Clinical trial NCT00540995
Conditions: Adult Acute Myeloid Leukemia in Remission Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Blastic Phase Chronic Myelogenous Leukemia Childhood Acute Myeloid Leukemia in Remission Childhood Chronic Myelogenous Leukemia Childhood Myelodysplastic Syndromes Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Myeloid Leukemia Refractory Anemia With Excess Blasts
Sponsor: City of Hope Medical Center
Start date: 2007-06-11; Completion date: 2011-08-09
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
RATIONALE: Giving chemotherapy drugs, such as busulfan and etoposide, and intensity-modulated radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving intensity-modulated radiation therapy together with busulfan and etoposide before a transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects and best dose of intensity-modulated radiation therapy when given together with busulfan and etoposide followed by a donor stem cell transplant and to see how well it works in treating patients with advanced myeloid cancer.

Detailed description:
OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of a large field image-guided IMRT, using helical tomotherapy, when given in combination with IV busulfan and VP-16 as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical sibling in patients with advanced myeloid malignancies. (Phase I) II. To describe the toxicities at each dose level studied. (Phase I) III. To estimate the radiation doses to the whole body, normal organs, and bone marrow through serial imaging studies following the administration of IMRT. (Phase I) IV. To estimate the overall survival probability, disease-free survival probability, and relapse rate associated with this preparative regimen. (Phase II) V. To characterize the treatment related mortality and toxicity profile (early/late) associated with this regimen. (Phase II) VI. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population conditioned with whole-body radiotherapy. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of intensity-modulated radiation therapy followed by a phase II study.

PREPARATIVE CHEMOTHERAPY: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive GVHD prophylaxis that excludes methotrexate.

After completion of study treatment, patients are followed periodically for 1 year and then annually for 2 years thereafter.

Arms: arm 1: 1200cGy = 150cGy x 8 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive GVHD prophylaxis that excludes methotrexate. arm 2: 1350cGy = 150cGy x 9 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5.
Interventions: intervention 1: busulfan intervention 2: etoposide intervention 3: intensity-modulated radiation therapy intervention 4: allogeneic hematopoietic stem cell transplantation intervention 5: allogeneic bone marrow transplantation intervention 6: peripheral blood stem cell transplantation intervention 7: tomotherapy
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Initially 150 cGy X 8 doses with gradual dose escalation to 200 cGy X 10 doses intervention 4: Stem cell transplantation occurs on Day 0 after High Dose Therapy intervention 5: Stem cell transplantation occurs on Day 0 after High Dose Therapy intervention 6: Stem cell transplantation occurs on Day 0 after High Dose Therapy intervention 7: Initially 150 cGy X 8 doses with gradual dose escalation to 200 cGy X 10 doses

Protocol documents:
Prot_SAP_000.pdf: 
IRB 05013 
 
06/29/11 
Packet: 14 
CITY OF HOPE 
1500 E. Duarte Road 
Duarte, CA 91010 
 
Department of Hematology and Hematopoietic Cell Transplantation 
 
TITLE: 
Phase I/II Study of Intravenous (IV) Busulfan and Etoposide (VP-16) Combined with Escalated Doses of Large 
Field Image-Guided Intensity Modulated Radiation Therapy (IMRT) using Helical Tomotherapy as a Preparative 
Regimen for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients with Advanced Myeloid 
Malignancies 
 
CITY OF HOPE PROTOCOL VERSION: 
IRB # 05013                  
Protocol Date: 06/29/11 
 
 
Amendment 01  
 
 
 
 
 
 
 
 
Version 01 
 
 
Amendment 02  
 
 
 
 
 
 
 
 
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Amendment 03  
 
 
 
 
 
 
 
 
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Amendment 04  
 
 
 
 
 
 
 
 
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Amendment 05  
 
 
Title Page dated 1/29/10 
 
 
Version 05 
 
 
Amendment 06  
 
 
Protocol Dated 07/29/2009 
 
 
Version 06 
 
 
Amendment 07  
 
 
Title Page dated 02/07/2011 
 
 
Version 07 
 
 
Amendment 08  
 
 
Protocol dated 5/23/11  
 
 
Version 08 
 
 
Amendment 09  
 
 
Protocol dated 6/29/11  
 
 
Version 09 
 
 
Amendment 10  
 
 
Title Page dated 01/15/13 
 
 
Version 10 
Amendment 11  
 
 
Title Page dated 09/25/13 
 
 
Version 11 
Amendment 12  
 
 
Title Page dated 06/30/16 
 
 
Version 12 
Amendment 13 at Continuation  
Title Page dated 06/23/17 
 
 
Version 13 
Amendment 14 at Continuation  
Protocol dated 06/29/11 (tp) 
 
 
Packet: 14 
 
 
HISTOLOGY:  
 
 
 
 
 
Myeloid Malignancies 
 
STAGE: 
 
 
 
 
 
 
Advanced  
MODALITY: 
 
 
 
 
 
 
Allogeneic BMT  
TYPE:  
 
 
 
 
 
 
Phase I/II 
 
Principal Investigator:  
 
 
 
 
Anthony Stein, M.D. 
 
 
Collaborating Investigators: 
 
 
 
 
 
Stephen J. Forman, M.D. 
 
 
 
 
 
 
 
 
Joycelynne Palmer, Ph.D. 
 
 
Participating Clinicians:   
 
 
 
 
Chatchada Karanes, M.D.,  
Amrita Krishnan, M.D., Ryotaro Nakamura, M.D.,  
Leslie Popplewell, M.D.,  
Ricardo Spielberger, M.D. 
Firoozeh Sahebi, M.D. 
Ji-Lian Cai, M.D., Len Farol, M.D., Nitya Nathwani M.D., 
Myo Htut, M.D., Samer Khaled, M.D., 
Tanya Siddiqi, M.D. 
 
Department of Medical Oncology: 
 
 
Warren Chow, M.D.  
 
 
 
 
 


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SCHEMA 
 
 
 
Thursday 
Friday 
Saturday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Monday 
Tuesday 
-19 
-18 
-17 
-16 
-15 
-14 
-13 
-12 
-11 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2^ 
-1 
0 
Dilantin x 3 doses (Day –19) then once per day x 14 days 
 
 
 
 
 
 
 
 
 
**Busulfan 
test dose 
#1 
 
**Busulfan 
test dose  
#2 
(as 
needed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Busulfan x 16 doses 
(including test doses) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMRT x 4-5 days* 
 
VP-
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSC/BM 
*: IMRT = Image-Guided Intensity Modulated Radiation Therapy 
 IMRT to begin on Monday and delivered over 4-5 days depending upon IMRT dose 
The start of IMRT can be delayed up to 24 hours to accommodate any holiday closures by the Department of Radiation. 
** When IMRT is given over 4 days (8 doses), Busulfan test dose #1 will start on Day -14, test dose #2, if needed, will be given 
on Day -12 and the remaining busulfan doses will be given starting on Day -11. 
** When IMRT is given over 5 days (>8 doses), Busulfan test dose #1 will start on Day -15, test dose #2 (if necessary) will be 
given on Day -13 and the remaining busulfan doses will be given starting on Day -12. 
^ If tacrolimus and sirolimus are used for GvHD prophylaxis, their administration will begin on Day -2. 
 
 


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TABLE OF CONTENTS 
 
 
Schema 
 
 
 
 
 
 
 
 
 
  2 
1.0 
Objectives 
 
 
 
 
 
 
 
 
 
  4  
2.0 
Background & Hypotheses  
 
 
 
 
 
 
  4 
3.0 
Drug Information 
 
 
 
 
 
 
 
 
10 
4.0 
Staging Criteria 
 
 
 
 
 
 
 
 
13 
5.0 
Eligibility Criteria 
 
 
 
 
 
 
 
 
14 
6.0 
Treatment Plan 
 
 
 
 
 
 
 
 
15 
7.0 
Study Design and Rules for Dose Escalation 
 
 
 
 
19 
8.0 
Study Calendar 
 
 
 
 
 
 
 
 
21 
9.0 
Criteria for Evaluation and Endpoint Definitions  
 
 
 
21 
10.0 Statistical Considerations  
 
 
 
 
 
 
23 
11.0 Registration Guidelines 
 
 
 
 
 
 
 
25 
12.0 Records to be Kept and Data Submission 
 
 
 
 
25 
13.0 Women and Minorities Guidelines 
 
 
 
 
 
25 
14.0 Data Management  
 
 
 
 
 
 
 
26 
15.0 Ethical and Regulatory Consideration 
 
 
 
 
 
26 
16.0 Data Safety Monitoring Plan 
 
 
 
 
 
 
27 
17.0 References  
 
 
 
 
 
 
 
 
29 
 
Appendix I 
IV Busulfan Kinetics Form  
 
 
 
 
32 
Appendix II 
Treatment Schema for Donors 
 
 
 
 
33 
Appendix III 
Acute GVHD Staging and Grading Table 
 
 
34 
Appendix IV 
Grading of Chronic GVHD  
 
 
 
 
35 
Appendix V 
Study Calendar 
 
 
 
 
 
 
36 
Appendix VI 
Common Toxicity Criteria (Version 3.0)  
 
 
37 
Appendix VII 
Guidelines for Reporting of Adverse Events 
 
 
38 
Appendix VIII 
Eligibility Checklist  
 
 
 
 
 
40 
Appendix IX 
Modified Bearman Scale 
 
 
 
 
 
42 
Appendix X 
Time Points to Grade Toxicities and Collect Data 
 
43 
Appendix XI 
Parameters for Targeted TBI 
 
 
 
 
44 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
OBJECTIVES 
This study will be initiated as a phase I trial in order to be certain that there are no unpredicted 
toxicities by the incorporation of intensity modulated radiation therapy (IMRT) with intravenous 
(IV) busulfan [targeted to AUC (area under curve) of 700-900] and etoposide (VP-16) as a 
preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Based on our 
evaluation of this treatments safety and feasibility, a phase II trial of 30 patients will be performed 
in subsequent years focused on overall survival, relapse-free survival, event-free survival, 
treatment related mortality, relapse and toxicity. Early stopping rules will be incorporated into the 
phase II portion for safety, however, there will be no early stopping based on efficacy.  
The objectives of the phase I portion of this study are: 
 
1.1 
To establish the maximum tolerated dose (MTD) of large field image-guided IMRT, using 
helical tomotherapy, when given in combination with IV busulfan and VP-16 as a 
preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) from an 
HLA-identical sibling in patients with:  
 
advanced myeloid malignancies with a disease status of >2nd remission, 
induction failure, or relapse  
 
chronic myeloid leukemia in blast crisis 
 
myelodysplasia, refractory anemia with excess blasts (RAEB). 
 
1.2 
To describe the toxicities at each dose level studied. 
 
1.3 
To estimate the radiation doses to the whole body, normal organs, and bone marrow 
through serial imaging studies following the administration of IMRT. 
The objectives of the phase II portion of the study are: 
1.4 
To estimate the overall survival probability, disease free survival probability, and relapse 
rate associated with this preparative regimen. 
 
1.5 
To characterize the treatment related mortality and toxicity profile (early/late) associated 
with this regimen.  
 
1.6 
To descriptively compare the outcomes of patients treated on this protocol to a 
comparable patient population conditioned with whole body radiation. 
2.0 
BACKGROUND AND HYPOTHESES 
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 myeloid leukemia and chronic myeloid leukemia.  If the 
transplant procedure is performed in first complete remission/chronic phase of acute 
leukemia/chronic myeloid 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 myeloid 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 


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transplant centers have performed several phase I-II trials of preparative regimens using 
alternative chemotherapeutic agents or methods of administering total body irradiation 
(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, cyclophosphamide 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 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 allogeneic bone marrow transplant (ABMT) for AML in first and 
second remission.(23,24)  The dose limiting toxicity (DLT) occurred at 12mg/kg the maximum 
total dose (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 intravenous (IV) busulfan was conducted at City of Hope which 
has resulted in Food and Drug Administration (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) 
 
At City of Hope 15 patients with poor risk acute myeloid leukemia have been treated with 
allogeneic HSCT utilizing targeted Busulfan/FTBI and VP-16 as conditioning regimen and 
Mycophenolate + Cyclosporin for graft versus host disease (GVHD) prophylaxis between 
1999 and December 2003.  The disease free survival and probability of relapse at 18 
months is 50% and 20%, respectively.  The non-relapse mortality from infectious causes 
and chronic GVHD is 24%.  Most patients treated on the protocol developed significant 
mucositis and gastrointestinal toxicity. 
 
2.1 
Rationale for Increasing Dose of Radiation 
 


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Two randomized and one large non-randomized trial, have explored the importance of 
radiation dose on post transplant relapse rates.  In total, 71 patients with Acute Myeloid 
Leukemia (AML) in first remission were treated with cyclophosphamide and either 12 Gy 
(n=34) or 15.75 Gy (n=37) of TBI followed by HLA-matched sibling transplantation and 
methotrexate and cyclosporine as GVHD prophylaxis.  The relapse rate in the group 
receiving the lower TBI dose was 35% compared to 12% with the higher TBI dose 
(P=0.06)29.  In a similar prospective randomized trial in patients with chronic myeloid 
leukemia (CML) in chronic phase, the relapse rate in the 57 patients treated with the lower 
TBI dose was 25% compared to 0% in the 59 recipients of the higher TBI dose 
(P=0.008)30.  In both studies, non-relapse mortality was higher with the higher TBI dose, 
thus balancing the reduction in relapse rates, with a result that in neither study overall 
survival was improved. 
 
Marks et al recently analyzed the outcome of 502 patients reported to the International 
Bone Marrow Transplant Registry (IBMTR) following matched sibling transplantation for 
acute lymphoblastic leukemia (ALL) in first and second remission.  They concluded that 
the TBI dose was the most significant factor they could identify for predicting relapse rates.  
Doses of TBI in excess of 13 Gy resulted in 40% reduction in the chance of relapse 
(P=0.01), and also translated into a 37% reduction in the risk of death31. 
 
2.2 
Rationale for Large Field Image-Guided Intensity Modulated Radiation Therapy (IMRT) 
 
Rapid advances in computer and medical imaging technologies have resulted in the ability 
to deliver radiotherapy with greater precision and conformality. External beam 
radiotherapy has traditionally relied on radiologic imaging to direct therapy to appropriate 
anatomic regions.  The integration of computerized tomography (CT) imaging into 
radiation treatment planning, allows for a three dimensional (3D) view of each patient’s 
tumor relative to dose-limiting adjacent normal organs, allowing for customized beam 
shaping, beam orientation and dose conformality. The use of 3D conformal radiotherapy 
allows for further escalation of dose, which has resulted in higher tumor control, while 
maintaining risks and side effects at acceptable levels. 
 
Intensity modulated radiation therapy (IMRT) has opened a new era in radiation oncology.  
By delivering therapy from multiple directions using multiple segmented or modulated 
beamlets, one can now sculpt radiation doses to fit the unique shape of each patient’s 
tumor, optimizing radiation delivery to complex volumes and regions of the body.  Some 
compare IMRT to “painting” radiation with a finer brush, where more precise, conformal 
and sophisticated dose patterns are now possible.  This has also resulted in a greater 
degree of conformal dose avoidance of adjacent normal organs.  Dose escalation is now 
possible with IMRT, which was not possible with technology just a decade ago.  For 
example, radiation doses for prostate cancer, which have been limited to approximately 
7000 cGy with conventional technologies, are now >8000cGy using IMRT.  As a result, a 
significant improvement in tumor control and a reduction in bladder and rectal toxicities 
have been reported.(32) 
 
Helical tomotherapy (HT) represents a convergence of technological advances in CT 
image-guided radiation therapy (RT) and IMRT. HT is a FDA approved radiation therapy 
delivery device, which is a marriage of spiral CT and IMRT technology.  Specifically, a 6 
MV linear accelerator is mounted on a CT ring gantry and rotates around the patient as 
the patient translates through the ring.  The treatment fan beam is segmented using a 64-
leaf collimator.  Each leaf casts a 0.6 mm width shadow at 85 cm isocenter distance with 


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the fan beam, which varies in width (slice thickness) from 0.5 to 5cm.  The minimum voxel 
or beamlet size is therefore 5 x 6 mm.  The maximum couch length is 160 cm. Therefore 
the maximum target size is up to 40 cm wide by 160 cm long. By rapid opening and 
closing of leaves as a function of gantry angle while the patient slides trough the ring, 
helical tomotherapy provides unprecedented ability to sculpt radiation doses to large 
complex shaped target regions while simultaneously avoiding dose to normal organs.(33,34)  
Grigorov et al.(35) evaluating HT treatment plans for prostate cancer, demonstrated rapid 
drop-off of dose around the target (prostate gland) in all directions resulting in excellent 
sparing of rectum, bladder and femoral heads superior to prior IMRT techniques.  
Scrimger et al(36) predicted that for select patients with lung cancer, tumor doses as high 
as 16,000 cGy will be achievable while maintaining normal lung doses (and therefore 
risks) at comparable levels as with conventional delivery methods, which are limited to 
doses of 6,000 cGy to the tumor in most patients.  
 
In addition, an array of detectors mounted on the same rotating gantry and positioned 
directly opposed to the beam source, gives the HT delivery system two unique capabilities 
not found on any other delivery systems.  First, these detectors allow for the generation of 
megavoltage CT (MVCT) images using the 6 MV beam.  Resolution and contrast of MVCT 
is more than adequate to easily distinguish tissue planes and organ boundaries.(33)  This 
allows the HT system to automatically align beam orientation to anatomic external 
landmarks and internal organs in 3 dimensions prior to each daily session, improving the 
precision of radiation delivery.  Second, these same arrays can be used to monitor output 
of the beam as it exits through the patient, providing an additional level of dose verification 
in 3 dimensions.  In the future, it is anticipated that future software and hardware 
modifications will allow for this type of ‘adaptive radiotherapy’ to occur in real time, 
constantly modulating beam output to account for minute-by-minute variations in tumor 
and organ motion and delivered dose. 
 
The advent of HT brings for the first time to the clinic the potential to deliver highly 
conforming dose distributions to large complex target shapes.  For example, with HT 
shaping the dose to the entire pleural surface, while sparing lung parenchyma is now 
possible for patients with mesothelioma. At the City of Hope (COH), TBI is often used as 
part of the preparatory regimen for many patients undergoing bone marrow transplants.  
Although TBI will effectively treat the target region which includes the marrow space and, 
in some patients, extramedullary hematopoietic sites, such as spleen and lymph nodes, 
TBI also delivers the same dose to all other normal organs resulting in dose-limiting 
toxicity, such as nauseas and vomiting, mucositis and pneumonitis. Working with 
collaborators at the University of Wisconsin and Tomotherapy, Inc. (manufacturers of HT), 
we have recently evaluated the feasibility of delivering conformal radiation doses to just 
the skeletal bone containing the marrow spaces as a possible alternative to TBI.  Total 
marrow irradiation (TMI) using HT would dramatically reduce dose to normal tissues, 
reducing short-term and long-term toxicities.  Using whole body CT images captured on 
the COH Radiation Oncology Picker CT treatment planning system, normal organs and 
target skeletal bone compartments were contoured.  After defining appropriate target and 
organ dose constraints, inverse planning using the HT planning station was used to 
generate dose distributions and dose volume histograms. 
 
 
 
 
 


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An example of TMI dose distribution plan is shown in the following figure: 
 
 
High dose
Low dose
Breast 
Lung & Heart
Brain
GI tract
Pharynx & Thyroid
 
 
 
In this example the prescribed dose is 12.0 cGy, which will take an estimated 23 minutes 
to deliver by HT.  Demonstrated is conformality of the dose to the skeletal bone and a 
significant reduction in dose to normal organs, such as brain, oral cavity, oropharynx, lung, 
heart, soft tissue and gastrointestinal (GI) tract.   
 
The prescription dose to the target volume will be prescribed to cover 85% of the target 
volume. 
 
 
 
 
 
 
 
 
 
 


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Recently studies have been performed using the COH tomotherapy treatment planning 
system to perform comparative dose and dose-volume histogram studies for the following 
scenarios: 1) 1320 cGy TMI (total marrow or skeletal bone IMRT); 2) 1320 cGy TMLI (TMI 
+ liver, spleen, and sanctuary sites such as brain also as target regions); 3) 1580 cGy 
TMLI; and 4) 2000 cGy TMLI (2000 cGy TMI + liver, spleen, sanctuary sites, rib cage and 
skull at 1200 cGy). For the last scenario, the rib and skull bones were kept at 12 Gy to 
allow for greater dose uniformity within the immediately adjacent liver, spleen and brain.  
The graph below compares the median doses to normal organs, which are all substantially 
lower than conventional TBI. Also shown for comparison are dose-volume histograms for 
lung for scenarios 1,3 and 4.  For each scenario of dose escalation lung DVHs are to the 
left of the DVH for conventional TBI predicting for lower risk of pneumonitis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lungs
Esophagus
Kidneys
Bowel
Bladder
Eyes
Parotids
Oral Cavity
Stomach
Ovaries
Breasts
Heart
Thyroid
Lens
0
2
4
6
8
10
12
14
Median Dose (Gy)
TMI 13.2 Gy
TMLI 13.2 Gy
TMI 15.8 Gy + TLI/liver/spleen/brain 13.2 Gy
TBI 1320


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Such dose sparing or conformal dose avoidance of normal tissues should result in 
clinically important reductions in acute toxicities and potential to reductions in long-term 
complications such as hypothyroidism, pneumonitis, second malignancy induction, and, in 
the pediatric population, effects on growth and development.  Finally, reduced morbidities 
should allow for escalation of the dose to the target compartment to levels not achievable 
with conventional TBI, which has the potential of increasing control rates. The starting 
TMLI dose level will be 1200 cGy at 150 cGy per fraction BID with a minimum 6-hour 
interval between fractions.  The TMLI dose will be increased to 1350 (150 x 9), 1500 (150 
x 10), 1750 (175 x 10) and 2000 (200 x 10) cGy.  Conformal avoidance of dose is planned 
for the following organs:  lung, kidneys, heart, thyroid gland, oral cavity, oropharynx, lens, 
GI tract, breasts, esophagus, and parotids. The ribs, liver and spleen dose of TMLI will be 
fixed at 1200 cGy. 
 
 
3.0 
DRUG INFORMATION 
 
3.1 
Busulfan (Myleran) 
Lungs
0
10
20
30
40
50
60
70
80
90
100
0
2
4
6
8
10
12
14
16
Dose (Gy)
TMI 15.8Gy TLI+L+S+B 13.2Gy
Lt Lung
TMI 15.8Gy TLI+L+S+B 13.2Gy
Rt Lung
TBI Lt Lung 13.2Gy
TBI Rt Lung 13.2Gy
Lungs
0
10
20
30
40
50
60
70
80
90
100
0
2
4
6
8
10
12
14
16
Dose (Gy)
TMLI 20 / 12Gy Lt Lung
TMLI 20 / 12Gy Rt Lung
TBI 12 Gy Lt Lung
TBI 12 Gy Rt Lung


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3.11 
Mechanism of Action: Busulfan is a bi-functional 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. 
 
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 IV push or bolus. 
 
3.14 
Supplier: This drug is commercially available. This drug is manufactured by  
 
Orphan Medical Inc. 
 
3.15           Toxicity: Toxicities from busulfan include: 
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 
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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, 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.   
 


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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. 
 
3.28 
Supplier: VP-16 is commercially available. 
 
 
4.0 
STAGING CRITERIA: 
 
4.1 
Definition of Disease Phases in Chronic Myeloid 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. 
White blood count (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. 
 
 8. 
Additional chromosome changes (evolving new clone). 
 
 9. 
Increasing splenomegaly unresponsive to conventional doses of hydroxyurea or 
busulfan. 
 


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 10. 
Development of chloromas or myelofibrosis. 
 11. 
Patients in a second (or subsequent) chronic phase after blast crisis.  
 Blastic Phase/Blast Crisis 
 1. 
> 30% blasts plus promyelocytes in the blood or bone marrow. 
5.0 
ELIGIBILITY CRITERIA 
5.1 Inclusion Criteria 
 
5.1.1 Patients with the following diagnoses are eligible for this study:  
 
advanced myeloid malignancies with a disease status of >2nd remission, 
induction failure, or relapse  
 
chronic myeloid leukemia in blast crisis 
 
myelodysplasia, subtype: refractory anemia with excess blasts (RAEB) 
 
5.1.2 All candidates for this study must have a HLA (A, B, C, DR) identical sibling who is 
willing to donate bone marrow or primed blood stem cells or a 10/10 allele matched 
unrelated donor or minor mismatches as per BMT SOP that allows Tacrolimus and 
Sirolimus to be given for GVH prophylaxis.  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). 
5.1.3 Prior therapy with VP-16, busulfan, hydrea and gleevec are allowed. 
5.1.4 Patients must be older than 6 years and the upper age limit for this study is 55 
years. 
5.1.5 A cardiac evaluation with electrocardiogram and MUGA or echocardiogram is 
required for 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. 
5.1.9 Time from the end of last induction or reinduction attempt should be greater than or 
equal to 21 days.   
5.1.10 A signed (IRB approved) informed consent document is required. The patient, 
donor family member, and transplant team (physician, nurse, and social worker) 
meet together at least once prior to starting the transplant procedure to review all 


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pertinent risk/benefit information as part of the consenting process. Alternative 
treatment modalities are also discussed at this meeting. 
 
 
5.2 
Exclusion Criteria 
 
5.2.1 Prior radiation therapy/exposure that prevents the patient from receiving IMRT. 
(Determination will be made by the Radiation Oncologist.) 
 
5.2.2 Patients who have previously undergone a blood/marrow transplant and now have 
relapsed disease. 
 
5.2.3 Patients with a psychological or medical condition that the treating physician 
deems unacceptable to proceed to allogeneic bone marrow transplant.   
 
5.2.4 Pregnancy 
 
5.2.5 EKG showing ischemic changes or abnormal rhythm and echocardiogram showing 
ejection fraction <50% or abnormal wall motion. 
 
5.3 
Donor Inclusion/Exclusion Criteria 
 
5.3.1 Any sibling donor who is histocompatible with the prospective recipient will be 
considered 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).  Complete blood count (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 
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 carbon dioxide, 
BUN, creatinine, Ca, Mg, Phosphorous, total bilirubin, total protein, 
albumin, SGPT, SGOT, LDH, alkaline phosphatase, glucose.  
iii. 
Urine analysis 
HIV test 


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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 electrocardiogram (EKG) 
vi. 
CT scan of chest, abdomen and pelvis. 
vii. 
Pregnancy test 
c. 
Initial coagulation studies prothrombin time, APTT. 
d. 
MUGA scan or echocardiogram 
e. 
Pulmonary function tests, including DLCO 
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). 
g. 
Patients with acute leukemia or chronic myeloid 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 central nervous system (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 patient’s platelet count can be kept above 75,000.   
 
6.2   
Preparative Chemotherapy Regimen 
(Note: Patient to sign consent form before starting Dilantin.) 
 
Thursday/Day -19 
Begin dilantin 300mg/p.o. t.i.d. times 1 day, then 
300mg/p.o./IV daily times 14 days. 
Monday/Day -15 
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 6:00 to 8:00 a.m. as a single dose.  
The IV dose is calculated as follows: 
 
 
1. 
Body surface area (BSA) is calculated by the 
equation: 
 
BSA= (Actual body wt. (kg) x height (cm) 
 
 
 
 
 
 
 
                                3600 
 
2. 
22mg/m2 IV Busulfan will be given over 2 hours.  
Blood levels will be obtained with the first dose as per 
appendix 1 and will be performed per current 
Hematopoietic Cell Transplant Program Clinical 
Manual of Standard Operating Procedures. 
 


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Tuesday/Day -14 
Busulfan AUC will be calculated per current Hematopoietic Cell 
Transplant Program Clinical Manual of Standard Operating 
Procedures.  The resulting AUC will be used to determine 
the dose required to achieve an AUC of 800 μM* min 
according to the following formula: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
Wednesday/Day -13 
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.  
 
Thursday/Day -12 
Patient admitted to Bone Marrow Transplant (BMT) unit or 
receive further dose of Busulfan in clinic.   
 
Busulfan dosing restarted at 12-noon if only one test dose of 
busulfan administered and at 6 p.m. if two doses 
administered.  The adjusted dose is repeated every 6 hours 
for a total of 16 doses (including the test doses). 
 
Monday/Day -8 
See Section 6.5 for treatment planning and delivery of total 
marrow and lymphoid irradiation. 
 
Saturday/Day -3 
VP-16 30mg/kg based on adjusted ideal body weight will be 
administered. 
  
 
Tuesday/Day 0 
 
PSC reinfusion/or BM infusion 
 
 
PSC Collection as per current Hematopoietic Cell Transplant Program Clinical Manual of 
Standard Operating Procedures. 
 
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 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 
Graft Versus Host Disease (GVHD) Prophylaxis and Treatment 
 
6.31 
GVH prophylaxis regimen will consist of the best available regimen excluding 
methotrexate. 
 
 
 
 
    800μMx min 
Adj dose =  Current dose   x  
 
 
 
 
    test dose AUC 


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6.32 
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. 
 
6.33 
Graft-versus-host disease will be graded according to previously defined criteria 
(Appendix III, IV).  
 
6.4 
Supportive Care will be given as per current Hematopoietic Cell Transplant Program 
Clinical Manual of Standard Operating Procedures. 
 
6.5 
Treatment Planning and Delivery of Total Marrow and Lymphoid Irradiation (TMLI). 
 
6.5.1. TMLI will be delivered using Helical Tomotherapy.  Tomotherapy is an image-
guided IMRT delivery device and is the only device currently capable of delivering 
the proposed TMLI radiation therapy.  Therefore, for this trial all patients will be 
treated using the Tomotherapy system.  In addition, all treatment planning will take 
place on the Tomotherapy HiArt treatment planning system. 
 
6.5.2. Simulation.  All patients will undergo CT simulation with scanning from the top of 
the scalp to the level of the distal femurs.  Prior to simulation, the patients will be 
fitted for an immobilization cast they will be treated in.  Aquaplast facemask will be 
utilized for head positioning.  A full-body immobilization cast will also be used 
(Vaclok).  CT scans will be acquired at full inspiration, full expiration, and mid-
inspiration. 
 
6.5.3. Treatment Planning.  Treatment planning will take place on the Tomotherapy HiArt 
treatment planning system.  The following organs will be contoured: lungs, heart, 
small and large intestine, kidneys, orbits, lenses, oral cavity, bladder, parotid 
glands, stomach, ovaries (if clipped for localization), testes, liver, spleen, 
esophagus, bone, and major lymph node chains.  The target regions will include 
the bone, major lymph node chains, liver, spleen, testes, and brain.  All other 
contoured organs will be treated as avoidance structures.  Contouring for lungs, 
spleen, and kidneys will take into account organ position as full inspiration, full 
expiration, and mid-inspiration.  The bone compartment will be contoured such that 
the entire ribcage bilaterally will be contoured as a separate region of interest.  The 
skull will also be contoured as a separate region of interest.  The gross tumor 
volume (GTV) will be the planning tumor volume (PTV).  It is recommended that 
the treatment planning use a 25 mm slice thickness and a pitch of a least 0.35.  A 
minimum of 80% of the targeted region is to receive the prescribed dose with a 
primary objective being to reduce the median dose (D50) and maximum dose of 
which 90% of the organ receives (D90) to a minimum.  The table below provides 
guidelines for treatment planning parameters. 
 
6.5.4. Delivery of Treatment Fraction.  Patient is positioned on the treatment couch in the 
immobilization device with Aquaplast head mask in place.  Treatment is delivered 
on the Tomotherapy unit in the cranial causes direction (Patient travels through the 
Tomotherapy unit head first).  Prior to delivery of therapy, a mega voltage CT 
(MVCT) scan is performed on the Tomotherapy unit.  It is recommended that 
scanning be over a segment of at least 5 cm, and the initial scans in the head 
region travel through the entire orbital and oral cavity regions.  The MVCT is then 


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aligned with the treatment planning kilovoltage CT (KVCT) scan using the 
Tomotherapy system.  Therapy then commences treating from the top of the scalp 
to approximately the sternal notch.  At that point in time, a second MVCT is 
obtained thru the level of the kidneys.  Alignment of MVCT to KVCT again occurs 
and treatment of the rest of the upper torso and abdomen and pelvic regions is 
accomplished.  If deemed appropriate by the M.D., the physicist and/or radiation 
therapist, a third MVCT scan may be acquired through the pelvic region prior to 
treating through the pelvis. 
 
The Tomotherapy TMLI inferior border will be clearly identified and marked 
(tattooed) prior to start of therapy.  This marked inferior border of the TMLI field will 
serve as the “matchline” for matching the AP and PA lower extremity fields used to 
treat the distal femur and rest of the distal lower extremities.  The AP ad PA fields 
will treat the lower extremities through equally weighted opposed AP/PA fields to 
the same dose as the TMI fraction and be prescribed to midplane. 
 
6.5.5. The Phase 1 portion of this study will escalate the dose of TMLI through five 
planned dose levels as described in the section 7.0.  For patients receiving two 
fractions on the same day, there must be a minimum of six hours between 
fractions. 
 
As dose is escalated to the TMI target region, the ribs, liver, spleen, brain and skull 
will be fixed at 12 Gy (See Appendix XII). 
7.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION 
This is a single center phase I/II trial that consists of dose escalation (phase I portion), 
followed by expanded enrollment at the MTD (phase II portion). Registration and 
assignment to the dose level will be done at City of Hope (see section 11.0). The rules for 
dose escalation, dose expansion and termination of escalation are given in sections 7.1 
and 7.2. Study design considerations and targeted response rates for the phase II portion 
of the trial are given in sections 10.2-10.4. 
 
The goal of the phase I study is to evaluate the toxicity results for the combination of 
intensity modulated radiation therapy (IMRT) with IV busulfan [targeted to AUC (area 
under curve) of 700-900] and VP-16 as a preparative regimen for hematopoietic stem cell 
transplantation from an HLA-identical sibling or HLA-fully-matched unrelated donor. For 
the phase I portion of the study, the assessment will be done in two strata: 
 
 
Stratum 1: Adult patients ( 18 years, 
55 years) with advanced myeloid 
malignancies or high-risk myelodysplasia. 
 
Stratum 2: Pediatric patients (6-17 years) with advanced myeloid malignancies or 
high-risk myelodysplasia. 
The primary endpoint for the phase I portion of the study is the determination of the MTD 
in five doses to be tested in each of the above stratum.  
 
`


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7.1 
Dose limiting toxicity (DLT) 
 
 
 
Toxicities will be recorded using two distinct grading systems; the modified Bearman Scale 
(Bearman, S., et al, JCO, Vol 6, No 10 (Oct), 1988, pp1562-1568. See appendix X for 
details.) and the NCI CTCAE 3.0 Scale.  
 
 
 
Generally, the modified Bearman Scale will be used to define DLT events and the CTCAE 
3.0 Scale will be used for reporting adverse events. The only exceptions relate to defining 
hematologic DLT events, for this the CTCAE 3.0 Scale will be used, and for capturing 
veno-occlusive disease (VOD), for this the CTCAE 2.0 Scale will be used. (The NCI 
CTCAE 3.0 and 2.0 can be found at http://ctep.cancer.gov/reporting/ctc.html.) To be 
evaluable for toxicity, a patient must start treatment and be observed for at least 30 days 
following the completion of the transplant procedure or have experienced DLT. All patients 
who are not evaluable for toxicity will be replaced. No dose escalation will occur until DLT 
evaluations are complete for all patients on a dose level.  
 
 
As mentioned dose limiting toxicities (DLTs) will be graded according to the modified 
Bearman Scale. Dose limiting toxicity (DLT) in a given patient is defined as: any grade 3 or 
4 toxicity per the modified Bearman Scale (appendix X). Hematologic DLT is defined as: 
grade 4 neutropenia associated with fever or infection and lasting beyond three weeks, or 
grade 4 neutropenia lasting for more than 28 days per CTCAE 3.0 toxicity criteria. 
 
The maximum tolerated dose (MTD) is defined as the highest dose tested in which fewer 
than 33% of patients experienced DLT attributable to the study treatment when at least six 
patients were treated at the dose and are evaluable for toxicity. The MTD is one dose level 
below the DLT level. At least six patients will be treated at the MTD. If the MTD does not 
satisfy these conditions, no expansion at the MTD will occur, as the treatment will be 
considered lacking adequate safety.  
 
7.2 
Dose Escalation Schedule: IMRT 
 
The initial dose level will be 1200 cGy, with dose escalation according to the schedule 
below.  
 
1. 1200 cGy = 150cGy x 8 doses 
2. 1350 cGy = 150cGy x 9 doses 
3. 1500 cGy = 150cGy x 10 doses  
4. 1750 cGy = 175cGy x 10 doses 
5. 2000 cGy = 200cGy x 10 doses 
 
Three patients will be treated at each new dose level. If 0/3 patients experience DLT, 3 
patients will be treated at the next dose level. If DLT attributable to the study treatment is 
experienced in exactly 1/3 patients, 3 more patients (for a total of 6) will be treated at that 
dose level. If no additional DLT is observed at the expanded dose level (e.g., 1/6 with 
DLT), the dose will be escalated. Escalation will terminate as soon as two or more patients 
experience any DLT attributable to the study treatment, at a given dose level. The Phase I 
trial will be closed when 6 patients have been treated at the next lower dose level, and at 
most 1/6 patients experience DLT. If more than 1/6 patients experience DLT, the next 
lower dose will be expanded. There will be no dose escalation within a patient. 
 


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The two strata will proceed independently through the dose escalation with the following 
exceptions: no pediatric patients are to be enrolled on dose level 1 until the adult stratum 
has been escalated to dose level 2.  No pediatric patients will be enrolled to dose level 2 
until dose level 2 has been determined to be safe in the adult population, and the same is 
true for levels 3, 4 & 5. 
7.3  
Design considerations for a phase II trial. 
All patients accrued to the MTD dose level will be included in the response assessment for 
the phase II portion of the trial.  
 
8.0 
STUDY CALENDAR 
See appendix V for Study Calendar. 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
9.1 
Criteria for Evaluation: Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS) 
 
Response and progression will be evaluated in this study using the Revised 
Recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials 
in Acute Myeloid Leukemia [JCO 21:4642-4649, 2003]. The following categories from the 
Revised Recommendations of the International Working Group will be used: 
 
Morphologic leukemia-free state: Less than 5% blasts in an aspirate sample with marrow 
spicules and with a count of at least 200 nucleated cells. There are no Auer rods or 
persistence of extramedullary disease. (The presence of a unique phenotype by flow 
cytometry identical to what was found in the pre-treatment specimen is viewed as 
persistence of leukemia.) 
 
Morphologic complete remission (CR): The patient achieves the morphologic leukemia-
free state and has an absolute neutrophil count of >1000/uL and a platelet count 
100,000/uL. The patient is independent of blood transfusions. No duration of response is 
required to fulfill these criteria. 
 
Cytogenetic complete remission (CRc): Patients who achieve a morphologic CR along 
with reversion to a normal karyotype by cytogenetic analysis. For patients who have 
unique markers by routine cytogenetics or by FISH upon enrollment, these markers will be 
followed on subsequent bone marrow examinations using the same technique(s) to 
evaluate for CRc. 
 
Molecular complete remission (CRm): Patients who achieve a morphologic CR with no 
residual disease by molecular or flow cytometic detection methods. For patients with 
unique multi-dimensional flow cytometry markers at the time of enrollment, these will be 
repeated on subsequent bone marrow studies to evaluate for CRm. 
  
Morphologic CR with incomplete blood count recovery (Cri): Patient fulfills the criteria for 
morphologic CR except for residual neutropenia (<1000/uL) and/or thrombocytopenia 
(<100,000/uL). 


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Partial Remission (PR): This requires the same hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to a post-treatment value of 5% to 
25% in the bone marrow aspirate. (If the pre-treatment blast percentage was 50-100%, 
this must decrease to a value between 5-25%. If the pre-treatment blast percentage was 
20-49%, this must decrease by at least half to a value greater than 5%.) A value 5% is 
also considered a PR if Auer rods are present. 
9.2 
Criteria for Evaluation: Chronic Myeloid Leukemia (CML) 
 
Response will be evaluated in this study using the recommendations of the City of Hope 
CML Disease Committee. The following categories from the Revised Recommendations of 
the International Working Group will be used: 
 
Morphologic complete remission (CR): The patient must satisfy the following conditions: 
a. WBC < 10,000/ul 
b. Hemoglobin > 11.0 gm/dl 
c.    Platelet count < 500,000/ul 
 
d.   No immature cells in peripheral blood  
e.   No palpable splenomegaly 
Cytogenetic complete remission (CRc): The patient must have 0% Ph+ metaphases (when 
a minimum of 20 cells are analyzed) or < 1% by FISH* (minimum of 200 cells analyzed). 
(Note*: For outside institutions conducting FISH analysis, note background for outside 
institution.) 
 
Molecular complete remission (CRm): The patient must have no detectable bcr-abl mRNA 
by RT-PCR. 
 
Morphologic partial remission (PR): The patient must satisfy one or more of the following 
conditions: 
a. WBC > 10,000/ul but < 50,000/ul and 50% below pretreatment values 
b. Hemoglobin > 9.0 but < 11.0 gm/dl 
c. Platelet Count > 500,000/ul 
d. Differential > 1% precursor cells 
e. Palpable splenomegaly 
9.3 
Treatment Failure: 
 
 
Resistant disease: Patient does not achieve CR or PR upon repeat bone marrow 
examination after transplant, persistent leukemia in blood or bone marrow. 
 
Aplasia: Patient dies, death occurs while cytopenic with aplastic bone marrow. 
 
Indeterminate cause: Patient dies with no blasts in peripheral blood but no bone marrow 
examination. 
 
Morphologic relapse: Reappearance of blasts post-CR in peripheral blood or bone 
marrow. 
 


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Molecular or cytogenetic relapse: Reappearance of the molecular or cytogenetic 
abnormality. 
 
9.4 
Endpoint Definitions: 
 
a. Overall survival. Defined as the time from transplant to death due to any cause. If a patient 
is alive, survival time is censored at the time of last follow-up.  
 
b. Relapse-free survival. Defined as the time from transplant to the first observation of 
relapsed disease or death due to any cause, whichever occurs first. If the patient has not 
relapsed or died, relapse-free survival is censored at the time of last follow-up. 
 
c. Event-free survival. Defined as the time from transplant to treatment failure or death due to 
any cause, whichever occurs first. If the patient has not experienced an event of interest or 
died, event-free survival is censored at the time of last follow-up 
  
d. Remission duration. Defined as the time from transplant to the first observation of relapsed 
disease. (Note: Morphologic, molecular and cytogenetic remission duration will be 
calculated separately.) 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Phase I 
 
The primary objective of the phase I portion of this study is the determination of the MTD 
of IMRT when used in conjunction with IV busulfan and VP-16 as a conditioning regimen 
for allogeneic stem cell transplantation for patients meeting the specified eligibility 
requirements. The definition of dose limiting toxicity and MTD are given in section 7.1. The 
number of patients to be treated at each dose level in the phase I trial and the rules for 
dose escalation are given 7.2. This study is likely to require 18 patients per stratum if the 
highest dose is well tolerated. It should take approximately 12-18 months to complete this 
portion of the trial. 
 
The toxicities observed at each dose level will be summarized in terms of type (organ 
affected or laboratory determination such as absolute neutrophil count), severity (by NCI 
CTCAE v3.0 and nadir or maximum values for the laboratory measures), date of onset, 
duration, reversibility, and attribution. Tables will be created to summarize these toxicities 
and side effects by dose level. Baseline information (e.g., the extent of prior therapy) and 
demographic information will be presented, as well, to describe the patients treated in this 
study. All disease responses will be reported. Survival and time to failure will be 
summarized both by pooling across dose levels and within each dose level, although the 
primary outcome of the phase II portion will include only patients accrued at the MTD.  
 
10.2 
Phase II 
 
An aim of this study is to estimate the efficacy of this regimen in eligible patients. The 
study is designed to estimate whether 1) the relapse rate and disease-free survival 
probability at two years is broadly comparable to that obtained with conventional 
treatment, and 2) to establish whether the more selective radiation targeting yields an 
improvement in the incidence duration and severity of mucositis. The primary endpoints 


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will be relapse rate to be estimated for informal comparison to published historical rates, 
and the fraction of patients experiencing grade 3-5 mucositis. While mucositis grading is 
subject to variability, 100% of comparable patients receiving previous preparatory 
regimens involving TBI experience unequivocal high-grade mucositis.  
 
For the adult stratum: the phase II portion will enroll 30 additional patients to the MTD 
established in the phase I trial, in order to estimate the two-year relapse rate to an 
accuracy of 18% with 95% confidence (s.e. = 9.1%). If, as hoped, the true (long-run) 
mucositis rate is better than 70%, there would likely be (e.g., with >95% probability) at 
least 5 subjects spared high-grade mucositis, which would be a highly significant 
improvement (p < 0.002) compared to historical data (0 out of > 70). Based on the current 
referral patterns to the City of Hope, it is expected that approximately 6-10 patients per 
year will be eligible for this study. With a goal of 30 additional patients treated at the MTD, 
(23 patients already treated) approximately one and a half year of accrual will be required 
just for the phase II portion.  
 
For the pediatric stratum: the phase II portion will be an exploratory analysis conducted to 
characterize outcomes for the pediatric population. In addition to the six pediatric cases 
treated at the ‘pediatric’ MTD (which may different from the adult population), additional 
pediatric patients will be enrolled and treated at the MTD, with a maximum of nine 
additional pediatric patients enrolled during the phase II portion of the study.  
 
10.3 
Phase II Monitoring 
 
Early stopping rules are incorporated into the phase II portion of the study for excessive 
toxicity. However there will be no interim analysis for efficacy during the phase II stage. 
Toxicities will be recorded using two distinct grading systems; the modified Bearman Scale 
(Bearman, S., et al, JCO, Vol 6, No 10 (Oct), 1988, pp1562-1568. See appendix X for 
details.) and the NCI CTCAE 3.0 Scale.  
 
 
Generally, the modified Bearman Scale will be used to define (grade) ‘early stopping’ 
events (toxicities), and the NCI CTCAE 3.0 Scale will be used for reporting adverse 
events. The only exception relates to how hematologic toxicities are graded and 
incorporated into the early stopping criteria. For hematologic toxicities the CTCAE 3.0 
Scale will be used. The table below will be consulted as relevant toxicities are 
encountered, so there will be no accrual-based interim analysis point. 
 
Early Stopping Criteria: For each adverse outcome, stop if the cumulative number of 
patients reaches or exceeds the following limits: 
 
 
Table of Early Stopping Criteria 
 
 
# of patients treated at 
the MTD 
 
 
# of patients expired 
due to treatment 
related causes that 
would stop the study*  
 
# of patients with 
grade 3 toxicities that 
would require an 
evaluation for safety 
per Bearman Scale** 
Probability that the early 
stopping rule will be invoked 
given a failure rate of: 
10% 
15% 
20% 
12 
3 
3 
0.11 
0.26 
0.45 
18 
5 
5 
0.12 
0.27 
0.47 
24 
6 
6 
0.12 
0.31 
0.53 
30 
8 
8 
0.13 
0.31 
0.53 


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36 
9 
9 
0.13 
0.32 
0.55 
* Note:  The stopping rules are not statistically based; expected treatment related mortality should not to exceed 25%. 
** Note: For hematologic toxicities: Any grade 4 neutropenia associated with fever or infection and lasting beyond three  
 
weeks, or grade 4 neutropenia lasting for more than 28 days per CTCAE 3.0 toxicity criteria should be counted  
 
toward the early stopping rule. 
 
Any patient who receives treatment as part of the phase II portion of this protocol will be 
evaluable for toxicity. Each patient will be assessed periodically according to the treatment 
schedule for the development of any toxicity. The toxicity rule for safety will be assessed 
as each patient reaches day +30 post transplantation. If more than the specified number of 
patients (noted in the table above) have significant treatment related toxicities, then the 
safety of the study will be evaluated.  
 
10.4 
Analysis of Clinical Endpoints 
 
There will be one combined statistical analysis for efficacy. In accordance with the primary 
study objectives, we will perform descriptive statistical analyses on these data after the 
phase II study is complete. Our primary endpoints will be OS, RFS, EFS, TRM, and RR 
with infection and acute- chronic- GVHD as secondary endpoints. Confidence Intervals will 
be estimated by calculating exact 95% confidence limits for a binomial parameter. The 
time-to-event endpoints, such as RFS and OS, will be estimated using the product limit 
method of Kaplan-Meier and tested using the Log-Rank test. 
 
 
11.0 
REGISTRATION GUIDELINES 
 
Once a signed informed consent has been obtained and all pre-treatment evaluations 
have been performed, patients will be entered on study after review of patient eligibility 
criteria by the assigned Clinical Research Associate from the City of Hope Department of 
Biostatistics.  Patients may be screened for registration by calling the Department of 
Biostatistics at extension 62468. 
 
 
12.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
 
 
12.1 
Confidentiality of Records: 
The original data collection forms will be stored in secured cabinets in the Department of 
Biostatistics. 
 
12.2 
Patient Consent Form: 
At the time of registration, three signed and dated copies of the patient Informed Consent 
form with the Human Rights must be available (for patient, patient’s medical chart, and 
one for the City of Hope Biostatistics Office). 


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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 HSCT 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% 
 
 
14.0 
DATA MANAGEMENT 
 
The assigned Clinical Research Associate from the Department of Biostatistics will maintain all 
primary data, including eligibility checklist, pre-study and initial data forms, consolidation, 
transplant data, pathology reports and off-study information.  Data will be collected by the CRA at 
the time of each patient evaluation. Records will be stored in a secure location within the 
Biostatistics Department. See Study Calendar and Appendix XI for time points for grading 
toxicities. 
 
 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
This study is to be approved by the Institutional Review Board (IRB) according to City of Hope 
ethical and regulatory guidelines.  All patients will have signed an informed consent for 
participation in research activities, and will have been given a copy of the Experimental Subject’s 
Bill of Rights. 
 
When results of this study are reported in medical journals or at meetings, identification of those 
taking part in this study will be withheld.  The medical records of subjects will be maintained in 
strictest confidence, according to current legal requirements.  However, these records will be 
made available for review, as required by the Food and Drug Administration (FDA) or other 
authorized users such as the National Cancer Institute (NCI), under the guidelines established by 
the Federal Privacy Act. 


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16.0 
DATA AND SAFETY MONITORING PLAN 
 
A.  
Definition of Risk Level 
 
This is a risk level 4 study as defined in the Guidance Policy and Procedures for Data and Safety 
Monitoring for In-House trials at City of Hope. http://www.infosci.coh.org/gcrc/doc/dsmp.doc This 
study involves tissue transplant and chemotherapy. 
 
 
B.  
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator(s), 
CRA/protocol nurse and statistician are responsible for monitoring the data and safety of this 
study, including implementation of the stopping rules for safety and efficacy, including 
implementation of the stopping rules for safety and efficacy (see section 10.3). 
 
For phase I of the trial, monitoring by the PMT will be done using the phase I tracking log, the 
objective will be to monitor data and safety for dose escalation. Data and safety will be reported to 
the City of Hope DSMB after each dose level, and the PMT will decide before patients are 
enrolled on the phase II portion of the trial. 
 
For phase II of the trial, data and safety will be reported to the City of Hope DSMB annually. In 
addition to the annual report, any early evaluations for safety and/or treatment related mortality 
will also be reported as these assessments are made (per guidelines set in section 10.3 and 10.4 
of the protocol). This report (the PMT report) will include a summary of accrual, adverse events 
and treatment related mortality. 
 
 
C. 
Adverse Events 
 
The frequency for the recording of toxicities are outlined in Appendix V and Appendix X. 
 
 
 
C.1.  
Reporting 
Adverse events must be reported to the City of Hope DSMB and IRB according to 
definitions 
and 
guidelines 
at 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc 
and 
http://resadmin.coh.org/doc/irb3810.doc which are defined below.  SAE’s will be monitored 
by the PMT.  Less than serious adverse events will be reported only at the time of protocol 
continuation reports.  All AE’s occurring during the study will be recorded in the CRF.  
Grade 3, 4 toxicity will be reported to the IRB except Grade 3, 4 laboratory abnormalities 
which will be reported only if clinically significant. 
 
C.2. 
Adverse Event  
An adverse event (AE) is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be related 
to the protocol intervention. All AEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be recorded on the City of Hope National 
Medical Center Adverse Events (CTCAE version 3.0) form.   
 
C.3. 
Serious Adverse Event  


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A serious adverse event (SAE) is defined as any expected or unexpected adverse event 
(AE, generally equivalent to CTCAE grades 3, 4 or 5) that is related or unrelated to the 
intervention that results in any of the following outcomes: 
 
Death 
 
A life-threatening event 
 
In-patient hospitalization (not required as part of the treatment) or prolongation 
of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Causes cancer 
 
Is an overdose 
 
Certain medical events that may not result in death, be life-threatening, or require 
hospitalization, may also be considered a serious adverse event when appropriate 
medical or surgical intervention is necessary to prevent one of the outcomes listed above. 
C.4.  
Unexpected Adverse Event 
Any event in which the severity or specificity is not consistent with the risk information 
described in the protocol, and the event is not anticipated from the subject's disease 
history or status. 
 
C.5.  
Expected Adverse Event 
Any event in which the severity or specificity is consistent with the risk information 
described in the protocol or is anticipated based on the subject's medical history. 
C.6. 
Attribution  
For reporting purposes, attribution is the assessment of the likelihood that an AE is caused 
by the research agent or protocol intervention. The attribution is assigned by the Principal 
Investigator after considering the clinical information, the medical history of the subject, 
and past experience with the research agent/intervention. This is recorded using the 
Adverse Event Report (COH AER) form (http://resadmin.coh.org/doc/irb3820.doc) in one 
of 5 categories scored as the following: 5=related, 4=probably related, 3=possibly related, 
2=unlikely related and 1=unrelated. The attribution is subject to change as follow-up 
information becomes available, and it can be changed by the DSMB or by the IRB in the 
process of review. 
 


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17.0 
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.   
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.   


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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 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 
29. 
Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, 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. 
30. 
Clidt RA, Buckner CD, Applebaum FR, Bryant E, Bearman SI, Petersen FB et al.  Allogeneic 
marrow tranplantation in patients with chronic myeloid leukemia in the the chronic phase: a 
randomized trial of two irradiation regimens.  Blood 1991; 77:1660-1665. 
31. 
Marks DI. A comparison of two myeloablative regimens for allogeneic hematopoietic cell 
transplantation for patients with acute lymphoblastic leukemia. Presented at The Aamerican 
Society of Blood and Marrow Transplantation meeting on February 13, 2004. Orlando Florida. 
32. 
Leibel SA, Fulks Z, Zelefsky MJ, Hunt M, Burman CM, Mageras GS, Chui CS, Jackson A, 
Amols HI and Ling CC.  Technological advances in external-beam radiation therapy for the 
treatment of localized prostate cancer.  Seminars in Oncology 30: 596-615; 2003. 
33. 
Mackie TR, Kapatoes J, Ruchala K, Lu W, Wu C, Olivera G, Forrest L, Tome W, Welsh J, 
Jeraj R, Harari P, Reckwerdt P, Paliwal B, Ritter M, Keller H, Fowler J, and Mehta M.  Image 
guidance for précis conformal radiotherapy.  Int J Radiation Oncology Biol Phys.  56: 89-103; 
2003. 


IRB#05013 
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34. 
Balog J, Mackie TR, Pearson D, Hui S, Paliwal B, and Jeraj R.  Benchmarking beam 
alignment for a clinical helical tomotherapy device.  Med Phys. 30: 1118-1127; 2003. 
35. 
Grigorov G, Kron T, Wong E, Chen J, Sollazzo J, and Rodriguez G.  Optimization of helical 
tomotherapy treatment plans for prostate cancer.  Phys. Med Biol 48: 1933-1943, 2003 
36. 
Scrimger RA, Tome WA, Olivera GH, Reckwerdt P, Mehta MP and Fowler JF.  Reduction in 
radiation dose to lung and normal tissues using helical tomotherapy to treat lung cancer in 
comparison to conventional field arrangements.  Am J Clin Oncol 26: 70-78, 2003. 
 


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 
MD/Pager # _________________ 
 
 
Stop Time: ___________________  Adjusted IBW _____________ 
PATIENT ___________________  
 
 
DOSE #_____________________   Actual Body Weight ________ 
Medical Record #_____________ 
 
 
Start time: ___________________   Ideal Body Weight _________ 
IRB#:  ______________________ 
 
 
DATE: ______________________  (CIRCLE WEIGHT USED) 
** ALL samples to be obtained in 7cc green top tubes (Sodium Heparin) and kept on ice at Nurses Station. 
Page 32 of 44 
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Coordinator/Pager #___________ 
 
    
DOSE: ____________mg 
INFUSION TO RUN OVER 2 HOURS 
IV BUSULFAN KINETICS FORM  
APPENDIX I 
RN SIGNATURE _________________________________ 
Then send to Clinical Pathology. 
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Appendix II 
TREATMENT SCHEMA FOR DONORS 
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).
3.
Bone Marrow collection:  Donors may undergo bone marrow collection in lieu of 
PBSC’s.  Bone marrow collection will be done per current Hematopoietic Cell 
transplant Program Clinical Manual of Standard Operating Procedures (Section 
B.004).
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APPENDIX III 
ACUTE GRAFT VERSUS HOST DISEASE STAGING AND GRADING  
See current Hematopoietic Cell Transplant Program Clinical  
Manual of Standard Operating Procedures 
Standardized Grading of Acute and Chronic GVHD 
G.003.01
 
 
 
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APPENDIX IV 
GRADING OF CHRONIC GRAFT VERSUS HOST DISEASE 
See current Hematopoietic Cell Transplant Program Clinical  
Manual of Standard Operating Procedures 
Management of Chronic Graft vs Host Disease 
G.004.01
 
 


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APPENDIX V 
STUDY CALENDAR 
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 
admit 
Day 
-19 
Day 
-15 
Day 
-14 
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 
30* 
Day 
100* 
Day 
180**
Yearly 
X 2 yrs** 
Week Day 
 
Th 
M 
T 
W 
Th 
F 
Sa 
Su 
M 
T 
W 
Th 
F 
Sa 
Su 
M 
T 
W 
Th 
F 
Sa 
- 
- 
- 
- 
CBC, Diff, PLT  
2, 3
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
BMP4
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
CMP 1
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
MG, uric acid 1
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
LDH, 
phosphorus 1
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Hepatitis A,B,C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT, PTT 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24hr CLcr  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy t
 
est
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV, 
HSV/HZV 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immuno-
globulin 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT 9
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR 7, 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan Chest, 
ABD 9
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or 
MUGA 9
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LP/MTX see 
6.1.G 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM asp, bx, 
cytogenetics 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilantin lev   
el
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan levels 
 
 
XX
 
XX8
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilantin 10
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan 
 
 
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IM
 
RT
 
 
 
 
 
 
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VP-
 
16
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSC’s or BM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
CNS Disease patients - see section 6.1.G 
TOXICITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity 
Monitoring 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Every Monday, Wednesday, Friday during hospitalization or as clinically indicated 
    2 CBC and platelets done daily during hospitalization  
3 Diff. should be done daily until no blasts are present in peripheral blood then started again when WBCs  500 
 until ANC >500 for 3 consecutive days and then on Mondays, Wednesdays and Fridays until discharge 
    7 CXR to be done weekly until day 30 
4 Basic Metabolic Panel (Sodium, Potassium, Chloride, Carbon Dioxide, Blood Urea Nitrogen, Creatinine, Glucose, Calcium) 
    8 If required 
6 Comprehensive Metabolic Panel (Sodium, Potassium, Chloride, Carbon Dioxide, Calcium, Urea Nitrogen, Creatinine, Glucose,      9 Tests are good for 3 months if transplant delayed for non-medical reason.  
Albumin, Bilirubin Total, Alk Phos, Total Protein, SGPT, SGOT) with magnesium, uric acid, LDH & phosphorous                           10 Dilantin will be given daily consecutively until day –6 or day after last busulfan dose 
XX blood sample shipment                                                                                                                                                                        * Day 30 through Day 100 tests evaluations are +/- 7 working days 
 ** Evaluations post Day 100 are +/- 14 days
IRB# 05013
Version: 09 


IRB# 05013 
Page 37 of 44 
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Version: 09 
APPENDIX VI 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (VERSION 3.0 & 2.0) 
A copy of CTCAE version 3.0 and 2.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html
 
 
 
 
 


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Version: 09 
APPENDIX VII 
GUIDELINES FOR REPORTING ADVERSE EVENTS 
City of Hope Adverse Event Reporting guideline can be found at: 
http://resadmin.coh.org/doc/irb3810.doc
 
 
 
 
 


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Page 39 of 44 
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Version: 09 
APPENDIX VIII 
ELIGIBILITY CHECKLIST 
Inclusion Criteria 
The answers to the following criteria must all be marked YES. 
1 
____Yes ____No 
Does the patients have documented acute myeloid leukemia 
not in first remission or second remission i.e. after failing 
remission induction therapy or in relapse or beyond second 
remission?
OR
Does the patients have chronic myeloid leukemia in blastic 
phase of the disease? 
NOTE: Patients with refractory anemia with excess blasts and 
in transformation will be eligible. 
2 
____Yes ____No 
Does the subject have a HLA (A, B, C, DR) identical sibling or 
fully-matched unrelated donor who is willing to donate bone 
marrow or primed blood stem cells?
NOTE: 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). 
3 
____Yes ____No 
Has the patient had prior therapy? 
NOTE: Prior therapy with VP-16 and busulfan is allowed. 
 
4 
____Yes ____No 
Patient must have reached their 6th birthday and must not have 
passed their 55th birthday. 
Age_________
 
5 
____Yes ____No 
Does the subject have an ejection fracture of greater than or 
equal to 50% by MUGA or echocardiogram?  (Either method for 
measuring cardiac function is acceptable, however, the same 
scan must be used throughout treatment and follow-up to 
monitor the patient for cardiac toxicity.) 
Ejection fracture______________ Date Obtained___________ 
 
6 
____Yes ____No 
Has the subject had an electrocardiogram?
Date Obtained______________ 
7 
____Yes ____No 
Does the patients have a serum creatinine of less than or equal 
to 1.2 or creatinine clearance > 80ml/min?
Serum Creatinine__________
        IULN___________ 
Date obtained_______________ 


IRB# 05013 
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Version: 09 
Creatinine Clearance 
(estimated or measured – circle one)________________ 
Date obtained____________ 
8 
____Yes ____No 
Does the patient have a bilirubin of less than or equal to 1.5?
Bilirubin____________
Date obtained____________ 
9 
 
 
Does the patient have a SGOT and SGPT less than 5 times the 
upper limit of normal. 
SGOT____________
  ULN______________ 
Date obtained______________ 
SGPT____________
    ULN______________ 
Date obtained____________________
10 ____Yes ____No 
Does the patient have FEV1and DLCO greater than 50% of 
predicted normal value based on Pulmonary function tests?
FEV1________________     Predicted Normal Value________ 
DLCO_______________     Predicted Normal Value________ 
Date obtained___________________
11 ____Yes ____No 
Is the time from the end of last induction or reinduction attempt 
greater than or equal to 21 days? 
End Date of treatment____________ 
12 ____Yes ____No 
Has the patient signed the informed consent form approved by 
the IRB?
Date informed consent form signed_____________ 
NOTE: 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.
Exclusion Criteria 
The answers to the following criteria must all be marked NO. 
1 
____Yes ____No 
Has the patient had prior radiation therapy that will exclude the 


IRB# 05013 
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06/29/11
Version: 09 
use of total body irradiation? 
2 
____Yes ____No 
Has the patients undergone a previous bone marrow 
transplantation and relapsed? 
3 
 
 
Does the patient have a psychological or medical condition that 
the physician deems unacceptable to proceed to allogeneic 
bone marrow transplant? 
4 
____Yes ____No 
Is the patient currently pregnant or nursing?  Patient must not 
be pregnant or nursing because of the teratogenic potential of 
the drugs/radiation in this study.  Women/men of reproductive 
potential must have agreed to use an effective contraceptive 
method.
 
 
 


IRB# 05013 
Page 42 of 44 
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Version: 09 
Appendix IX: Modified Bearman Scale 
Grade I
Grade II
Grade III
Cardiac  
toxicity
Mild EKG abnormality, not requiring 
medical  
intervention; or noted heart enlargement 
on chest x-ray with no clinical symptoms
Moderate EKG abnormalities requiring 
and responding to medical intervention; or 
requiring continuous monitoring without 
treatment; or congestiveheart failure 
responsive to digitalis or diuretics 
Severe EKG abnormalities with no or 
only partial response to medical 
intervention; or heart failure with no 
or only minor response to medical 
intervention; or decrease in voltage 
by more than 50% 
Bladder  
toxicity
Macroscopic hematuria after 2 days 
from last chemotherapy dose with no 
subjective symptoms of cystitis and not 
caused by infection 
Macroscopic hematuria after 7 days from 
last chemotherapy dose not caused by 
infection; or hematuria after 2 days with 
subjective symptoms of cystitis not caused 
by infection 
Hemorrhagic cystitis with frank 
blood, necessitating invasive local 
intervention with installation of 
sclerosing agents, nephrostomy or 
other surgical procedure 
Renal  
toxicity 
Increase in creatinine up to twice the 
baseline value (usually the last recorded 
before start of conditioning) 
Increase in creatinine above twice 
baseline but not requiring dialysis 
Requirement of dialysis 
Pulmonary 
 
toxicity 
Dyspnea without chest x-ray changes 
not caused by infection or congestive 
heart failure; or chest x-ray showing 
isolated infiltrate or mild interstitial 
changes without symptoms not caused 
by infection or congestive heart failure 
Chest x-ray with extensive localized 
infiltrate or moderate interstitial changes 
combined with dyspnea and not caused by 
infection or CHF; or decrease of PO2 (> 
10% from baseline) but 
not requiring mechanical ventilation or > 
50% O2 on mask and not caused by 
infection or CHF
Interstitial changes requiring 
mechanical ventilatory support or > 
50% oxygen on mask and not caused 
by infection or CHF 
Hepatic  
toxicity
Mild hepatic dysfunction with bilirubin 
 2.0 mg/dL and  6.0 mg/dL or weight 
gain > 2.5% and < 5% from baseline, of 
non-cardiac origin; or SGOT increase 
more than 2-fold but less than 5-fold 
from lowest preconditioning 
Moderate hepatic dysfunction with 
bilirubin > 6.0 mg/dL and < 20 mg/dL; or 
SGOT increase > 5-fold from 
preconditioning; or clinical ascitis or 
image documented ascitis > 100 mL; or 
weight gain > 5% from baseline of non-
cardiac origin 
Severe hepatic dysfunction with 
bilirubin > 20 mg/dL; or hepatic 
encephalopathy; or ascitis 
compromising  
respiratory function 
CNS  
toxicity
Somnolence but the patient is easily 
arousable and oriented after arousal 
Somnolence with confusion after arousal; 
or other new objective CNS symptoms with 
no loss of consciousness not more easily 
explained by other medication, bleeding or 
CNS infection 
Seizures or coma not explained 
(documented) by other medication, 
CNS  
infection, or bleeding 
Stomatitis
Pain and/or ulceration not  
requiring a continuous IV  
narcotic drug 
Pain and/or ulceration requiring a 
continuous IV narcotic drug (morphine 
drip) 
Severe ulceration and/or  
mucositis requiring  
preventive intubation; or  
resulting in documented  
aspiration pneumonia with or  
without intubation 
GI toxicity
Watery stools > 500 mL but  
< 2,000 mL every day not  
related to infection 
 
Watery stools > 2,000 mL every day not 
related to infection; or macroscopic 
hemorrhagic stools with no effect on 
cardiovascular status not caused by 
infection; or subileus not related to 
infection
Ileus requiring nasogastric  
suction and/or surgery and not 
related to infection; or hemorrhagic 
enterocolitis affecting cardiovascular 
status and requiring transfusion 
 
 



IRB# 05013 
Page 43 of 44 
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Version: 09 
APPENDIX X 
TIME POINTS TO GRADE TOXICITIES AND COLLECT DATA 
1. 
30 days post PBSCT/BMT 
Complete Common Toxicity Criteria (CTC) Form 
2. 
31 to 100 days post PBSCT/BMT 
Complete Common Toxicity Criteria (CTC) Form every month 
Complete allogeneic transplant and disease specific forms 
3. 
Day 101 – 365 post transplant 
Complete long-term follow-up form 
4. 
Yearly for two years 
Complete long-term follow-up form 


IRB# 05013 
Page 44 of 44 
06/29/11
Version: 09 
APPENDIX XI 
PARAMETERS FOR TARGETED TBI 
Phase I - II Study of IV Busulfan and Etoposide (VP16) Combined with Escalated Doses of Large field 
Image-guided Intensity Modulated Radiation Therapy (IMRT) using Helical Tomotherapy as a Preparative 
Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation for Patients with Advanced 
Myeloid Malignancies 
TARGET STRUCTURES WITH DOSE ESCALATION
Skeletal Bone: C, T and L spine, clavicles, scapula, pelvis, sacrum, all bones of the bilateral upper and 
lower extremities. 
Major Lymph Node Chains: 
cervical, supraclavicular, axillary, mediastinal, para-aortic, pelvic, 
inguinal-femoral
Testes
TARGET STRUCTURES KEPT AT 1200 cGy (NO DOSE ESCALATION) 
Spleen and splenic-hilar nodes 
Liver and porta-hepatic nodes 
Ribs
Sternum
Brain and skull 
NON-TARGET STRUCTURES
Scalp
Orbits
Lens
Thyroid
Oral Cavity 
Mandible
Parotids
Larynx/Hypopharynx
Esophagus 
Lungs
Heart
Breasts
Kidneys
Stomach
Small and Large Intestine 
Rectum
Bladder


IRB# 05013 
Page 45 of 44 
06/29/11
Version: 09 
TARGET DOSE, FRACTION SIZE, SCHEDULE AND DOSE ESCALATION SCHEME
Initial Dose Level:    
1200 cGy 
Fraction and Schedule: 
150 cGy QD or BID (minimum 6 hours between fractions) 
Dose Escalation Scheme:  
Level
Fraction and Schedule 
Total Dose 
1
150 cGy BID x Days 1-4 
1200 cGy 
2
150 cGy BID Day 1 -4 then 
150 cGy QD Day 5 
1350 cGy 
3
150 cGy BID Days 1-5 
1500 cGy 
4
175 cGy BID Days 1-5 
1750 cGy 
5
200 cGy BID Days 1-5
2000 cGy