Phase II Study of IV Busulfan Combined With 12 cGy of Fractionated Total Body Irradiation (FTBI) and Etoposide (VP-16) as a Preparative Regimen for Allogeneic Bone Marrow Transplantation for Patients With Advanced Hematological Malignancies
Phase: PHASE2
Conditions: Leukemia, Myelodysplastic Syndromes
Sponsor: City of Hope Medical Center

 
IRB # 99041 
 
04/20/04 
Packet: 11 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. Duarte Road 
Duarte, CA 91010 
 
Division of Hematology and Hematopoietic Cell Transplantation 
 
TITLE: 
Phase II Study of IV Busulfan Combined with 12 Gy of Fractionated Total Body Irradiation (FTBI) and 
Etoposide (VP16) as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) 
Transplantation for Patients with Advanced Hematological Malignancies 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION NUMBER: IRB# 99041 
PROTOCOL DATE: 04/20/2004 
 
DATE(S) AMENDMENT(S)/REVISION(S) 
Amendment 1  
 
 
 
08/28/00 
 
 
 
 
 
Version 01 
Amendment 2  
 
 
 
11/08/01 
 
 
 
 
 
Version 02 
Amendment 3  
 
 
 
03/11/02 
 
 
 
 
 
Version 03 
Amendment 4  
 
 
 
06/13/02 
 
 
 
 
 
Version 04 
Amendment 5  
 
 
 
08/12/02 
 
 
 
 
 
Version 05 
(Consent form change  
 
 
10/16/02 
 
 
 
 
 
Version 05) 
Amendment 6  
 
 
 
11/18/02 
 
 
 
 
 
Version 06 
Amendment 7  
 
 
 
04/20/04 
 
 
 
 
 
Version 07 
Amendment 8  
 
 
 
09/28/17 
 
 
 
 
 
Version 08 
Amendment 9  
 
 
 
07/26/19 
 
 
 
 
 
Version 09 
Amendment 10 at Continuation 
 
07/01/20 
 
 
 
 
 
Version 10 
Amendment 11 at Continuation 
 
Protocol Dated 04/20/04 (TP) 
 
 
Packet 11 
 
 
 
 
 
HISTOLOGY:  Advanced Hematological Malignancies 
 
STAGE: 
Advanced 
MODALITY: Allogeneic BMT 
 
TYPE:  
Phase II 
 
Principal Investigator at COH: 
 
Anthony Stein, M.D. 
 
 
Collaborating Investigator(s): 
 
Stephen J. Forman, M.D. 
 
 
 
 
 
 
Joyce Niland, Ph.D. 
 
Participating Clinicians:   
 
 
 
 
Amrita Krishnan, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leslie Popplewell, M.D. 
Eileen Smith, M.D. 
 
 
 
 
 
 
Jasmine Zain, M.D. 
 
 
 
 
 
 
Ricardo Spielberger, M.D. 
Department of Medical Oncology 
 
Kim Margolin, M.D. 
 
 
 
 
 
 
Tim Synold, Ph.D. 
Department of Pediatric/BMT  
 
Joseph Rosenthal, M.D. 
Department of Radiation Oncology  
Nayana Vora, M.D. 
City of Hope Samaritan Bone Marrow 
Joseph C. Alvarnas, M.D. 
Transplantation Program 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
Rev. 11/8/01 
 
 
-18    
 -14   -12 -11  -10 -9    -8     -7   -6       -5      -4           -3 
 -2     -1       0 
 
                                           Dilantin x 14 days   
 
 
  
  
             
          
 
Busulfan                             FTBI 
          VP-16                PSC/BM 
Revised 6/13/02 
22mg/m2/dose    
1200 cGy             30mg/kg  
X 16 doses 
         (120cGyx10) 
 
 

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TABLE OF CONTENTS 
 
 
1.0 
Objectives 
 
 
 
 
 
 
 
 
 
3 
2.0 
Background & Hypothesis  
 
 
 
 
 
 
3 
3.0 
Drug Information 
 
 
 
 
 
 
 
 
4 
4.0 
Staging Criteria 
 
 
 
 
 
 
 
 
9 
5.0 
Eligibility Criteria 
 
 
 
 
                                           10 
6.0 
Treatment Plan 
 
 
 
                                                      11 
7.0 
Toxicities to be Monitored and Dose Modifications                                       15 
8.0 
Toxicity Grading Scale 
 
 
 
 
 
 
 
16 
9.0 
Study Calendar 
 
 
 
 
 
 
 
 
16 
 
10.0 Criteria for Evaluation and Definition 
 
 
 
 
 
16 
11.0 Criteria for Removal from Study  
 
 
 
 
 
17 
12.0 Statistical Considerations  
 
 
 
 
 
 
17 
13.0 Women and Minorities Guidelines 
 
 
 
 
 
18 
14.0 Guidelines for Reporting Adverse Events 
 
 
 
 
18 
15.0 References  
 
 
 
 
 
 
 
 
19 
 
Appendix I 
IV Busulfan Kinetics Form  
 
 
 
 
 
22 
Appendix II Fractionated Total Body Irradiation Schema 
 
 
 
23 
Appendix III  
 
 
 
 
 
 
 
 
 
24 
Appendix IV Acute GVHD staging and grading table  
 
 
 
25 
Appendix V Grading of Chronic GVHD  
 
 
 
 
 
26 
Appendix VI Study Calendar 
 
 
 
 
 
 
 
27 
Appendix VII Common Toxicity Criteria (Version 2.0)  
 
 
 
28 
Appendix VIII Guidelines for reporting of adverse events 
 
 
 
66 
Appendix IX Eligibility Checklist  
 
 
 
 
 
 
67 
Appendix X Time points to grade toxicities and collect data  
 
 
68 
 
 
 
 
 
 
 
 
 
 
 

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1.0OBJECTIVES 
 
1.1 
To determine the efficacy of intravenous busulfan, dose targeted to achieve AUC 
of 700-900 combined with fractionated total body irradiation and VP16 as a 
preparative regimen for marrow transplantation from an HLA-identical sibling in 
patients with advanced hematological malignancies (AML or ALL) beyond 2nd 
remission, induction failure, in relapse, chronic myelogenous leukemia in blast 
crisis and myelodysplasia (RAEB and RAEBIT). 
 
1.2 
To determine the efficacy of this regimen in patients with AML in first remission 
with unfavorable cytogenetics. 
 
Rev. 6/13/02 
1.3 
To evaluate the early and late toxicities of this regimen. 
 
2.0 
BACKGROUND AND HYPOTHESIS 
 
During the last 20 years clinical bone marrow transplantation from a 
histocompatible sibling donor has evolved into an important treatment modality for 
patients with acute lymphoblastic leukemia, acute myelogenous leukemia and 
chronic myelogenous leukemia.  If the transplant procedure is performed in first 
complete remission of acute leukemia or during chronic phase or chronic 
myelogenous leukemia, approximately 50-70% of patients become disease free 
long-term survivors.(1-8)  In contrast, the chances for an ultimately successful 
outcome of bone marrow transplantation drops to 10-40% if this is performed 
during second or subsequent complete remission, during relapse of acute 
leukemias, or while patients with chronic myelogenous leukemia are in accelerated 
or blast phase of this disease.  In the latter group of patients the probability of 
leukemic relapse is in the range of 40-70%.(9-16)  Many transplant centers have 
performed several phase I-II trials of preparative regimens using alternative 
chemotherapeutic  agents or methods of administering TBI.  Some of these studies 
suggest a decrease in the post-transplant relapse rate that are often associated 
with increased transplant related morbidity and mortality from regimen related 
toxicity.(17-20)  At the City of Hope a phase I/II trial was conducted in 1986 to 
determine the efficacy of substituting etoposide (VP-16) for cyclophosphamide in 
combination with fractionated total body irradiation (FTBI).  This trial was done in 
33 patients with acute leukemia beyond first remission, and resulted in a 43% long-
term disease free survivorship.  Despite this improved survival compared to 
previous studies there still is significant relapse rate, particularly in patients with 
advanced leukemia.  This regimen has subsequently been utilized to treat 100 
patients with acute leukemia in remission.  There was only one case of fatal veno-
occlusive disease; otherwise the regimen was well tolerated. (21)  Studies 
combining busulfan and cyclophosphamide as a preparative regimen for patients 
with advanced hematological malignancies have been reported to result in similar 
or superior outcomes when compared with standard cyclophosphamide and TBI 
regimens, suggesting that busulfan has important anti-leukemic effects.  A 
randomized Southwest Oncology Group study (SWOG) comparing busulfan, 
cyclosphophamide  with FTBI VP-16 showed 20% disease free survival for patients 
transplanted with advanced leukemia. (22)  At City of Hope a phase I study was 
conducted utilizing escalating doses busulfan in combination with fixed doses of 

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FTBI and VP-16 in an attempt to decrease the relapse rate in those patients 
transplanted for advanced hematological malignancies.  The rationale behind the 
study was that we combined three non-cross resistant anti-leukemic agents with 
non-overlapping extramedullary toxicities.  An in vitro synergy has been 
demonstrated between busulfan/VP-16 and busulfan/VP-16 has been  proven to 
be an effective regimen for relapsed leukemia and for ABMT for AML in first and 
second remission.23,24  The dose limiting toxicity occurred at 12mg/kg the MTD was 
defined at 11mg/kg.  At this dose level median first dose AUC for these patients 
was 892µM*min (460-1267).  With a median follow-up of 11.5 months, the disease-
free survival is 32%, and the probability of relapse is 40%.  The only variable 
predictive of a disease-free survival and relapse was the busulfan dose of 7-8 
mg/kg.  In this phase I study there was a wide variability of the AUC of busulfan 
due to the variability of absorption of oral busulfan.  An AUC of 700-950 showed a 
trend to a decreased relapse rate and improved disease free survival. 
 
 
A phase II study utilizing IV busulfan was conducted at City of Hope which has 
resulted in FDA approval of IV busulfan and it is proposed to substitute IV busulfan 
which has been shown to have more predictable pharmacokinetic properties than 
the oral preparation resulting in a better toxicity profile. (25,26,27) 
 
 
*Patients with AML in first complete remission (CR1) with unfavorable cytogenetics 
have a relapse rate of 40% with our current transplant regimen consisting of 
fractionated radiation and etoposide.  We propose to use this new preparative 
regimen to see if it can improve the DFS and relapse rate for this subset of patients 
with AML in first CR. 
Rev. 6/13/02 
 
3.0 
DRUG INFORMATION 
 
3.1 
Busulfan (Myleran) 
 
 
3.11  
Mechanism of Action:  Busulfan is a bifunctional alkylating agent.  In 
aqueous media, busulfan hydrolyses to produce reactive carbonium 
ions that can alkylate DNA. 
 
 3.12 
Formulation and stability:  Busulfan injection is a sterile, pyrogen-free 
solution provided in a mixture of dimethylacetamide (DMA) and 
polyethlyeneglycol 400 (PEG 400).  It is supplied in 10-ml single use 
ampules at a concentration of 6-mg Busulfan per ml.  Each ampule 
contains 60mg of Busulfan in 3.3 ml of DMA and 6.7 ml of PEG 400.  
When diluted in normal saline or D5W to a concentration of 0.5mg/mL, 
the resulting solution must be administered within eight (8) hours of 
preparation; including the 2 hours of infusion of the drug. 
 
 
 
 
 
Stable at 4º C for at least twelve months.  Ampules should be stored 
refrigerated at 2-8º C.  Do not freeze.  Ampules may be stored for up to 
seven days at room temperature. 
 
 
 
 
 
 
 
Solution preparation: prepare the Busulfan solution as follows:  Use 
sterile, non-pyrogenic, disposable containers, syringes, needles, 
stopcocks, and transfer tubing, etc.  Calculate the amount of drug to be 
administrated based on the dosage and the patient’s body weight. 

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Prepare a solution of 0.9% sodium chloride injection USP (normal 
saline) calculated Busulfan dose in ml from the step above. 
 
 
 
 
 
 
 
 
 
Break off the top of the ampule and remove the calculated volume of 
Busulfan from the container by using a syringe fitted with a filter needle 
or equivalent.  Transfer the contents of the syringe into the calculated 
amount of either normal saline or D5W making sure that the drug flows 
into and through the solution.  Mix by inverting the bag. 
 
3.13 
Administration:  Each dose of the drug will be given by slow central 
intravenous infusion over 2 hours.  Caution: Do not administer as an 
intravenous push or bolus. 
 
 
3.14 
Supplier:  This drug is commercially available; manufactured by Orphan 
Medical Inc. 
 
3.15 
Toxicity:  Toxicity from busulfan includes: 
a). 
Severe bone marrow hypoplasia, which would be fatal without 
administration of bone marrow, stem cells. 
b). 
Nausea and vomiting which can be decreased by the use of 
sedation and anti-emetics. 
c). 
Stomatitis and diarrhea which can be treated symptomatically 
with fluid replacement and atropine or diphenoxylate  H C1. 
d). 
Pulmonary fibrosis characterized by delayed onset of cough, 
shortness of breath and low-grade fever. 
e). 
Hepatic damage, which can occur in combination with cytoxan 
or as a single agent and can result in significant hepatic 
toxicity which, can be fatal. 
f). 
Temporary hyperpigmentation of the skin and nail bed 
changes. 
g). 
Grand mal seizures which can be prevented by the 
prophylactic administration of Dilantin. 
 
3.2 
VP-16 (VP-16-213) (Etoposide) (Vepesid) 
3.21  
Chemistry: VP-16 is a semi-synthetic podophyllotoxin  derivative from 
the plant podophyllum pletatum, has anti-neoplastic properties in 
experimental animals and in man. The empiric formula C29 H32 013 has a 
molecular weight of 588. 
 
 
 
3.22  
Mechanism of Action: The epipodophyllotoxin exert phase-specific 
spindle poison activity with metaphase arrest, but in contrast to the 
vinca alkaloids, have an additional activity of inhibiting cells from 
entering mitosis. Suppression of tritiated thymidine, uridine, and leucine 
incorporation in human cells in tissue culture suggest effects against 
DNA, RNA and protein synthesis. 
 
 
 
3.23  
Animal Tumor Data:  Significant anti-tumor effect has been 
demonstrated in L-1210, mouse sarcoma 37 and 180, Walker 
carcinosarcoma and Erlich ascites tumor.  With the L 1210 system, 

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7
activity was schedule-dependent, having greater effect with a twice a 
week administration than with daily dosing or the administration of 
single large doses.  The drug is active given intraperitoneally or orally in 
L 1210.  No effect was demonstrated intracerebrally inoculated L 1210.  
 
3.24  
Animal Toxicology:  The predominant toxicities of VP-16 in animal 
studies involve the hematopoietic system, with toxicity to the liver and 
GI tract occurring only at doses producing profound myelosuppression.  
Anemia, leukopenia, and lymphoid involution occur in mice, rats and 
monkeys. Acute toxicity investigations have been complicated by the 
toxicity of the solvent system.  The LD-50 of the solvent plus drug 
approached that of the solvent alone. Immuno-suppressive effects occur 
with an inhibition of antibody production in mice and monkeys, and 
prevention of experimental allergic encephalomyelitis in rats (cell 
mediated immunity).  
 
 
 
  3.25  
Human Toxicology:   Reversible myelotoxicity has been uniformly 
observed to be the major toxicity of VP-16 and to represent the only 
clinically significant side effect.  Following a single IV injection, peak 
myelotoxicity occurs at 7 to 9 days. Following daily IV injections for 5 to 
7 days, myelotoxicity is maximal between 12 to 16 days from the 
initiation of therapy.  Bone marrow suppression is mainly manifested as 
granulocytopenia with thrombocytopenia and anemia occurring to a 
lesser extent.  Transient, modest nausea, usually without vomiting, is 
common.  Occasional alopecia is reported.  VP-16 does not produce 
stomatitis, phlebitis, neurotoxicity, hepato-toxicity or nephro-toxicity. 
Hypotension and anaphylaxis are occasional side effects.  Hypotension 
can be managed by infusing the drug over at least a 30 minute period. 
Occasionally, fever may be a result of VP-16 administration.   
 
 
 
3.26  
Pharmaceutical Data: Formulation: 100 mg of VP-16 is supplied as 5 ml 
of solution in clear ampules for injection.  Each ampule also contains 
anhydrous citric acid 10 mg, benzylalcohol 150 mg, polysorbate 80 
purified 400 mg, polyethylene glycol and absolute alcohol. The contents 
of the ampule are non-aqueous and must be diluted with 20 to 50 
volumes of sodium chloride injection USP.  The time before precipitation 
depends on concentration.   
 
 
 
Dilution     Time
 
 
 
1:20       30 minutes 
 
 
1:50        3 hours  
 
 
1:100       6 hours  
 
 
 
3.27  
Storage and stability:  The drug is available as a box of 10 ampules that 
are stored at room temperature.  Each ampule should be kept in the box 
to protect it from light.  VP-16 is less stable in 5% Dextrose injection and 
precipitation is reported.  VP-16 has a minimum infusion time of 30 
minutes to reduce hypotension. 
 

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3.28  
Supplier: VP-16 is commercially available. 
 
3.3 Cyclosporine:
 
 
 
3.31  
Mechanism of Action:  Cyclosporine is an immunosuppressant used to 
prevent the rejection of transplanted kidneys, hearts and livers.  It is 
also effective in treating bone marrow recipients with acute graft vs host 
disease.  The drug inhibits T lymphocyte function with minimal activity 
against B cells. 
 
 
 
3.32  
Human Toxicology:  Nephrotoxicity is the most frequent side effect of 
cyclosporine.  Other frequently observed side effects include 
hypertension, 
hirsutism, 
tremors, 
paresthesias, 
hepato-toxicity, 
hypomagnesemia and hyperkalemia.  Transient gastrointestinal 
symptoms have also occurred, to include anorexia, nausea and ileus.  
The drug has demonstrated a relative lack of myelotoxicity. 
   
 
 
3.33  
Pharmaceutical Data:  Formulation:  Cyclosporine is available for oral 
and intravenous administration.  Cyclosporine is an olive oil solution 
supplied in 50 ml bottles containing 100 mg/ml.  The intravenous 
solution is available as 5 ml ampules containing 50 mg/ml.  
Cyclosporine is also available as 25mg and 100mg capsules. 
 
 3.34  
Storage and Stability:  The oral solution of cyclosporine should be 
stored and dispensed in the original container at temperatures below 
86oF and should be used within two months after opening bottle.  Do not 
store in the refrigerator.  The intravenous solution should be stored at 
temperatures below 86oF and protected from light.   
 
 
 
3.35  
Administration:  The oral solution may be mixed with whole milk, 
chocolate milk or fruit juice to mask the taste and should be taken 
immediately after mixing.  Cyclosporine should be administered 
intravenously over 2 to 6 hours.  Longer infusion times are acceptable 
and sometimes better tolerated.  The contents of the ampule should be 
diluted with 50-250 ml of 0.9% sodium chloride injection or 5% dextrose 
injection.  
 
3.36 
Supplier: This drug is commercially available. 
 
3.4 
Methotrexate 
 
3.41 
Chemistry:  Methotrexate is a well known antimetabolite which has 
been intensively studied. 
 
3.42 
Biochemistry:   As a folic acid analog, methotrexate is considered to act 
as an inhibitor or dihydrofolate reductase to which it tightly binds. 
 
3.43 
Human Pharmacology:  Methotrexate is well absorbed in low doses 
from the gastrointestinal tract and is well absorbed when given 
intramuscularly.  Large doses are completely absorbed when given 

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orally.  About 40-50% of small doses and about 90% of large doses are 
excreted unchanged in the urine within eight hours.  Toxicity is directly 
related to the duration of blood levels and thus, renal insufficiency can 
significantly increase toxicity.  In man, there is insignificant metabolism 
of methotrexate. 
 
3.44 
Human Toxicity: Human toxicity includes myelosuppression, mucositis, 
nausea and abdominal discomfort, generalized malaise, rashes, 
photosensitization, decreased renal function, fetal death, hepatic toxicity 
and pulmonary toxicity (methotrexate lung). 
 
3.45 
Pharmaceutical Data: Formulation; 50mg vials containing 25mg/cc. 
 
3.46 
Storage:  Room temperature. 
 
3.47 
Administration:  In this study, administered intravenously. 
 
3.48 
Supplier:  Methotrexate is commercially available for purchase by the 
third party.  
 
 
 
4.0 
STAGING CRITERIA: 
 
 
4.1 
Definition of Disease Stages of  Chronic Myelogenous Leukemia 
 
 
Chronic Phase
 
 
1. 
No significant symptoms which are not readily controlled by conventional 
doses of hydroxyurea or busulfan. 
 
 
2. 
None of the features of accelerated phase or blastic phase. (Note:  
Granulocytic hyperplasia and the Philadelphia chromosome may be present in 
the bone marrow). 
 
 
Accelerated Phase (any one or more of the following criteria) 
 
 
1. 
WBC difficult to control with conventional use of busulfan/hydroxyurea in 
terms of doses required or shortening of intervals between courses.  
 
 
2. 
Rapid doubling of WBC (< 5 days).  
 
 
3. 
> 10% blasts in blood or marrow.  
 
 
4. 
> 20% blasts plus promyelocytes in blood or marrow. 
 
 
5. 
> 20% basophils plus eosinophils in blood.  
 
 
6. 
Anemia or thrombocytopenia unresponsive to busulfan/hydroxyurea. 
 
 
7. 
Persistent thrombocytosis (> 1,000,000/ 1) unresponsive to conventional 
doses of hydroxyurea or busulfan. 

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8. 
Additional chromosome changes (evolving new clone). 
 
 
9. 
Increasing splenomegaly unresponsive to conventional doses of hydroxyurea 
or busulfan. 
 
 
10. 
Development of chloromas or myelofibrosis. 
 
 
11. 
Patients in a second (or subsequent) chronic phase after  blast crisis.  
 
 
Blastic Phase
 
 
1. 
> 30% blasts plus promyelocytes in the blood or bone marrow. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 Inclusion Criteria 
 
5.1.1 Patients with acute myelogenous or lymphocytic leukemia who are not in 
first remission or second remission i.e. after failing remission induction 
therapy or in relapse or beyond second remission, or patients with chronic 
myelogenous leukemia in blastic phase of the disease are eligible for the 
study.  Patients with refractory anemia with excess blasts and in 
transformation will be eligible. 
 
5.1.2 All candidates for this study must have a HLA (A,B,C,DR) identical siblings 
who is willing to donate bone marrow for marrow grafting.  All ABO blood 
group combinations of the donor/recipient are acceptable since even major 
ABO compatibilities can be dealt with by various techniques.  (Red cell 
exchange or plasma exchange). Peripheral blood stem cells or bone 
marrow can be used. 
 
5.1.3 Prior therapy with VP-16 and busulfan is allowed. 
 
5.1.4 Patients must be older than 16 and the upper age limit is physiological age 
of 50. 
 
5.1.5 A cardiac evaluation with electrocardiogram and MUGA or echocardiogram 
is required in all patients.  Patients must have an ejection fracture of greater 
than or equal to 50%.   
 
5.1.6 Patients must have a serum creatinine of less than or equal to 1.2 or 
creatinine clearance > 80ml/min.   
 
5.1.7 A bilirubin of less than or equal to 1.5.  Patients should also have an SGOT 
and SGPT less than 5 times the upper limit of normal. 
 
5.1.8 Pulmonary function tests including DLCO will be performed.  FEV1 
and DLCO should be greater than 50% of predicted normal value. 

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11
 
5.1.9 The time from the last induction or reinduction attempt should be greater 
than or equal to 28 days.   
 
5.1.10 Signed informed consent form approved by the IRB is required.  The 
patient, family member and transplant staff physician (physician, nurse, and 
social worker) meet at least once prior to starting the transplant procedure.  
During this meeting all pertinent information with respect to risks and 
benefits to donor and recipient will be presented.  Alternative treatment 
modalities will be discussed.  The risks are explained in detail on the 
enclosed consent forms.   
 
Revised 8/28/00 
Revised 3/11/02 
5.1.11 Patients with AML in first remission with poor risk cytogenetics (11q 
abnormalities, -7,-5, complex abnormalities i.e. > 3 abnormalities, 6;9 
translocation and 3q abnormalities del (7q), del (5q), complex abn > 
abnormalities, 9q, 20q, 21q, 17p, t(9;21). 
 
Revised 6/13/02 
5.2 
Exclusion Criteria 
5.2.1 Prior radiation therapy that will exclude the use of total body irradiation. 
 
5.2.2 Patients who have undergone bone marrow transplantation previously and 
who have relapsed. 
 
5.2.3 Patients with psychological or medical condition that patients physician 
deems unacceptable to proceed to allogeneic bone marrow transplant.   
 
5.2.4 Pregnancy 
 
Revised 8/28/00 
5.3 
Donors 
5.3.1 Any sibling donors who are histocompatible with the prospective recipient 
will be considered as a suitable donor. 
 
5.3.2 Donors will be excluded if for psychological or medical reasons they are 
unable to tolerate the procedure. 
 
5.3.3 Donor should be able to donate peripheral blood stem cells or bone marrow. 
 
6.0 
TREATMENT PLAN 
 
All patients will have a right atrial catheter, hickman type inserted.  This catheter 
will be used for collection of blood specimens, administration of drug, bone 
marrow, blood components, and for hyperalimentation. 
 
6.1 
Pre-transplant evaluation will be performed within four weeks of beginning 
treatment except for the following: 1) Bone marrow aspirate and biopsy + 
cytogenetics within 14 days of starting treatment, 2).  CBC, differential, platelets, 
comprehensive metabolic panel within 5 days of starting treatment.  
a).  
Prior to admission patient will have a complete history and physical 
examination performed.  Special attention will be given to prior 
Revised 8/28/00 

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12
chemotherapy, height, weight and body surface area should also be 
noted.   
b).  
Patients will have the following laboratory tests performed: 
i. 
CBC with diff platelets 
ii. 
Sodium, potassium, chloride, bicarbonate or total carbone 
dioxide, BUN, creatinine, Ca, Mg, Phosphorous, total bilirubin, 
total 
protein, 
albumin, 
SGPT, 
SGOT, 
LDH, 
alkaline 
phosphatase, cholesterol, glucose.  
iii. 
Urine analysis 
HIV  test 
 
 
 
 
 
Hepatitis A,B + C 
 
 
 
 
 
24-hr urine for creatinine clearance 
 
 
 
 
 
CMV, HSV – HZV ab 
 
 
 
 
 
Immunoglobulin levels 
iv. 
24-hour urine collection for creatinine clearance. 
v. 
Chest x-ray and EKG 
vi. 
CT scan chest, abdomen and pelvis. 
vii. 
Pregnancy test 
Revised 8/28/00 
c). 
Initial coagulation studies prothrombin time, APTT. 
d). 
MUGA scan or echocardiogram 
e). 
Pulmonary function tests 
f). 
A bone marrow aspirate and biopsy, and cytogenetics needs to be 
done within 2 weeks of admission (if bone marrow not aspirable and 
> 20% blasts in blood this may be done on peripheral blood sample). 
Rev. 11/8/01 
g). 
Patients with acute leukemia or chronic myelogenous leukemia in 
blast crisis will have a lumbar puncture performed.  Methotrexate 
(10mg/m2 but not more than a total dose of 12mg) will be 
administered intrathecally.  The spinal fluid will be examined for the 
presence of malignant cells.  Those patients who had leukemic CNS 
involvement prior to the time of admission before transplantation will 
receive five weekly intrathecal methotrexate injections with the dose 
described above from the time patients platelet count is greater than 
75,000 to day 100, then monthly intrathecal methotrexate injections 
with the dose described above between day 100 and 12 months after 
transplantation.  The initial spinal tap will only be performed if 
patients platelet count can be kept above 75,000.   
Revised 8/28/00 
 
6.2 Preparative Chemotherapy Regimen 
* Patient to sign consent form before starting Dilantin. 
 
Friday/Day -18 
Begin dilantin 300mg/p.o. t.i.d. times 1 day, then 
300mg/p.o./IV daily times 14 days. 
Tuesday/Day -14 
Admission or outpatient, dilantin blood levels will be 
checked and dose adjusted as needed to meet 
therapeutic range.  Further adjustments if clinically 
indicated.  Busulfan test dose administered at 6 a.m. as 
a single dose.  The I/V dose is calculated as follows: 
 
1. 
Body surface area (BSA) is calculated by the 
equation: 
Rev. 8/12/02 
Rev. 11/8/01 

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13
 
BSA= (Actual body wt.(kg) x height (cm) 
 
 
 
 
 
 
 
                                3600 
 
2. 
22mg/m2 I/V Busulfan will be given over 2 hours.  
Blood levels will be obtained with the first dose 
as per appendix 1 and will be performed at City 
of Hope. 
 
Rev. 6/13/02 
 
 
 
Wednesday/Day -13 
Busulfan AUC will be calculated by standard methods 
available in the City of Hope Analytical Pharmacology 
Core Facility (APCF).  The resulting AUC will be used 
to determine the dose required to achieve an AUC of 
800 µM* min according to the following formula: 
Rev. 11/8/01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
    800µMx min 
Adj dose = Current dose x  
 
 
 
 
    test dose AUC 
 
 
 
 
 
The maximum dose given will not exceed 32mg/m2. 
There is no limit on dose reduction Busulfan dose will 
only be adjusted for AUC’s <700 or >900 µM*min. 
Rev. 6/13/02 
 
Thursday/Day  -12 
The adjusted dose Busulfan dose will be given at 6 a.m. 
and blood levels will be repeated.  Further dose 
adjustments will be performed if AUC >1000.  
 
Friday/Day -11 
Patient admitted to BMT or receive further dose of 
Busulfan in clinic.   
 
Busulfan dosing restarted at 6 p.m. and is repeated 
every 6 hours for a total of 14 doses. 
Tuesday/Day -7 
Fractionated TBI will be given at 120 cGy per fraction 
for a total of 4 days for a total of 10 fractions for a total 
dose of 1200 cGy.  See Appendix II. 
  
Saturday/Day -3 
VP-16 30mg/kg based on adjusted ideal body weight 
will be administered. 
  
 
Tuesday/Day 0 
 
PSC reinfusion/or BM infusion 
 
 
 
See Appendix 3 for PSC Collection 
 
Toxicities of the marrow infusion are very rare.  Volume overload may be 
prevented by removal of plasma from the marrow aspirate or by phlebotomy of the 
recipient prior to marrow infusion.  Pulmonary emboli are theoretically possible and 
would require management with 02 or IPPB.  However, our clinical observations 
over the last 20 years indicate that pulmonary embolism in this clinical setting does 

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14
not occur at any increased rate.  The most frequently encountered problem is that 
of chills, hives, and fever.  Those allergic reactions occur rarely (in 1 to 2%) and 
can be prevented by intravenous injections of dyphenhydrimine 25mg and 
hydrocortisone (50mg) prior to the bone marrow infusion. 
 
 
6.3  
Recommended 
   
6.3 
Graft Versus Host Disease Prophylaxis and Treatment 
1. 
MMF
Both intravenous and oral doses of MMF will be calculated using 
adjusted ideal body weight.  If actual body weight is less than ideal 
body weight, actual body weight will be used.  All patients will initiate 
the intravenous formulation of MMF on the day of transplantation 
(Day 0), a minimum of 2 hours after the end of the stem cell infusion.  
MMF will be administered at 30mg/kg/day in two divided daily doses 
from day 0 until day 27.  At day 27 the MMF will be tapered by 
250mg to be off by Day 56.  If patient does not develop evidence of 
GVH.  The intravenous formulation will be administered until at least 
day 14 after transplant.  MMF will be administered as a 2 hour IV 
infusion.  MMF will be induced with 5% dextrose.  When patients 
have recovered from radiation-induced gastroenteritis and are 
capable of taking the oral MMF, they will be converted at an oral to 
intravenous ratio of 1:1.  This can be done because of the high 
bioavailability of MMF.  The oral formulation of MMF is available in 
250mg capsules.  The prescribed dose will be rounded to the nearest 
dose possible with these capsules.   
Revised 6/13/02 
 
 
 
2. 
Cyclosporine 
All patients will receive cyclosporine 3mg/kg/day IV or 12.5 
mg/kg/day orally from day –1 until day 50.  Dosing should be based 
on adjusted ideal body weight.  If GVHD is absent, cyclosporine will 
then be tapered by 5% week until day 180 when the drug is 
discontinued.  Cyclosporine whole blood levels will be monitored. 
 
 
 
 
6.31 If moderate to severe graft-versus-host disease occurs (Grade II-IV), 
patients will be treated with the administration of higher doses of methyl-
prednisolone, anti-thymocyte globulin, etc.  
 
6.32 Graft-versus-host disease will be graded according to previously defined 
criteria (Appendix IV,V).  
 
6.4 
Supportive Care during Transplant 
 
On the day of admission menstruating females will start Provera 10mg p.o. daily 
and Nystatin vaginal suppositories 1 b.i.d.  In addition, all patients will start, 
levofloxacin 500mg/p.o or I/V q daily, Bactrim DS 1 tablet p.o. b.i.d. or IV will be 
started and continue until day –2. 
 
 
 
Hyperalimentation will be given while patient is unable to eat.   
 

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15
 
It is recommended that platelet transfusions will be given to maintain platelet count 
greater than 20,000/µl at all times.  Single donor platelets will be used with an 
attempt to use family members when possible.  All platelets will be filtered to 
remove contaminated leukocytes which may harbor cytomegalovirus (CMV).  
Packed RBC transfusions will be used to keep the hemoglobin greater than 
8.5gm/dl.  All blood products will be irradiated with 2500cGy prior to tranfusions.   
 
The management of infections in these immunocompromised patients must by 
necessity be individualized, but the following general approach will be utilized.  If a 
specific infection is documented, patients will be placed on specific anti-microbial 
agents to treat that infection.  For temperatures greater than 38.5°C without an 
obvious source in patients with less than 1000granulocytes/l, cultures of blood will 
be obtained.  Following this, a third generation cephalosporin will be used as initial 
empiric antibiotic coverage.  For persistent or recurrent fevers an aminoglycoside 
and or ancef will be added.  Prophylactic intravenous amphotericin B will be used 
and the dose can be increased as clinically indicated.  If a specific organism or site 
of infection is identified after starting empiric antibiotic coverage, therapy will be 
changed as needed.   
 
While hospitalized, patients will have daily CBC’s with platelet count, and SMA-7 
(Na, K, C1, CO2, BUN, creatinine, glucose).  SMA12 (total protein, albumin, 
phosphatase, Ca, SGPT, SGOT, alkaline phosphatase, total bilirubin, cholesterol) 
determinations will be performed on Monday, Wednesday and Fridays and chest x-
rays will be done weekly.  CSA levels q Mon & Thurs, and CMV blood cultures q 
Mon & Thurs when WBC >2000. 
Rev. 11/8/01 
 
 
7.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
7.1 
Radiation toxicities:  The short term complications of TBI are: a). nausea and 
vomiting.  This problem will be managed symptomatically. b) Oral mucositis is 
expected in all patients.  All patients will receive oral care with hydrogen peroxide 
and clotrimazole.  Only sponge toothbrushes will be allowed.  Pain will be 
managed with morphine and dilaudid, c) Temporary alopecia will also be expected 
in all patients.  Long-term complications of TBI include: a) cataracts, these can be 
managed successfully in the same way as cataracts unrelated to radiation. b) Solid 
tumors have been seen following TBI. c) Radiation fibrosis of the lungs, d) 
hypothyroidism and patient will be required to take supplemental thyroid 
medication, e). Sterility. 
7.2 
Chemotherapy Toxicities: 
 
7.2.1 Toxicities of VP-16 
a) 
VP-16 may cause nausea, vomiting lasting for a few hours. 
 
b). 
Occassionally VP16 can cause allergic reactions, hemorrhagic 
cystitis and hepatotoxicity. 
b) 
Can cause mucositis, and dermatitis.   
7.2.2 Busulfan Toxicities are myelosuppression, pulmonary fibrosis, increased 
pigmentation, grand mal seizures and temporary or permanent alopecias 
have also been seen.   
 

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16
If 2 of first 6 patients develop grade 3 liver or lung toxicity related to the 
preparative regimen the Busulfan dose will be decreased to the equivalent 
of 9mg/kg of the oral dose and AUC range will be changed to 600-800. 
 
If 2 of first 6 patients require ventilator support for mucositis the VP-16 will 
be omitted. 
 
7.3 
The dose of methotrexate will be modified for impaired liver function based on 
serum direct bilirubin as follows: 
Direct Bilirubin mg/dl 
 
 
% MTX dose 
 
 
 
 
< 2 
 
 
 
 
      100% 
2.1 – 3.0 
 
 
 
        50% 
> 3.0  
 
 
 
          0% 
 
 
7.4 
The dose of cyclosporine and methotrexate will be modified for impaired renal 
function based on serum creatinine. 
Creatinine mg/dl 
 
 
 
% CSA + MTX 
 
< 1.5  
 
 
 
      100% 
 
 
 
 
1.6 – 1.7 
 
 
 
        75% 
 
 
 
 
1.8 – 2.0 
 
 
 
        50% 
 
 
 
 
> 2.0  
 
 
 
          0% 
 
8.0 
Toxicities will be graded per CTC 2.0 (Appendix VII) publish date April 30, 1999.  
 
Rev. 11/8/01 
9.0 
STUDY CALENDAR SEE APPENDIX VI. 
 
10.0 CRITERIA FOR EVALUATION AND DEFINITION
10.1 Achievement of a lymphohematopoietic graft is defined as recovery from post-
transplant. 
10.2 Complete remission is defined as attainment of M-1 marrow status, and no 
evidence of recurrent extramedullary disease. 
10.3 Length of survival is measured from entry on study to death or time of last contact. 
10.4 Treatment failure is defined as death from toxicities associated with transplant 
procedure of recurrence of malignancy. 
10.5 All registered patients including those removed from the treatment protocol will be 
followed for survival every six months. 
 
11.0 CRITERIA FOR REMOVAL FROM STUDY 
 
There are two situations that will determine removal of a patient from the study: 
 
 
11A. The patient may always be removed from the study whenever he/she wishes. 
 
 
11B. If the scheduled bone marrow donor decides not to provide bone marrow. 
 
12.0 STATISTICAL CONSIDERATIONS 
 
12.1 Primary and Secondary Endpoints:  The primary endpoint of the Phase II study is 
to evaluate the efficacy of FTBI/BU/VP-16 with a targeted Busulfan dose of AUC 
700-900 as a preparative regimen for allogeneic BMT in patients with advanced 
hematological malignancies (AML or ALL beyond second remission, in induction 

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17
failure, or in relapse; CML in blast crisis; and myelodysplasia, RAEB and RAEBIT).  
Secondary endpoints will include early and late toxicities of this regimen. 
 
Efficacy will be estimated based on 2 and 5 year disease-free survival (DFS).  The 
effects of cytogenetics, WBC at presentation, and number of courses of induction 
therapy to achieve remission will be evaluated as possible prognostic factors for 
relapse, DFS, and overall survival. 
 
12.2 Sample size Estimation and Length of Accrual:  A total of 50 patients with 
advanced malignancies and less than 50 years old (physiological age) will be 
accrued to this trial, so that in estimating the engraftment and relapse rates the 
maximum standard error will be 0.7.  We expect to accrue approximately 10-12 
patients per year so that this trial will require 4-5 years of completion. 
 
12.3 If at any time the severe treatment related complication rate (e.g. severe VOD, 
interstitial pneumonia, neurotoxicity at day 100 post BMT) or regimen related 
mortality exceeds 20% with a high probability (i.e. >95%) then further accrual to 
the trial will be terminated.  This would occur if the following numbers of events 
have been observed, monitoring after every set of 10 patients is accrued: 
 

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18
 
 
Number of Patients 
Accrued 
Number of Events Leading to Early 
Termination 
10 
5 
20 
8 
30 
11 
40 
14 
 
12.4 Statistical Analyses:  The rate of engraftment and median time to engraftment will 
be estimated, defined as time to ANC > 500 and platelets >20,000. 
 
The Kaplan-Meier method will be used to estimate time to relapse, DFS, and 
overall survival, and 95% confidence intervals will be calculated using 
Greenwood’s variance. 
 
 
The intent-to-treat group will include all patients receiving the preparative regimen 
for BMT.  For overall survival, failure time will be calculated from the day of first 
treatment to the day of death due to any cause for those patients who fail.  For 
DFS, the failure time will be calculated from the day of first treatment to the day of 
disease relapse or death due to any cause.  For patients who remain alive and well 
at the time of analysis, the survival time will be censored as of the date of last 
contact.  The Cox proportional hazard regression model will be used to analyze 
possible prognostic factors for relapse, DFS and overall survival. 
 
12.5 Patients with AML with unfavorable cytogenetics will be a subset analysis that will 
include approximately 12 patients.  This number is too small for formal hypothesis 
testing.  It will give us some experience with this population of patients and 
descriptive analysis will be used along with estimation of relapse rate and 95% C.I.  
 
Revised 
9/26/00 
13.0 WOMEN AND MINORITIES GUIDELINES 
 
All eligible patients from both genders and from all racial/ethnic groups will be recruited 
equally  into this trial, with the only exclusionary criteria being those stated in Section 5.0.  
Based on our patient populations and previous experience with BMT for advanced 
hematological malignancies, the anticipated rates of entry into this study by gender and 
race/ethnicity are as follows: 
 
Race/Ethnicity by Gender for Advanced Malignancy Patients  
Receiving BMT at City of Hope 
 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, not of 
Hispanic 
Origin 
Hispanic
White, not 
of Hispanic 
Origin 
Other or 
unknown
Female 
0% 
8% 
1% 
32% 
58% 
1% 
Male 
<1% 
8% 
3% 
33% 
54% 
3% 
Total 
<1% 
8% 
2% 
33% 
55% 
2% 
 

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19
14.0 GUIDELINES FOR REPORTING ADVERSE EVENTS (AE) ADVERSE DRUG 
REACTIONS ADR OCCURRING WITH COMMERCIAL AGENTS. APPENDIX VIII. 
 
 
 
Rev. 11/8/01 

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20
15.0 REFERENCES: 
 
1. 
Slattery JT, Clift RA, Buckner CD, et al.  Marrow transplantation for chronic myeloid 
leukemia: The influence of plasma busulfan levels on the outcome of transplantation.  
Blood 1997; 89:3055-3060. 
 
2. 
Snyder DS, Negrin RS, O’Donnell MR, et al.  Fractionated total body irradiation and high 
dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients 
with chronic myelogenous leukemia.  Blood 1994;84: 1672-1679. 
 
3. 
Clift RA, Buckner CD, Thomas ED, et al.  Marrow transplantation for chronic myeloid 
leukemia: A randomized study comparing cyclophosphamide and total body irradiation 
with busulfan and cyclophosphamide.  Blood 1994; 84: 2036-2043. 
 
4. 
McGlave PB, Haake RJ, Bostrom BC, et al.  Allogeneic bone marrow transplantation for 
acute nonlymphocytic leukemia in first remission.  Blood 1988;72: 1512-1517. 
 
5. 
Forman SJ, Spruce WE, Farbstein MJ, et al. Bone marrow ablation followed by allogeneic 
marrow grafting during first complete remission of acute nonlymphocytic leukemia. Blood 
1983; 61:439-442. 
 
6. 
Blume KG, Beutler E, Bross KJ, et al.  Bone-marrow ablation and allogeneic marrow 
transplantation in acute leukemia.  N Engl J Med 1980;302:1041-1046. 
 
7. 
Blume KG, Forman SJ, Krance RA, Henke M, Findley DO, Hill LR. Bone marrow 
transplantation for acute leukemia. Hematol Blood Transfusion 1985; 29:39-41. 
 
8. 
Thomas ED, Sanders JE, Flournoy N, et al. Marrow transplantation for patients with acute 
lymphoblastic leukemia in remission.  Blood 1979;54:468-476. 
 
9. 
Martin PJ, Clift RA, Fisher LD, et al. HLA-identical marrow transplantation during 
accelerated phase chronic myelogenous leukemia: Analysis of survival and remission 
duration. Blood 1988;72:1978-1984. 
 
10. 
Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for patients in 
accelerated phase of chronic myeloid leukemia.  Blood 1994;84:4368-4373. 
 
11. 
Mehta J, Powles R, Horton C, et al. Bone marrow transplantation for primary refractory 
acute leukemia. Bone Marrow Transplant 1994;14:415-418. 
 
12. 
Forman SJ, Schmidt GM, Nademanee AP, et al.  Allogeneic bone marrow transplantation 
as therapy for primary induction failure for patients with acute leukemia.  J. Clin Oncol 
1991;9:1570-1574. 
 
13. 
Clift RA, Buckner CD, Appelbaum FR, et al.  Allogeneic marrow transplantation during 
untreated first relapse of acute myeloid leukemia. J. Clin Oncol 1992;10:1723-1729. 
 
14. 
Appelbaum FR, Clift RA, Buckner CD, et al.  Allogeneic marrow transplantation for acute 
nonlymphoblastic leukemia after first relapse.  Blood 1983;61:949-953. 
 

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21
15. 
Blume KG, Forman SJ, O’Donnell MR, et al.  Total body irradiation and high-dose 
etoposide : A new preparatory regimen for bone marrow transplantation in patients with 
advanced hematologic malignancies.  Blood 1987;69:1015-1020. 
 
16. 
Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for leukemia following a 
new busulfan and cyclophosphamide regimen.  Blood 1987;70: 1382-1388. 
 
17. 
Clift RA, Buckner CD, Appelbaum FR, et al.  Allogeneic marrow transplantation in patients 
with acute myeloid leukemia in first remission: A randomized trial of two irradiation 
regimens.  Blood 1990;76: 1867-1871. 
 
18. 
Santos GW, Tutschka PJ, Brookmeyer R, et al.  Marrow transplantation for acute 
nonlymphocytic leukemia after treatment with busulfan and cyclosphosphamide. N Engl J 
Med 1983;309:1347-1353. 
 
19. 
Brown RA, Wolff SN, Fay JW, et al. High-dose etoposide, cyclophosphamide, and total 
body irradiation with allogeneic bone marrow transplantation for patients with acute 
myeloid leukemia in untreated first relapse:  A study by the North American Marrow 
Transplant Group.  Blood 1995;85:1391-1395. 
 
20. 
Demirer T, Buckner CD, Appelbaum FR, et al.  Busulfan, cyclophosphamide and 
fractionated total body irradiation for allogeneic marrow transplantation in advanced acute 
and chronic myelogenous leukemia: Phase I dose escalation of busulfan based on 
targeted plasma levels. Bone Marrow Transplant 1996;17:341-346. 
 
21. 
Snyder DS, Chao NJ, Amylon MD, et al.  Fractionated total body irradiation and high-dose 
etoposide  as a preparatory regimen for bone marrow transplantation for 99 patients with 
acute leukemia in first complete remission.  Blood 1993;82:2920-2928. 
 
22. 
Blume KG, Kopecky KJ, Henslee-Downey JP, et al.  A prospective randomized 
comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as 
preparatory regimens for bone marrow transplantation in patients with leukemia who were 
not in first remission: A Southwest Oncology Group study. Blood 1993; 81:2187-2193. 
 
23. 
Linker CA, Ries CA, Damon LE, Rugo HS, Wolff JL.  Autologous  bone marrow 
transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative 
regimen.  Blood 1993; 81: 311-318. 
 
24. 
Chao NJ, Stein AS, Long GD et al.  Busulfan/Etoposide-Initial experience with a new 
preparatory regimen for autologous bone marrow transplantation in patients with acute 
non-lymphoblastic leukemia.  Blood 1993; 81: 319-323.  
 
25. 
Kashyap, S.J. Forman, P. Cagnoni, H. Fernandez, W. Hu, V. Gian, J. Wingard, S. 
Tarantolo, B.S. Andersson. (1998) Intravenous Busulfan (Busulfex™)/Cytoxan (CY) 
Preparative Regimen for Allogeneic (ALLO) and Autologous (AUTO) Hematopoietic Stem 
Cell Transplantation (BMT) is well Tolerated by Patients Over 50 Years of Age. ASH, 
December 1998, Miami Beach 
 
26. 
W.P. Vaughan, P. Cagnoni, H. Fernandez, W. Hu, A. Kashyap, V. Gian*, J. Wingard, S. 
Tarantolo, B.S. Andersson (1998) Decreased Incidence of and Risk Factors for Hepatic 

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22
Veno-Occlusive Disease with an Intravenous Busulfan (BU) Containing Preparative 
Regimen for  Hematopoietic Stem Cell  Transplantation (HSCT). ASH, December 1998, 
Miami Beach 
 
27. 
B.S. Andersson, K. McWilliams, H. Tran, H. Fernandez, P. Cagnoni, R. Jones, V. Gian, S. 
Tarantolo, A. Kashyap, S.J. Forman, WW Hu, KG Blume, R.E. Champlin (1998) IV 
Busulfan, Cyclosphosphamide (Bu/Cy) and Allogeneic Hemopoietic Stem Cells (BMT) for 
Chronic Myeloid Leukemia (CML), ASH, December 1998, Miami Beach 
   
28. 
Vaughan WP, Soong S, Cagnoni P, Fernandez H, et al.  Body surface area (BSA) Dosing 
using actual body weight (ABW) yields less variation in Area under the concentration x 
time curve (AUC) for high dose I/V Busulfan  (Bu) than BSA dosing using ideal body 
weight (IBW), Adjusted ideal body weight (AIBW) or dosing using ABW, IBW or AIBW 
directly. 
 
ASCO, 
May 
15- 
19, 
1999

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APPENDIX I 
IV BUSULFAN KINETICS FORM  
 
IRB#:  ______________________ 
 
 
DATE: ______________________  (CIRCLE WEIGHT USED) 
PATIENT ___________________  
 
 
DOSE #_____________________   Actual Body Weight ________ 
Medical Record #_____________ 
 
 
Start time: ___________________   Ideal Body Weight _________ 
MD/Pager # _________________ 
 
 
Stop Time: ___________________  Adjusted IBW _____________ 
Coordinator/Pager #___________ 
 
    
DOSE: ____________mg 
 
INFUSION TO RUN OVER 2 HOURS 
Tube # 
Collection Schedule 
Proposed Collection Time 
Actual Collection Time 
1 
Immediately prior to beginning of infusion 
APPROX. 0555 
 
2 
Immediately prior to end of infusion 
APPROX. 0755 
 
3 
15 minutes post infusion 
APPROX. 0815 
 
4 
30 minutes post infusion 
APPROX. 0830 
 
5 
60 minutes post infusion (1 hour) 
APPROX. 0900 
 
6 
180 minutes post infusion (3 hours) 
APPROX. 1100 
 
7 
240 minutes post infusion (4 hours) 
APPROX. 1200 
 
 
 
 
 
 
 
 
 
** ALL samples to be obtained in 7cc green top tubes (Sodium Heparin) and kept on ice at Nurses Station. 
Then send to Clinical Pathology. 
RN SIGNATURE _________________________________ 
 
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Appendix II 
 
FRACTIONATED TOTAL BODY IRRADIATION SCHEMA 
Session 
Day 
Time 
Beam 
Direction 
Energy (MeV) 
Dose (rads) 
Notes 
 
1 
-7 
0730 
AP 
AP 
8/10X 
Electron 
120 
TLD 
Testes male 
(ALL only) 
2 
-7 
1200 
AP 
Electron 
400 
TLD 
3 
-7 
1630 
PA 
8/10X 
120 
 
4 
-6 
0730 
AP 
8/10X 
120+ 
(PA Chestwall 
Boost) 300 
5 
-6 
1200 
PA 
8/10X 
120+ 
(AP Chestwall 
Boost) 300 
6 
-6 
1630 
AP 
8/10X 
120 
 
7 
-5 
0730 
AP 
AP 
8/10X 
electron 
120 
300 
 
Chest wall boost 
8 
-5 
1200 
PA 
8/10X 
120+ 
(PA Chestwall 
Boost –300) 
9 
-5 
1630 
PA 
8/10X 
120 
 
10 
-4 
0730 
PA 
8/10X 
120 
 
 
Photon dose is calculated at mid-depth, central axis.  Electron chest wall dose is calculated 
at 90% isodose level, where electron energy is selected to place 90% isodose level at 
pleural surface.  At the first AP and PA sessions for total body irradiation, portal films with 
the treatment beam will be obtained prior to treatment to assure proper lung block 
placement.  The x-ray total body irradiation dose given during portal film will be subtracted 
from the total dose planned for that session.  Subsequent placement of lung blocks at the 
remaining sessions will be documented by verification films obtained during the actual 
treatment.  
 
During the first AP and PA sessions for total body irradiation, the radiation dose received by 
the patient will be monitored by means of thermoluminescent dosimeters placed on the 
anterior surface of the patient’s skin at the following anatomic locations: forehead, supra-
sternal notch, xiphoid process, umbilicus, pelvis, mid-thigh, knee, mid-calf, and ankle.  The 
midline dose to the patient can be calculated from the sum of entrance and exit doses 
recorded by the thermoluminescent dosimeter.  If  thermoluminescent dosimeter indicates a 
deviation of greater than + 10% in the planned dose, either the compensating filter, the 
machine monitor units, or both may be modified for subsequent sessions.  
 
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Appendix III 
 
1). 
G-CSF Administration to Donors:  All donors will receive G-CSF 10 µg/kg/day for 6 
consecutive days from day –5 to day 0.  G-CSF will be administered by a 
subcutaneous injection daily beginning 5 days prior to day 0 (defined as the day 
marrow would ordinarily be given).   
 
2). 
PBSC Collection:  Donors may undergo vein to vein collections or may receive an 
appropriate catheter inserted on or before day of the treatment regimen.  Donors will 
receive -5 daily doses of G-CSF, 10µg/kg/day by subcutaneous injection 
commencing on day –5.  These doses will be administered each day in the 
Outpatient Department or at home. 
 
Treatment Schema for Donor 
Days 
-5 
-4 
-3 
-2 
-1 
0 
G-CSF 10µg/kg/SQ 
X 
X 
X 
X 
X 
 
PBSC Collection 
 
 
 
 
X 
X 
 
 
PBSC’s will be collected in the afternoon of day -1 and reinfused on day 0.  *If the 
collection on day -1 contains less than 5.0 x 106 CD34+ cells per kg recipient weight, 
a second collection will be performed the following morning and transfused on day 0.  
 
 
If PBSC’s cannot be collected by a vein to vein technique, a percutaneous Mahurkar 
catheter will be inserted. 
 
 
General procedures will include the use of a standard apheresis machined (COBE 
Spectra, Lakewood Colo.), and processing up to 16 l of whole blood during the 
collection.  (Refer to Standard Practice Manual for collection procedure).  
 
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APPENDIX IV 
 
Acute Graft Versus Host Disease Staging and Grading Table 
 
Clinical Stage of acute GVHD according to Organ System 
 
Stage 
Skin 
Liver 
Intestine 
+ 
Maculopapular rash <25% of 
body surface 
Bilirubin 2-3mg/dl 
>500-1000 ml diarrhea per 
day or (nausea, anorexia or 
vomiting with biopsy (EGD) 
confirmation of upper GI 
GVHD 
++ 
Maculopapular rash 25-50% 
of body surface 
Bilirubin 3-6mg/dl 
>1000-1500 ml diarrhea per 
day 
+++ 
Maculopapular rash >50% 
body surface area or 
Generalized erythroderma 
Bilirubin 6-15mg/dl 
>1500 ml diarrhea per day 
++++ 
Generalized erythroderma 
with bullous formation and 
desquamation 
Bilirubin >15mg/dl 
>1500 ml diarrhea per day 
plus severe abdominal pain 
with or without ileus 
 
 
Overall Clinical Grading of Severity of acute GVHD 
 
Grade 
Skin 
Liver 
GI 
I 
1-2 
0 
0 
IIA
0 
0 
1-3 
1-3 
3 
0-1 
1 
0-1 
1 
0 
1 
0-1 
1 
0-1 
0 
IIIA
0-3 
0-3 
0-3 
2-3 
0-3 
4B
0-2 
2-3 
0-3 
IVA
0-3 
4 
0-4 
0-4 
4 
0-4 
 
A. Grade II-IV GVHD with only single organ involvement should be biopsy confirmed. 
B. If Karnofsky performance status is < 30%, then Grade IV. 
 
 
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APPENDIX V 
 
Grading of Chronic Graft Versus Host Disease 
 
Definitions: 
 
Progressive: 
 
Direct continuation from preceding acute GVHD. 
 
Quiescent: 
 
Arising after complete resolution of acute GVHD. 
 
de Novo: 
 
No preceding GVHD. 
 
Subclinical disease: 
Characteristic pathology findings on both blind oral and skin biopsies in 
absence of clinical signs or symptoms. 
 
Clinical disease: 
Multi-organ clinical manifestations and positive skin and oral biopsies 
 
 
Limited cGVHD: 
Either or both of the following: 
 
1. 
Localized skin involvement 
2. 
Hepatic dysfunction due to cGVHD 
 
Extensive cGVHD: 
Either 
 
1. 
Generalized skin involvement 
2. 
Localized skin involvement and/or hepatic 
dysfunction due to chronic GVHD 
 
PLUS 
 
3. 
Liver histology showing chronic aggressive 
hepatitis, bridging necrosis or cirrhosis, OR 
4. 
Eye involvement with Schirmer’s test with less 
than 5 mm wetting, OR 
5. 
Positive lip biopsy 
6. 
Involvement of any other target organ 
 
 
Reference: 
Chronic Graft Versus Host Disease: Pathology, diagnosis, treatment and prognostic 
factors, BMT – Exp Hem Today 1988 
 
 
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28
APPENDIX VI 
HD Therapy/Transplant therapy  (All testing (except BM bx 4 weeks) has to be completed no more than 28 days prior to starting treatment) 
Required 
studies 
Pre 
adm
it 
Day 
-17 
Day 
-13 
Day 
 -12 
Day 
-11 
Day  
-10 
Day 
-9 
Day 
-8 
Day 
-7 
Day 
-6 
Day 
 -5 
Day 
–4 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
0 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
6 
Day 
7 
Day 
100 
Day 
180 
Yearly 
X 2 
years 
CBC,Diff, 
PLT++*
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sma- 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SMA-12 ++ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
X
X
X
X
X
X
MG ++ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
X
X
Hepatitis a,b,c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT,PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24hr Crea cl  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV,HSV/HZ
V  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
++CXR  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan  
Chest, ABD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LP see 6.1g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM asp, bx, 
cytogenetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dilantin level  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan levels 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XX
XX*
*
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilantin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
X
X
X
X
X
X
X
X
Busulfan 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X** 
FTBI 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X
 
 
 
 
 
 
 
 
 
 
 
 
VP-16 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X
 
 
 
 
 
 
 
 
 
 
 
PSC’s or BM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
CNS Disease 
patients   see 
section 6.53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
$ Dilantin will be given daily consecutively until day –14  
++ Every Monday, Wednesday, Friday during hospitalization, CXR to be done weekly 
XX blood sample shipment 
** If required
Rev. 11/8/01