase. The monophosphate F-araAMP, once incorporated 
into DNA, is an effective DNA chain terminator. 
 
Fludarabine monophosphate, 50 mg/vial, is reconstituted with 2 ml sterile water, 
resulting in a 25mg/ml solution. The desired dose is further diluted to 
concentrations of 0.04-1 mg/ml in normal saline or 5% dextrose (50-100ml) for 
injection and will be administered by IV infusion over 30 minutes or longer. 
 
Following IV administration, the drug is metabolized to 2-F-araA and widely 
distributed in tissues.  2-F-araA is excreted primarily in urine and has a terminal 
elimination half-life of 7 to 12 hours. 
 
Clinical toxicities of fludarabine monophosphate include: myelosuppression, 
primarily lymphopenia and granulocytopenia, alopecia, rash, dermatitis, nausea, 
vomiting, anorexia, stomatitis, diarrhea, somnolence, fatigue, peripheral 
neuropathy, mental status changes, cortical blindness, hepatocellular toxicity with 
elevation in serum transaminases, and interstitial pneumonitis. These effects are 
reversible when the drug is discontinued. 
 
Fludarabine will be administered by IV infusion over 30 minutes in a dose of 30 
mg/m2/day on days -6 to -2. 
 
Fludara® will be dispensed by the Oncology Pharmacy and is produced by Berlex 
Pharmaceuticals. 
 
3.2 Cyclophosphamide (Cytoxan®) 
 
Cyclophosphamide is commercially available. 
 
Cyclophosphamide is an alkylating agent which prevents cell division primarily by 
cross-linking DNA strands.  Cyclophosphamide is cell cycle non-specific. 
 
Cyclophosphamide for injection is available in 2000 mg vials which are 
reconstituted with 100 ml sterile water for injection.  The concentration of the 
reconstituted product is 20 mg/ml.  The calculated dose will be diluted further in 
250-500 ml of Dextrose 5% in water.  Each dose will be infused over 1-2 hr 
(depending on the total volume). 
 

 
 
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Clinical toxicities of cyclophosphamide include alopecia, nausea and vomiting, 
headache and dizziness, hemorrhagic cystitis, cardiotoxicity, immunosuppression, 
myelosuppression, pulmonary fibrosis, increased hepatic enzymes and syndrome 
of inappropriate anti-diuretic hormone (SIADH). 
 
Cyclophosphamide will be dispensed by the Oncology Pharmacy and is produced 
by Mead Johnson Pharmaceuticals. 
 
3.3 
Mesna (sodium-2-mercapto ethane sulphonate) 
 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxasophosphorines (cyclophosphamide and ifosphamide).  It has no intrinsic 
cytotoxicity and no antagonistic effects on chemotherapy.  Mesna binds with 
acrolein, the urotoxic metabolite produced by the oxasophosphorines, to produce 
a non-toxic thioether and slows the rate of acrolein formation by combining with 4-
hydroxy metabolites of oxasophosphorines. 
 
Mesna is available in 200 mg, 400 mg and 1000 mg vials containing a 100 mg/ml 
solution.  Each dose of mesna will be diluted further in 50 ml of normal saline to 
be infused over 15 minutes (or as per institutional standards). Mesna dose will be 
based on the cyclophosphamide dose being given.  The total daily dose of mesna 
is equal to 80% of the total daily dose of cyclophosphamide. 
 
At the doses used for uroprotection mesna is virtually non-toxic.  However, 
adverse effects which may be attributable to mesna include nausea and vomiting, 
diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint or limb 
pain, hypotension and fatigue. 
 
Mesna will be dispensed by the Oncology Pharmacy and is produced by Mead 
Johnson Pharmaceuticals. 
 
3.4 
Thiotepa  
 
Antineoplastic and alkylating agent, that reacts with DNA phosphate groups to 
produce cross-linking of DNA strands leading to inhibition of DNA, RNA, and 
protein synthesis; mechanism of action has not been explored as thoroughly as 
the other alkylating agents, it is presumed that the aziridine rings open and react 
as nitrogen mustard; reactivity is enhanced at a lower pH 
 
No dosage adjustment provided in manufacturer’s labeling. For renal or hepatic 
impairment, caution and dose adjustment may be required. Extensively hepatic; 
major metabolite (active): TEPA.  
 
Half-life elimination: Terminal (dose-dependent clearance): ~2 hours; 
Excretion: Urine (as metabolites and unchanged drug) 
 
b) Solution Reconstituted, Injection: Generic: 15 mg (1 ea); I.V.: Administer as a 
rapid injection. Infusion times may be longer for high-dose (unlabeled use) 
treatment. On Day  

 
 
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c) The most common adverse reactions include: Fertility effects: May be 
mutagenic and teratogenic; Myelosuppression, secondary malignancies: 
Potentially carcinogenic; myelodysplastic syndrome and acute myeloid leukemia 
(AML) have been reported; Use with caution in patients with hepatic and renal 
impairment; dosage reduction recommended. 
 
Thiotepa will be administered by IV infusion over 2 hours in a dose of Thiotepa 5 
mg/kg IV q 12h (10 mg/kg total)on days -7 prior to thymoglobulin infusion. 
 
Thiotepa will be dispensed by the Oncology Pharmacy and is produced by 
Adienne Pharma & Biotech 
 
 
3.5 
Sirolimus (rapamycin, Rapamune®) 
 
Sirolimus is an immunosuppressant that inhibits cytokine-stimulated T-cell 
activation and proliferation, and also inhibits antibody formation.   
The mean bioavailability of sirolimus after administration of the tablet is ~27% 
higher than the oral solution. Sirolimus oral tablets are not bioequivalent to the 
oral solution. Clinical equivalence has been demonstrated at the 2-mg dose level; 
however, it is not known if higher doses are clinically equivalent on a mg to mg 
basis. 
 
a) Sirolimus oral solution: Sirolimus oral solution (1 mg/mL) should be stored 
protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). For dilution, the 
appropriate dose should be measured using an amber oral syringe, then added to 
a glass or plastic container that holds at least 60 mL.  Before taking the dose, it 
should be diluted with water or orange juice then taken immediately; it should not 
be diluted with grapefruit juice.  The syringe should be discarded after one use.  
Sirolimus oral solution provided in bottles may develop a slight haze when 
refrigerated, which does not affect product quality; allow the product to stand at 
room temperature and shake gently until the haze disappears.  
 
b) Sirolimus tablets: Sirolimus tablets are available in 1 mg and 2 mg tablets that 
cannot be crushed or broken. Sirolimus tablets should be stored at 20° to 25° C 
(68°–77°F), protected from light. 
 
The most common adverse reactions of sirolimus are: peripheral edema, 
hypertriglyceridemia, hypercholesterolemia, hypertension, increased creatinine, 
constipation, abdominal pain, nausea, diarrhea, headache, fever, urinary tract 
infection, anemia, thrombocytopenia, arthralgia, pain. Adverse reactions that have 
resulted in rates of sirolimus discontinuation >5% were increased creatinine, 
hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP) / thrombotic 
microangiopathy (TMA).  Sirolimus toxicities are summarized below: 

 
 
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Toxicity Summary Table: Sirolimus 
Timing 
Common (>20%) 
Occasional (5-20%) 
Rare (<5%) 
Immediate (within 1-2 
days) 
Headache (L), 
hypertension (L), 
immunosuppression 
(L), fever, nausea, 
diarrhea, constipation 
Chest pain, insomnia, 
dyspepsia, vomiting, 
dyspnea 
Hypotension, asthma, 
cough, flu-like 
syndrome, 
tachycardia, anorexia, 
hypersensitivity 
reactions 
Prompt (within 2-3 
weeks) 
Tremor (L), renal 
dysfunction, pain 
(abdominal, back, 
arthralgias), 
hyperlipidemia c 
(hypercholesterolemia, 
hypertriglyceridemia), 
hyperglycemia, edema 
including peripheral 
edema, anemia 
Elevated LFT’s (with 
elevated sirolimus 
levels) a, stomatitis, 
infections (including 
UTI, URI), mild 
thrombocytopenia, 
leukopenia, 
electrolyte 
disturbances 
(hyper/hypokalemia 
[L], 
hypophosphatemia, 
hypomagnesemia [L]), 
rash, hives, pruritus, 
delayed wound 
healing or 
dehiscence (L), 
proteinuria, 
TTP/HUS/TMA b 
especially with 
concurrent CNI 
Pleural and pericardial 
effusions, pulmonary 
toxicity (non-
infectious pneumonitis, 
BOOP, pulmonary 
fibrosis),  thombosis, 
myalgias 
Delayed (any time 
later during therapy, 
excluding above 
conditions) 
Acne 
 
Kidney disease, CHF, 
ascites, arthrosis, 
bone necrosis, 
osteoporosis 
Late (any time after 
completion of 
treatment) 
 
 
Lymphoproliferative 
disorders, skin 
malignancies 
Unknown frequency 
and timing 
Embryo/fetotoxic; unknown whether excreted in human milk 
 
(L): Toxicity may also occur later. 
a Significant transaminitis, generally without sequelae, may occur. 
Sirolimus has been associated with higher rates of venoocclusive disease 
after myeloablative conditioning. 
b Incidence 3% to < 20% in a trial of kidney transplantation.  In allogeneic 
BMT, increase in TMA from 4.2% with tacrolimus or cyclosporine alone, 
versus 10.8% with tacrolimus/sirolimus combination was noted.66  
c Lipid-lowering agent may be required; consider if fasting serum 
triglycerides are > 2.5 x ULN, and recommend starting if > 800 mg/dL. 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Drug interactions: Sirolimus is known to be a substrate for both cytochrome 
CYP3A4 and P-glycoprotein.  Agents that may increase sirolimus levels include 
tri-azole drugs (especially voriconazole and posaconazole*), amiodarone, calcium 
channel blockers, macrolide antibiotics (but not azithromycin), micafungin, 
gastrointestinal prokinetic agents (cisapride, metoclopramide), cimetidine, 
cyclosporine, grapefruit juice, and HIV protease inhibitors. Agents that may 
decrease sirolimus levels include anticonvulsants (carbamezepine, phenobarbital, 
phenytoin), rifamycins, St. John’s Wort.  
 
Dose adjustments: The sirolimus dose is adjusted to maintain a serum trough 
level of 5-15 ng/mL. Due to the long and variable half-life of sirolimus, wait 7 days 
from initiation to monitor first trough level. Monitor levels twice weekly and wait 7-
10 days after dosage adjustments to reassess. For sirolimus without CNI as in this 
study, a 20-25% reduction of sirolimus dose is recommended for trough levels 
>15 – 20 ng/mL, and a 20-25% increase is recommended for trough levels < 5 
ng/mL. 
 
Renal failure does not affect the excretion of sirolimus. Excretion is reduced in 
liver failure; impaired hepatic function should prompt consideration of reduction in 
sirolimus maintenance doses but no dose adjustment of the loading dose is 
necessary. 
 
Due to extreme interactions with voriconazole and posaconazole, these 
drugs are relatively contraindicated during sirolimus therapy. Sirolimus 
dose is to be reduced by 90% when voriconazole is initiated and should also 
be significantly reduced with posaconazole.  
 
 
 
3.6  
Mycophenolic Acid Mofetil (Cellcept®) 
 
Mycophenolate Mofetil is an ester prodrug of the active immunosuppressant 
mycophenolic acid (MPA). This active metabolite is a noncompetitive, reversible 
inhibitor of inosine monophosphate dehydrogenase (IMPDH). There are no 
pharmacokinetic interactions with ganciclovir, cotrimoxazole, oral contraceptives 
and cyclosporine.  
 
Side effect profiles include diarrhea, leukopenia, sepsis, allergic reactions, and 
vomiting. There is also an increase in certain types of infection mainly from the 
herpes virus family (CMV, HSV & VZV) and Candida.  
 
3.7  
Rabbit antithymocyte globulin (ATG) 
 
Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a purified, pasteurized, 
gamma immune globulin, obtained by immunization of rabbits with human 
thymocytes. This immunosuppressive product contains cytotoxic antibodies 
directed against antigens expressed on human T-lymphocytes. This drug is 
commonly used to treat graft rejection in kidney transplantation. It is also 
commonly used in bone marrow transplantation as part of the conditioning 
regimen to avoid graft failure and to prevent graft-versus-host disease. 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 16 of 46 
Thymoglobulin is a sterile, freeze-dried product for intravenous administration 
after reconstitution with Sterile Water for Injection, USP (SWFI). Each 10 mL vial 
contains 25 mg anti-thymocyte globulin (rabbit) as well as 50 mg glycine, 50 mg 
mannitol, and 10 mg sodium chloride. After reconstitution with 5 mL SWFI, each 
vial of reconstituted product contains approximately 5 mg/mL of Thymoglobulin, of 
which >90% is rabbit gamma immune globulin (IgG). The reconstituted solution 
has a pH of 7.0 ± 0.4. Human red blood cells are used in the manufacturing 
process to deplete cross-reactive antibodies to non-T-cell antigens. The 
manufacturing process is validated to remove or inactivate potential exogenous 
viruses. All human red blood cells are from US registered or FDA licensed blood 
banks. A viral inactivation step (pasteurization, i.e., heat treatment of active 
ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is 
released following potency testing (lymphocytotoxicity and E-rosette inhibition 
assays), and cross-reactive antibody testing (hemagglutination, platelet 
agglutination, anti-human serum protein antibody, antiglomerular 
 
Adverse side effects include immunodeficiency, infusion related toxicities such as 
hypertension, chills, rigors, tachycardia, capillary leak syndrome, hyperglycemia, 
cytopenias, transient hepatitis, anaphylaxis, serum sickness, myalgias, sensory 
changes including hearing loss, headaches, renal toxicity, dyspnea and bronchial 
spasm, fevers. The drug is potentially teratogenic and is unknown if it can be 
passed to children in breastfeeding. 
 
Thymoglobulin will be dispensed by the Central Pharmacy and is produced by 
Genzyme. ATG–rabbit must be infused through a 0.22 micro filter with 
premedications: acetaminophen 650 mg orally and diphenhydramine 25mg orally 
as well as a steroid taper (or per institutional guidelines). The dose to be used is 
0.5 mg/kg on day -9 and 2 mg/kg/day on days -8 and -7. Note: Keep anaphylaxis 
kit at bedside during ATG administration. Patient should be given a skin test 
intradermal 1 hour prior to dose of ATG. If positive skin test contact MD/NP prior 
to continuing. ATG should not be administered during the weekend. 
 
3.8 
Filgrastim 
 
Donors will receive G-CSF (Filgrastim® at 5 μg/kg/d subcutaneously for 5 
consecutive days until the day of the harvest (i.e. days -5, -4, -3, -2, and -1). 
 
3.9 
Corticosteroids 
Corticosteroids may not be used as an anti-emetic agent and should not be 
administered until 24 hours after the completion of post-transplantation 
cyclophosphamide, unless used for adrenal support or during a medical 
emergency (e.g. treatment of anaphylaxis). Corticosteroids may be used as a pre-
medication during Thymoglobulin infusion and discontinued immediately 
thereafter. 
 
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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3.10 
Total Body Irradiation 
Total body irradiation will be administered (200 cGy).  This dose is a fraction of the 
irradiation delivered in typical myeloablative conditioning regimens, thus 
modulated toxicity is anticipated.  Nonetheless, irradiation can cause short-term 
and long-term toxicities, particularly in children.  The long-term toxicities include a 
risk of malignancy secondary to the exposure and a risk of infertility. 
 
• 
Testicular shielding will be administered to all male patients.   
The testis is one of the most radiosensitive tissues, and even low doses of 
radiation can cause impairment of function.  In adult men, doses as low as 
10 cGy can cause damage to spermatogonia 15.  At single fraction doses 
of 200 to 300 cGy there is overt damage to spermatocytes in adult men 
and return to pre-irradiation sperm concentrations and germinal cell 
numbers may take up to 30 months 16.  Fractionated doses are more toxic 
to spermatogenesis, and complete sterilization may occur if the 
fractionated dose exceeds 100 – 200 cGy.  However, in the pre-pubertal 
state, the impact of radiotherapy is mitigated. In one study of 12 pre-
pubertal boys who received 2400 cGy testicular irradiation to treat ALL, it 
was observed that testosterone levels were normal in all 12 and basal LH 
was normal in 9 and elevated in 3 17.  Nonetheless, to preserve fertility and 
Leydig cell function in post-pubertal males, we propose to administer 
testicular shielding to all males during the single fraction of TBI.  This 
shielding will have no impact on the immunosuppressive effect of the 
radiotherapy. 
 
• 
There will be no gonadal shielding in female patients.   
The effects of radiotherapy on ovarian function and fertility are dose- and 
age-dependent.  However, ovarian doses of less than 400 cGy do not 
result in permanent ovarian dysfunction and the calculated LD50 of the 
human oocyte dose is approximately 400 cGy 18, 19, 20.  Thus, ovarian 
shielding to preserve ovarian function will not be necessary for the dose of 
TBI administered in this investigation; moreover, shielding in this setting 
could reduce the immunosuppressive effects of TBI if intra-abdominal 
lymph nodes were inadvertently shielded. 
 
 
4.0 PATIENT SELECTION 
 
4.1  Criteria for recipient eligibility 
 
4.1.1 Patients who are ineligible for BMT from an HLA-matched sibling donor 
can proceed to a Haplo-BMT. Patients with an HLA-matched related donor 
will proceed to a matched BMT. 
 
4.1.2   Age 1-70 years 
 
4.1.3 Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100) 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 18 of 46 
4.1.4 Patients and donors must be able to sign consent forms. First degree 
relative should be willing to donate 
 
4.1.5 Patients must be geographically accessible and willing to participate in all 
stages of treatment. 
 
4.1.6  Eligible diagnoses: Patients with sickle cell anemia such as sickle cell 
anemia (Hb SS), Hb Sβ° thalassemia, Hb Sβ+ thalassemia, Hb SC 
disease, Hb SE disease, Hb SD disease, Hemoglobin SO- Arab disease 
HbS with hereditary persistence of fetal hemoglobin. Other significant 
hemoglobinopathies that also fulfill criterion from 4.1.7.                                
 
Plus one of the following: 
 
4.1.7:   Attenuation of progressive disease (adults):  
a. Severe and debilitating vaso-occlusive pain despite hydroxyurea or regular 
blood transfusion therapy. 
b. Stroke and silent infarct; stroke or central nervous system event lasting 
more than 24 hours; MRI changes indicative   of brain parenchyma 
damage and MRA evidence of cerebrovascular disease. 
c. Recurrent acute chest syndrome requiring exchange hospitalization. 
 
d. Chronic lung disease as defined by progressive restrictive disease 
irrespective of oxygen requirements. 
e. Chronic kidney disease, CKD stage II - IV 
f. Transfusion dépendent thalassemia 
 
4.2 Criteria for recipient ineligibility  
 
 
4.2.1 Poor performance status (ECOG>1). 
 
4.2.2 Poor cardiac function: left ventricular ejection fraction<35%. 
 
4.2.3 Poor pulmonary function: FEV1 and FVC<40% predicted. 
 
4.2.4 Pulmonary hypertension moderate to severe by echocardiographic 
standards. 
 
4.2.5  Poor liver function: direct bilirubin >3.1 mg/dl 
 
  
4.2.6    HIV-positive 
 
4.2.7 Minor (donor anti-recipient) ABO incompatibility if an ABO compatible 
donor is available. 
 
4.2.8 Prior transfusions from donor or recipient if caused alloimmunization vs. 
donor cells. 
 
4.2.9 Women of childbearing potential who currently are pregnant (Beta-HCG+) 
or who are not practicing adequate contraception. 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 19 of 46 
4.2.10 Patients who have any debilitating medical or psychiatric illness that would 
preclude their giving informed consent or their receiving optimal treatment 
and follow-up.  However, patients with history of stroke and significant 
cognitive deficit,that would preclude giving informed consent or assent will 
not be excluded, if they have a family member or significant other with 
Power of Attorney to also consent of their behalf.   
 
4.3 Criteria for donor eligibility 
 
4.3.1 Weight ≥ 20kg and age ≥ 18 years or per institutional guidelines 
 
4.3.2 Donors must meet the selection criteria as defined by the Foundation for 
the Accreditation of Hematopoietic Cell Therapy (FAHCT) and will be 
screened per the American Association of Blood Banks (AABB).  (AABB 
guidelines and the recipients will be informed of any deviations.) 
 
4.3.3 HLA-haploidentical first-degree relatives of the patient.   
 
Participants must be HLA typed at high resolution using DNA based typing 
at HLA-A, -B, -C and DRB1 and have available: 
An HLA haploidentical first degree relative donor (parents, siblings or half 
siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is 
willing and able to donate bone marrow.  A unidirectional mismatch in 
either the graft versus host or host versus graft direction is considered a 
mismatch.  The donor and recipient must be HLA identical for at least one 
antigen (using high resolution DNA based typing) at the following genetic 
loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1.  Fulfillment of this criterion 
shall be considered sufficient evidence that the donor and recipient share 
one HLA haplotype, and typing of additional family members is not 
required. 
 
When more than one donor is available, the donor with the lowest number 
of HLA allele mismatches will be chosen, unless there is HLA cross-match 
incompatibility or a medical reason to select otherwise, in which case 
donor selection is the responsibility of the PI, in consultation with the 
immunogenetics laboratory.  In cases where there is more than one donor 
with the least degree of mismatch, donors will be selected based on the 
most favorable combination of: 
(i) 
HLA compatibility in cross-match testing and  
(ii) ABO compatibility 
(iii) Donor age <40 years  
(iv) Avoid female donors for male recipients and  
(v) Avoid CMV mismatched donor-recipient transplants: 
 
HLA cross-matching (in order of priority) 
1. Mutually compatible (no cross-matching antibodies) 
2. Recipient non-cross-reactive with donor, donor cross-reactive with 
recipient 
3. Mutually cross-reactive 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 20 of 46 
ABO compatibility (in order of priority) 
1. Compatible 
2. Major incompatibility 
3. Minor incompatibility 
4. Major and minor incompatibility 
 
4.3.4 Donors will be selected to minimize HLA mismatch in the Host-versus-graft 
direction. 
 
4.3.5 Donors fulfilling the following criteria are ineligible for registration onto this 
study: 
1. All donors will be screened by hemoglobin electrophoresis; donors with 
a clinically significant hemoglobinopathy are ineligible. Sickle trait is 
acceptable.   
 
                   
 
5.0 
TREATMENT PLAN 
 
5.1 
Indwelling central venous catheter  
 
Placement of a double lumen central venous catheter will be required for 
administration of IV medications and transfusion of blood products. 
 
5.2 
Pre-treatment Evaluation 
 
All patients will require documentation of a detailed history and physical 
examination and standard evaluation of cardiac, pulmonary, liver and renal 
function.  
 
Baseline disease evaluation will be performed by collecting the following 
laboratory tests: hemoglobin S, hemoglobin electrophoresis, hemoglobin F (fetal), 
free hemoglobin, reticulocyte count. 
 
In those patients who have a Hgb S fraction > 30%, a partial exchange transfusion 
will be performed to reduce the hemoglobin (Hgb) S to 30% or lower within one 
week before commencing conditioning regimen (prior to Day -9) 
 
5.3 
Preparative regimen 
 
Thymoglobulin will be infused through a 0.22 micro filter with premedications: 
acetaminophen 650 mg orally and diphenhydramine 25mg orally. Keep 
anaphylaxis kit at bedside during ATG administration. Patient should be given a 
skin test intradermally 1 hour prior to dose of ATG.  If positive skin test contact 
MD/NP prior to continuing. ATG should not be administered during the weekend. 
The dose will be 0.5 mg/kg IV on day -9 over 6 hours and 2mg/kg IV on days -8 
and -7 over 4 hours. A steroid taper will be given to prevent reactions to ATG as 
follows: Solumedrol 1mg/kg IV 1 hour prior ATG on days -9 to -7. This dose may 
be repeated once 3 hours after the first dose. On day -6 and -5, solumedrol 0.75 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 21 of 46 
mg/kg/ IV as a single dose; on days -4 and -3, solumedrol 0.5 mg/kg/ IV as a 
single dose; on day -2 solumedrol 0.25 mg/kg/ IV as a single dose. 
 
Thiotepa will be infused prior to thymoglobulin over 2 hours on day -7 only. The 
dose will be 5 mg/kg IV q 12h (10 mg/kg total). 
 
Fludarabine will be administered by intravenous infusion over 30 min. on D-6 to D-
2. The dose will be 30 mg/m2.  
 
For decreased creatinine clearance (< 61 ml/min) determined by the Cockcroft 
formula: 
 
 
 
 
CCr = (140 – age) x IBW (kg) x 0.85 (for women)  
PCr x 72 
 
In pediatric patients (<18 years of age) the creatinine clearance must be 
measured using a radionuclide scan. 
 
Fludarabine dosage should be reduced as follows: 
 
 
 
CCr 46-60 ml/min, fludarabine = 24 mg/m2  
CCr 31-45 ml/min, fludarabine = 22.5 mg/m2  
CCr 21-30 ml/min, fludarabine = 19.5 mg/m2  
CCr <20 ml/min, fludarabine = 15 mg/m2 
 
Cyclophosphamide will be administered as an IV infusion over 1- 2 hr, (depending 
on volume) on D-6 and D-5. The dose of pre-transplantation cyclophosphamide is 
14.5 mg/kg/day. Dose is calculated based on the 25% adjusted ideal body weight 
or actual body weight whichever is less. (Refer to Appendix 2.) Body weight and 
height are measured directly. An approximate weight for height would be 
calculated from a standard table or equations that reflect ideal “values”. 
 
Note: Hydration and Mesna will be utilized for the Day 3 and Day 4 post BMT 
cyclophosphamide doses, not for the pre-BMT cyclophosphamide doses.  
Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8-12 cGy/min 
at the point of prescription (average separation of measurements at mediastinum, 
abdomen, and hips) will be administered in a single fraction on day -1. 
 
5.4  
Bone marrow transplantation and graft information  
 
Bone Marrow will be harvested and infused on day 0. All donors will receive 5 
μg/kg per day of filgrastim as a single subcutaneous injection for 5 consecutive 
days (days -5 to -1). Bone marrow harvest will be performed on the sixth day. The 
BM will be infused the same day of collection.  
 
Donor bone marrow will be harvested with to minimum yield of 2.5 x 108 with a 
target yield of 4 x 108 nucleated cells per kilogram of recipient’s IBW or actual BW, 
whichever BW is lower. A harvest yielding less than 2.5 x 108 renders the 
participant ineligible. Participants ineligible due to insufficient yield are deemed off 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 22 of 46 
study and should be treated in accordance with institutional practice.  We 
recommend taking no more than 10 mL per aspirate. In addition to calculating the 
total nucleated cell dose /kg, a sample of the product will be sent for flow 
cytometry to determine the content of CD34+cells.  The use of cryopreserved 
marrow is not permitted. 
 
Given that there is always uncertainty about the feasibility of harvesting certain 
patients, the harvesting team will have the ability to stop the surgery if the 
minimum target of 2.5 x 108 cells has not been reached and it is believed that will 
be unsafe or technically unfeasible to reach the mentioned target if the surgery 
was to continue after a reasonable effort has been made. In this case, the study 
PI will be notified immediately and efforts should be made to assure at least a cell 
count of 2.5-4 x 108/kg of recipient ideal body weight.  
 
Major incompatible ABO graft will have red blood cell depleted by buffy coat 
preparation. Minor ABO incompatible graft will have plasma removed. Guidelines 
for the infusion of bone marrow have been established and are outlined in the 
ABO compatible/minor mismatched allo BMT or the ABO incompatible allo BMT 
standing orders. 
 
5.5 
Post-Transplantation cyclophosphamide 
 
Cyclophosphamide [50mg/kg (IBW)] will be given on D+3 post-transplant (within 
60-72 hr of marrow infusion) and on D+4 post-transplant. Cyclophosphamide will 
be given as an IV infusion over 1- 2 hr (depending on volume).  
 
Patients will be instructed to increase fluids overnight before cyclophosphamide 
administration. Hydration with normal saline at 3 cc/kg/hr iv will be started 2 hr 
prior to cyclophosphamide, then the rate will be reduced to 2 cc/kg/hr for 8 hr 
post-cyclophosphamide or administered per institutional standards. Mesna will be 
given in divided doses iv 30 min pre- and at 3, 6, and 8 hr post-cyclophosphamide 
or administered per institutional standards. Mesna dose will be based on the 
cyclophosphamide dose being given. The total daily dose of mesna is equal to 
80% of the total daily dose of cyclophosphamide. 
 
 
It is crucial that no immuno suppressive agents are given from the time of 
the transplant until 24 hours after the completion of the post-transplant Cy. 
This includes steroids as anti-emetics. 
 
5.6 
GVHD prophylaxis  
 
On day +5, patients will begin prophylaxis with Sirolimus and Mycophenolic Acid 
Mofetil (MMF). 
 
Sirolimus for patients > 18 years old: A one-time sirolimus loading dose, 6 mg PO, 
is given on Day 5, at least 24 hours after Cytoxan completion. Sirolimus is then 
continued at a maintenance dose (start 2 mg PO QD), with dose adjustments to 
maintain a trough of 5 – 15 ng/mL as measured by HPLC or immunoassay. Due 
to the long and variable half-life of sirolimus, wait 7 days from initiation to monitor 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 23 of 46 
first trough level. Monitor levels twice weekly and wait 7-10 days after dosage 
adjustments to reassess. There is no planned taper. Sirolimus prophylaxis is 
discontinued after the last dose on Day 365, or may be continued if there is 
GVHD.  
 
For patients < 18 years old: Sirolimus dosing is based on actual body weight; 
however an adjusted body weight may be used if the actual weight is > 50% 
greater than IBW. A one-time sirolimus loading dose, 3 mg/m2 PO with the dose 
not to exceed 6 mg, is given on Day 5, at least 24 hours after Cytoxan completion. 
Sirolimus is then continued at a maintenance dose (start 1 mg/m2 PO QD, 
maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 – 15 
ng/mL as measured by HPLC or immunoassay. Due to the long and variable half-
life of sirolimus, wait 7 days from initiation to monitor first trough level. Monitor 
levels twice weekly and wait 7-10 days after dosage adjustments to reassess. 
There is no planned taper. Sirolimus prophylaxis is discontinued after the last 
dose on Day 365, or may be continued if there is GVHD.  
 
Mycophenolic acid mofetil will be given at a dose of 15 mg/kg po TID (based upon 
actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g 
po TID).  
 
MMF prophylaxis will be discontinued after the last dose on D35 and Sirolimus 
prophylaxis will be discontinued after the last dose around day 365. 
 
5.7 
Infection prophylaxis and therapy 
 
During pre-transplant evaluation patients will be screened for respiratory syncitial 
virus, influenza A, B and parainfluenza viruses if symptomatic. Assays of these 
viruses must be negative for symptomatic patients to be admitted for transplant. 
Strong consideration should be given to institution of ribavirin therapy if positive 
for adenovirus or nalidixic acid if positive for BK virus.  
Oral hygiene will be maintained according to institutional standards. 
  
Prophylactic anti-microbial therapy will be given per the BMT unit Standards or 
institutional preference.  
 
An oral antibiotic for gastrointestinal decontamination will be administered 
according to institutional preference until the ANC is >1000 for 3 consecutive days 
following BMT. 
 
Empiric therapy with broad-spectrum antibiotics will be instituted for the first 
neutropenic fever (specific agents as per current practice).  
 
Antifungal prophylaxis will be administered according to institutional preference. It 
is important to follow sirolimus levels on patients receiving azoles as the 
combination of both drugs can raise the levels of the immunosuppressant to toxic 
levels. If the patient on sirolimus is started on azoles, a dose reduction of sirolimus 
is required and levels should be obtained to be sure the levels are not in the toxic 
range (see section 3.5).  

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Pneumocystis jiroveci pneumonia (PCP) prophylaxis will be administered 
according to institutional preference, starting around Day 30 (or after engraftment) 
and should continue for at least the first year following BMT and while on 
immunosuppression. If the patient cannot tolerate po then a comparable dose of 
Bactrim will be given IV. Patients intolerant of Bactrim will receive either dapsone, 
atovaquone, or pentamidine as PCP prophylaxis. 
 
On Day 0, all patients should start pneumococcal prophylaxis with Penicillin-V 250 
mg PO BID, or if less than 5-years old, 125 mg PO BID and should continue 
indefinitely. If patient has a Penicillin-V allergy, Bactrim SS every day should be 
utilized. Patient can also use other antibacterial prophylaxis with pneumococcal 
coverage in-lieu of Penicillin-V based on institutional preference. 
  
Viral prophylaxis for HSV will be administered according to institutional preference 
 
Although not required, CMV viremia (by PCR) or antigenemia (by ELISA) should 
be documented weekly or every other week beginning once the WBC>1000 and 
until discharge. Monitoring of CMV viremia or antigenemia is recommended to 
continue on a weekly or every other week basis until day 100, then bi-weekly until 
day 180 (or based on institutional guidelines). Patients who are viremic or 
antigenemic will be treated pre-emptively with ganciclovir (5 mg/kg iv q12 hr) for 
14 d and then with maintenance ganciclovir (5 mg/kg iv qd) until CMV testing is 
negative for at least 2 wk. Consideration should be given to administration of CMV 
hyperimmune globulin (Cytogam), concomitant with ganciclovir at a dose of 150 
mg/kg iv qod times 4 doses and then weekly thereafter if the patient continues to 
be treated with ganciclovir for persistent viremia or antigenemia. If the patient is 
diagnosed with CMV disease, more frequent Cytogam administration may be 
considered.  
 
Unless the patient is being treated for CMV infection or CMV disease, ganciclovir 
should be discontinued for development of neutropenia (ANC<500). If 
neutropenic, G-CSF may be used if clinically indicated. Ganciclovir should then be 
restarted, if appropriate. Ganciclovir will be dose-adjusted appropriately for renal 
failure. 
 
5.8 
Growth factor support  
 
Patients will receive G-CSF (Filgrastim®) only if clinically required (i. e. sepsis) but 
will not routinely be given after transplant to speed recovery given the high 
incidence of musculoskeletal pain that may aggravate a pain crisis in these 
patients. 
 
5.9 
Transfusion support  
 
In those patients who have a Hgb S fraction > 30%, a partial exchange transfusion 
will be performed to reduce the hemoglobin (Hgb) S to 30% or lower before 
commencing the conditioning regimen. The Hgb and Hgb S% should be re-
checked 4 hours after the exchange transfusion. All blood products will be 
irradiated. 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 25 of 46 
The hemoglobin level must be maintained between 9.0 and 11.0 g/dL and platelet 
count > 50,000/mL after transplantation to minimize the risk of neurological 
adverse events. Irradiated blood products should be administered universally, and 
Cytomegalovirus (CMV) negative or leuko-filtered blood products are 
recommended for CMV sero-negative recipients.  
 
5.10 
Prevention of post-BMT Neurological Events and Posterior 
Reversible Encephalopathy Syndrome (PRES) 
 
Prophylaxis against seizures is mandatory in all recipients and should be 
commenced at the start of conditioning day -9. Levetiracetam (Keppra) is the 
suggested agent however anti-seizure prophylaxis may be tailored per institution 
preference. Keppra will be administered at a dose of 500 mg p.o. b.i.d (peds 
dosing of 50 mg/kg divided bid to max of 500 bid). Seizure prophylaxis should be 
continued until sirolimus is discontinued.  
 
Platelets should be kept at all times over 50,000/ml. Serum magnesium level 
should be maintained > 1.5 mg/dL during the period of treatment with immune-
suppressive therapy to reduce the risk of seizures.  
 
Hypertension should be strictly controlled to prevent central nervous system 
(CNS) toxicity. Blood pressure should be monitored closely and both systolic and 
diastolic hypertension should be treated promptly to maintain blood pressure at 
the patient’s pre-transplant baseline. Explicit orders must be written to intervene if 
systolic or diastolic blood pressure exceeds 10% over baseline.   
 
5.11  Anti-ovulatory treatment  
 
Menstruating females should be started on an anti-ovulatory agent prior to the 
initiation of the preparative regimen. 
 
5.12 
Hepatic prophylaxis 
 
Prophylactic Ursodiol 300 mg PO 2-3 times daily will be administered to all 
patients or those with history of hepatitis C, hyperbilirubinemia, or bridging fibrosis 
or cirrhosis. Patients will begin prior to start of conditioning regimen. 
 
5.13 
Contraception Practices 
Females of child bearing potential (to include all female participants > 10 years of 
age, unless postmenopausal for a minimum of 1 year before the screening visit or 
surgically sterilized), must agree to practice two (2) effective methods of 
contraception at the same time, or agree to practice true abstinence when this is 
in line with the preferred and usual lifestyle of the subject, from the time of signing 
of informed consent through 12 months post-transplant. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
 
Male subjects (even if surgically sterilized) must agree to one of the following: 
practice effective barrier contraception, or practice true abstinence when this is in 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 26 of 46 
line with the preferred and usual lifestyle of the subject, from the time of signing of  
informed consent through 12 months post-transplant. Periodic abstinence and 
withdrawal are not acceptable methods of contraception.   
 
5.14 
Management of Slow Engraftment and Graft Failure 
Slow engraftment or graft failure shall be managed according to institutional 
practices, and may include the administration of colony stimulating factors and 
prophylactic antibiotics. 
 
Graft failure following BMT in patients with sickle cell disease is usually associated 
with autologous reconstitution of the bone marrow with host hematopoiesis. It is 
associated with a steady decline in donor chimerism, increasing representation of 
hemoglobin S (in the absence of ongoing RBC transfusion therapy) and clinical 
manifestations of sickle cell disease. A second transplant or donor cellular infusion 
should not be considered unless the patient has < 5% donor chimerism. 
 
 
6.0                           PATIENT MONITORING  
 
The following parameters will be obtained according to this schedule: (for details 
of these evaluations, see text sections 6.1-6.3) 
 
 
 
 

 
BMT12108 Protocol v5: December 04, 2017 
 
Page 27 of 46 
SCHEDULE OF ASSESSMENTS 
Assessments 
Initial 
Allowable time 
frame prior to 
enrollment**  
Day < 60 
post SCT 
≈Day 
30 ± 7 
post 
SCT 
≈Day 
60 ± 7  
post 
SCT 
≈Day 
100 ± 7  
post 
SCT 
≈Day 
180± 7  
post 
SCT 
Suspected 
GVHD 
Annually 
X 3yrs 
+/- 2 or 3 
months 
Informed Consent 
X 
Within 30 days 
 
 
 
 
 
 
 
History and Physical 
X 
within 30 days 
 
X 
X 
X 
X 
 
X 
Performance status 
X 
within 30 days 
 
X 
X 
X 
X 
 
 
Disease re-evaluation 
X 
within 30 days 
 
X 
X 
X 
X 
 
X 
CBC & Diff. + reticulocyte count 
X 
within 30 days 
*weekly 
X 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel; Liver function  
test 
X 
within 30 days 
weekly 
X 
X 
X 
X 
 
X 
Hemoglobin electrophoresis (HPLC), (Hgb F); 
plasma free hemoglobin,  LDH, reticulocyte count 
X 
within 30 days 
 
X 
X 
X 
X 
 
X 
CXR- Pa/Lat 
X 
within 60 days 
 
 
 
 
 
 
X 
Pregnancy test (women, childbearing age) 
X 
within 7 days 
 
 
 
 
 
 
 
Chimerism analysis (Including unsorted and 
CD3) ¥ 
 
 
 
X 
X 
X 
X 
 
X 
PT, PTT 
X 
within 30 days 
 
 
 
 
 
 
X 
EKG 
X 
within 60 days 
 
 
 
 
 
 
X 
Cardiac Function by 2D-Echo, TRJ Velocity and 
BNP 
X 
within 60 days 
 
 
 
 
 
 
X 
HepB Ag, HBC Ab, HCV Ab, HSV IgG, CMV IgG, 
RPR, HIV, VZV IgG (if possible) 
X 
within 30 days 
 
 
 
 
 
 
X 
Toxicity assessment 
X 
 
X 
X 
X 
X 
X 
 
 
HLA typing/ lymphocytotoxic  screen (PRA 
testing of donors and patient) 
 
within 60 days 
 
 
 
 
 
 
 
PFTs (Spirometry and lung volumes; DLCO) 
 
within 60 days  
 
 
 
 
 
 
X 
GVHD and other co-morbidity assessments€ 
 
 
weekly 
X 
X 
X 
X 
 
X 
Sinus CT*** 
 
within 30 days 
 
 
 
 
 
 
 
Fasting lipid profile 
 
within 30 days 
 
 
X 
 
 
 
X 
Skin Biopsy  
 
 
 
 
 
 
 
X 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 28 of 46 
 
* Once ANC >100, this will be obtained daily until ANC >500 for three days or two consecutive measurements over a three day 
period, then weekly. 
**Baseline laboratory tests and radiology studies time frame will follow institutional BMT standards and practices.  
***Optional tests (optional at physician’s discretion) 
¥ Chimerism frequency may be increased based on institutional standards 
ǂ TCD evaluation in eligible children with SCD 
€ GVHD assessments to be performed at these time points per institutional practices 
Ω Brain MRI/MRA should be performed within 30 days prior to SCT for patients whose indication for transplant is stroke 
Assessments 
Initial 
Allowable time 
frame prior to 
enrollment** 
Day< 60 
post SCT 
≈Day 
30 ± 7 
post 
SCT 
≈Day 
60 ± 7  
post 
SCT 
≈Day 
100 ± 7  
post 
SCT 
≈Day 
180± 7  
post 
SCT 
Suspected 
GVHD 
Annually 
X 3yrs 
+/- 2 or 3 
months 
Renal Function (eGFR and/or radio-nuclide 
scan); micro-albuminuria 
 
within 60 days 
 
 
 
 
 
 
X 
Baseline TCD evaluation ǂ 
 
X 
 
 
 
 
 
 
X 
BrainΩ: MRI/MRA without contrast*** 
 
Within 30 days 
prior to SCT 
 
 
 
 
 
 
X 
Neurocognitive Assessment: (Weschler (WISC 
IV) for children and adolescents which is similar 
to the WAIS used for adults) 
 
Within 6 months 
prior to SCT 
 
 
 
 
 
 
X 
Serum ferritin and assessment of liver (R2*) 
and/or cardiac (T2*) iron by imaging; liver biopsy 
is optional 
 
Within 3 months 
prior to SCT 
 
 
 
 
 
 
X 
QOL measurement (PROMIS ) 
 
Within 7 days 
prior to SCT 
 
 
 
 
 
 
X 

 
BMT12108 Protocol v5: December 04, 2017 
 
Page 29 of 46 
6.1 Complete medical history which should include particular attention to 
the following details: 
a) Previous treatment and response 
b) Previous transfusions and transfusion reactions 
c) Previous serious infections 
d) Allergies 
e) Current medications 
f) Assessment of performance status 
 
6.1.1. Thorough general medical evaluation which should include: 
a) A careful physical examination 
b) Evaluation for placement of a central venous access device, if the 
patient does not already have such a catheter. 
 
6.1.2. Baseline investigations including: 
a) Hematologic 
i. CBC with platelets, differential, reticulocyte count 
ii. PT, PTT 
iii. ABO and Rh typing 
 
b) Chemistries 
i. Comprehensive chemistry panel, LDH 
ii. Routine and microscopic urinalysis with C&S, microalbumin 
iii. Fasting lipid profile. 
iv. G6PD screen of donors will be at institutional discretion. 
 
c) Cardiac 
i. EKG  
ii. Echocardiogram or MUGA scan with Left Ventricular Ejection 
Fraction (LVEF) + Right Ventricular Systolic Pressure and 
evaluation for pulmonary hypertension, estimation of TRJ 
velocity and BNP 
iii. Patients with suspected pulmonary hypertension, if indicated may 
require Cardiology referral for evaluation and possible RHC for 
confirmation. 
 
d) Pulmonary 
i. Chest X-ray – Pa/Lat 
ii. Sinus CT scan – optional at physician’s discretion 
iii. Pulmonary function tests including at least FEV1, lung-total lung 
capacity and FVC (pediatric patients under the age of 8 are excluded 
from this test) 
 
e) Immunologic / Infections 
i. HBsAg, anti-HBC, anti-HCV 
ii. RPR 
iii. HIV antibody 
iv. Serology for CMV and HSV (plus VZV – blood samples permitting) 
v. HLA typing/lymphocytotoxic antibody screen 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 30 of 46 
f) RFLP studies will be drawn as a baseline for subsequent engraftment 
studies including myeloid (unsorted- CD33 vs CD14 or CD15) and CD3 
chimerism. 
- 
CD36 platelet expression testing of donors at institutional discretion. 
- 
RBC chimerism will be at institutional discretion (flow cytometry vs 
extended RBC phenotyping for minor red cell antigens). 
 
g) Disease specific studies: The following are minimal recommended: 
i. Sickle Cell Disease:  Hemoglobin electrophoresis (HPLC), 
hemoglobin F (fetal), plasma free hemoglobin, LDH, reticulocyte 
count 
ii. CNS: MRI/MRA of the brain and Neurocognitive testing (assessment 
of the brain- Cognitive evaluation is optional at physician’s discretion, 
and will include Weschler (WISC IV) for children and adolescents 
which is similar to the WAIS used for adults within 6-12 months prior 
to, 1 and 2 years post-transplant. 
iii. Renal function test (assessment of kidney function): include eGFR 
and radio-nuclide scan, urine micro-albuminuria 
iv. Iron overload: Patients will be evaluated by serum ferritin and 
assessment of liver MRI (T2* or R2*) and/or cardiac (T2*) MRI 
imaging; liver biopsy is optional at physician’s discretion. A 
Gastroenterology and/or Hepatology consultation is recommended 
for patients with severe iron overload with elevated liver function 
tests.  
 
6.2  
Post-transplant Evaluation 
 
6.2.1. Day 0 through Day 100 (+ 7 days) evaluation.  
These represent the minimum required. More frequent determinations and 
additional investigations may be indicated by the clinical condition of the patient. 
1. CBC daily with a WBC differential once the total WBC is greater than 100 
until ANC > 500 for three days or two consecutive measurements over a 
three day period; then CBC weekly with differential through day 60. 
2. Comprehensive metabolic panel once a week through day 60. 
3. Patients will have evaluations for infectious complications as clinically    
indicated. Surveillance cultures according to institutional guidelines or BMT 
program standards are recommended. 
4. Evaluations by history and physical examination for GVHD will be   
performed as per institutional guidelines or BMT program standards.  (See 
also section 6.2).  For study purposes, weekly GVHD summaries will be 
taken from these standard examinations from day 14 through day 60. 
 
6.2.2 Evaluations on day ~ 30 (± 7 days) 
1. History and physical examination. 
2. RFLP donor chimerism on peripheral blood (including myeloid (unsorted) 
and CD3 chimerism). 
3. Disease evaluation. 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 31 of 46 
4. CBC and white blood cell differential, reticulocyte count, comprehensive 
panel. 
5. GVHD evaluation  
 
6.2.3 Evaluations on day ~60 (± 7 days) 
1. History and physical examination. 
2. Disease evaluation. 
3. Studies for donor cell chimerism on peripheral blood. 
4. CBC and white blood cell differential, reticulocyte count, comprehensive 
panel. 
5. GVHD evaluation  
6. Fasting lipid profile. 
 
6.2.4 Evaluations on day ~100 (± 7 days) 
1. History and physical examination. 
2. Disease evaluation. 
3. Studies for donor cell chimerism on peripheral blood. 
4. CBC and white blood cell differential, reticulocyte count, comprehensive 
panel. 
5. GVHD evaluation 
 
6.2.5 Evaluations on day ~180 (± 7 days) 
1. History and physical examination. 
2. Disease evaluation. 
3. Studies for donor cell chimerism on peripheral blood. 
4. CBC and white blood cell differential, reticulocyte count, comprehensive 
panel. 
5. GVHD evaluation 
 
6.2.6 Evaluations for suspected GVHD 
1. Comprehensive panel 
2. Biopsies if needed. 
 
 
 
6.2.7 Annual evaluations ~ (± 7 days): 
1. History and physical examination. 
2. Disease evaluation. 
3. Studies for donor cell chimerism on peripheral blood. 
4. CBC and white blood cell differential, reticulocyte count, comprehensive 
panel. 
5. GVHD evaluation  
6. Fasting lipid profile. 
7. Organ function studies will be done (per section 6.0) 
8. Repeat Neurocognitive testing x2 
9. QOL assessment (PROMIS) 
 
In the event that the patient is unable to return to Vanderbilt University for these 
visits, every attempt will be made to obtain data from the patient and referring 
physician.  
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 32 of 46 
7.0 
POST-BMT EVALUATION 
 
Patients will be followed during (i) the initial post-BMT period (ii) in VU Long term 
transplant clinic (LTTC) and (iii) after discharge to the referring physician as per 
standard practice.  
 
7.1      Chemotherapy toxicities  
 
The agents being used in the study are FDA approved.  These agents are used 
extensively in the Bone Marrow Transplant setting and have well defined toxicity 
profiles.  In addition, there are many expected toxicities related to a bone marrow 
transplant.  For these reasons, toxicities will be captured and recorded/graded if 
the adverse event interferes with the subject’s daily function and are considered 
clinically significant.  We will capture and grade all these events structured around 
the categories of the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 for the first 60 days post BMT.  
 
Since this trial is an out-patient trial, the definition of an adverse event ‘interfering 
with daily function’ and ‘clinically significant’ will be events that require 
hospitalization.  For example, if a patient has a neutropenic fever that requires 
hospitalization, then ‘neutropenic fever’ will be captured and graded as an 
adverse event.  An example of a non-captured event is if a patient has 
hypotension that is corrected by fluid administration in the outpatient setting.  This 
will not be captured as an adverse event unless the patient requires a hospital 
admission for further treatment of the hypotension. 
 
Once the patient becomes hospitalized, the above definition of ‘requiring 
hospitalization’ cannot be used to capture adverse events.  For these already 
hospitalized patients, events will only be recorded once the event is greater than a 
grade 3 or 4 as stated below. 
 
The following is a list of categories that will not be recorded unless the event 
becomes a grade 4 or meets the criteria of a SAE, as stated in section 8.1.1.  
 
• 
Allergy/Immunology 
• 
Auditory/Hearing 
• 
Cardiovascular (Arrhythmia) 
• 
Cardiovascular (General) 
• 
Coagulation 
• 
Constitutional symptoms 
• 
Dermatology/Skin 
• 
Endocrine 
• 
Hemorrhage 
• 
Hepatic 
• 
Infection/Febrile neutropenia 
• 
Lymphatic’s 
• 
Metabolic/Laboratory 
• 
Secondary Malignancy 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 33 of 46 
• 
Sexual/Reproductive Function 
 
The following categories will be recorded only if the event becomes a grade 3 or 
grade 4 or meets the criteria of a SAE. 
 
• 
Gastrointestinal 
• 
Musculoskeletal 
• 
Neurology 
• 
Ocular/Visual 
• 
Pain 
• 
Pulmonary 
• 
Renal/Genitourinary 
 
The Blood/Bone Marrow category is captured as endpoints to the study.  Thus for 
this category, we will not record data according to the NCI Common Toxicity 
Criteria. 
 
7.2 
GVHD 
 
A major toxicity of allogeneic BMT from an unrelated or mismatched donor is 
GVHD.  Acute graft-versus-host disease (GVHD) shall be graded clinically 
according to the criteria developed by the consensus conference on acute GVHD9 
(Appendix 1).  All suspected cases of acute GVHD must be confirmed 
histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract).  
For purposes of reporting, a pathologist at Vanderbilt University will be ultimately 
responsible for determining whether a patient does or does not have histologic 
evidence of GVHD. Diarrhea and/or hyperbilirubinemia in a patient with 
histologically documented skin GVHD may be assumed to be a manifestation of 
visceral GVHD and will be graded as such.  All patients with histologically 
documented, clinical grade >2 acute GVHD should receive initial treatment with 
corticosteroids (or a corticosteroid containing regimen if a protocol is available) 
according to institutional preference.  If skin GVHD resolves with treatment but 
suspected visceral GVHD does not, biopsy of the affected organ (liver or 
gastrointestinal tract) should be obtained to rule out other causes of 
hyperbilirubinemia and/or diarrhea.  Steroid refractory acute GVHD will be treated 
according to institutional preferences. 
 
The following information shall be collected on all patients with acute GVHD: 
 
• 
Date of onset (defined as the date of first biopsy confirming GVHD) 
• 
GVHD evaluation form at the time of onset, weekly until GVHD resolves, 
Day 60 and Day 100 
• 
Initial overall clinical grade 
• 
Maximum overall clinical grade 
• 
Date of onset of grade III-IV acute GVHD, if any 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 34 of 46 
The occurrence and severity of acute and chronic GVHD after Day 100 will be 
captured at the patients’ six month and annual evaluations per institutional 
standards. 
  
            7.3 
Transplant-related mortality (TRM) 
 
Causes of TRM, i.e., death in the absence of recurrent sickle cell disease or 
hemoglobinopathy, will be documented as important indicators of procedure-
associated toxicity, particularly as these causes relate directly or indirectly to 
GVHD.  Analysis will stratify mortality with respect to the peri-transplant period 
(<100 d post-BMT) or later times post-BMT. 
 
7.4 
Disease Evaluation 
 
Disease evaluations will be performed at ~Day 30, ~Day 60, ~Day 100, ~Day 180, 
~Day 365, and then yearly per Vanderbilt University standards.  Disease 
evaluations will be performed by collecting the following laboratory tests:  
hemoglobin S, hemoglobin electrophoresis, hemoglobin F (fetal), free hemoglobin, 
reticulocyte count. 
 
 
8.0    STUDY PARAMETERS 
 
8.1    Transplant-related mortality 
 
Transplant-related mortality, which is defined as death in the absence of recurrent 
sickle cell disease or hemoglobinopathy, will be characterized at 100 days and at 
one year after BMT. 
 
8.2 
Hematologic toxicity 
 
A secondary endpoint of this study is time to recovery of circulating neutrophils and 
platelets (following chemotherapy).  Neutrophil recovery is defined as the first day of 
three consecutive laboratory values on different days, after the conditioning regimen-
induced nadir of blood counts, that the absolute neutrophil count is> > 500 x 109/L.  
Platelet recovery is defined as the first day of three consecutive laboratory values on 
different days, after the conditioning regimen-induced nadir of blood counts, that the 
platelet count is ≥ 20,000 µL without platelet transfusion support in the seven days 
prior. 
 
8.3 
Donor Chimerism 
 
Donor chimerism will be measured in the peripheral blood around day 30, day 60 
and day 100.  Patients with >5% donor whole blood or myeloid chimerism 
(myeloid is preferable) assessed by bone marrow or peripheral blood chimerism 
assays by day +42 post-transplant  will be considered as having engrafted.  
Chimerism determinations will be made on peripheral blood by a number of 
different methods depending on the specific patient.  Methods may include (i) the 
usual standard of restriction fragment length polymorphism (RFLP) if the donor 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 35 of 46 
and recipient RFLPs are informative, (ii) fluorescence in-situ hybridization (FISH) 
for Y-chromosome markers on PBMC if the donor is male, (iii) cytogenetic 
analysis, (iv) flow cytometric analysis of HLA-A, B or DR on lymphocytes in the 
peripheral blood if haploidentical and suitable reagents exist or (v) PCR analysis 
of variable nucleotide tandem repeats (VNTR) in PBMC if informative. Mixed 
donor chimerism will be defined as >0%, but <95%.  Complete donor chimerism 
will be defined as >95%.  
 
8.3.1 Primary Graft Failure 
Primary graft failure is defined as never achieving >5% donor whole blood or 
myeloid chimerism (myeloid is preferable) assessed by bone marrow or peripheral 
blood chimerism assays by day +42 post-transplant. Second infusion of stem cells 
is also considered indicative of primary graft failure by day +42 post-transplant. 
 
8.3.2. Secondary Graft Failure 
Secondary graft failure is defined as < 5% donor whole blood or myeloid 
chimerism (myeloid is preferable) in peripheral blood or bone marrow beyond day 
+42 post-transplant in patients with prior documentation of hematopoietic recovery 
with >5% donor cells by day +42 post-transplant. Second infusion of stem cells is 
also considered indicative of secondary graft failure. 
 
Management of Slow Engraftment and Graft Failure 
 
Slow engraftment or graft failure shall be managed according to institutional 
practices, and may include the administration of colony stimulating factors and 
prophylactic antibiotics. 
 
Graft failure following BMT in patients with sickle cell disease is usually associated 
with autologous reconstitution of the bone marrow with host hematopoiesis. It is 
associated with a steady decline in donor chimerism, increasing representation of 
hemoglobin S (in the absence of ongoing RBC transfusion therapy) and clinical 
manifestations of sickle cell disease. A second transplant or donor cellular infusion 
should not be considered unless the patient has < 5% donor chimerism. 
 
8.4 
Disease Status 
 
Disease status will be evaluated through the following laboratory tests:  
hemoglobin S, hemoglobin electrophoresis (HPLC), hemoglobin F (fetal), free 
hemoglobin, reticulocyte count.  These disease evaluations will be performed at 
~Day 30, ~Day 60, ~Day 100 ~Day 180, ~Day 365, and then yearly per 
institutional standards. Relapse will be defined as complete loss of donor 
chimerism in all cell lines. 
 
 
 
 
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 36 of 46 
8.5 
GVHD 
 
Patients will be followed for development of acute and chronic GVHD using 
institutional criteria.  Chronic GVHD is assessed according to institutional criteria.  
 
To allow for flexibility in patient scheduling, all time points may be approximated.  
 
9.0 
DATA MANAGEMENT 
 
Data will be maintained on case report forms and appropriate Graft Engineering 
Laboratory spreadsheets.  The research team will make assessments of GVHD. 
GVHD assessment will be evaluated and scored by the GVHD team, the 
Research Nurse, the attending BMT physician and PI.  Hematopoietic engraftment 
will be assessed by the BMT attending and the PI.  The PI will be responsible for 
evaluation of chimerism data and weekly overall toxicities.  
 
The data gathered will be entered into REDCap data repository with each ID 
having a unique identifier for each participant. REDCap is a secure, web-based 
application for building and managing online databases. All data will be de-
identified and samples will only have a unique identifier that will link the unique 
identifier with the patient’s name.  
This will be accessible to all participating investigators. 
The REDCap clinical database will be maintained and coordinated at Vanderbilt 
University Medical Center under Dr. DeBaun and Dr. Kassim.    
 
The study team members are trained in HIPAA privacy regulations and other 
applicable site privacy policies. No information will be released, nor will 
participation in the research be acknowledged, to any party except where 
compulsory according to law or intuitional policy.  
 
The results of the research study may be published, but volunteers’ names or 
identities will not be revealed. Records will remain confidential. In order that 
confidentiality can be maintained, the principal investigators will keep records in 
locked cabinets and results of tests will be coded to prevent association with 
volunteers’ names. Volunteers’ records will be available to the study staff and to 
each site’s IRB. 
 
This study is being conducted at sites both inside and outside the U.S. Each site 
is conducting the study independently with no sharing of PHI;  
no one site serves as the coordinating center. Vanderbilt has entered into a 
Memorandum of Understanding (MOU) with other sites conducting the study. The 
MOU will allow sites to share and aggregate de-identified data for analysis and 
publishing purposes. The trial and participating sites will be listed in clinical 
trials.gov 
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 38 of 46 
o Hospital admissions persisting > 14 days if related to study 
participation 
 
 
Investigators must submit written safety reports as required by their Institutional 
Review Board (IRB) or Institutional Ethics Committee (IEC) within timelines set by 
regional regulations (European Union common technical document or US FDA). 
The study site should retain documentation of the submission of expedited safety 
reports to the IRB/IEC, and their receipt. 
 
9.1.2 Data Monitoring and Auditing 
 
 The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and 
data monitoring for its investigator-initiated and NIH-NCI funded clinical trials 
through its Data and Safety Monitoring Committee (DSMC). The purpose of 
the DSMC is to ensure the efficient implementation and management of VICC 
Data and Safety Monitoring Plan (DSMP). The Committee maintains authority 
to intervene in the conduct of studies as necessary to ensure clinical research 
performed at VICC achieves the highest quality standards.  
 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and 
safety monitoring of clinical trials and to oversee the VICC DSMP. Internal 
audits for compliance with adverse event reporting, regulatory and study 
requirements, and data accuracy and completion are conducted according to 
the VICC DSMP according to study phase and risk. The committee reviews all 
serious adverse events (SAE) on Vanderbilt sponsored investigator-initiated 
studies on a quarterly basis and provides DSMC SAE review reports to the 
Vanderbilt IRB. 
 
A Data Safety and Monitoring Board (DSMB), comprised of three independent 
external experts, will convene as requested by the PI to review serious toxicities 
and adverse events for the purpose of determining whether the trial should be 
modified or stopped. Triggers for referral to the DSMB are described in the 
Stopping Rules Criteria of section 10.0. 
 
9.1.3 Monitoring the Progress of the Trial and the Safety of Participants  
 
The Vanderbilt University Medical Center Principal Investigator is charged with 
ensuring the safety of participants and the validity and integrity of the data and the 
appropriate closure of studies for which significant benefits or risks have been 
uncovered.  
 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating 
Center. The actual frequency of monitoring will depend on the enrollment rate and 
performance of the site. Monitoring will be conducted through onsite and remote 
monitoring, teleconferences with the Investigator and site staff, and appropriate 
communications by mail, fax, email, or telephone.  The purpose of monitoring is to 
ensure that the study is conducted in compliance with the protocol, standard 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 39 of 46 
operating procedures (SOPs), and other written instructions, and to ensure the 
quality and integrity of the data. 
 
During scheduled monitoring visits, investigators and the investigational site staff 
must be available to discuss the progress of the trial, make necessary corrections 
to case report form entries, respond to data clarification requests, provide required 
regulatory documents, and respond to any other trial-related inquiries of the 
monitor. 
 
10.0  STATISTICAL CONSIDERATIONS  
 
The primary objective of this clinical trial is to obtain risk-stratified estimates of 
two-year progression-free survival with a precision of +/- 20 percentage points 
(95% confidence bound). To achieve this precision, it will be necessary to accrue 
at least 25 patients. We expect the accrual to take 7 years based on a recruitment 
of 6-7 patients per year once the study reaches a steady accrual of patients.  
 
Stopping criteria: As outlined in Section 2.0 (Background), the overall transplant 
related mortality (TRM) attributable to HLA-identical sibling bone marrow 
transplantation (BMT) is 20-30%, with approximately half of these deaths 
occurring in the first 100 days. The incidence of severe GVHD (defined as grade 4 
acute GVHD and/or NIH severe chronic GVHD) is approximately 13-17% after 
HLA-identical sibling BMT. The working hypothesis is that the overall toxicity of 
mini-haploBMT is not significantly greater than HLA-identical sibling BMT after 
myleoablative conditioning. Consequently, if we accumulate enough evidence that 
the probability of graft failure is greater than 20% or the probability of severe 
GVHD is greater than 10%, it would raise concerns of excessive toxicity and 
would trigger a referral to the DSMC for evaluation. This trigger would be met, for 
instance, if graft failures occurred in 3 or more in the first 5 patients, 4 or more in 
the first 10 patients (see Table 10.1 for details). As for severe GVHD (defined as 
grade 4 acute GVHD and/or NIH severe chronic GVHD), 3 or more incidences in 
the first 10 or 4 or more incidences in the first 20 would be considered too toxic 
(see Table 10.1). As this study is unblinded, we will review the patients’ safety 
data sequentially and halt the study as soon as the required numbers of toxicities 
are observed. If the stopping criterion is met, accrual to the trial will be halted 
temporarily, and the DSMB will review the toxicity data and recommend either 
modification or termination of the trial. 
 
N 
Graft failures to initiate safety review 
Severe GVHD to initiate safety review 
5 
X ≥ 3 
- 
10 X ≥ 4 
X ≥ 3 
15 X ≥ 5 
- 
20 X ≥ 6 
X ≥ 4 
25 X ≥ 7 
- 
30 X ≥ 9 
X ≥ 5 
35 X ≥ 10 
- 
40 X ≥ 11 
X ≥ 6 
45 X ≥ 12 
- 
50 X ≥ 13 
X ≥ 8 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Table 10.1: Stopping rule for safety review for graft failures and severe 
GVHD. N is the number of accrued patients, and X is the number of 
patients with graft failure or severe GVHD.  
 
Details of stopping rule calculations. 
 
Graft failure:  
 
We acknowledge uncertainty of the probability of graft failures, and we modeled it 
using a Bayesian beta-binomial model. We used a very weak prior distribution, 
Beta (0.2, 0.8), which was derived in a discussion among the investigators. The 
amount of the prior information is equivalent to that from one patient in the clinical 
trial. The unacceptable toxicity is defined as the probability of graft failure 
exceeding 20%. The probability of graft failure will be estimated at each interim 
look, and if the data indicate that unacceptable toxicity is highly likely (exceeding 
80%), , then we will halt the accrual and review safety data. The corresponding 
critical values (X) are summarized in Table 10.1. For example, if we observe 5 or 
more graft failures in the first 15 patients, the estimate of unacceptable toxicity will 
exceed 80%. Operational characteristics of this procedure were evaluated through 
simulations, and Table 10.2 summarizes the cumulative probability of stopping 
under the different assumptions for the true probability of graft failure. According 
to this simulation study, the probability of unnecessary stops is controlled at 3% if 
the true toxicity probability is 10%. And if the true probability of graft failure is as 
high as 30%, this procedure will halt for safety review with probability greater than 
50% within the first 15 patients and 75% within the first 30 patients. 
 
N 
P[Safety review] 
if p = 10% 
P[Safety review] 
if p = 15% 
P[Safety review] 
if p = 20% 
P[Safety review] 
if p = 25% 
P[Safety review] 
if p = 30% 
5 
0.01 
0.03 
0.07 
0.10 
0.16 
10 
0.02 
0.06 
0.14 
0.25 
0.37 
15 
0.02 
0.09 
0.21 
0.37 
0.53 
20 
0.02 
0.11 
0.26 
0.46 
0.65 
25 
0.03 
0.13 
0.31 
0.53 
0.73 
30 
0.03 
0.13 
0.32 
0.55 
0.75 
35 
0.03 
0.13 
0.33 
0.58 
0.78 
40 
0.03 
0.14 
0.35 
0.61 
0.81 
45 
0.03 
0.14 
0.36 
0.63 
0.84 
50 
0.03 
0.14 
0.38 
0.67 
0.87 
 
 
Table 10.2. Probabilities of stopping for safety review for different assumed 
true toxicity probability (p) based on simulation studies. 
 
Severe GVHD:  
 
Similarly, we used the same Bayesian approach based on Beta-Binomial models 
to develop the stopping criteria and compute/simulate the design characteristics. 
The prior distribution of the severe GVHD probability is Beta (0.10, 0.90). For 
severe GVHD, the unacceptable toxicity probability is 10%, and the critical values 
in Table 10.1 were set so that the accrual will be halted if the data indicate that the 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 41 of 46 
unacceptable toxicity is highly likely (80%). With the decision rule shown in Table 
10.1, we computed the operating characteristics (probability of early stopping) 
shown below in Table 10.3. According to this, if the toxicity probability is 
acceptable (5%) we have very small probability to conduct unnecessary data 
review, and if it is 20%, we will have high probabilities, 62%, and 78%, to halt the 
study reasonably early at 20, and 30 patients, respectively.  
 
N 
P[Safety review] 
if p = 5% 
P[Safety review] 
if p = 10% 
P[Safety review] 
if p = 15% 
P[Safety review] 
if p = 20% 
10 
0.01 
0.06 
0.14 
0.33 
20 
0.02 
0.15 
0.26 
0.62 
30 
0.03 
0.22 
0.32 
0.78 
40 
0.03 
0.28 
0.35 
0.87 
50 
0.04 
0.29 
0.38 
0.90 
 
Table 10.3 Probabilities of stopping for safety review for different assumed 
true toxicity probability (p) based on simulation studies.  
 
10.2 
PLANNED PROTOCOL AMENDMENTS 
 
 
Graft Failure: If the stopping rules for graft failure are met, the protocol will be 
amended by modifying conditioning regimen, such as addition of 
immunosuppressive chemotherapy and/or TBI to decrease graft rejection rate 
after consultation with the group. 
 
Graft versus host disease:  If the stopping rules for graft versus host disease are 
met, the protocol will be amended to reduce incidence of GVHD such as 
increasing dose of thymoglobulin for in-vivo purging of T-cells, after consultation 
with the group. 
 
TRM: If the stopping rules for TRM are met, the protocol will be amended to 
reduce toxicity of regimen after consultation with the group. 
 
11.0  RECORDS 
 
Clinical records will be maintained as confidentially as possible. Collection of 
CRFs at standard intervals is the primary method of collecting data from 
collaborating centers. The PI at Vanderbilt will maintain a patient database to 
allow storage and retrieval of patient data collected from a wide variety of sources. 
The principal investigator will ensure that data collected conform to all established 
guidelines for coding collection, key entry and verification. These data are then 
entered into a secure dedicated database operated by a data manager. Any 
publication or presentation will refer to patients by a unique patient number and 
not by name to assure patient confidentiality.  
 
Archiving Records: 
Patient Shadow files will be archived once the PI has confirmed individual file is 
completed and all data needs completed, CRFs pulled and review completed.  

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 42 of 46 
Some patient shadow files will be archived before the study is closed with the IRB 
and some will be archived with IRB study closure.   
 
Regulatory files will be archived when study is closed with the IRB.   
 
12.0  ON-STUDY DATE:  
 
Date of consent signing. 
 
13.0  OFF-STUDY DATE:  
 
Upon completion of “Day 100” evaluations, patients have completed their 
treatment except for sirolimus, which continues until day 365. Patient follow-up 
beyond day 100 will consist of collecting information regarding ongoing 
engraftment, disease status, late effects of this protocol, acute and chronic graft-
vs-host disease, immune reconstitution, additional therapies, and survival.  
 
Patients will go off study early in the event of:  
 
• 
Death  
• 
Patient decision (or decision by a parent or guardian on behalf of a minor)  
• 
Unacceptable toxicity associated with protocol therapy, as determined by 
the treating physicians in consultation with the investigators.  
 
An eligibility form must be completed for every subject and must be kept in the 
research chart. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
Page 43 of 46 
Reference List 
 
 
(1)  Walters MC, Patience M, Leisenring W et al. Bone marrow transplantation 
for sickle cell disease. N Engl J Med. 1996;335:369-376. 
 
(2)  Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity 
haemopoietic stem-cell transplantation for treatment of non-malignant 
diseases in children. Lancet. 2004;364:156-162. 
 
(3)  Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic 
stem cell transplantation for multiply transfused patients with sickle cell 
disease and thalassemia after low-dose total body irradiation, fludarabine, 
and rabbit anti-thymocyte globulin. Bone Marrow Transplant. 2005;35:171-
177. 
 
(4)  Iannone R, Casella JF, Fuchs EJ et al. Results of minimally toxic 
nonmyeloablative transplantation in patients with sickle cell anemia and 
beta-thalassemia. Biol Blood Marrow Transplant. 2003;9:519-528. 
 
(5)  Blaise D, Kuentz M, Fortanier C et al. Randomized Trial of Bone Marrow 
Versus Lenograstim-Primed Blood Cell Allogeneic Transplantation in 
Patients With Early-Stage Leukemia: A Report From the Societe Francaise 
de Greffe de Moelle. Journal of Clinical Oncology. 2000;18:537. 
 
(6)  Bensinger WI, Martin PJ, Storer B et al. Transplantation of bone marrow 
as compared with peripheral-blood cells from HLA-identical relatives in 
patients with hematologic cancers. N Engl J Med. 2001;344:175-181. 
 
(7)  Schmitz N, Beksac M, Hasenclever D et al. Transplantation of mobilized 
peripheral blood cells to HLA-identical siblings with standard-risk leukemia. 
Blood. 2002;100:761-767. 
 
(8)  Couban S, Simpson DR, Barnett MJ et al. A randomized multicenter 
comparison of bone marrow and peripheral blood in recipients of matched 
sibling allogeneic transplants for myeloid malignancies. Blood. 
2002;100:1525-1531. 
 
(9)  Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on 
Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828. 
 (10)  Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hematopoietic 
progenitor cells with purine analog-containing chemotherapy: harnessing 
graft-versus- leukemia without myeloablative therapy. Blood. 
1997;89:4531-4536. 
 (11)  Slavin S, Nagler A, Naparstek E et al. Allogeneic nonmyeloablative stem 
cell transplantation (NST) as an emerging new modality for 
immunotherapy of hematologic malignancies and non-malignant disorders 
[abstract]. Blood. 1998;92:519a. 

 
 
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 (12)  Greenberg P, Cox C, LeBeau MM et al. International Scoring System for 
Evaluating Prognosis in Myelodysplastic Syndromes. Blood. 
1997;89:2079-2088. 
 (13)  Greenberg P, Cox C, LeBeau MM et al. International Scoring System for 
Evaluating Prognosis in Myelodysplastic Syndromes. Blood. 
1997;89:2079-2088. 
 
(14)  Bernaudin F, Socie G, Kuentz M et al. Long-term results of related 
myeloablative stem-cell transplantation to cure sickle cell disease. Blood 
2007; 110(7):2749-2756. 
 
(15)  Shalet SM. Effect of irradiation treatment on gonadal function in men 
treated for germ cell cancer. Eur Urol 1993:23:148-51 discussion 152. 
 (16)  Howell S, Shalet S. Gonadal damage from chemotherapy and 
radiotherapy. Endocrinology and Metabolism Clinics of North Amereica. 
1998:27:927-43. 
 (17)  Thorner MO, Rogol AD, Blizzard RM et al. Acceleration of growth rate in 
growth hormone-deficient children treated with human growth hormone-
releasing hormone. Hormone Research. 1988:30:111-4. 
 (18)  Van Dorp W, van der Geest I, Laven JSE, van den Heuvel-Eibrink M. 
Gonadal function recovery in very long-term male survivors of childhood 
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1990; 19:873-80 
 (19)  Faddy MJ, Gosden RG, Gougeon A et al. Accelerated disappearance of 
ovarian follicles in mid-life: implications for forecasting menopause. Human 
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Radiology 1989; 62:995-8 

 
 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Appendix 1.  Consensus conference clinical grading of acute GVHD 
 
Clinical Staging 
Stage 
Skin 
Liver: Total 
Bilirubin 
Intestinal Tract: 
Diarrhea 
0 
No rash 
<2.0 mg/dL 
<500 ml/day 
1 
<25% of skin surface 
2.0-3.0 
500-1000 ml/day 
2 
25-50% 
3.1-6.0 
1001-1500 ml/day 
3 
Erythroderma 
6.1-15.0 
>1500 ml/day 
4 
Erythroderma with 
bullae and 
desquamation 
>15.0 
Severe abdominal pain 
with or without ileus 
 
Clinical Grading 
Grade 
Skin* 
Liver 
GI 
I 
1-2 
0 
0 
II 
3 
1 
1 
III 
- 
2-3 
2-4 
IV 
4 
4 
- 
*Each column identifies minimum stage for organ grade 
 
 

 
BMT12108 Protocol v5: December 04, 2017 
 
 
 
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Appendix 2.  Ideal Body Weight and Adjusted Ideal Body Weight Calculations 
 
 
Ideal Body Weight Formula 
 
Males: 50 kg + (2.3 x the number of inches > 5 feet) 
Females: 45 kg + (2.3 x the number of inches > 5 feet) 
 
 
Adjusted Ideal Body Weight Formula 
 
[(actual weight – ideal weight) x 25%] + ideal weight 
 
Note:  If actual weight < ideal, use actual weight. 
 
If actual weight > ideal, use corrected ideal.