Phase I Study of Escalating Doses of 90Y-DOTA-Anti-CD25 Monoclonal Antibody Added to the Conditioning Regimen of Fludarabine, Melphalan, and Organ Sparing Total Marrow and Lymphoid Irradiation (TMLI) as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Leukemia or Myelodysplastic Syndrome
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Secondary Acute Myeloid Leukemia
Sponsor: City of Hope Medical Center

 
IRB 21016 
 
10/01/2024 
Packet : 14 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF RADIATION ONCOLOGY 
 
TITLE:  
Phase I Study of Escalating Doses of 90Y-DOTA-anti-CD25 Monoclonal Antibody Added to the 
Conditioning Regimen of Fludarabine, Melphalan and Organ Sparing Total Marrow and 
Lymphoid Irradiation (TMLI) as Conditioning for Allogeneic Hematopoietic Cell Transplantation 
in Patients with High-Risk Acute Leukemia, Myelodysplastic Syndrome or Non-Hodgkin’s 
Lymphoma 
 
CITY OF HOPE PROTOCOL NUMBER/ 
IRB # 21016   
 
PROTOCOL DATE:10/01/2024 
 
 
 
 
 
 
 
 
 
 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Approval  
 
Protocol Dated 03/02/21 
 
 
 
 
Packet: 00 
Amendment 01 
 
 
Protocol Dated 05/26/22 
 
 
 
 
Packet 01 
Amendment 02 
 
 
Protocol Dated 07/06/22 
 
 
 
 
Packet 02 
Amendment 03 
 
 
Protocol Dated 08/02/22 
 
 
 
 
Packet 03 
Amendment 04 
 
 
Protocol Dated 10/20/22 
 
 
 
 
Packet 04 
Amendment 05 at Continuation  
Protocol Dated 10/20/22 
 
 
 
 
Packet 05 
Amendment 06 
 
 
Protocol Dated 02/20/23 
 
 
 
 
Packet: 06 
Amendment 07 
 
 
Protocol Dated 04/03/23 
 
 
 
 
Packet: 07 
Amendment 08 
 
 
Protocol Dated 08/03/23 
 
 
 
 
Packet: 08 
Amendment 09                        
Protocol Dated 08/03/23 (TP) 
 
 
 
Packet: 09 
Amendment 10                        
Protocol Dated 09/20/23 (v8)  
 
 
 
Packet: 10 
Amendment 11                        
Protocol Dated 11/02/23 (v9)  
 
 
 
Packet: 11 
Amendment 12                        
Protocol Dated 02/22/24 (v10) 
 
 
 
Packet: 12 
Amendment 13                                 Protocol Dated 04/15/24 (v11)                                            Packet: 13 
Amendment 14                                 Protocol Dated 10/01/24 (v12)                                            Packet:14 
 
SITE:  
 
 
 
 
 
STAGE (If applicable): 
 
 
 
MODALITY:  
 
 
 
 
TYPE:  
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
Jeffrey Wong, M.D 
Co-Investigator:                                           Jasmine Zain, M.D. 
COLLABORATING INVESTIGATORS: 
Anthony Stein, M.D., Monzr Al-Malki, M.D., Susanta Hui, Ph.D., 
Eileen Smith, M.D., Guido Marcucci, M.D., Ryotaro Nakamura, 
M.D., Joseph Rosenthal, M.D., Anna Wu, Ph.D., John Shively, 
Ph.D., Paul Yazaki, Ph.D. 
 
PARTICIPATING CLINICIANS: 
 
Savita Dandapani, M.D., Vikram Adhikarla, Ph.D., Joo Song, 
M.D., An Liu, Ph.D., Chunhui Han, Ph.D., Ibrahim Aldoss, M.D., 
Haris Ali, M.D., Ahmed Aribi, M.D., Shukaib Arslan, M.D., Andrew 
Artz, M.D., Elizabeth Budde, M.D., Len Farol, M.D., Stephen 
Forman, M.D., Nicole Karras, M.D., Joshua Mansour, M.D., 
Matthew Mei, M.D., Anna Pawlowska, M.D., Vinod Pullarkat, M.D., 
Michael Rosenzweig, M.D., Amandeep Salhotra, M.D., Karamjeet 

 
IRB 21016 
 
10/01/2024 
Packet : 14 
S. Sandhu, M.D., Ricardo Spielberger, M.D., Paul Koller, M.D., 
Idoroenyi Amanam, M.D. 
 
 

This document is confidential and for research purposes only. Distribute and use ONLY as authorized.  
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
Phase I Study of Escalating Doses of 90y-DOTA-Anti-CD25 Basiliximab Monoclonal 
Antibody Added to the Conditioning Regimen of Fludarabine, Melphalan and Organ 
Sparing Total Marrow and Lymphoid Irradiation (TMLI) as Conditioning for Allogeneic 
Hematopoietic Cell Transplantation in Patients with High-Risk Acute Leukemia, 
Myelodysplastic Syndrome, or Non-Hodgkin’s Lymphoma 
Version Date: ...10/01/2024... 
Protocol Version: 
12  
 
City of Hope #: ...21016... 
Agents: 
90y-DOTA-Anti-CD25 Basiliximab Monoclonal and TMLI  
IND Number: 
157127 
IND Holder: 
City of Hope 
Funding Support: 
NIH-R21 …  
NCT Number: 
NCT05139004 
Participating Sites: 
City of Hope (Duarte) … 
Short Title 
90Y-Basiliximab and TMLI added to Flu/Mel conditioning for 
allogeneic HCT for high-risk acute leukemias and MDS 
 
 
Principal Investigator 
Jeffrey Wong, MD …  
City of Hope National Medical Center 
Dept. of Radiation Oncology 
T: 626-218-2247 
Email: jwong@coh.org 
 
Co-Principal Investigator 
Anthony Stein, MD 
City of Hope National Medical Center 
Dept. of Dept. of Hematology and Hematopoietic Transplantation 
T: 626-301-4673 
Email: astein@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
T: (626)-218-7904 
Email: DCC@coh.org 
 
 

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PROTOCOL TEAM 
Biostatistician 
Dongyun Yang, PhD 
City of Hope National Medical 
Center 
Dept. of Information Sciences 
T: 626-471-7106 
Email: donyang@coh.org 
Protocol Development Scientist 
Sally Mokhtari, PhD 
City of Hope National Medical 
Center 
Dept. of Clinical and Translational 
Project Development 
T: 626-218- 
Email : smokhtari@coh.org 
Co-Investigator 
Monzr Al Malki, MD 
City of Hope National Medical 
Center 
Dept. of Hematologic 
Malignancies and HCT 
T: 626-301-4673 
Email:malmalki@coh.org 
Co-Investigator 
Jasmine Zain, MD 
City of Hope National Medical 
Center 
Dept. of Hematologic 
Malignancies and HCT 
T: 626-301-4673 
Email:jzain@coh.org 
Co-Investigator 
Susanta K. Hui, PhD 
City of Hope National Medical 
Center 
Dept. of Radiation Oncology 
T: 626-218-0556 
Email : shui@coh.org 
 
Co-Investigator 
Eileen Smith, MD 
City of Hope National Medical 
Center 
Dept. of Hematology 
T: 626-301-4673 
Email: esmith@coh.org  
Co-Investigator 
Anna Wu, PhD 
Beckman Research Institute 
Dept. of Immunology and 
Theranostics 
T: 626-301-4673 
Email: awu@coh.org 
Co-Investigator 
John Shively, PhD 
Beckman Research Institute 
Dept. Of Immunology and 
Theranostics 
T : 626-301-4673 
Email : jshively@coh.org 
Co-Investigator 
Paul Yazaki, PhD 
Beckman Research Institute 
Dept. of Immunology and 
Theranostics 
T: 626-301-4673 
Email: pyazaki@coh.org 
 
Co-Investigator 
Ryotaro Nakamura, MD 
City of Hope National Medical 
Center 
Dept. of Hematology 
T: 626-301-4673 
Email: rnakamura@coh.org  
Co-Investigator 
Guido Marcucci, MD, PhD 
Department of Hematology 
City of Hope 
T: 626-301-4673 
Email: gmarcucci@coh.org 
 
 
 

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STUDY SCHEMA 
 
 
Schema created with BioRender.com 
 
 
HCT: Hematopoietic cell transplantation.  
Note:  A window of ±2 days is allowed for stem cell infusion. 
The infusion of 90Y-DOTA-anti-CD25 Basiliximab will be followed by serial blood (5 cc) samples at approximately 
time 1-2 hours, 3-4 hours, and at scan times of 1 day and 5/6 days after radiolabeled antibody infusion.   
Planar serial nuclear scans will be performed on the day of infusion, 1 day post infusion and the day prior to 
TMLI start (day 5 or 6 post infusion). A SPECT scan will be performed at the 1 day post infusion timepoint. 
 
 
 

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PROTOCOL SYNOPSIS 
 
Protocol Title 
Phase I Study of Escalating Doses of 90y-DOTA-Anti-CD25 Basiliximab Monoclonal Antibody Added to the 
Conditioning Regimen of Fludarabine, Melphalan and Organ Sparing Total Marrow and Lymphoid Irradiation 
(TMLI) as Conditioning for Allogeneic Hematopoietic 
Study Detail 
Population/Indication(s): Acute leukemia/myelodysplastic syndrome, non-Hodgkin’s lymphoma 
Phase: 1 
Sample Size: 12-15 
Estimated Accrual Duration: 60 months 
Estimated Study Duration 60 months 
Participant Duration: 24 months 
Study Agents: 
90y-DOTA-Anti-CD25 Basiliximab Monoclonal and TMLI..…  
  
  
Study Design 
Myeloablative radiation and chemotherapy containing conditioning regimens followed by allogeneic HSCT 
rescue is an important treatment modality to improve long-term survival in patients with leukemia in first 
remission (1-3) as well as patient with more advanced acute myeloid leukemia (AML) and those with 
relapsed/refractory non-Hodgkin’s lymphoma (NHL). The principal high-dose preparative or conditioning 
regimens administered before bone marrow transplantation include total-body irradiation (TBI) together with 
cyclophosphamide (CY) or other chemotherapy (4;5) (6;7).  Various studies utilizing different myeloablative 
regimen have shown a long-term survival for AML patients in first remission between 50-80% (2;8-13). Three-
year survival rates after HCT for patients with refractory or relapsed acute leukemia are significantly worse at 
20% and new and novel conditioning regimens are needed for this population (14;15).  
TMLI is a form of targeted systemic radiotherapy that utilizes CT imaging to identify where to preferentially 
target radiotherapy. Radioimmunotherapy (RIT) is also a form of targeted systemic radiotherapy that utilizes 
monoclonal antibodies or related immunoconstructs linked to radionuclides to preferentially target cells that 
express a specific antigen. 
Studies to date demonstrate the promise of targeted systemic radiotherapy using either TMLI or RIT. Rather 
than being viewed as competing approaches, these two forms of targeted therapy should be viewed as 
complementary which when rationally combined can address the limitations of each modality. 
The addition of RIT to TMLI will likely add additional dose to marrow and leukemia cells without a significant 
increase in mucositis. Finally, the addition RIT helps to address the theoretical concern of sparing of leukemia 
cells in circulation and in areas of reduced dose with TMLI. 

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Objectives 
Primary Objective(s) 
 Determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of 90Y-DOTA-anti-CD25 
radioimmunotherapy with fixed doses of organ sparing TMLI, fludarabine and melphalan (FM 100) as 
conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) for treatment of High-Risk 
Acute Leukemias or Myelodysplastic Syndrome (MDS) or non-Hodgkin’s lymphoma (NHL), in patients who 
are not eligible for standard myeloablative regimens.   
 Describe toxicities attributable to 90Y-DOTA-anti-CD25 Basiliximab radioimmunotherapy containing 
regimen by dose level in patients treated under this regimen. 
Secondary Objective(s) 
Evaluate the safety of the regimen, at each dose level, by assessing the following: 
• 
type, frequency, severity, attribution, time course and duration of adverse events, including 
acute/chronic GVHD, infection and delayed engraftment 
Estimate overall survival (OS), event-free survival (EFS), GVHD Relapse Free Survival (GRFS), cumulative 
incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years 
 Describe biodistribution, pharmacokinetics and organ dosimetry of 90Y-DOTA-anti-CD25 Basiliximab. 
Endpoints 
o The primary endpoint is: Toxicity 
 Secondary Endpoints are Overall survival, event-free survival, cumulative incidence of relapse/progression, 
CR proportion at day +30, non-relapse infection, neutrophil recovery, acute GVHD of grades 2-4 and 3-4, 
chronic GVHD, and incidence, frequency and severity of CRS. 
Intervention Description 
This is a single-institution, non-randomized phase I trial to determine the maximum tolerated dose/ 
recommended phase II dose (MTD/RP2D) of 90Y-DOTA-antoCD25 Basiliximab MAB when given in combination 
with fixed doses of fludarabine, melphalan, and 1200 cGy TMLI as conditioning regimen to patients with high-
risk acute leukemia (lymphocytic or myelogenous), myelodysplastic syndrome or non-Hodgkin’s lymphoma 
(NHL), who undergo alloHCT with matched related/unrelated donor.  
Dose escalation will be based on a modified rolling 6 Phase I design, with dose level 1 starting at 0.3 mCi/Kg to 
a maximum dose level of 0.5 mCi/kg. There will also be a dose level -1 of 0.2 mCi/kg in the case that dose level 
1 is too toxic 

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Main Eligibility Criteria 
Main Inclusion Criteria 
 
Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in acute 
myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or non-Hodgkin’s 
lymphoma. 
 
Demonstration of CD25 expression by flow cytometry, immunohistochemistry or elevated CD25 
serum levels  
 
Patients must be ≥ 18 years of age. 
 
Karnofsky performance status ≥70 
 
Eligible for allogeneic hematopoietic cell transplantation 
 
Patients should have discontinued all previous intensive therapy, chemotherapy or radiotherapy for 2 
weeks prior to commencing therapy on this study. 
 
Adequate organ function. 
 
All candidates for this study must have an HLA (A, B, C, and DRB1) identical sibling who is willing to 
donate peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 allele matched 
unrelated donor. A single allele mismatch at DQ will be allowed. 
Main Exclusion Criteria 
 
Have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection. 
 
Receiving any other investigational agents or concurrent biological, intensive chemotherapy or 
radiation therapy for the previous 2 weeks from conditioning*.  
*(NOTE: Low dose Chemotherapy or maintenance chemotherapy given within 7 days of 
planned study enrollment is permitted. These include: Hydroxyurea, 6-meraptopurine, oral 
methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 
inhibitors can also be given up to 3 days before conditioning regimen.)  
 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
any in the regimen.  
 
Patients with other active malignancies are ineligible for this study, other than non-melanoma skin 
cancers.  
 
The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her 
ability to be compliant with the medical regimen and to tolerate transplantation or would prolong 
hematologic recovery which in the opinion of the principal investigator would place the recipient at 
unacceptable risk. 
 
Patients may not have had a prior allogeneic transplant. 
 
No prior transplant BCNU conditioning 
 
For patients with leukemia or MDS: Patients may not have received more than 3 prior regimens, 
where the regimen intent was to induce remission. 
 
All patients with prior radiation treatment to the lung, liver, and kidney will be excluded.  
 
Patients who have recived prior total skin electron beam therapy for lymphoma are excluded 
 
Patients who have recived prior radiopharmaceutical therapy are excluded  
 
Inclusion of other patients with previous radiation exposure will be determined based on the 
radiation oncologist MD PI evaluation and judgement. 
Special Assessments and Monitoring 
 Correlative blood, bone marrow samples 
 Special monitoring immune-related Aes, etc. 
 
 

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TABLE OF CONTENTS 
SECTION ............................................................................................................................................................... PAGE 
1.0 
Objectives .................................................................................................................................................... 11 
1.1 
Primary Objective(s) 
11 
1.2 
Secondary Objective(s 
11 
2.0 
Background .................................................................................................................................................. 11 
2.1 
Myeloablative Conditioning Regimens for HCT in Acute Myelogenous Leukemia (AML) 
11 
2.2 
Total Body Irradiation: The Earliest Form of Systemic Radiotherapy 
12 
2.3 
Limitations to TBI 
12 
2.4 
Development of Organ Sparing Targeted TMI and TBI Using IG-IMRT 
12 
2.5 
Dose escalation of TMI or TMLI to improve disease control in advanced refractory leukemia 
14 
2.6 
TMI or TMLI added to reduced intensity conditioning (RIC) regimens 
15 
2.7 
Radioimmunotherapy, a Form of Biologically Targeted Systemic Radiotherapy 
16 
2.8 
Dose escalation of TBI with the Addition of RIT 
18 
2.9 
The Rationale for Combining TMLI and RIT 
18 
2.10 
RIT Directed Against CD25 in Hematopoietic Malignancies 
19 
2.11 
Rationale for Anti-CD25 in Leukemia 
21 
2.12 
Study Rationale 
21 
3.0 
Eligibility Criteria ......................................................................................................................................... 22 
3.1 
Patient Inclusion Criteria 
22 
3.2 
Patient Exclusion Criteria 
23 
3.3 
Donor Specific Criteria 
24 
4.0 
Participant Enrollment, Assignment ............................................................................................................ 25 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
25 
4.2 
Participant Enrollment 
25 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
26 
4.4 
Dose Level Assignment 
26 
5.0 
Treatment Program ..................................................................................................................................... 26 
5.1 
Treatment Program Overview 
26 
5.2 
Cycle Definition 
26 
5.3 
Treatment Plan 
26 
5.4 
Agent Administration and Pre-medications 
28 
5.5 
Special Assessments and Monitoring 
28 
5.6 
Duration of Protocol Therapy and Criteria for Removal 
28 
5.7 
Follow-Up 
29 
5.8 
Duration of Study Participation 
29 
5.9 
Concomitant Therapies/Medications 
29 
5.10 
Supportive care 
29 
6.0 
Anticipated Adverse Events ......................................................................................................................... 29 
6.1 
Basiliximab 
29 
6.2 
111In-Basiliximab/DOTA 
30 
6.3 
90Y-Basiliximab/DOTA 
30 
6.4 
Fludarabine 
30 
6.5 
Melphalan 
30 
6.6 
TMLI 30 
6.7 
Tacrolimus 
31 
6.8 
Sirolimus 
31 
7.0 
Dose Delay / Modification Guidelines ......................................................................................................... 31 
8.0 
Agent Information ....................................................................................................................................... 31 

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8.1 
Basiliximab 
31 
8.2 
111In-Basiliximab/DOTA 
32 
8.3 
90Y-Basiliximab/DOTA 
32 
8.4 
Fludarabine phosphate (2-fluoro-ara-AMP) 
33 
8.5 
Melphalan (L-phenylalanine mustard, L-PAM, Alkeran) 
33 
8.6 
Tacrolimus 
33 
8.7 
Sirolimus 
35 
8.8 
Total Marrow and Lymphoid Irradiation (TMLI) 
36 
9.0 
Correlative/ Special Studies ......................................................................................................................... 37 
9.1 
Laboratory Studies Performed 
37 
9.2 
Research Sample Collection and Dispensation 
39 
10.0 
Study Calendar ............................................................................................................................................ 40 
10.1 
Pre-transplant Study Calendar 
40 
10.2 
Post-Transplant Study Calendar 
42 
11.0 
Endpoint Definitions/Measurement of Effect ............................................................................................. 43 
11.1 
Primary Endpoint(s) 
43 
11.2 
DLT Definition 
43 
11.3 
Secondary Endpoint(s) 
43 
11.4 
Response Criteria Definition 
44 
12.0 
Statistical Considerations ............................................................................................................................ 49 
12.1 
Study Design 
49 
12.2 
Dose Escalation Schedule: Adapted Rolling 6 Design 
49 
12.3 
DLT Window 
51 
12.4 
Participant Evaluability and Replacement 
51 
12.5 
Sample Size, Accrual Rate and Study Duration 
51 
12.6 
Additional Toxicity Monitoring 
51 
12.7 
Statistical Analysis Plan 
52 
13.0 
Data Handling, Data Management, Record Keeping ................................................................................... 52 
13.1 
Source Documents 
52 
13.2 
Data Capture Methods and Management 
52 
13.3 
Case Report Forms 
52 
13.4 
All data will be collected using electronic data collection.Regulatory Records 
52 
14.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest ................................... 52 
14.1 
Assessment of Adverse Events 
53 
14.2 
Adverse Events of Special Interest (AESI) 
53 
14.3 
Pregnancies 
54 
14.5 
Expedited Reporting 
55 
14.6 
Reporting to the FDA 
55 
15.0 
Adherence to the Protocol & Reporting of Protocol Deviations ................................................................. 56 
16.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .......................................................... 56 
16.1 
All Investigator Responsibilities 
56 
16.2 
Study Principal Investigator Responsibilities 
56 
16.3 
Protocol Management Team (PMT) 
56 
16.4 
Quality Assurance 
56 
16.5 
Risk Determination 
57 
16.6 
City of Hope Data and Safety Monitoring Committee 
57 
17.0 
Ethical and Regulatory Considerations ........................................................................................................ 57 
17.1 
Ethical Standard 
57 
17.2 
Regulatory Compliance 
57 

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17.3 
Institutional Review Board 
57 
17.4 
Informed Consent 
58 
17.5 
Participant Withdrawal 
58 
17.6 
Special and Vulnerable Populations 
59 
17.7 
Participant Confidentiality 
59 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial 
60 
17.9 
Conflict of Interest 
60 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants 
60 
17.11 
Publication/ Data Sharing 
61 
18.0 
References ................................................................................................................................................... 62 
Appendix A: Performance Status Scales ................................................................................................................... 69 
Appendix B: TOXICITY SCALES .................................................................................................................................. 70 
Appendix C: Response Criteria/Grading/staging Criteria ......................................................................................... 72 
Appendix D: Antibody preperation, radiolabeling, and quality control ................................................................... 79 
Appendix E: Imaging protocols ................................................................................................................................. 80 
Appendix F. Immunohistochemistry ........................................................................................................................ 82 
Appendix G: HCT-CI INDEX ....................................................................................................................................... 84 
 
 
 

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ABBREVIATIONS  
Abbreviation 
Meaning 
AE 
ALL 
AML 
Adverse Event 
Acute Lymphoblastic Leukemia 
Acute Myeloid Leukemia 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRC 
Clinical Research Coordinator 
CRF 
CRS 
Case Report Form 
Cytokine Release Syndrome 
CTCAE 
Cy 
Common Terminology Criteria for Adverse Events 
Cyclophosphamide 
DCC 
Data Coordinating Center 
DLT 
Dose Limiting Toxicity 
DSMC 
Data & Safety Monitoring Committee 
DSMP 
Data & Safety Monitoring Plan 
EOT 
End of Treatment 
FDA 
FM 
Food and Drug Administration 
Fludarabine/Melphalan 
GCP 
GRFS 
GVHD 
HCT 
Good Clinical Practice 
GVHD-free Relapse-free survival 
Graft-versus-Host Disease 
Hematopoietic Cell Transplantation 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug 
IRB 
MAC 
MDS 
Institutional Review Board 
Myeloablative Conditioning 
Myelodysplastic Syndrome 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NIH 
NRM 
National Institutes of Health 
Non-Relapse Mortality 
OCTM  
Office of Clinical Trials Monitoring 
OIDRA 
OS 
Office of IND Development and Regulatory Affairs 
Overall Survival 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Management Team 
PR 
RIC 
RIT 
Partial Response 
Reduced Intensity Conditioning 
Radioimmunotherapy 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable disease 
TBI 
Total Body Irradiation 
TMI 
Total Marrow Irradiation 
TMLI 
Total Marrow and Lymphoid Irradiation 
UT 
Unacceptable Toxicity 

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1.0 OBJECTIVES 
1.1 Primary Objective(s)  
o Describe toxicities attributable to 90Y-DOTA-anti-CD25 Basiliximab radioimmunotherapy by dose level in 
patients treated under this regimen. 
o Determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of 90Y-DOTA-anti-
CD25 Basiliximab radioimmunotherapy with fixed doses of organ sparing TMLI (12 Gy), fludarabine and 
melphalan (FM100) as conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) for 
treatment of High-Risk Acute Leukemias or Myelodysplastic Syndrome (MDS) or non-Hodgkin’s 
lymphoma (NHL), in patients who are not eligible for standard myeloablative regimens.     
1.2 Secondary Objective(s 
o Evaluate the safety of the regimen, at each dose level, by assessing the following: 
• 
type, frequency, severity, attribution, time course and duration of adverse events, including 
acute/chronic GVHD, infection and delayed engraftment. 
o Estimate overall survival (OS), event-free survival (EFS), GVHD relapse free survival (GRFS), cumulative 
incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years 
o Describe biodistribution, pharmacokinetics and organ dosimetry of 90Y-DOTA-basiliximab 
2.0 BACKGROUND 
2.1 Myeloablative Conditioning Regimens for HCT in Acute Myelogenous Leukemia (AML)  
Myeloablative radiation and chemotherapy containing conditioning regimens followed by allogeneic HSCT rescue 
is an important treatment modality to improve long-term survival in patients with AML in first remission (1-3) as 
well as patient with more advanced AML. The principal high-dose preparative or conditioning regimens 
administered before bone marrow transplantation include total-body irradiation (TBI) together with 
cyclophosphamide (CY) or other chemotherapy (4;5) (6;7).  Various studies utilizing different myeloablative 
regimen have shown a long-term survival for AML patients in first remission between 50-80% (2;8-13). Three-year 
survival rates after HCT for patients with refractory or relapsed acute leukemia are significantly worse at 20% and 
new and novel conditioning regimens are needed for this population (14;15).  
An alternative to CY/TBI treatment in pretransplant conditioning is the use of chemotherapy only, mostly busulfan 
and cyclophosphamide (BU/CY).  Two Bu/CY regimens are commonly used: Bu/CY4, busulfan 16 mg/kg and 
cyclophosphamide 200 mg/kg each given over 4 days, and Bu/CY2, busulfan 16 mg/kg given over 4 days and 
cyclophosphamide 120 mg/kg given over 2 days (16;17).  These regimens have been extensively studied in acute 
myelogenous leukemia (AML) and chronic myelogenous leukemia (CML). Several randomized trials have shown 
superior outcomes using fractionated total body irradiation (FTBI) compared with non-TBI containing regimens 
(11;18-21). 
2.1.1 
Allogeneic HCT for non-Hodgkin’s Lymphomas 
Although substantial therapeutic innovations in particular for B-cell lymphoma have entered the clinical stage 
recently, or are at the doorstep, Allogeneic HCT remains as a potential curative treatment for advanced non-
Hodgkin's lymphoma (NHL), especially for patients with chemo-refractory disease, relapsed after prior 
autologous HCT and those with relapsed lymphoma who failed to collect adequate stem cells for autologous 
HCT. Unfortunately, cure rates with allogeneic HCT is only 55% and potent conditioning regimens including 
radiotherapy in conditioning are needed to improve outcomes in this patient population. 

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2.2 Total Body Irradiation: The Earliest Form of Systemic Radiotherapy 
Since the initial pioneering efforts of Thomas and colleagues (22) radiation therapy continues to be an important 
part of conditioning regimens in patients undergoing hematopoietic cell transplantation (HCT). Radiation therapy 
is used primarily as a form of systemic therapy utilizing high energy photons and large fields to deliver total body 
irradiation (TBI). TBI is often part of the conditioning regimen in patients with leukemia undergoing allogeneic 
HCT. The primary indications for allogeneic HCT in acute myelogenous leukemia (AML) and acute lymphoblastic 
leukemia (ALL) are patients in first remission with intermediate to high risk features, induction failure, relapse, or 
in second remission or beyond. Patients with myelodysplastic syndrome (MDS) with high risk features or evolving 
to an acute state are also candidates for allogeneic HCT. The role of TBI in patients with multiple myeloma 
undergoing HCT is less well defined but has been used in patients undergoing autologous or allogenic HCT.  
There are several advantages to using TBI as part of the conditioning regimen. TBI is effective at eradicating 
malignant cells, which for most hematologic malignancies are very radiosensitive. TBI also provides a powerful 
means of immunosuppression to prevent rejection of donor hematopoietic cells in patients undergoing allogeneic 
HCT. TBI offers distinct advantages compared to chemotherapy. Delivery of radiation therapy to the tumor site is 
not dependent on blood supply or influenced by inter-patient variability of drug absorption, metabolism, 
biodistribution, or clearance kinetics. Radiation therapy can reach potential sanctuary sites, such as testes and 
brain. Chemotherapy resistant clones that develop may still be sensitive to irradiation. Finally, non-TBI 
chemotherapy only conditioning regimens offer no obvious advantage in reducing toxicities or improving control 
rates compared to TBI containing regimens (23-28). 
2.3 Limitations to TBI 
Understanding the limitations of TBI in the context of evolving strategies being used in HCT provide the basis for 
developing new more targeted radiotherapy approaches.  A major limitation is that the recent technological 
advances in image guided organ sparing IMRT delivery have not been applied to the delivery of TBI. The traditional 
methods of delivering TBI developed over 30 years ago, utilize large opposed whole body fields, and are the least 
conformal in radiation oncology (29). This can result in dose heterogeneity of over 30% which would be 
unacceptable in any other clinical scenario (30). Although lung blocking has reduced the risks of pneumonitis and 
lethal pulmonary toxicity, recent studies have demonstrated that mean lung doses below 8 Gy, which are 
challenging to achieve using conventional TBI delivery methods, are needed to further reduce lung toxicity risks 
and improve overall survival.   
A second challenge is the utilization of TBI is declining due to lack of new strategies to reduce TBI toxicities and 
the introduction of alternative non-TBI approaches. In a survey of the Center for International Blood and 
Transplant Research (CIBMTR) Database which surveyed 596 centers in 52 countries and included 219,341 
patients from 1995-2010, TBI utilization decreased for both autologous (13% to 2% p < 0.0001) and allogeneic HCT 
(53% to 39%, p < 0.0001)(31). Reasons for this decline include the additional resources needed to perform TBI and 
concerns for TBI related acute and late effects, including second malignancies (32). Patients older than age 60, 
with co-morbidities or with poor performance status are not able to undergo TBI. As a result there has been 
increasing use of chemotherapy only myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) 
regimens. In addition, the perspective of hematologists has evolved from viewing allogeneic HCT primarily as a 
cytotoxic tool to more of an immunologic tool which relies more on graft versus tumor effects for disease control.  
In an increasing number of clinical scenarios, TBI is no longer the primary modality but added when increased 
cytoreduction and immunosuppression are needed, and only if it can be added without significant additional 
toxicity.  
2.4 Development of Organ Sparing Targeted TMI and TBI Using IG-IMRT 
More targeted forms of TBI are needed to address these challenges and to redefine and expand the role of 
radiotherapy in HCT. Recent technological advances in radiotherapy systems now allow for the delivery of image 

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guided intensity modulated radiation therapy (IG-IMRT) to large regions of the body allowing for more targeted 
forms of TBI. These new forms of image guided targeted TBI are often referred to as total marrow irradiation (TMI) 
or total marrow and lymphoid irradiation (TMLI) and represent a spectrum of targeted TBI dose distributions now 
being performed at multiple institutions (Figure 2.1). The Tomotherapy HiArt System was the first system used 
to deliver targeted TMI which integrated CT image-guided radiotherapy and helical delivery of IMRT in a single 
device (33). The first delivery of TMI was in 2005 (34) . More recently, linear accelerators with volumetric arc-
based image guided IMRT capabilities have been used to deliver TMI and TBI (35-40). 
This approach offers the radiation oncologist and transplant team unprecedented control of TBI radiation dose 
delivery to target regions and organs. The physician can simultaneously reduce dose to critical organs or any other 
user-defined avoidance structure, while simultaneously increasing dose to target regions depending on the tumor 
burden and clinical situation.  Figure 2.1 shows conformal dose distribution patterns that have been delivered to 
designated target structures, with simultaneous reduction of dose to critical organs. The term TMI (total marrow 
irradiation) has been used if the target structure is bone, although it has also been used if additional sites of 
disease (i.e. extramedullary leukemia) have been targeted. The term TMLI (total marrow and lymphoid irradiation) 
has been used to reflect the addition of the major lymph node chains as target regions. In some studies and clinical 
scenarios liver, brain and testes have been included as target regions.  (41) 
Table 2.1 compares the median (D50) doses for various normal organs at risk (OAR) delivered through standard 
TBI to 12 Gy with 50% transmission blocks for lung shielding and electron boost to the underlying chest wall versus 
TMI to 12 Gy to the skeletal bone in an initial test case (34).  Significant reduction in dose and volume of organ 
receiving full dose is observed compared to standard TBI for all critical organs. Initial planning comparison studies 
Figure 2.1. conformal dose distribution patterns that have been delivered to designated target 
structures, with simultaneous reduction of dose to critical organs. The term TMI (total marrow 
irradiation) has been used if the target structure is bone, although it has also been used if additional 
sites of disease (i.e. extramedullary leukemia) have been targeted.  

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demonstrated that TMI could result in median organ doses that were approximately 15-65% of the prescribed 
dose to the target structure and predicted a reduction of acute and late toxicities compared to TBI. At TMI doses 
up to 20 Gy, median doses to all organs were still below that of TBI to 12 Gy. Comparison of lung DVH plots 
demonstrated that at 20 Gy TMI median (D50) lung doses remained below that of TBI 12 Gy with lung shielding 
and the D80 (minimum dose to at least 80% of the lung volume) was comparable, predicting for similar 
pneumonitis risks with TMI 20 Gy compared to TBI 12 Gy (34).  
 
Table 2.1. Comparison of median doses TMI versus TBI  
Organ at Risk 
 
Median Dose (Gy) TMI 
Median Dose (Gy) TBI 
TMI/TBI Median Dose 
Bladder 
7.5 
12.3 
0.61 
Brain 
7.1 
12.2 
0.58 
Breast 
7.7 
12.4 
0.62 
Esophagus 
4.9 
11.7 
0.42 
Orbits 
6.0 
12.0 
0.50 
Heart 
6.1 
11.5 
0.53 
Lens 
2.3 
10.5 
0.22 
Liver 
6.9 
11.7 
0.59 
Left Kidney 
7.4 
11.9 
0.62 
Right Kidney 
6.9 
11.9 
0.58 
Left Lung 
6.3 
9.0 
0.70 
Right Lung 
6.4 
9.7 
0.66 
Optic Nerve 
6.4 
12.3 
0.52 
Oral Cavity 
2.5 
12.5 
0.20 
Ovary 
7.0 
12.5 
0.56 
Parotids 
4.6 
13.1 
0.35 
Rectum 
4.8 
12.6 
0.38 
Small Intestine 
5.0 
12.5 
0.40 
Stomach 
4.6 
11.5 
0.40 
Thyroid 
4.4 
12.6 
0.35 
2.5 Dose escalation of TMI or TMLI to improve disease control in advanced refractory leukemia 
The available clinical data indicate that there is a dose response for acute leukemia, particularly with AML. Chak 
et al. (42) demonstrated local control rates for chloromas treated at 2 Gy per day of approximately 20% at doses 
less than 10 Gy, 40% at doses of 10-20 Gy and over 80% at doses of > 20 Gy. A dose response relationship is also 
suggested from the TBI experience. Retrospective studies have observed a decrease in relapse rate with higher 
TBI doses (43-45).  Two randomized phase II single institution trials have compared cyclophosphamide (Cy) 
combined with 12 Gy at 2 Gy/day or 15.75 Gy at 2.25 Gy/day. In a trial of 116 patients with CML in chronic phase, 
the higher dose resulted in a significantly lower relapse rate (0% versus 25% p = 0.008), but higher treatment 
related mortality (TRM) rate (24% 12 Gy and 34% 15.75 Gy, p = 0.13), and as a result no significant change in 
overall survival (46). In a separate report of 71 patients with AML in first remission, relapse rate was also decreased 
with the higher dose (14% versus 39% p = 0.06), but an increase in TRM rate was observed (38% versus 19%, p = 
0.05), resulting in no difference in overall survival between the two arms (47). In summary escalation of TBI dose 
has been difficult. Gains in disease control are offset by an increase in regimen related toxicities, resulting in no 
improvement in overall survival(48). TMI offers the potential to escalate dose to reduce relapse rates without a 
significant increase in acute or late toxicities due to critical organ sparing.  

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In younger patients (< 60 years of age) with acute leukemia dose escalation of TMLI has been feasible with 
acceptable toxicities. TMLI dose escalation was also evaluated in combination with Cy and VP-16 (49). A phase I 
trial in 51 patients with relapsed or refractory AML and ALL underwent a conditioning regimen of escalating doses 
of TMLI (range 12-20 Gy, days -10 to -6) with Cy (100 mg/kg day -3) and VP-16 (60 mg/kg day -5). Fifty patients 
had detectable blasts in marrow (median 52%, range 5-98% involvement) and 27 patients had circulating blasts in 
the week prior to HCT conditioning. Dose-limiting toxicity was observed in only one patient at the 15 Gy dose level 
(grade 3 mucositis Bearman scale (48) and no further dose limiting toxicities were observed up to 20 Gy. All 
patients engrafted without delays. The maximum tolerated dose was declared at 20 Gy since, as noted earlier, 
TMI planning studies resulted in comparable lung D80 doses and predicted pneumonitis risks compared to 
standard 12 Gy TBI. Treatment related mortality (TRM) rates were 3.9% at day 100 and 8.1% at one year. With a 
median follow-up of 24.6 months in surviving patients, the overall one-year survival was 55.5% and progression 
free survival 40.0%. The authors concluded that the TMLI/CY/Etoposide conditioning regimen was feasible with 
acceptable toxicities at TMLI doses up to 20 Gy and with encouraging results in this very poor risk population. A 
phase II trial is currently ongoing with the primary endpoint of 2 year progression free survival. Recently reported 
interim results for the Phase II study are similar to those previously reported for the phase I study (50). All patients 
engrafted. The complete remission rate at day +30 was 92%. With a median follow-up of 16.1 months, the two-
year estimates of overall survival (OS) and progression free survival (PFS) were 41% (95% CI:25-56) and 27% (95% 
CI: 13-42), respectively. Disease relapse/progression at 2 year was 64.6% (95% CI: 50-82). The estimates of TRM 
at 100 days and 1 year were 6% (95% CI: 1-21) and 8% (3-25). 
2.6 TMI or TMLI added to reduced intensity conditioning (RIC) regimens 
Older patients (older than age 55-60) or patients with co-
morbidities are often not able to tolerate standard myeloablative 
TBI containing regimens. For this population reduced intensity 
conditioning (RIC) regimens have been developed which utilize 
lower chemotherapy or TBI doses (51). These regimens are better 
tolerated, less cytotoxic, and rely more on the graft versus tumor 
(GVT) effects to eradicate disease. RIC regimens being less 
myeloablative can be associated with increased relapse rates. In a 
recent multi-center phase III randomized trial in patients with 
AML in first remission or with MDS, the relapse rate was 
significantly higher (48.3% versus 13.5%, p < 0.01) and the relapse 
free survival (RFS) rate was significantly lower (47.3% versus 
67.7%, p < 0.01), resulting in an 18 month overall survival 
difference of 67.7% versus 77.4% (p = 0.07) (52). Adding standard 
9 Gy TBI to an RIC regimen has resulted in unacceptable toxicities 
in adults (53). Recently a regimen of low dose TBI (2 Gy x 2) 
combined with fludarabine and reduce dose melphalan was 
better tolerated with improved survival and disease control 
compared to standard RIC regimen of fludarabine and melphalan 
(54).  
The addition of TMI to RIC regimens has the potential to improve 
outcomes with acceptable toxicities. In general trials have added 
myeloablative doses of TMI and TMLI to RIC. Rosenthal et al. (COH 
IRB 04199) evaluated the feasibility of combining TMLI (1.5 Gy 
BID, days -7 to -4) with the established RIC regimen of fludarabine (25 mg/m2/d Days -7 to -4) and melphalan (140 
mg/m2 Day -2) in patients who were ineligible for standard TBI myeloablative regimens due to age greater than 
Table 2.2. Mean organ doses in 61 patients 
treated with TMLI 
Organ 
Mean (range) 
Bladder 
8.2 (4.6-11.8) 
Brain 
7.3 (4.1-14.7) 
Breasts 
9.5 (7.6-11.9) 
Esophagus 
4.5 (2.8-6.1) 
Eyes 
5.1 (1.4-7.2) 
Heart 
6.1 (4.7-8.1) 
Kidneys 
6.0 (2.5-8.1) 
Lens 
2.2 (1.2-3.1) 
Liver 
6.9 (4.8-8.2) 
Lungs 
5.8 (4.7-7.2) 
Optic Nerve 
6.6 (3.7-13.6) 
Oral Cavity 
3.0 (1.7-5.5) 
Ovary 
7.0 (3.9-9.7) 
Parotids 
5.5 (3.0-9.0) 
Rectum 
4.7 (3.1-7.7) 
Small Intestine 
5.0 (3.5-6.8) 
Stomach 
4.6 (3.3-6.8) 
Testis 
7.5 (3.3-13.0) 
Thyroid 
6.3 (3.5-13.2) 

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50 years old or existing co-morbidities. (55;56). Study entry criteria required that marrow blasts be < 10% or 
reduced by over 50% after induction chemotherapy. The target structures for TMLI included bone, as well as major 
lymph node regions (TLI) and spleen to optimize the immunosuppression needed for allogeneic HCT and since 
these regions potentially harbored disease. Brain and testes were included as target regions in patients with ALL. 
Jensen et al. recently reported an update of this experience in 61 patients (56). The median patient age was 55 
years (range, 9-70 years) and the median follow-up was 7.4 years. The 72% of patients had acute leukemia and 
49% had high/very high-risk disease. The most common toxicity was mucositis. All patients engrafted without 
delays. Two-year OS, EFS, and TRM were 54%, 49%, and 30%, respectively. Five-year OS and EFS were 42% and 
41%. The addition of TMLI to Flu/Mel conditioning was feasible, with favorable outcomes and with a TRM rate 
that was comparable that previously reported for fludarabine and melphalan alone. At COH this regimen has been 
utilized in the most patients to date and continues to be used as a standard regimen years after closure of this 
trial.  
Table 2.2 shows median organ doses from the 61 patients treated with TMLI on IRB protocol 04199 titled 
“Allogeneic Stem Cell Transplantation with a Novel Conditioning Therapy Using Helical Tomotherapy, Melphalan, 
and Fludarabine in Hematological Malignancies” (56) 
Dose escalation of TMLI/Flu/Mel was not possible on a successor trial (IRB 08076) which attempted to dose 
escalate TMLI using the same conditioning regimen as 04199 in the same patient population. DLT was observed 
at the first dose level of 12 Gy. A phase I trial (IRB 17505) has been initiated to determine whether dose escalation 
is feasible if TMLI is delivered prior to fludarabine and melphalan compared to IRB 04199 which administered the 
fludarabine and TMI on the same days. In addition, the fludarabine and melphalan doses are reduced. This trial is 
ongoing and it is not clear whether dose escalation will be possible beyond 14-16 Gy due to GI toxicities and 
mucositis.  
2.7 Radioimmunotherapy, a Form of Biologically Targeted Systemic Radiotherapy 
TMLI is a form of targeted systemic radiotherapy that utilizes CT imaging to identify where to preferentially target 
radiotherapy. Radioimmunotherapy (RIT) is also a form of targeted systemic radiotherapy that utilizes monoclonal 
antibodies or related immunoconstructs linked to radionuclides to preferentially target cells that express a specific 
antigen. Radiolabeled antibodies have been evaluated as a form of therapy in solid tumors and hematopoietic 
malignancies. Several detailed reviews on this topic have been published (57;58).  
The following will focus on the use of RIT as a form of targeted TBI for leukemia. Table 2.3 lists just some of the 
antigens that radiolabeled antibodies have been developed against to target AML and ALL.  
Table 2.3. Radioimmunotherapy Target Antigens in Acute Leukemia 
Target  
Disease  
Expressed by  
CD33  
Myeloid 
leukemia  
Promyelocytes to mature myeloid cells 
AML blasts (not ALL blasts) 
Not hematopoietic stem cells or ALL blasts  
CD45  
AML, ALL  
Virtually all hematopoietic stem cells except plasma 
cells 
90% of AML and ALL  
CD66  
AML, ALL  
Mature myeloid and monocytic cells 
Not on AML blasts (relies on cross-fire effect)  
CD22  
ALL  
B-cell acute lymphoblastic leukemia  
RIT directed against CD33 has been evaluated as single modality therapy in pilot and phase I trials in acute myeloid 
leukemia. The CD33 antigen is a 67-kD glycoprotein expressed on most myeloid leukemias and leukemia 

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progenitors but not on normal stem cells. Anti-CD33 RIT has been developed and evaluated using the murine 
M195 and the HuM195 (linituzumab) humanized antibodies by the group at Memorial Sloan-Kettering Cancer 
Center (MSKCC). A phase I trial at MSKCC reported on the feasibility of administering 131I-CD33 antibodies (M195 
and HuM195) in 31 patients and demonstrated that dose escalation to 135mCi/m2 achieved myelosuppression 
and allowed 8 patients to proceed to bone marrow transplant, with three patients remaining in complete 
remission at 59, 87, and 90 months (59). Rosenblat et al. (60) evaluated HuM195 anti-CD33 radiolabeled with the 
α-emitter 213Bi administered after cytarabine in a Phase I/II trial in patients with newly diagnosed, refractory or 
relapsed AML. The RIT agent was shown to be tolerable at all dose levels. Due to the short half-life of 213Bi, 
HuM195 has recently been evaluated in a phase I trial labeled with the α-emitter 225Ac by the same group with 
an overall response rate of 29% reported (61).  
RIT has also been evaluated as part of conditioning regimens in patients with leukemia undergoing allogeneic 
HCT. RIT has been combined with established myeloablative or reduced intensity regimens. Table 2.4 lists select 
trials that have combined RIT with non-TBI conditioning regimens. Almost all trials have demonstrated the 
feasibility of combining RIT with established conditioning regimens and acceptable TRM rates. Results have been 
encouraging, although the experience to date has been limited to phase I and II trials, at a limited number of 
centers, and in a relatively small number of patients. 
Table 2.4. Select HCT Trials Combining RIT with Myeloablative or Reduced Intensity Conditioning 
Regimens 
First Author 
Year  
Antibody 
(target)  
No.  
Disease  
HCT  
Toxicities  
Burke 
2003 (59) 
Phase I  
131I-M195 or 
Hu195 
(CD33)  
31  
AML relapsed 
AML refractory 
CML-AP 
MDS advanced  
Bu/Cy  
TRM 65%  
Pagel 
2006 (62) 
Phase I/II  
131I-BC8 
(CD45)  
46  
AML CR1  
Bu/Cy  
3 yr TRM 
21%  
Pagel 
2009 (63) 
Phase I  
131I-BC8 
(CD45) 
58  
AML advanced 
MDS high risk 
Age > 50  
RIC: Flu+TBI (2Gy)  
1 yr TRM 
22%  
Mawad 
2014 (64) 
 Phase I  
131I-BC8 
(CD45) 
58  
AML advanced 
MDS high risk 
Age < 50  
RIC: 
Flu+TBI (2Gy)  
1 yr TRM 
0%  
Koenecke 
2008 (65) 
Phase I/II  
188Re-BW 
250/183 
(CD66) 
21  
AML high risk 
MDS advanced  
Bu/Cy or RIC  
1 yr TRM 
28.6%  
Ringhoffer  
2005 (66) 
Phase I/II  
188Re- or 90Y-
BW 250/183 
(CD66) 
20  
AML, MDS 
Age 55-65  
Flu + ATG or Mel  
Cumulative 
TRM 25%  
Lauter  
2009 (67) 
Phase II  
188Re-BW 
250/183 
(CD66) 
22  
AML advanced 
Age > 54  
RIC: Flu/Bu/campath 
2 yr TRM 
23%  

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HCT = hematopoietic cell transplantation; RIT = radioimmunotherapy; AML = acute myelogenous 
leukemia; CML-AP = chronic myelogenous leukemia in acute phase; MDS = myelodysplastic syndrome; 
CR = complete remission; CR1 = first complete remission; Bu = busulfan; Cy = cyclophosphamide; RIC = 
reduced intensity conditioning regimen; Flu = fludarabine; TBI = total body irradiation; Gy = Gray; ATG 
= anti-thymocyte globulin; Mel = melphalan; DFS = disease free survival; RFS = relapse free survival; 
OS =  overall survival; TRM = treatment related mortality. 
2.8 Dose escalation of TBI with the Addition of RIT 
As summarized earlier, attempts to dose escalate TBI by the Seattle group were not possible due to an increase in 
TRM related to an increase in toxicities (46;47), which were primarily mucositis, hepatic and renal (48). A number 
of groups have therefore evaluated radiation dose escalation by adding RIT to standard TBI (Table 5). Matthews 
et al. (68) combined 131I-BC8 anti-CD45 RIT with the myeloablative conditioning regimen of 12 Gy TBI and Cy is a 
phase I trial. RIT was escalated based on estimated dose to the bone marrow. One case of non-engraftment 
occurred with the combination of 12 Gy TBI and 31 Gy RIT. A RIT marrow dose of 24 Gy in combination with 12 Gy 
TBI was determined to be the MTD.  Bunjes et al. (69) combined 188Re labeled anti-CD66 RIT with myeloablative 
conditioning regimen which included TBI to 12 Gy. This agent has greater biodistribution and dose to kidney than 
other agents. Late renal toxicity was seen in 14% and in 4 of 6 patients if the total renal dose exceeded 12 Gy. 
Renal toxicity was reduced in a subsequent study of the same agent when renal shielding was utilized with TBI 
(70). 
Table 2.5. Select HCT Trials Combining RIT and TBI (12 Gy) 
First Author 
year  
Antibody 
(target)  
No.  
Disease  
HCT  
Toxicities  
Appelbaum  
1992 (71) 
Phase I  
131I-p67 
(CD33)  
4  
AML 
Relapse, 
 second CR  
Cy/TBI (12 Gy)  
  
Matthews 
1999 (68) 
Phase I  
131I-BC8 
(CD45)  
44  
AML, ALL 
beyond first 
remission  
Cy/TBI (12 Gy) 
One engraftment failure at 
31 Gy RIT + 12 Gy TBI  
Bunjes 
2002 (69) 
Phase I/II  
188Re-
BW 
250/183 
(CD66)  
57  
High risk AML 
and MDS 
< 25% marrow 
blasts  
Cy/TBI (12 Gy) 
TBI/Cy/TT 
Bu/Cy  
14% late renal toxicity 
Radiation nephropathy in 6 
patients (4/6 if > 12 Gy) 
26 month TRM 30%  
Zenz 
2006 (70) 
Phase I  
188Re-
BW 
250/183 
(CD66)  
20  
Ph+ ALL 
Advanced CML  
Bu/Cy or 
Cy/TBI (12 Gy) 
Kidney shielded 
to 6 Gy 
1 yr TRM 20%  
HCT = hematopoietic cell transplantation; RIT = radioimmunotherapy; AML = acute myelogenous 
leukemia; ALL = acute lymphoblastic leukemia; CML = chronic myelogenous leukemia; MDS = 
myelodysplastic syndrome; CR = complete remission; CR1 = first complete remission; NED = no 
evidence of disease; Bu = busulfan; Cy = cyclophosphamide; TT = thiotepa; TBI = total body irradiation; 
Gy = Gray; DFS = disease free survival; OS = overall survival; TRM = treatment related mortality 
2.9 The Rationale for Combining TMLI and RIT 
Studies to date demonstrate the promise of targeted systemic radiotherapy using either TMLI or RIT. Rather than 
being viewed as competing approaches, these two forms of targeted therapy should be viewed as complementary 
which when rationally combined can address the limitations of each modality. With RIT there is unintended 

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normal organ uptake, depending on the agent, to liver or kidney which limits dose escalation alone or when added 
to TBI. TMLI can significantly reduce doses to these organs without compromising dose to marrow and is better 
positioned to be combined with RIT than standard TBI. With RIT, doses to target areas such a bone marrow are 
subject to inter-patient variability and in general are lower than can be achieved with TMLI which is able to deliver 
higher doses to bone, bone marrow and lymph nodes with minimal variability between patients. TMLI dose 
escalation has proven to be challenging especially in the older population with mucositis and GI toxicities being 
the most common toxicity. The addition of RIT to TMLI will likely add additional dose to marrow and leukemia 
cells without a significant increase in mucositis. Finally, the addition RIT helps to address the theoretical concern 
of sparing of leukemia cells in circulation and in areas of reduced dose with TMLI.  
2.10 RIT Directed Against CD25 in Hematopoietic Malignancies 
CD25 is the interleukin-2 receptor α-subunit (IL-2αR) and is a 55 kD transmembrane glycoprotein. CD25 is 
expressed at high frequency by abnormal T and B cells in patients with lymphoid malignancies, and on Reed-
Sternberg cells and the surrounding lymphoid tissue in Hodgkin’s lymphoma.  There have been several RIT trials 
evaluating antibodies directed against CD25. 90Y is a radiometal commonly used in RIT and is a pure β emitter. The 
mean β emission range is approximately 2.7 mm compared to 0.8 mm for 131I. 90Y β emissions travel only a few 
mm and thus mainly affect the cells which are targeted or adjacent malignant cells through what is termed a cross-
fire effect.  
Waldmann and colleagues administered 90Y-murine anti-CD25 anti-Tac to 18 patients with adult T-cell leukemia 
lymphoma. The first 9 were treated in a dose escalation phase I trial and the remaining 9 patients in a subsequent 
phase II trial at 10 mCi per cycle. Administered doses ranged from 185 to 555 Mbq (5-15 mCi) per cycle with 
patients receiving up to 9 total cycles. For the phase I trial a total of 10 mg antibody protein and for the phase II 
trial 2-10 mg antibody protein was administered. Estimated organ doses for a patient receiving a 10 mCi 
administered dose was 105 cGy to the marrow, 228 cGy to the liver, and 336 cGy to the spleen. Tumor doses 
ranged from 140-243 cGy. The predominant toxicity was hematologic, with transient hepatotoxicity and 
proteinuria seen in 3 and 4 patients, respectively. They reported 2/16 complete responses (one for more than 3 
years duration) and 7/16 partial responses of 1.6 to 22.4 months duration (72).  
Dancey and colleagues reported results of a Phase I trial of 131I-basiliximab, a chimeric anti-CD25 monoclonal 
antibody, in 15 patients with Hodgkin’s and non-Hodgkin’s lymphoma (73). Dose levels were 370, 740, 1,480, 
2,220, and 2,960 MBq/m2 (10, 20, 40, 60, and 80 mCi/m2) Three complete response and 3 partial response were 
observed in 9 patients that received > 1.2 GBq/m2..  
A phase I trial also evaluated the humanized anti-CD25 daclizumab radiolabeled with 90Y in 46 patients with 
Hodgkin’s lymphoma. Fifteen mCi per cycle was given up to 7 cycles. Total cumulative activity ranged from 10-90 
mCi. Complete responses were observed in 14 patients and partial responses in 9 (74). The estimated tissue 
radiation dose per 15 mCi of 90Y-daclizumab was 173 cGy to bone marrow, 263 cGy to liver, 1,062 cGy to spleen, 
and 33 cGy to the whole body. The estimated tumor dose with 15 mCi ranged from 210 to 365 cGy. 
Anti-CD25 Basiliximab RIT has also been evaluated as part of the conditioning regimen in patients undergoing 
autologous HCT. AT COH IRB 08179 (PI Eileen Smith) is a Phase I trial recently completed which added 90Y-anti-
CD25 basiliximab radioimmuno-conjugate combined with BEAM conditioning prior to AHCT in patients with 
relapsed/refractory HL (aTac-BEAM). With 27 patients imaged with 111In-basiliximab pre-therapy, the 
biodistribution of the imaging agent was evaluated over the course of a week for the four cohorts treated at 0.3, 
0.4, 0.5 and 0.6 mCi/kg doses of 90Y-basiliximab. 25 patients received a therapeutic dose of 90Y-basiliximab-DOTA 
and proceeded to aTac-BEAM HCT. Administered activity ranged from 20.2 to 60 mCi. Of the 22 patients who 
received a therapeutic dose of 90Y-basiliximab-DOTA, 3 patients were treated at a dose of 0.3mCi/kg, 10 patients 
were treated at 0.4mCi/kg, 3 patients were treated at 0.5mCi/kg, and 6 were treated at 0.6mCi/kg (Table 2). No 
DLTs were observed at any dose level and 0.6mCi/kg was determined to be the recommended phase II dose. No 

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patients experienced graft failure after aTac-BEAM autoHCT. The median time to neutrophil engraftment was 10 
days (range, 9-14 days) and the median time to platelet engraftment was 12 days (range, 9-21 days). Following 
aTac-BEAM autoHCT, the best overall response and CR rate were 95% (21/22) and 91% (20/22), respectively. 
Seven (32%) patients relapsed.  The median follow-up time in surviving patients is 59 months (range, 18.3-65.7 
months).  
Dosimetry was performed to evaluate the radiation doses for 3 patients on each dose level, and two patients with 
altered biodistribution with potential lung uptake or elevated blood pool activity (one each on 0.4 and 06 mCi/kg 
dose). Whole body planar scans were acquired at 2, 24, 48, 120 and 144-168 hours post- 111In-anti-CD25 
basiliximab injection. Blood activity and urine clearance were used to calculate the red marrow dose and the 
residual activity in the body. Heart, liver, lungs, kidney and spleen were segmented on the images and were used 
to quantify the time activity curves (TACs) for the organs. Background-corrected organ activity measurements 
were further corrected for attenuation and overlying tissue activity. 111In-basiliximab time activity curves (TACs) 
were used to calculate 90Y-basiliximab TACs and the corresponding residence times which were then used to 
calculate (in OLINDA) the radiation doses to the different organs. Absorbed dose estimates were calculated using 
the standard adult human model in OLINDA/EXM (Table 1). A phase II trial is planned at a dose level of 0.6 mCi/kg. 
Table 2.6. Organ doses calculated in mGy/MBq and Gy/mCi (14 patients) 
Organ 
Average dose 
(mGy/MBq) 
Average dose  
(Gy/mCi) 
total dose (Gy) assuming 
administered activity of 45 mCi 
Heart wall 
10.30 
0.38 
17.17 
Kidneys 
5.20 
0.19 
8.67 
Liver 
6.30 
0.23 
10.50 
Lungs 
6.30 
0.23 
10.50 
Spleen 
13.10 
0.49 
21.83 
IRB 14349 (PI Jasmine Zain) also evaluated the same conditioning regimen in patients with peripheral T cell 
lymphomas (PTCL). CD25 is a targetable protein expressed differentially in PTCL.  From 07/29/2015 to 05/29/2018, 
14 PTCL patients underwent ASCT on this trial; n=4 at the 0.4mCi/kg dose, n=4 at the 0.5mCi/kg dose and n=6 at 
the 0.6mCi/kg dose. Patient characteristics are as follows: Median age at ASCT (years): 51(range: 18 – 76); Mature 
T-cell lymphoma, NOS n=7; alk-ve ALCL n=3; Angioimmunoblastic T-cell lymphoma n=2; and Intestinal T-cell 
lymphoma n=2; Disease status at HCT: 1CR n=12, 2CR n=2; Median number of prior therapies: 1 (1-2). No dose 
limiting toxicities were experienced. The 0.6mCi/kg dose level was declared as the recommended phase II dose. 
The most common/highest grade toxicity experienced (per Bearman Scale) was grade 2 stomatitis. 0.4mCi/kg n=3; 
0.5 mCi/kg n=4; 0.6mCi/kg n=3. The only other grade 2 toxicities seen were: at 0.4mCi/kg dose n=2 grade 2 GI and 
at 0.6mCi/kg dose n=1 grade 2 bladder. Toxicities >grade 2 were not seen. Issues with engraftment were not seen, 
Median FU (months) was 14.4 (range: 0.9-26.2). There were complete responses in 8 and relapses in 4. Overall 
Survival at 100-days was 100% (95% CI: N/A) and at 1-year 89% (95% CI: 43-98). Non-relapse mortality at 100-days 
and 1-year, 0% (95%CI: N/A). The combination of 90Y- basliximab plus BEAM was safe as a conditioning regimen 
for PTCL with no added toxicities seen undergoing transplants.  
Recently, Conlon et al. reported on 4 patients with refractory and relapsed Hodgkin’s disease with 3 patients who 
received a single dose of 90Y-anti CD25 daclizumab (564.6 - 574.6 MBq or 15.26 – 15.53 mCi) and the fourth patient 
two doses of 580.9 to 566.1 MBq (15.7 – 15.3 mCi) and BEAM conditioning followed by AHCT. Four of 6 patients 
achieved CR and remain in CR 4.5-7 years out from transplant (75). 

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2.11 Rationale for Anti-CD25 in Leukemia 
Saito et al. (76) examined CD25 expression on the surface of leukemia stem cells from 61 patient samples. CD25 
was expressed on the cell surface in 24.6% of the cases. CD25 positive cells from AML patients initiated AML when 
transplanted into mice. CD25 expression was seen on the cell cycle quiescent AML-initiating cells residing within 
the endosteal niche that may be responsible for AML relapse, indicating that CD25 is expressed by leukemia stem 
cells. Elimination of normal human CD25 expressing hematopoietic stem cells did not compromise normal 
hematopoietic development. For these reasons the authors concluded that CD25 directed therapies to AML 
leukemia stem cells in the consolidation or pre-transplant conditioning period should be explored and have 
therapeutic promise since CD25 was frequently expressed in AML patients in which 85% were poor risk and in 
need of more effective therapies.  
These findings are consistent with the findings of Terwijn et al (77), who analysed by flow cytometry CD25 
expression of AML blasts in 72 newly diagnosed patients with AML. Patients with CD25 expression of >10% had a 
significantly shorter overall survival (p=0.0005) and relapse free survival (p=0.005). In multi-variate analysis, CD25 
expression was an independent prognostic factor. In addition, after the first cycle of chemotherapy there was 
significantly higher rate of minimal residual disease (MRD) in patients with higher CD25 expression.  
In B lymphoblastic leukemia/lymphoma CD25 expression was greater in Ph+ patients (80%) than Ph – patients 
(17%). In addition in Ph- patients CD25 expression was associated with an increased incidence of residual disease 
(78). 
Finally, Waldmann and colleagues administered 90Y-murine anti-CD25 anti-Tac to 18 patients with adult T-cell 
leukemia lymphoma. The first 9 were treated in a dose escalation phase I trial and the remaining 9 patients in a 
subsequent phase II trial at 10 mCi per cycle. Administered doses ranged from 185 to 555 Mbq (5-15 mCi) per 
cycle with patients receiving up to 9 total cycles. For the phase I trial a total of 10 mg antibody protein and for the 
phase II trial 2-10 mg antibody protein was administered. Estimated organ doses for a patient receiving a 10 mCi 
administered dose was 105 cGy to the marrow, 228 cGy to the liver, and 336 cGy to the spleen. Tumor doses 
ranged from 140-243 cGy. The predominant toxicity was hematologic, with transient hepatotoxicity and 
proteinuria seen in 3 and 4 patients, respectively. They reported 2/16 complete responses (one for more than 3 
years duration) and 7/16 partial responses of 1.6 to 22.4 months duration (72).  
Both Hodgkin’s Lymphoma and NHL malignant cells have demonstrated expression of CD25 [2, 3]. NHL tumors 
with high levels of surface CD25 expression include DLBCL, follicular lymphoma, peripheral T cell lymphoma 
including angioimmunoblastic T cell lymphoma and anaplastic large cell lymphoma[4], and anti-CD25 drugs 
including 131I-basiliximab. LMB-2, and ADCT-301 have been used in treatment of NHL in phase 1 and 2 trials[4]. 
2.12 Study Rationale 
This is a single-institution, non-randomized phase I trial to determine the maximum tolerated dose/recommended 
phase II dose (MTD/RP2D) of 90Y-DOTA-anti-CD25 Basiliximab MAB in combination with fixed doses of fludarabine, 
melphalan and 1200 cGy TMLI as part of the conditioning regimen to patients with high-risk acute leukemia 
(lymphocytic or myelogenous), myelodysplastic syndrome, or non-Hodgkin’s Lymphoma (NHL) who undergo 
alloHCT with matched related/unrelated. The rationale for combining TMLI and RIT is detailed in Section 2.9 and 
the rationale for administration of anti-CD25 in leukemias and NHL could be found in Section 2.11. 
 
 

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3.0 ELIGIBILITY CRITERIA 
Participants must meet all of the following criteria on screening examination to be eligible to participate in the 
study:  
3.1 Patient Inclusion Criteria 
Informed Consent  
Documented informed consent of the participant and/or legally authorized representative. 
 
Assent, when appropriate, will be obtained per institutional guidelines 
Age Criteria, Performance status, Language 
__1. Age  ≥ 18 years old 
 
__2. Karnofsky performance status ≥70 (see Appendix A) 
Nature of Illness and Illness Related Criteria 
__3. Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one 
of the following categories : 
• 
Acute myelogenous leukemia: 
__Patients with de novo or secondary disease in unfavorable risk group including poor risk 
cytogenetics according to NCCN guidelines for AML[5] i.e., monosomal karyotype, -5,5q-,-7,7q-
,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated 
abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ 
disease, OR 
__Patients with a complete morphological remission (CR) with MRD-positive status by flow 
cytometry (≥ 0.1% by flow cytometry) or cytogenetic after at least 2 prior induction therapies, 
OR 
__Patients with chemosensitive active disease defined as at least 50% reduction in their blast 
count after last treatment. 
• 
Acute lymphocytic leukemia: 
__Patients with de novo or secondary disease according to NCCN guidelines for ALL[6] hypoploidy 
(<44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or 
more chromosomal abnormalities); high WBC at diagnosis (≥ 30,000 for B lineage or ≥50,000 for 
T lineage); iAMP21loss of 13q, and abnormal 17p [7], OR 
__Patients with a CR with MRD-positive status by flow cytometry (≥ 0.1% by flow cytometry) or 
cytogenetics after at least 2 prior induction therapies, OR 
__Patients with chemosensitive active disease defined as at least 50% reduction in their blast count 
after last treatment. 
• 
Myelodysplastic syndrome in high-intermediate (int-2) and high-risk categories per IPSS-R [8] 
• 
T cell Non-Hodgkin’s Lymphoma with a confirmed diagnosis as defined by WHO 2022 criteria[9] 
including but not limited to PTCI-nos, TFH- T cell lymphoma, ALCL, HSCTCL, Intestinal T cell 
lymphoma, cutaneous T cell lymphoma including TMF, and ATLL. Diagnosis should be confirmed 
at COH. 

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__4. Demonstration of CD25 expression by flow cytometry for patients with leukemia or MDS.  
__5. Demonstration of CD25 tumor cell expression by flow cytometry or immunohistochemistry for 
patients with NHL 
Clinical Laboratory and Organ Function Criteria (To be performed within 30 days prior to Day 1 of protocol therapy unless 
otherwise stated) or (acceptable windows for tests are indicated in the Study Calendar Section 10.0). 
__6. A pretreatment measured creatinine clearance (absolute value) of ≥60 ml/minute. 
__7. Patients must have a serum bilirubin ≤2.0 mg/dl (unless has Gilbert’s disease), SGOT and SGPT ≤2.5 
times the institutional upper limits of normal. 
__8. Ejection fraction measured by echocardiogram or MUGA ≥50% 
__9. DLCO and FEV1 > 50% predicted. 
Contraception 
__10. Agreement by females and males of childbearing potential* to use an effective method of birth 
control or abstain from heterosexual activity for the course of the study through at least 6 months after 
the last dose of protocol therapy. … 
* Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses 
for > 1 year (women only).  
3.2 Patient Exclusion Criteria 
Prior and concomitant therapies 
__1.  Patients who had a prior allogeneic transplant. 
__2.  No prior transplant BCNU conditioning 
__3.  All patients with prior radiation treatment to the lung, liver, and kidney.  
__4.  Patients who have received prior total skin electron beam therapy for lymphoma. 
__5.  Patients who have received prior radiopharmaceutical therapy. 
__6.  Inclusion of other patients with previous radiation exposure will be determined based on the radiation 
oncologist MD PI evaluation and judgement.  
__7.  Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation 
therapy for the previous 2 weeks from conditioning.  
__8.  Patients should have discontinued all previous intensive therapy, chemotherapy, or radiotherapy for 2 
weeks prior to commencing therapy on this study. Note: Low dose chemotherapy or maintenance chemotherapy 
given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral 
methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given 
up to 3 days before conditioning regimen. 
Other illnesses or conditions 
__9.  History of allergic reactions attributed to compounds of similar chemical or biologic composition to study 
agent 
__10.  Patients with other active malignancies are ineligible for this study, other than non-melanoma skin 
cancers. 
__11.  Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal 
infection.  

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__12.  The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her 
ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic 
recovery which in the opinion of the investigator (treating physician) would place the recipient at unacceptable 
risk. 
__13.  Females only: Pregnant or breastfeeding 
__14.  Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation 
in the clinical study due to safety concerns with clinical study procedures. 
Noncompliance 
__15.  Prospective participants who, in the opinion of the investigator, may not be able to comply with all study 
procedures (including compliance issues related to feasibility/logistics). 
 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
3.3 Donor Specific Criteria 
All candidates for this study must have an HLA (A, B, C, and DR) identical sibling who is willing to donate 
mobilized peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele 
matched unrelated donor. DQ or DP mismatch is allowed per discretion of the Principal Investigator. COH SOP 
(B.001.11) will be used for allogeneic donor evaluation, selection, and consent. Donor screening will be in 
compliance with all requirements of FDA regulation 21 CFR Part 1271 including donor screening for COVID-19 
exposure or infection.  
 
 
 

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4.0 PARTICIPANT ENROLLMENT, ASSIGNMENT  
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after obtaining 
written informed consent. Studies or procedures that are performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values and/or to determine pre-eligibility, even if the 
studies were done before informed consent was obtained. 
The informed consent process is to be fully documented (see Section 17.4), and the prospective participant must 
receive a copy of the signed informed consent document. Screening procedures are listed in Section 10.0 (Study 
Calendar). 
4.2 Participant Enrollment 
Registration of participants will be according to the following steps: 
Prospective participants must complete the informed consent process, including a signed informed consent, 
prior to proceeding to study screening. 
Once all the pre-study requirements have been fulfilled, including a completed eligibility checklist (Section 3.0) 
the study coordinator will register the eligible patient into the OnCore Clinical Trials Management System. 
Patients failing to meet all protocol eligibility criteria, including informed consent, may not be registered for the 
trial. 
Eligible participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City of 
Hope.   
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except 
holidays).  
E-mail: DCC@coh.org 
4.2.1 
Slot verification and reservation 
A designated study team member should email the DCC to verify current slot availability, and to reserve a slot 
for a specific prospective subject (provide DCC with subject initials), including a tentative treatment date. Slots 
can only be held for a limited time, at the discretion of the study PI. 
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible.   
4.2.2 
Registration Process  
Allow up to 24 hours for the DCC to review. To register a participant the following procedure must be followed: 
1. The study team should contact the DCC via email to provide notification regarding the pending 
registration and communicate desired timeline of the registration, especially if it must be completed 
promptly to meet the registration window.  
2. The study team will email a Complete Registration Packet to the DCC, which consists of a copy of the 
following documents: 
Completed eligibility checklist (printed from Section 3.0 of the protocol) with required signature(s) 
Signed Informed Consent  
Signed HIPAA authorization form (if separate from informed consent) 
Signed subject’s bill of Rights (California only) 

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3. When all documents are received, the DCC will review and work with the study team to resolve any 
missing elements. Any missing documents may delay registration.  A participant failing to meet all 
requirements will not be registered and the study team will be immediately notified. 
4. The DCC will send a Confirmation of Registration Form, including the Subject Study Number and cohort 
assignment to:  
The COH Study PI and COH study team designees (including but not limited to study monitor(s) and 
statistician(s)). 
5. Upon receipt of the Confirmation of Registration Form, COH study team will register the patient in OnCore.  
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC immediately if the participant screen fails after registration or if the participant does not start 
treatment. 
Issues that would cause treatment delays should be discussed with the Study Principal Investigator. 
4.4 Dose Level Assignment 
During the dose escalation stage, eligible Phase 1 participants will be assigned a dose level (Section 5.3) based 
on the study design rules (Section 12.1). Escalation/de-escalation to the next dose level, patient replacement, or 
expansion of a dose level must be approved by the study PI and biostatistician, who will inform the DCC prior to 
enrollment of the next patient.  
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This is a single-institution, non-randomized phase I trial to determine the maximum tolerated dose/recommended 
phase II dose (MTD/RP2D) of 90Y-DOTA-anti-CD25 Basiliximab MAB in combination with fixed doses of fludarabine, 
melphalan and 1200 cGy TMLI as part of the conditioning regimen to patients with high-risk acute leukemia 
(lymphocytic or myelogenous), myelodysplastic syndrome (MDS), or Non-Hodgkin’s Lymphoma (NHL) who 
undergo alloHCT from a matched related/unrelated donor.  
Dose escalation will be based on a modified rolling 6 Phase I design with dose level 1 starting at 0.3 mCi/kg and 
escalating in increments of 0.2 to a maximum of 0.5 mCi/Kg (dose level 3). There will also be a dose level -1 of o.2 
mCi/Kg in the case that dose level 1 is too toxic. 
5.2 Cycle Definition 
There will be only one cycle of treatment for this study. 
5.3 Treatment Plan 
The conditioning regimen will start on day -15 or day -14 consisting of an infusion of 5 mg cold basiliximab followed 
by the radiolabeled dose of 5 mg of antibody protein 111In-DOTA-anti CD25 Basiliximab Mab (5 mCi) and 90Y-DOTA-
anti-CD25 Basiliximab (therapy mCi activity). 
This will be followed by serial blood (5 cc) samples at approximately time 1-2 hours, 3-4 hours, and at scan times 
of 1 day and 5/6 days after radiolabeled antibody infusion.  Blood samples will be analyzed for total activity and 

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by radiometric HPLC.  These studies will acquire data on antibody 
metabolism and pharmacokinetics. Planar serial nuclear scans will be 
performed at Day 0, Day 1 and Day 5/6. A SPECT scan will be performed at 
Day 1. 
A maximum administered activity will be capped at 45 mCi regardless of 
dose level.  
(Note: The dose of In-111 or Y-90 administered may be +/- 20% of 
prescribed dose in accord with Nuclear Regulatory Commission Guidelines.) 
5.3.1 
Pre-dosing with unlabeled anti-CD25 antibody (basiliximab) 
Prior to the infusion of radiolabeled antibody (combined 111In-/90Y- basiliximab/DOTA on day -15), 5 mg unlabeled 
“cold” anti-CD25 antibody (basiliximab) will be administered intravenously to block the circulating soluble antigen 
(sCD25) and to improve the radioimmunoconjugate biodistribution and tumor targeting of the radiolabeled 
basiliximab.  Pre-medication with acetaminophen and diphenhydramine will be given 30-60 minutes prior to the 
cold antibody infusion (alternative pre-medication for patients who are allergic to acetaminophen and/or 
diphenhydramine to be discussed with the study P.I.). Basiliximab should be administered as an intravenous 
infusion over 20-30 minutes.  The infusion of cold basiliximab should be completed within 1-2 hours prior to the 
administration of the radiolabeled antibody. 
5.3.2 
Administration of 111In- and 90Y- basiliximab/DOTA 
111In- and 90Y- basiliximab/DOTA will be administrated intravenously. The radioimmunoconjugate for the day -15/-
14 therapeutic infusion will be prepared in a single syringe containing 5 mg of basiliximab conjugated to the non-
myeloablative, therapeutic dose of either 0.3, 0.4, or 0.5 mCi/kg 90Y, plus 1 mg of basiliximab conjugated to 5 mCi 
111In for imaging.   
Within 1-2 hours following the completion of the “cold” basiliximab infusion, the patient will be given the 
therapeutic dose of 90Y-basiliximab/DOTA (along with 5 mCi 111 In-basiliximab/DOTA in the same syringe).  
Maximum dose = 45 mCi 90Y-basiliximab/DOTA.  The combined 111In/90Y-basiliximab/DOTA dose will be 
administered IV using a syringe pump over approximately 20-40 min.  Line will then be flushed with at least 10ml 
of normal saline.  
Nursing and physician personnel will be present at all times during the administration of the radiolabeled 
antibody.  Nursing personnel will be present for 2 hours following administration of the radiolabeled antibody.  
An “Emergency Drug Reaction Kit” will be at the bedside. VS will be monitored prior to administration and every 
5–15min during administration and the immediate post administration period x 1hr, then at 3-4 hr time point 
when pharmacokinetic blood samples are drawn. After study drug administration, the IV will be flushed with 
normal saline, then set at TKO during the immediate post, and up to 2 hours post administration period, for use if 
necessary, during an adverse event. If pt is stable after 2 hours, may DC IV and discharge patient. Pt to return for 
blood draw at the 3-4 hour time point post end of infusion of study drug.  
After 111In/90Y-basiliximab/DOTA administration on day -15/-14, serial gamma camera images will be obtained as 
defined above.  Nuclear scan images will be used to estimate the distribution of activity and absorbed radiation 
doses in various normal organs, especially liver, lungs, kidney, heart and spleen.  After 111In/90Y-basiliximab/DOTA 
administration on day -15/-14, blood samples will be collected as defined above.  Blood samples will be used for 
analysis of antibody clearance, metabolism and pharmacokinetics. 

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5.3.3 
TMLI, and Flu/Mel 
One week after the infusion of the 111In/90Y-DOTA-anti-CD25 Basiliximab, the patient will receive 1200 cGy of 
TMLI delivered over 4 days (days -8 to -5), fludarabine 30 mg/m² based on adjusted body weight (days -4 to -2) 
and melphalan 100 mg/m2 (day -2). 
Each fraction of TMLI is 150 cGy, with two fractions delivered each day for 4 days.  There will be a minimum of 6 
hours between each fraction.  Treatment will utilize helical tomotherapy (6MV) or rapid arc IMRT as a means of 
conformal avoidance or minimization of radiation dose to normal organs.   
• 
The target region will include bone marrow compartments and major lymph node regions (mediastinal, 
para-aortic, pelvic) 
• 
Brain and testes will be treated to 1200 cGy for patients with ALL.  
• 
Avoidance organs with dose sparing include brain (except ALL), liver, spleen, eyes, lens, parotids, 
thyroid, esophagus, oral cavity, lungs, heart, kidneys, stomach, upper GI and lower GI tract, rectum, 
bladder, and in women breast, uterus and ovaries.  
• 
Mean organ dose constraints for right and left lung 4 Gy, right and left kidney 4 Gy, liver 4 Gy and heart 
6 Gy.  
5.3.4 
GVHD prophylaxis 
Patients will receive a loading dose of and Sirolimus (12mg) once on day -1 then 4 mg daily starting on day 0 and 
tacrolimus 1mg CIV/daily starting on day -1. 
5.4 Agent Administration and Pre-medications 
Fludarabine, melphalan, tacrolimus, and sirolimus will be administered per City of Hope HCT Standard Operating 
Procedures (COH intranet SOPs)  
See Sections 5.3.1.1 and 5.3.1.2 for Pre-dosing with unlabeled anti-CD25 antibody (basiliximab) and 
Administration of 111In- and 90Y- basiliximab/DOTA, respectively. 
5.5 Special Assessments and Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 10.0.  
5.6 Duration of Protocol Therapy and Criteria for Removal 
Initial therapy will require ~4 weeks of inpatient treatment during transplantation 
Participants will receive protocol therapy until one of the below criteria are met: 
o (Confirmed) Disease progression  
o Completed full prescribed protocol therapy 
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose modification/ 
delay  
 
Note: If one agent is discontinued due to toxicity, then the participant may continue to receive the 
other study agents  
General or specific changes in the patient's condition which render the patient unacceptable for further 
treatment in the judgment of the investigator 
Withdrawal of consent for further protocol therapy (See Section 17.5) 

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Once participants meet criteria for removal from protocol therapy, the participant should then proceed to End 
of Treatment assessments, and then to follow-up (Refer to the Follow-Up section below). 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF. 
5.7 Follow-Up 
Outpatient follow-up will be twice weekly for the first 100 days post-transplant, twice monthly until 6 months 
post-transplant, and monthly until the patient discontinues immunosuppressive therapy without evidence of 
GVHD (see Study Calendar Section 10.0), with at least yearly study follow-up extending 2 years beyond the date 
of stem cell infusion. Patients will be encouraged to be co-enrolled in the COH long-term follow-up protocol for 
allogeneic transplantation (Protocol #00029) and Protocol #07173 Correlating Organ Dose and Dose-Volume with 
Toxicities after Total Marrow Irradiation (TMI) Using Helical Tomotherapy in Patients Undergoing Hematopoietic 
Cell Transplantation (HCT). Once a patient has relapsed after transplant, the subject will be taken off trial and 
followed only for survival, and the study calendar requirements are no longer required. 
5.8 Duration of Study Participation 
Study participation may conclude when any of the following occur: 
o Completion of study activities (treatment and 2 years of follow-up after protocol treatment) 
o Withdrawal of consent (Refer to Withdrawal Section for Ethical Considerations) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative reasons. 
Documentation of the reason for discontinuing study participation and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF.  
5.9 Concomitant Therapies/Medications  
Participant should receive prophylactic or supportive care as indicated in instructional policies.  
5.10 Supportive care 
Participants should receive prophylactic or supportive as clinically indicated per institutional policies. 
6.0 ANTICIPATED ADVERSE EVENTS 
6.1 Basiliximab 
  Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been reported for 
both on initial exposure to basiliximab and following re-exposure.  These reactions include hypotension, 
tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, 
rash, pruritus, and/or sneezing, as well as capillary leak syndrome and cytokine release syndrome.  If a severe 
hypersensitivity reaction occurs, therapy with basiliximab should be permanently discontinued. Medications for 
the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. 
Per the basiliximab package insert, of renal transplantation patients treated with basiliximab (Simulect®) and 
tested for anti-idiotype antibodies, 4/339 developed an anti-idiotype antibody response, with no deleterious 
clinical effect upon the patient.  In none of these cases was there evidence that the presence of anti-idiotype 
antibody accelerated Simulect® clearance or decreased the period of receptor saturation.  In Study 2, the 

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incidence of human anti-murine antibody (HAMA) in renal transplantation patients treated with Simulect® was 
2/138 in patients not exposed to muromonab-CD3 and 4/34 in patients who subsequently received 
muromonab-CD3.  The available clinical data on the use of muromonab-CD3 in patients previously treated with 
Simulect® suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody 
preparations is not precluded. 
6.2 
111In-Basiliximab/DOTA 
There are no additional acute drug toxicities associated with the In-111 labeled basiliximab above that 
associated with the basiliximab alone.  There is a small risk from the radiation exposure of the In-111 considered 
appropriate for the patient population under study. 
6.3 
90Y-Basiliximab/DOTA 
There are no additional acute drug toxicities associated with the Y-90 labeled basiliximab above that associated 
the basiliximab alone except for occasional nausea and diarrhea.  The radiation exposure of the Y-90 in 
combination with the high-dose chemotherapy conditioning regimen will cause severe myelosuppression 
requiring hematopoietic stem cell support.  There is potential for radiation damage to heart, lung, kidney, and 
liver.  There is a risk for developing secondary malignancies. 
6.4 Fludarabine 
Human Toxicity: The major human toxicity has been myelosuppression. At higher dose levels or in patients with 
renal impairment, central nervous system toxicity has been seen and is characterized by numbness, paraparesis 
and cortical blindness. 
6.5 Melphalan 
Human Toxicity: The dose-limiting toxicity of melphalan is myelosuppression. Other toxicities after IV melphalan 
include mucositis, nausea, vomiting, and diarrhea. Alopecia is generally seen only with high doses associated 
with bone marrow transplant settings. Rarely reported reactions include pulmonary fibrosis, skin rash, vasculitis, 
and allergic reactions. With high dose chemotherapy, gastrointestinal toxicity becomes dose limiting. At such 
high doses, elevated transaminases, syndrome of inappropriate antidiuretic hormone secretion, depression, 
interstitial pneumonitis, and hepatic veno-occlusive disease have been reported. Acute non-lymphocytic 
leukemia and myeloproliferative syndromes may occur as secondary cancers from any alkylating agent such as 
melphalan. Amenorrhea, permanent in many cases, have been noted when melphalan was used in 
premenopausal women undergoing adjuvant therapy for breast cancer. Azoospermia would be expected, but is 
not well documented in the literature. 
6.6 TMLI 
Acute toxicities: Toxicities from TMLI may include bone marrow suppression, alopecia, fatigue, and skin erythema. 
Other acute toxicities, which occur with traditional total body irradiation and may also occur with TMI, include 
mucositis, esophagitis, enteritis, cystitis, proctitis, pneumonitis, nausea and vomiting, and sterility.  
Potential Late Toxicities: Because of conformal avoidance of dose to normal organs, late toxicities from TMI are 
anticipated to be less frequent and/or severe compared with total body irradiation. Potential late toxicities may 
include sterility, endocrinopathies (i.e., hypothyroidism), cataract formation, pneumonitis, veno-occlusive 
disease, and second malignancy induction. 

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6.7 Tacrolimus 
Human Toxicity: Common toxicities: anorexia, constipation, nausea, vomiting, myelosuppression. Less common: 
Convulsions, anaphylaxis, hemiparesis, dizziness, ataxia, confusion, dysphagia, anxiety, thrombo-embolism; 
prolonged lymphopenia with increased risk of infection or death, amnesia, insomnia, depression, myalgia, 
diplopia, visual changes; Secondary tumors or cancer. 
6.8 Sirolimus 
Human Toxicity: The most common (> 30%) adverse reactions are: peripheral edema, hypertriglyceridemia, 
hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary 
tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. 
7.0 DOSE DELAY / MODIFICATION GUIDELINES  
The treatment involves a single cycle of the planned regimen; there are no planned dose delays. One dose 
reduction (dose level -1) to 0.2 mCi/kg will be considered if dose limiting toxicity is seen at 0.3 mCi/kg (dose level 
1). Dose levels above 0.5 mCi/kg will not be considered, as radiation exposure to non-targeted organs would 
approach levels received during standard myeloablative TBI. 
8.0 AGENT INFORMATION 
8.1 Basiliximab 
Simulect® (basiliximab) is a chimeric (murine/human) monoclonal antibody (IgG1k), produced by recombinant 
DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the 
interleukin-2 receptor a-chain (IL-2Ra, also known as CD25 antigen) on the surface of activated T-lymphocytes. 
Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kilodaltons. It is a 
glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to 
express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light 
chain variable region genes encoding the RFT5 antibody that binds selectively to the IL-2Ra.  Simulect® is indicated 
for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an 
immunosuppressive regimen that includes cyclo-sporine, USP (MODIFIED) and corticosteroids.  The efficacy of 
Simulect® for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been 
demonstrated. 
A. 
Drug formulation and Procurement 
  The active ingredient, basiliximab, is water soluble. The drug product, Simulect®, is a sterile lyophilisate which is 
available in 6 mL colorless glass vials and is available in 10 mg and 20 mg strengths.  Each 10 mg vial contains 10 
mg basiliximab, 3.61 mg monobasic potassium phosphate, 0.50 mg disodium hydrogen phosphate (anhydrous), 
0.80 mg sodium chloride, 10 mg sucrose, 40 mg mannitol and 20 mg glycine, to be reconstituted in 2.5 mL of 
Sterile Water for Injection, USP.  No preservatives are added.  Each 20 mg vial contains 20 mg basiliximab, 7.21 
mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium 
chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for 
Injection, USP.  No preservatives are added.  Basiliximab will be purchased from Novartis Pharmaceutical Corp. in 
20 mg glass vials. 
b. 
Drug storage, Reconstitution and Stability 
  The active ingredient, basiliximab, is water soluble. The drug product, Simulect®, is a sterile lyophilisate which is 
available in 6 mL colorless glass vials and is available in 10 mg and 20 mg strengths.  Each 10 mg vial contains 10 

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mg basiliximab, 3.61 mg monobasic potassium phosphate, 0.50 mg disodium hydrogen phosphate (anhydrous), 
0.80 mg sodium chloride, 10 mg sucrose, 40 mg mannitol and 20 mg glycine, to be reconstituted in 2.5 mL of 
Sterile Water for Injection, USP.  No preservatives are added.  Each 20 mg vial contains 20 mg basiliximab, 7.21 
mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium 
chloride, 20 mg sucrose, 80 mg mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for 
Injection, USP.  No preservatives are added.   
Simulect® is for central or peripheral intravenous administration only. Reconstituted Simulect® should be given 
either as a bolus injection or diluted to a volume of 25 mL (10 mg vial) or 50 mL (20 mg vial) with normal saline or 
dextrose 5% and administered as an intravenous infusion over 20 to 30 minutes.  Bolus administration may be 
associated with nausea, vomiting and local reactions, including pain.  
Parenteral drug products should be inspected visually for particulate matter and discoloration before 
administration.  After reconstitution, Simulect® should be a clear to opalescent, colorless solution.  If particulate 
matter is present or the solution is colored, do not use.  
Care must be taken to assure sterility of the prepared solution because the drug product does not contain any 
antimicrobial preservatives or bacteriostatic agents.  
It is recommended that after reconstitution, the solution should be used immediately.  If not used immediately, it 
can be stored at 2ºC to 8ºC for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if 
not used within 24 hours. 
8.2 
111In-Basiliximab/DOTA 
a. Drug formulation and Procurement 
Basiliximab will be conjugated with DOTA-NHS in the CBG facility at the City of Hope under cGMP conditions and 
vialed at 5mgs and stored at 2-8°C.  The material will be transferred to the investigational pharmacy once it has 
passed all required quality control testing. 
b. Drug storage, Reconstitution, and Stability 
The Indium-111 basiliximab/DOTA will be prepared in the RIT Radiopharmacy under SOPs.  The conjugated 
material will be obtained from the investigational pharmacy with 24 hours of planned labeling and stored in a 
monitored refrigerator at 2-8°C.  The antibody will be incubated with clinical grade 111InCl after neutralization with 
acetate buffer.  The radioimmunoconjugate will then undergo quality control testing before released to the 
radioimmunotherapist for administration to the patient.  The material will be held at 2-8°C prior to administration, 
which is to be performed within 6 hrs of radiolabeling. 
8.3 
90Y-Basiliximab/DOTA 
a. 
Drug formulation and Procurement 
Basiliximab will be conjugated with DOTA-NHS in the CBG facility at the City of Hope under CGMP conditions and 
vialed at 5mgs and stored at 2-8°C.  The material will be transferred to the investigational pharmacy once it has 
passed all required quality control testing. 
b. 
Drug storage, Reconstitution, and Stability 
The 90Y–basiliximab/DOTA will be prepared in the RIT Radiopharmacy under SOPs.  The conjugated material will 
be obtained from the investigational pharmacy within 24 hours of planned labeling and stored in a monitored 
refrigerator at 2-8°C.  The antibody will be incubated with clinical grade 90Ycl after neutralization with acetate 
buffer.  The radioimmunoconjugate will then undergo quality control testing before release to the physician for 
administration to the patient. The material will be held at 2-8°C prior to administration, which is to be performed 
within 6 hrs of radiolabeling. 

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8.4 Fludarabine phosphate (2-fluoro-ara-AMP) 
8.4.1 
Description 
Mechanism of Action: The mechanism of action of fludarabine phosphate is analogous to that of ara-C and ara-A. 
The active metabolite appears to be the triphosphate, F-ara-ATP. Like ara-CTP and ara-ATP, 2-F-ara-ATP is a 
substrate for DNA polymerase and is incorporated into DNA, causing strand breaks and inhibition of DNA 
synthesis. 
8.4.2 
Toxicology 
Human Toxicity: The major human toxicity has been myelosuppression. At higher dose levels or in patients with 
renal impairment, central nervous system toxicity has been seen and is characterized by numbness, paraparesis 
and cortical blindness 
8.4.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Sterile 50 mg/vial. When reconstituted with 2 mL sterile water, each mL will contain 25 mg of fludarabine 
phosphate. Administered intravenously (IV). Commercially available. 
8.5 Melphalan (L-phenylalanine mustard, L-PAM, Alkeran) 
8.5.1 
Description 
Mechanism of Action: The mechanism of action of fludarabine phosphate is analogous to that of ara-C and ara-A. 
The active metabolite appears to be the triphosphate, F-ara-ATP. Like ara-CTP and ara-ATP, 2-F-ara-ATP is a 
substrate for DNA polymerase and is incorporated into DNA, causing strand breaks and inhibition of DNA 
synthesis. 
8.5.2 
Toxicology 
Human Toxicity: The dose-limiting toxicity of melphalan is myelosuppression. Other toxicities after IV melphalan 
include mucositis, nausea, vomiting, and diarrhea. Alopecia is generally seen only with high doses associated with 
bone marrow transplant settings. Rarely reported reactions include pulmonary fibrosis, skin rash, vasculitis, and 
allergic reactions. With high dose chemotherapy, gastrointestinal toxicity becomes dose limiting. At such high 
doses, elevated transaminases, syndrome of inappropriate antidiuretic hormone secretion, depression, interstitial 
pneumonitis, and hepatic veno-occlusive disease have been reported. Acute non-lymphocytic leukemia and 
myeloproliferative syndromes may occur as secondary cancers from any alkylating agent such as melphalan. 
Amenorrhea, permanent in many cases, have been noted when melphalan was used in premenopausal women 
undergoing adjuvant therapy for breast cancer. Azoospermia would be expected, but is not well documented in 
the literature. 
8.5.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Sterile 50 mg/vial. When reconstituted with 2 mL sterile water, each mL will contain 25 mg of fludarabine 
phosphate. Administered intravenously (IV). Commercially available. 
8.6 Tacrolimus 
8.6.1 
Description 
Mode of Action: Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It 
prolongs the survival of the host and transplanted grafts in animal transplant models of liver, kidney, heart, bone 

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marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb. Tacrolimus inhibits T-lymphocyte 
activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus 
binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin 
is then formed, and the phosphatase activity of calcineurin is inhibited. 
Drug Interactions: Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of 
tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or 
discontinued. This process will be done according to COH standard of care.  
• 
Telaprevir: In a single dose study in 9 healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) 
with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-
fold and AUC by 70-fold compared to tacrolimus alone. 
• 
Boceprevir: In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with 
boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold 
compared to tacrolimus alone. 
• 
Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with 
nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the 
tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood 
concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless 
the benefits outweigh the risks. 
• 
Grapefruit juice: increased tacrolimus concentrations via CY3A inhibition; avoid concomitant use. 
• 
Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 
7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant 
increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin 
administration. 
• 
Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of 
tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and 
a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone. 
• 
Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% 
vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral 
clearance of tacrolimus during ketoconazole administration was significantly decreased compared to 
tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not 
significantly changed by ketoconazole coadministration, although it was highly variable between patients. 
• 
Voriconazole (see complete prescribing information for VFEND®): Repeat oral dose administration of 
voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus 
(0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-
fold (90% CI: 2.7, 3.8), respectively. 
• 
Posaconazole (see complete prescribing information for Noxafil®): Repeat oral administration of posaconazole 
(400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy 
subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively. 
• 
Caspofungin (see complete prescribing information for CANCIDAS®): Caspofungin reduced the blood AUC0-12 
of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood 
concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) 
was administered on the 10th day of caspofungin 100 mg daily, as compared to results from a control period 
in which tacrolimus was administered alone. 
• 
Vaccination: Immunosuppressants may affect response to vaccination. The use of live vaccines should be 
avoided; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella, and TY21a typhoid. 

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8.6.2 
Toxicology 
Human Toxicity: Common toxicities: anorexia, constipation, nausea, vomiting, myelosuppression. Less common: 
Convulsions, anaphylaxis, hemiparesis, dizziness, ataxia, confusion, dysphagia, anxiety, thrombo-embolism; 
prolonged lymphopenia with increased risk of infection or death, amnesia, insomnia, depression, myalgia, 
diplopia, visual changes; Secondary tumors or cancer. 
8.6.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Pharmaceutical Data: Injection: Tacrolimus is available as a sterile solution (tacrolimus injection) 
containing the equivalent of 5 mg anhydrous tacrolimus per 1 mL. Oral: It is also available for oral 
administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. 
Storage and Administration: Injection: Diluted infusion solution should be stored in glass or polyethylene 
containers and should be discarded after 24 hours. The polyoxyethylated castor oil contained in the concentrate 
for intravenous infusion can cause phthalate stripping from PVC. It is strongly recommended that glass bottles 
and non-PVC tubing be used to minimize patient exposure to DEHP. Because of the chemical instability of 
tacrolimus in alkaline media, tacrolimus injection should not be mixed or co-infused with solutions of pH 9 or 
greater (e.g., ganciclovir or acyclovir). Tacrolimus Injection must be diluted with NS or D5W before use to a 
concentration between 0.004 mg/mL and 0.02 mg/mL. Monitor closely for an acute allergic reaction for the first 
30 minutes and at frequent intervals thereafter. Oral: Store at 25°C (77°F); excursions are permitted (to 15-30ºC). 
Administer at a consistent time of day and at consistent intervals with regard to meals. Tacrolimus may be given 
with food as long as it is given the same way each time; however; administration with food significantly decreases 
the rate and extent of absorption. Grapefruit juice should be avoided during the entire course of tacrolimus 
administration. 
8.7 Sirolimus 
8.7.1 
Description 
Mode of Action: Rapamune (sirolimus) is a macrocyclic lactone produced by Streptomyces hygroscopic/I. Sirolimus 
inhibits T -lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin 
[IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. 
Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 
(FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on 
calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin 
(mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the 
progression from the G I to the S phase of the cell cycle. 
8.7.2 
Toxicology 
Human Toxicity: The most common (> 30%) adverse reactions are: peripheral edema, hypertriglyceridemia, 
hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary 
tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. 
8.7.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Drug Interactions: Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-
glycoprotein (Pgp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations, whereas inhibitors of 
CYP3A4 and P-gp may increase sirolimus concentrations. 

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• 
Strong inducers and strong inhibitors of CYP3A4 and P-gp: avoid concomitant use of sirolimus with a 
strong inducer (e.g., rifampin, rifabutin) or strong inhibitor (e.g., ketoconazole, voriconazole, itraconazole, 
erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp.  
• 
Grapefruit juice: Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must 
not be taken with or be used for dilution of sirolimus. 
Vaccination: Immunosuppressants may affect response to vaccination. The use of live vaccines should be avoided; 
live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid. 
8.8 Total Marrow and Lymphoid Irradiation (TMLI) 
Administration: Total marrow irradiation will be delivered using an Arc based IG-IMRT using a Helical Tomotherapy 
HiArt System (Tomotherapy, Inc) or Varian True Beam Rapid Arc (Varian, Inc.). The administration schedule and 
dose escalation scheme are described below. 
8.8.1 
Methodology:  
CT simulation and immobilization: All patients undergo CT simulation for treatment planning purposes. The 
patient is scanned supine with arms at side on a CT simulator. Two planning CT scans are performed, one to plan 
body regions from head to pelvis and the other to plan for lower extremities. The body CT scan is obtained with 
normal shallow breathing. 4D CT scan data are acquired for chest and abdomen. If 4D CT is not available, shallow 
inspiration and expiration breath hold CT scans can be acquired instead. The normal shallow breathing CT data 
set is used for dose calculation and planning. The 4D CT datasets are registered to the planning CT to account for 
any organ motion during respiration. AccuFormTM (CIVCO Medical Systems, Kalona, IA) cushion is used in 
combination with Silverman headrest to support and stabilize the head and neck. A body vac-lokTM bag (CIVCO 
Medical Systems, Kalona, IA) and a thermoplastic head and shoulder mask are used as additional immobilization 
devices. The patient’s arms, legs and feet are positioned using a vac-lok bag to enhance comfort and repositioning 
accuracy. Oral contrast is used to help visualize the esophagus. Couch height is approximately 10 cm below the 
isocenter of the gantry, and the patient is positioned on the couch so that the top of the head is approximately 5 
cm from the end of the couch. Those settings are used to maximize the available length for the CT scanning and 
treatment delivery. 
Target delineation: Target and avoidance structures and normal organs are contoured on an EclipseTM treatment 
planning system (Varian Medical Systems, Palo Alto, CA) or similar planning system. Avoidance structures 
contoured are user-defined and include lungs, heart, kidneys, liver, esophagus, oral cavity, parotid glands, thyroid 
gland, eyes, lens, optic chiasm and nerves, stomach, small and large intestine, breasts, rectum, ovary, and bladder. 
The 4D CT datasets are registered to the planning CT so that the contours of ribs, esophagus, kidneys, spleen and 
liver are enlarged to account for the organ movements during respiration. An additional 3 to 5 cm margin is usually 
added to the CTV to define the PTV target. Our center has added up to 10 cm margins in areas where larger setup 
uncertainty is observed, such as in the regions of the shoulder, arms, thighs, and posterior spinous processes. 
Spinal cord (part of the target) is outlined separately so to avoid hot spots in the spinal canal during planning. The 
mandible and maxillary bones are excluded from the target in an effort to minimize oral cavity dose and mucositis.  
Treatment planning with a helical tomographic delivery system (Tomotherapy): DICOM-RT images are transferred 
to the Hi-ArtTM Tomotherapy treatment planning system (Accuray Inc. Palo Alto, CA). Helical Tomotherapy plan 
is designed such that a minimum of 85% of the target receives the prescribed dose. For the body treatment plan, 
jaw size of 5 cm, pitch of 0.287 and modulation factor of 2.5 are used for most patients as a balance of treatment 
time and plan quality. Plan quality index comprises target dose uniformity and critical organ doses. Since the first 
TMI patient treated in 2005, TMI treatment planning efforts at City of Hope have continued to evolve. Our current 
approach is to perform plan optimization in two stages. Critical organ sparing is optimized before target dose 

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uniformity optimization is done resulting in being able to escalate target doses without a proportionate increase 
in normal organ dose. Legs and feet are planned in Tomo-Direct mode. A 5 cm jaw size is used. Gantry angles of 0 
and 180 degrees are selected. A composite dose of body plan and leg plan is generated to double check there is 
no dose gap or overlap at the junction. 
Treatment planning with a VMAT conventional linear accelerator system: TMLI can be planned and treated using 
a conventional linear accelerator with VMAT capability as well. Multiple dynamic IMRT arcs with usually 3 to 4 
isocenters are used to cover target regions. Collimator angles are varied for each arc to increase the planning 
degree of freedom and plan quality. After the plan of the body is finalized, the lower extremities are planned with 
two or three additional AP-PA fields given the lack of sensitive organs in this area. AP-PA fields are opened at 40 
cm x 40 cm and gapped at 50% isodose line at midplane. 
Treatment delivery: Our current procedure involves initial laser alignment of the patient in the vac-lok bag and 
thermoplastic mask. Verification CT positioning scans are performed prior to each treatment session using 
multiple cone beam CT scans (CBCTs) or one megavoltage CT (MVCT) scan from orbit to ischial tuberosities and is 
fused to the planning CT. Registration and couch shifts are reviewed and approved by attending physician before 
treatment is delivered. The Tomotherapy has a maximum treatment length of approximately 150 cm. A jaw size 
of 5 cm and pitch of 0.287 usually result a beam-on time of approximately 25 minutes to treat the upper body. On 
the Tomotherapy system, the patient translates through the unit head first to treat from the head to proximal 
thighs and is then re-setup and translates through the unit feet first to treat the lower extremities. Treatment of 
legs has a beam-on of time of approximately 10 minutes. With a conventional linear accelerator with VMAT 
capability, the verification CBCT will be performed for each isocenter before treatment delivery. The total 
treatment time is similar to TMI delivery using a helical topographic approach. 
Each fraction of TMLI is 150 cGy, with two fractions delivered each day for 4 days.  There will be a minimum of 6 
hours between each fraction.  Treatment will utilize helical tomotherapy or rapid arc IMRT as a means of 
conformal avoidance or minimization of radiation dose to normal organs.   
• 
The target region will include bone marrow compartments and major lymph node regions (mediastinal, 
para-aortic, pelvic) 
• 
Brain and testes will be treated to 1200 cGy for patients with ALL.  
• 
Avoidance organs with dose sparing include brain (except ALL), liver, spleen, eyes, lens, parotids, thyroid, 
esophagus, oral cavity, lungs, heart, kidneys, stomach, upper GI and lower GI tract, rectum, bladder, and 
in women breast, uterus and ovaries.  
Mean organ dose constraints for right and left lung 4 Gy, right and left kidney 4 Gy, liver 4 Gy and heart 8 Gy. 
9.0 CORRELATIVE/ SPECIAL STUDIES 
9.1 Laboratory Studies Performed 
9.1.1 
Pharmacokinetic Studies 
9.1.1.1 Specimen Collection 
All patients enrolled will be asked to undergo serial blood sampling to evaluate the systemic pharmacokinetics 
of 111In- and 90Y- basiliximab/DOTA. Prior to drug administration an indwelling heparin lock should be placed so 
that serial specimens can be collected. At each sampling time, 1 mL of blood will be withdrawn and discarded to 
assure that the solution used to maintain catheter patency does not dilute the sample. Alternatively, if the 
patient has a central venous catheter, it may be used for sample collection. In the event that the central venous 
catheter is used, sufficient blood should be withdrawn before each PK sample to assure that the solution used to 
maintain catheter patency does not dilute the PK sample.  

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9.1.1.2 PK Collection Time Points 
Serial blood (5 cc) samples will be done at approximately time 1-2 hours, 3-4 hours, and at scan times of 1 day and 
5/6 days after end of radiolabeled antibody infusion.  Blood samples will be analyzed for total activity and by 
radiometric HPLC.  These studies will acquire data on antibody metabolism and pharmacokinetics. 
9.1.2 
Bone marrow and blood samples - CD25 expression and histopathologic changes pre and post 90Y-CD25 
and TMLI conditioning.  
The primary objective of the correlative studies is to evaluate CD25 expression of leukemia cells by flow 
cytometry, immunohistochemistry and serum CD25 levels pre-HCT, at 1 year and at time of first relapse, as was 
performed in prior COH studies evaluating 90Y-CD25 in HL (IRB 08179). Serum levels of CD25 will be done at 
additional time-points, specified in the study calendar. In addition, histopathologic changes in bone marrow and 
estimated changes in bone marrow cellularity will be evaluated in patients with high-risk acute leukemia and 
myelodysplastic syndrome treated with the 90Y-anti-CD25 basiliximab and total marrow and lymphoid irradiation 
(TMLI)/FLU/MEL hematopoietic cell transplantation (HCT) conditioning regimen.  
9.1.2.1 Bone Marrow Aspirate Collection and Delivery 
Schedule of sample collection will occur as stated in the Study Calendar (see Section 10.0). 
1. Each bone marrow aspirate tube should be labeled with the study IRB number, research 
participant number (RPN), and sample collection time point. 
2. After material for diagnostic tests has been removed, approximately 10 ml of bone marrow 
aspirate in EDTA (lavender top) tube(s) will be collected. 
3. Gently invert tube several times after collection. 
4. Sample should be transferred to the Hematopoietic Tumor Bank (HTB) for registration. Once 
registration is complete, the HTB will inform the Hui laboratory that the de-identified 
specimen is ready to be picked up. A representative of the Wong/Hui laboratory will pick up 
the specimen and process it within 2-4 hours of harvest. 
5. Note: for cases in which the baseline bone marrow aspirate was collected per standard-of-
care at City of Hope prior to the patient’s consent on trial, we will use the banked sample from 
the HTB (if available) to perform these tests. This may not be possible if the baseline marrow 
was performed at an outside institution. 
9.1.2.2 Bone Marrow Trephine Sample Collection, Processing and Delivery 
Schedule of sample collection will occur as stated in the Study Calendar (see Section 10.0). 
1. As part of diagnostic tests, the BM biopsy core will be sent to and processed by COH 
Histopathology Core. 
2. Histopathology Core will prepare 1 H&E and 10 unstained slides from the core block and label 
each slide with the study IRB number, research participant number (RPN), and sample 
collection time point. 
3. Slides should be transferred to the Wong/Hui lab, Kaplan-Black, Room 109a (Susanta Hui 
x80556). 
4. Note: for cases in which the baseline bone marrow biopsy was collected prior to the patient’s 
consent on trial, we will obtain slides from the archived specimen, if available. 

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9.2 Research Sample Collection and Dispensation 
 
Study Analysis 
 
Sample 
Type 
Tube Type 
Volume 
(mls/tube) / 
# of tubes 
Collection 
Processing / 
Storage 
Deliver 
to Lab 
(time limit) 
CD25 serum 
levels 
Blood 
Red top tube 
5-7 ml 
1 tube 
N/A 
No processing 
Clinical Laboratory 
per COH SOPs 
Pharmacokinetics 
Blood 
Purple top 
(EDTA) and 
Red top 
2.5 ml per 
tube per 
time-point 
Invert 8 
times/ambie
nt 
No processing 
Radiopharmacy lab 
CD25 expression 
and BM damage 
Bone 
Marrow 
Aspirate 
And 
Biopsy 
Purple top 
(EDTA) 
(aspirate) 
(1)10 ml tube 
Invert 8 
times 
No processing  
HTB, then Joo Song 
MD in Pathology 
and Wong/Hui Lab 
1 H&E and 10 unstained slides 
from the core block 
N/A 
No processing 
Histopathology 
Core then Joo Song 
MD in Pathology 
and Wong/Hui Lab 
 
Note: The order of tube collection should be per Clinical and Laboratory Standards Institute (ex. Order of draw: 
sodium citrate tube, serum tube, heparin tube, EDTA tube). It is acceptable to use other available tube sizes to 
ensure collection of the required volume of blood. 

This document is confidential and for research purposes only. Distribute and use ONLY as authorized.  
 
10.0 STUDY CALENDAR 
All assessments may increase in frequency as clinically indicated.  
10.1 Pre-transplant Study Calendar 
Procedure 
Pre-Study 
Screening 
Day -15 
or -14 
Day -14 
or -13 
Day -9 
Day-8 
Day -7 
Day -6 
Day-5 
Day-4 
Day-3 
Day -2 
Day -1 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/vital signs3 
X1 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X1 
 
 
 
 
 
 
 
 
 
 
 
KPS score 
X1 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test4 
X14 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram/MUGA Scan 
X14 
 
 
 
 
 
 
 
 
 
 
 
CT Chest 
X14 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET/CT5 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Tests 
CBC with diff 
X1 
X15 
 
X 
 
 
 
 
 
 
 
 
CMP6 
X1 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel + PT/PTT 
X1 
 
 
 
 
 
 
 
 
 
 
 
Ferritin 
X1 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin/IgG level 
X1 
 
 
 
 
 
 
 
 
 
 
 
Serum thyroid panel7 
X1 
 
 
 
 
 
 
 
 
 
 
 
ABO/Rh type and antibody 
X14 
 
 
 
 
 
 
 
 
 
 
 
Serum HCG/urine pregnancy8 
X1 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X1 
 
 
 
 
 
 
 
 
 
 
 
24 hr. urine creatinine clearance9 
X14 
 
 
 
 
 
 
 
 
 
 
 
BM biopsy/Cytogenetics10 
X14 
 
 
 
 
 
 
 
 
 
 
 
CMV qPCR 
X14 
 
 
 
 
 
 
 
 
 
 
 
SOC HIV ag/ab combo  
X14 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis (B and C) 
X14 
 
 
 
 
 
 
 
 
 
 
 
Syphilis panel by RPR 
X14 
 
 
 
 
 
 
 
 
 
 
 
High resolution HLA typing  
X 
 
 
 
 
 
 
 
 
 
 
 
Consultation 
Surgery or IR11 
X 
 
 
 
 
 
 
 
 
 
 
 
Ancillary12  
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 “Cold” Basiliximab 
 
X 
 
 
 
 
 
 
 
 
 
 
111In/90Y-antiCD25 Basiliximab 
 
X 
 
 
 
 
 
 
 
 
 
 
111In-antiCD25 Basiliximab nuclear scans 
 
X 
X 
X 
 
 
 
 
 
 
 
 
TMLI (1200 cGy) 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Fludarabine 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Melphalan 
 
 
 
 
 
 
 
 
 
 
X 
 
Sirolimus and tacrolimus  
 
 
 
 
 
 
 
 
 
 
 
X 
Study evaluations 
Toxicity and/or GvHD grading 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for sCD25 
X 
X 
 
 
 
 
 
 
 
 
 
 
Research BM sample collection13 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for Pharmacokinetics 
 
X 
X 
X 
 
 
 
 
 
 
 
 

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1. To occur within 30 days prior to start of protocol therapy, or at the discretion of the physician. 
2. To include a review of treatment history, any ongoing medical conditions and medical history pertaining to 
eligibility on study and involvement during study 
3. Vital signs: heart rate, blood pressure, respiration rate, and temperature 
4. Pulmonary function test with DLCO and FEV1 
5. For patients with NHL, only 
6. CMP with lactate dehydrogenase (LDH), uric acid, magnesium, phosphorus, triglycerides 
7. Serum thyroid panel including Thyroid Stimulating Hormone (TSH), T3 and free Thyroxine  
8. For women of childbearing potential only 
9. Should the creatinine clearance be reported as below the level required for eligibility, a renal GFR scan may be 
performed to determine the renal status for eligibility 
10. Unilateral 
11. All patients must have a double lumen central venous catheter, Hickman catheter or PICC line in place to allow 
proper therapy and supportive care 
12. Dietitian, psycho-social team when indicated 
13. Correlative studies are to evaluate CD25 expression of leukemia cells by flow cytometry, immunohistochemistry 
and serum CD25 levels pre-HCT, at 1 year and at time of first relapse, as was performed in prior COH studies 
evaluating 90Y-CD25 in HL (IRB 08179). In addition, histopathologic changes in bone marrow and estimated 
changes in bone marrow cellularity will be evaluated in patients with high-risk acute leukemia and myelodysplastic 
syndrome treated with the 90Y-anti-CD25 basiliximab and total marrow and lymphoid irradiation (TMLI)/FLU/MEL 
hematopoietic cell transplantation (HCT) conditioning regimen. 
14. To occur within 8 weeks prior to start of protocol therapy, or at the discretion of the physician. 
15. CBC with differential should be done prior to infusion of study drug. 
 
 
 
 
 

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10.2 Post-Transplant Study Calendar 
Procedure 
Day 09 
Day +3 
Day +4 
Day +5 
Day +3010 
Day +6010 
Day 
+10010 
Day 
+18011 
Year 112 
Year 212 
At First 
relapse14 
Standard of care 
 
Physical exam/vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight1 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
FDG-PET/CT2 
 
 
 
 
X 
 
X 
X 
X 
X 
 
CBC with diff + platelet count1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CMP3 
 
 
 
 
X 
 
 
X 
X 
X 
 
IgG level 
 
 
 
 
X 
 
 
 
 
 
 
Serum thyroid panel4 
 
 
 
 
 
 
 
X 
X 
X 
 
Pulmonary function test 
 
 
 
 
 
 
 
 
X 
X 
 
Echocardiogram/MUGA scan 
 
 
 
 
 
 
 
 
X 
X 
 
EKG 
 
 
 
 
 
 
 
 
X 
X 
 
CMV qPCR5 
X 
 
 
 
X 
X 
X 
 
 
 
 
Coagulation panel + PT/PTT6 
X 
 
 
 
 
 
 
 
 
 
 
Engraftment status7 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Bone marrow biopsy/aspirate8 
 
 
 
 
X 
 
(X) 
X 
X 
X 
 
GVHD assessment and grading6 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Treatment 
 
Stem cell infusion 
X 
 
 
 
 
 
 
 
 
 
 
Tacrolimus/Sirolimus (Per Section 5.4) 
 
 
 
X 
 
 
 
 
 
 
 
Study intervention 
 
Toxicity and/or GvHD grading 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Blood draw for sCD25 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
Research BM sample collection and serum 
CD25 levels 13 
 
 
 
 
 
 
 
 
X 
 
X 
1. 
Daily during admission until discharge, then in every clinic visit (diff to be done when valid differential can be run per lab 
rules) 
2. 
Only for patients with NHL. The day 30 PET/CT will be done only if clinically indicated. CT NCAP can be done for restaging 
in cases in which PET/CT scan may not be feasible (example: insurance issues). 
3. 
CMP with lactate dehydrogenase (LDH), uric acid, magnesium, phosphorus, triglycerides 
4. 
Serum thyroid panel including Thyroid Stimulating Hormone (TSH), T3 and free Thyroxine  
5. 
Weekly from transplant through day 99 then monthly until off all immunosuppression 
6. 
Weekly from transplant until discharge then per COH SOPs 
7. 
Chimerism studies on peripheral blood for total CD3+, and CD15+ subsets 
8. 
For leukemia and MDS patients: with cytogenetics, FISH, chimerism and MRD. BMBx not required at day 100. 
For patients with NHL: BMBx only required at day 100 and should include chimerism as well as testing per standard of 
care. 
9. 
A window of ±2 days is allowed for stem cell infusion 
10. A window of ±7 days is allowed 
11. A window of ±14 days is allowed 
12. A window of ± 1 month is allowed 
13. Correlative studies are to evaluate CD25 expression of leukemia cells by flow cytometry, immunohistochemistry and 
serum CD25 levels  pre-HCT, at 1 year and at time of first relapse, as was performed in prior COH studies evaluating 90Y-
CD25 in HL (IRB 08179 ). In addition, histopathologic changes in bone marrow and estimated changes in bone marrow 
cellularity will be evaluated in patients with high-risk acute leukemia and myelodysplastic syndrome treated with the 90Y-
anti-CD25 basiliximab and total marrow and lymphoid irradiation (TMLI)/FLU/MEL hematopoietic cell transplantation 
(HCT) conditioning regimen. Note: When feasible, flow cytometry for CD25 may be done anytime a bone marrow 
examination is taken after transplant up until year 2 or 1st relapse, whichever comes first. 
14. Once a patient has relapsed after transplant, the subject will be followed only for survival, and the study calendar 
requirements are no longer required. 
 

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11.0 ENDPOINT DEFINITIONS/MEASUREMENT OF EFFECT 
11.1 Primary Endpoint(s) 
• 
Maximum tolerated dose/recommended phase II dose (MTD/RP2D) of 
90Y-DOTA-anti- 
radioimmunotherapy. 
• 
Toxicity: Toxicity will be scored on both the Bearman Scale (Appendix A) and NCI CTCAE v5 Scale 
(Appendix A).  
11.2 DLT Definition  
For the purposes of this study, Dose limiting toxicity (DLT) will be defined as any of the following that are 
assigned an attribution level of at least possibly related to the conditioning regimen (90Y-basiliximab-
DOTA, TMLI, fludarabine and melphalan) and other treatment related AE’s (non-related to the 
conditioning regimen): 
• 
For non-hematologic toxicities, any grade III/IV toxicity per Bearman Toxicity Grading Scale 
or 
• 
For non-hematologic toxicities (not part of the Bearman toxicity grading scale), any ≥grade 4 
toxicity per NCI CTCAE v5. 
• 
For hematologic toxicities, per NCI CTCAE v5 toxicity criteria, any grade 4 neutropenia 
associated with fever or infection and lasting for more than 21 days, or grade 4 neutropenia 
lasting for more than 28 days (engraftment failure). 
• 
Any other conditioning regimen-related cause of death.  
• 
In addition, septic DLT is defined as: any grade 5 sepsis-related toxicity that is assigned an 
attribution level of at least possibly related to the conditioning regimen. 
Note: The NCI CTCAE v5 scale will also be used for adverse event reporting. 
11.3 Secondary Endpoint(s) 
• 
Overall survival (OS): Patients are considered a failure for this endpoint if they die, regardless of 
cause. Time to this event is the time from start of protocol therapy to death, or last follow-up, 
whichever comes first. 
• 
Event-free survival (EFS): Patients are considered a failure for this endpoint if they 
relapse/progress or die, regardless of cause. Time to this event is the time from start of protocol 
therapy to death, relapse/progression, or last follow-up, whichever comes first. 
• 
Relapse/Progression (CIR): The event is relapse/progression. Time to this event is measured from 
start of therapy. Death without relapse/progression is considered a competing risk. Surviving 
patients with no history of relapse/progression are censored at time of last follow-up. 
• 
Graft versus host disease and relapse free survival (GRFS): The event is relapse/progression, acute 
grade 3 or 4 GVHD, or chronic GVHD requiring systemic therapy. Time to this event is measured 
from start of therapy. Death without relapse/progression, acute grade 3 or 4 GVHD or chronic 
GVHD requiring systemic therapy is considered a competing risk. Surviving patients with no 
history of relapse/progression or GVHD are censored at time of last follow-up 
• 
CR Proportion at Day +30: The event is documented complete remission (CR) at Day +30. Time to 
event is measured from the start of therapy to the time of biopsy proven CR. 
• 
Non-relapse Mortality (NRM): Patients are considered a failure for this endpoint if they die from 
causes other than disease relapse or progression. NRM is measured from start of therapy until 
non-disease related death, or last follow-up, whichever comes first. 

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• 
Incidence of Infection: Microbiologically documented infections will be reported by site of 
disease, date of onset, severity and resolution, if any. These data will be captured via case report 
form and will be collected from Day 0 until 100 days post-transplant. 
• 
Neutrophil Recovery: Measured from stem cell infusion to the first to three consecutive days with 
neutrophil count greater than 0.5x109/l.  
• 
Acute Graft versus Host Disease (aGVHD) of grades 2-4 and 3-4: Documented/biopsy proven acute 
graft versus host disease is graded according to the Consensus Grading (Appendix B). Time to 
event is measured from date of stem cell infusion to document/biopsy proven acute GVHD onset 
date (within the first 100 days post-transplant) and will be used to estimate the cumulative 
incidence.  
• 
Chronic Graft versus Host Disease (cGVHD): Documented/biopsy proven chronic graft versus host 
disease is scored according to NIH Consensus Staging (Appendix B). Time to event is measured 
from approximately 80-100 days post-transplant to the documented/biopsy proven chronic GVHD 
onset date and will be used to estimate the cumulative incidence. 
11.4 Response Criteria Definition 
Response criteria will be specific to each disease with only the following categories being relevant post-
transplant: 
a. Complete remission 
b. Relapse 
c. Disease persistence/progression 
d. Minimal residual disease 
For detailed description of the corresponding categories within the response criteria for each disease 
check the references: 
11.4.1 AML: Per Dohner et al.[10] 
a. Complete Remission: Remission is defined as <5% blasts with no morphological 
characteristics of acute leukemia (e.g., Auer rods) or myelodysplasia in a bone marrow 
with >20% cellularity, and peripheral blood counts showing ANC >1000/µL (including 
patients in CR with incomplete platelet recovery). In addition, normalization of 
cytogenetics must be demonstrated by the absence of previous cytogenetic abnormalities 
identified prior to transplantation in the bone marrow aspirate, without appearance of 
new abnormalities.  
b. Relapse 
Any of the following indicates relapse: 
• 
The reappearance of blast cells in the peripheral blood 
• 
>5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) 
• 
The appearance of new dysplastic changes within the bone marrow 
• 
Development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid 
• 
Reappearance of cytogenetic abnormalities present prior to transplantation 
c. Disease persistence/progression 
Patient does not achieve CR upon repeat bone marrow examination after therapy and displays persistent 
evidence of disease by cytogenetics in blood or bone marrow consistent with pre-transplant features, or 
consistent with progression of MDS to AML. 

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d. Minimal residual disease (MRD) 
MRD will be assessed from bone marrow aspirates on days 30, 100, and 180 post-transplant. 
11.4.2 ALL: NCCN guidelines for ALL Version 3.2017 
a. Complete remission: 
• 
No circulating blasts or extramedullary disease 
• 
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS 
involvement 
• 
Trilineage hematopoiesis (TLH) and 5% blast 
• 
Absolute neutrophil count (ANC)>1000/microL 
• 
Platelets>100,000/microL 
• 
No recurrence for 4 weeks 
b. Relapse 
• 
Reappearance of blasts in the blood or BM (>5%) or in any extramedullary site after CR 
c. Disease persistence/progression  
• 
Failure to achieve CR at the end of induction 
• 
Increase of at least 25% in the absolute number of circulating or BM blasts or development of 
extramedullary disease 
11.4.3 MDS: Savona, Malcovati et al. 2015[11] 
a. Complete Remission (presence of all of the following improvements) 
• 
Bone marrow:  
 
≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with 
normal maturation of all cell lines and return to normal cellularity 
 
Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤grade 1 fibrosis) 
• 
Peripheral blood 
 
WBC ≤10 × 109 cells/L 
 
Hgb ≥11 g/dL 
 
Platelets ≥100 × 109/L; ≤450 × 109/L 
 
Neutrophils ≥1.0 × 109/L 
 
Blasts 0% 
 
Neutrophil precursors reduced to ≤ 2% 
 
Monocytes ≤1 × 109/L 
• 
Extramedullary disease: Complete resolution of extramedullary disease present before 
therapy (eg, cutaneous disease, disease-related serous effusions), including palpable 
hepatosplenomegaly 

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• 
Provisional category of CR with resolution of symptoms: CR as described above, and complete 
resolution of disease-related symptoms as noted by the MPN-SAF TSS 
• 
Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia 
b. Relapse (Partial Remission) 
• 
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and 
blast equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of 
MDS/MPN with ≤5% bone marrow blasts at baseline. 
• 
Marrow response 
 
Optimal marrow response: Presence of all marrow criteria necessary for CR 
without normalization of peripheral blood indices as presented above. 
 
Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 
50%, but remaining >5% of cellularity, or reduction in grading of reticulin fibrosis 
from baseline on at least 2 bone marrow evaluations spaced at least 2 mo apart 
c. Disease persistence/progression: (Combination of 2 major criteria, 1 major and 2 minor criteria, 
or 3 minor criteria from list) 
• 
Major criteria 
 
Increase in blast count* 
o <5% blasts: ≥50% increase and to >5% blasts 
o 5-10% blasts: ≥50% increase and to >10% blasts 
o 10-20% blasts: ≥50% increase and to >20% blasts 
o 20-30% blasts: ≥50% increase and to >30% blasts 
 
 Evidence of cytogenetic evolution 
o Appearance of a previously present or new cytogenetic abnormality in 
complete cytogenetic remission via FISH or classic karyotyping 
o Increase in cytogenetic burden of disease by ≥50% in partial cytogenetic 
remission via FISH or classic karyotyping 
 
 New extramedullary disease 
o Worsening splenomegaly 
o Progressive splenomegaly that is defined by IWG-MRT: the appearance of a 
previously absent splenomegaly that is palpable at >5 cm below the left costal 
margin or a minimum 100% increase in palpable distance for baseline 
splenomegaly of 5-10 cm or a minimum 50% increase in palpable distance for 
baseline splenomegaly of >10 cm 
o Extramedullary disease outside of the spleen 
o To include new/worsening hepatomegaly, granulocytic sarcoma, skin lesions, 
etc. 
• 
Minor criteria 
 
 Transfusion dependence§ 

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 
 Significant loss of maximal response on cytopenias ≥50% decrement from 
maximum remission/response in granulocytes or platelets 
 
 Reduction in Hgb by ≥1.5g/dL from best response or from baseline as noted on 
complete blood count 
 
 Increasing symptoms as noted by increase in ≥50% as per the MPN-SAF TSS|| 
 
 Evidence of clonal evolution (molecular) 
11.4.4. Response Criteria for NHL  
This will be done using the Lugano Response Criteria ( cheson 2016) 
 
Revised Criteria for Response Assessment[12] 
Response and Site  
PET-CT–Based Response  
CT-Based Response 
Complete Response 
Complete metabolic response 
Complete radiologic response (all of the 
following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual mass 
on 5PSb.  It is recognized that in Waldeyer’s ring or 
extra-nodal sites with high physiologic uptake or 
with activation within spleen or marrow (e.g., with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake.  No evidence of FDG-
avid disease in marrow. 
Target nodes/nodal masses must regress to ≤ 1.5 
cm in LDi. 
No extra-lymphatic sites of disease. 
Bone Marrow 
No evidence of FDG-avid disease in marrow. 
Normal by morphology; if indeterminate, IHC 
negative. 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding 
disease. 
At end of treatment, these findings indicate 
residual disease. 
Or ≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extra-nodal sites. 
When a lesion is too small to measure on CT, 
assign 5 mm × 5 mm as the default value, when no 
longer visible, 0 × 0 mm. 
 For a node >5 mm× 5 mm, but smaller than 
normal, use actual measurement for calculation. 
Spleen must have regressed by > 50% in length 
beyond normal 
Bone Marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). 
If there are persistent focal changes in the marrow 
in the context of a nodal response, consideration 
should be given to further evaluation with MRI or 
biopsy or an interval scan. 
N/A 

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No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extra-nodal 
lesions 
Score 4 or 5b with no significant change in FDG 
uptake from baseline at interim or end of 
treatment  
< 50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met 
Bone Marrow 
No change from baseline 
N/A 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the 
following 
Individual target 
nodes/nodal Masses. 
Score 4 or 5b with an increase in intensity of 
uptake from baseline and/or New FDG-avid foci 
consistent with lymphoma at interim or end-of-
treatment assessment. 
New lesions New FDG-avid foci consistent with 
lymphoma rather than another etiology (e.g., 
infection, inflammation); if uncertain regarding 
etiology of new lesions, biopsy or interval scan 
may be considered 
PPD progression:   
An individual node/lesion must be abnormal with: 
LDi >1.5 cm and 
Increase in by ≥ 50% from PPD nadir and 
An increase in LD or SD from nadir: 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length 
must increase by > 50% of the extent of its prior 
increase beyond baseline. If no prior 
splenomegaly, must increase by at least 2 cm from 
baseline. 
New or recurrent splenomegaly 
New or clear progression of preexisting non-
measured lesions 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis. A new extra-
nodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must 
be attributable to lymphoma. Assessable disease 
of any size unequivocally attributable to 
lymphoma 
Bone Marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 

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5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LD = 
longest transverse diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product 
of the LD and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular 
diameters for multiple lesions. 
aA score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. 
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extra-
nodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Non-measured lesions: Any disease not 
selected as measured; dominant disease and truly assessable disease should be considered not measured. These sites include any 
nodes, nodal masses, and extra-nodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would 
be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extra-nodal sites 
(e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should 
be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth 
factors). 
bPET 5PS: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = uptake moderately > 
liver; 5 = uptake markedly higher than liver and/or new lesions: X = new areas of uptake unlikely to be related to lymphoma. 
Cheson, B.D., et al., Refinement of the Lugano Classification lymphoma response criteria in the era of 
immunomodulatory therapy. Blood, 2016. 128(21): p. 2489-2496. 
 
 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a single-institution, non-randomized phase I trial to determine the maximum tolerated dose/ 
recommended phase II dose (MTD/RP2D) of 90Y-DOTA-anti-CD25 Basiliximab MAB when given in 
combination with fixed doses of fludarabine, melphalan, and 1200 cGy TMLI as conditioning regimen to 
patients with high-risk acute leukemia (lymphocytic or myelogenous) or myelodysplastic syndrome who 
undergo alloHCT with matched related/unrelated or haploidentical donor. Dose escalation will be based 
on a modified rolling 6 Phase I design. There will also be a dose level -1 of 0.2 mCi/kg in the case that dose 
level 1 is too toxic (Table 12.1). 
Table 12.1. 90Y-DOTA-antiCD25 Basiliximab Mab dose escalation 
Dose Level 
Administration Dose 
-1 
0.2 mCi/kg 
1 
0.3 mCi/kg 
2 
0.4 mCi/kg 
3 
0.5 mCi/kg 
12.2 Dose Escalation Schedule: Adapted Rolling 6 Design 
This study will employ a modified, more conservative version of the rolling 6 design of Skolnik, J.M., et al, 
2008. In this design, at most 3 patients will be under observation for DLT on the current test dose level at 
any time. Patients who are not evaluable for DLT will be replaced. Once each patient is evaluable for 
toxicity and passes without a DLT, an additional patient may be accrued on that dose level, with up to 6 

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total patients treated per dose level. Once 3 patients are evaluable with no patient at that dose level 
experiencing a DLT, the dose can be escalated, or up to 3 additional patients may be treated at the current 
dose level at discretion of PI. Although this design does not require that 6 patients be treated at a given 
dose level, no more than 6 evaluable patients will be accrued to any dose level during the dose finding 
portion of this study. If at any time, the dose level has 1 documented DLT with fewer than 6 evaluable 
patients, accrual will continue until 6 patients are evaluable or a second DLT occurs.  Escalation will 
terminate as soon as two or more patients experience any DLT attributable to the study treatment, at a 
given dose level, and the next lower dose will be expanded. MTD/RP2D will be declared as the highest 
dose where 6 patients have been treated and at most one patient experiences DLT. There will be no dose 
escalation within a patient. Dose escalation rules are outlined in Table 12.2. 
Note: no more than 3 patients can be <30 days post stem cell infusion at any time. If at the starting dose, 
level 1, >1/6 patients experiences unacceptable toxicity within 30 days after stem cell infusion, 
subsequent patients will receive a de-escalated dose to dose level -1. Note: the fludarabine dose, 
melphalan dose and TMLI dose will remain fixed (see section 5.1) for all defined dose levels and will not 
be reduced at any point.  
At the MTD/RP2D, or if ≤ 1/6 patients treated at the highest dose experiences DLT, the trial will enroll up 
to an additional 6 patients at the that dose. 
Table 12.2. Dose escalation rules 
# Patients on Current Level 
Action 
DLT 
EVAL 
EVAL+At Risk 
0 
0 
1-2 
Accrue next patient at this level* 
0 
0 
3 
Hold accrual 
0 
1 
1-3 
Accrue next patient at this level 
0 
1 
4 
Hold accrual 
0 
2 
2-4 
Accrue next patient at this level 
0 
2 
5 
Hold accrual 
0 
3-6 
3-6 
Accrue next patient at the next higher level*,+ 
1 
1 
1-2 
Accrue next patient at this level 
1 
1 
3 
Hold Accrual 
1 
2 
2 
Accrue next patient at this level 
1 
2 
3-4 
Hold accrual 
1 
3-5 
3-5 
Accrue next patient at this level 
1 
3-5 
6 
Hold accrual 
1 
6 
6 
Accrue next patient at the next higher level* 
2** 
Any 
any 
Accrue next patient at the next lower level to a 
maximum of 6 
*During the dose-escalation portion, if higher dose level is already closed, the next lower dose will accrue 
to a total of 6 patients, with 2 or higher DLTs requiring further dose de-escalation. 
+Although under this scenario escalating to the next higher dose level is suggested, additional patients 
can be accrued to the current level -up to n=6 patients. 
**Patients treated on a higher dose will have their treatment modified to the dose below the dose level
with 2 DLTs, if pending patients have DLT. 
DLT: a patient with a documented DLT; PASS: a patient without a DLT fully evaluable for toxicity for the 
purpose of dose escalations (see section 10.1 for detail); EVAL: a patient who is either DLT or PASS; 
Inevaluable:  a patient who is off treatment without being DLT or PASS; At Risk: a patient who is on study 
and not yet DLT, PASS, or Inevaluable 

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12.3 DLT Window 
The DLT window is from the start of conditioning through 30 days post stem cell infusion. Based on our 
TMLI experience late breaking DLTs have not been seen and patients are continue to be followed on our 
Long-Term toxicity protocols. While not expected, patients with DLTs (beyond day +30) will be followed 
until resolution or stability. 
  Note: all transplant patients are followed for longer-term follow-up as part of the Survivorship Program 
and all TMLI patients as part of IRB#07173. The first TMLI patient was treated in 2005. 
12.4 Participant Evaluability and Replacement 
To be evaluable for toxicity, a patient must start conditioning. Patients are evaluable for DLTs if they 
receive the 90Y-basiliximab-DOTA and be followed for 30 days post-transplant or experience a DLT. 
Patients who are not evaluable for DLTs within the context of dose escalation will be replaced.     
(Note: A planned dose might not be received by a patient due to patient choice or treating physician’s 
judgment.)  
12.5 Sample Size, Accrual Rate and Study Duration  
Assuming the highest dose level is well tolerated, dose levels 1-2 will accrue 3 patients at each dose 
level, 6 patients will be enrolled at the top dose level (3), for a total of 12 patients. 
12.6 Additional Toxicity Monitoring 
 
To ensure patient safety, if >1 subject experiences any grade 3 or 4 toxicity per the Bearman Scale -among 
the first six subjects enrolled/treated, or at a rate ≥ 25% anytime thereafter, the study will halt the accrual 
of BM patients, the DSMC will then be notified, and an amendment will be submitted for approval by the 
CPRMC and IRB. 
 
Out of an abundance of caution, non-relapse mortality (NRM) by day 180 as a safety endpoint will also be 
monitored in all patients. NRM is defined as death occurring in a patient from causes other than relapse 
or progression. NRM is measured from date of stem cell infusion until non-disease related death. Deaths 
from relapse/progression are considered a competing risk. NRM will be censored at last follow-up if 
patients are alive and remain disease free. 
 
We will suspend accrual and perform safety review whenever the stopping boundary is crossed and 
submit reports to COH DSMC. DSMC approval is required before reopening the study for accrual. The 
stopping boundaries due to safety concerns are as follows and are based on a previously published 
TMLI/Flu/Mel trial in a similar population which reported an NRM rate of 30% (Jensen LG, Stiller T, Wong 
JYC, Palmer J, Stein A, Rosenthal J. Total Marrow Lymphoid Irradiation/Fludarabine/Melphalan 
Conditioning for Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and Marrow 
Transplantation. 2018;24(2):301-7. 
 
 
Stopping Boundary 
 
 
N=10 
N=20 
D180 NRM 
>=5 
>=6 
 

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12.7 Statistical Analysis Plan  
Toxicity information recorded in each patient will include the type, severity, and the probable association 
with the study regimen. Tables will be constructed to summarize the observed incidence by severity and 
type of toxicity, and dose levels. Baseline disease information (e.g. the extent of prior therapy) and 
demographic information will be presented, to describe the patients treated in this study. All patients who 
begin/receive treatment will be included as part of an ‘as treated’ analysis, in terms of survival, 
relapse/progression, non-relapse mortality and toxicities/complications. Survival estimates will be 
calculated using the Kaplan-Meier method. The cumulative incidence of relapse/progression, non-relapse 
mortality and acute/chronic GVHD will be calculated as competing risks. 
13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. 
The Investigator or their designee will prepare and maintain adequate and accurate source documents. 
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial. Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system (EDC) that is compliant 
with 21 CFR Part 11.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
13.3 Case Report Forms 
The Investigator is responsible for all information collected on subjects enrolled in this study. All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the Investigator. All case report forms must be completed by designated study personnel. The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
13.4 All data will be collected using electronic data collection.Regulatory Records 
The Investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
14.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST 
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) as 
defined in the relevant regulations and reporting to all applicable parties, including but not limited to the 
COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 

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14.1 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy. Adverse events will be characterized using the 
descriptions and grading scales found in NCI CTCAE v5.0. A copy of the scale can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
• 
Unrelated – The event is clearly NOT related to study treatment, and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
• 
Unlikely – The event is unlikely related to the study treatment, and is most likely related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
• 
Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration, but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
• 
Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.  
• 
Definite – The event is clearly related to the study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration and a known response pattern to the study drug, 
and is not reasonably explained by other factors such as the participant’s condition, therapeutic 
interventions, or concomitant drugs.  
14.2 Adverse Events of Special Interest (AESI) 
14.2.1 Overdose 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
the investigational drug of 111In/90Y-DOTA-basiliximab assigned to a given patient, regardless of any 
associated adverse events or sequelae. 
PO 
any amount over the protocol-specified dose 
IV 
10% over the protocol-specified dose   
On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol 
required schedule or frequency.   
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified rate.   
Complete data about drug administration, including any overdose, regardless of whether the overdose 
was accidental or intentional, should be reported.    

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14.3 Pregnancies 
14.3.1 Female participants: 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant occurring after the participant receives the first dose of protocol therapy up 
to 6 months following duration of study participation are considered immediately reportable events. 
Protocol therapy is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to the Study PI immediately within 24 hours of awareness (Sections 
14.5.1 and 14.5.2). The female subject may be referred to an obstetrician-gynecologist (preferably one 
with reproductive toxicity experience) or another appropriate healthcare professional for further 
evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 28 days of birth should be reported 
as an SAE per expedited reporting guidelines. 
Any infant death after 28 days that the Investigator suspects is related to the in utero exposure to protocol 
therapy should also be reported as an SAE per expedited reporting guidelines.  
14.3.2 Male participants: 
If a female partner of a male participant becomes pregnant, the male participant should notify the 
Investigator, and the pregnant female partner should be advised to call their healthcare provider 
immediately.  
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies. 
14.4 Routine AE Collection and Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation. Routine AE 
reporting will occur via data entry into the study eCRF. AEs will be monitored by the Protocol Management 
Team (PMT). AEs reported through expedited processes (e.g., reported to the IRB, DSMC, FDA, etc.) must 
also be reported in routine study data submissions. 
Routine recording of adverse events will occur via data entry into the study eCRF. Collect the start date 
and highest grade of toxicity using the Bearman Scale and CTCAE v5 for these time points:  
• 
Day -15 to Day -1,   
• 
Day 0 to Day +30, and  
• 
Day +31 to +100 post-transplant.  
After day 100, collect only AEs that are grade 3 or above(or any event that is considered an SAE) that are 
considered possibly, probably or definitely related to treatment (per table below), until the patient is off 
study. Note: for any grade 4 neutropenia, stop dates will also be collected. If a patient relapses and begins 
other anti-cancer therapy, only SAEs related to study therapy will be recorded (as per table below). 
Adverse events will be monitored by the Protocol Management Team (PMT). Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems do not require expedited reporting.  AEs 
reported through expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be reported 
in routine study data submissions.  

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14.5 Expedited Reporting  
Table 14.5 indicates what events must be reported expeditiously. 
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
Reporting of SAEs will begin once the patient receives the 90Y-basiliximab-DOTA dose, and must be 
followed until the event is resolved, stabilized, or determined to be irreversible by the investigator.  
Follow-up SAE reports must be submitted for all events that require expedited reporting when the status 
of the event changes and until the resolution or stabilization of the event. 
Table 14.5 Criteria for Expedited Reporting 
 
Time point 
What to report  
From signing of the consent to study completion 
 All UPs 
For the time period beginning at treatment 
through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, 
whichever is earlier 
 All SAEs regardless of relationship to protocol therapy  
 All UPs and AEs that meet the definition of a UP 
 
From Day 1 of protocol therapy up to 6 months 
following duration of study participation 
 Pregnancies and lactation  
Post Safety Follow-Up to removal from study  
 All SAEs that are considered possibly, probably or 
definitely related to treatment  
NOTE: All events reported expeditiously require follow-up reporting until the event is resolved, stabilized, or 
determined to be irreversible by the investigator.  
14.6 Reporting to the FDA 
The study PI (or designee) will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA. OIDRA will assist the PI 
with the preparation of the report and submit the report to the FDA in accordance with the approved City 
of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
o Any unexpected fatal or life threatening adverse experience associated with use of the drug must 
be reported to the FDA no later than 7 calendar days after initial receipt of the information [21 
CFR 312.32(c)(2)] 
o Any adverse experience associated with use of the drug that is both serious and unexpected must 
be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
o Any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 

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In addition, on behalf of the study PI, OIDRA will submit annually within 60 days of the anniversary of the 
date the IND went into effect, an annual report to the FDA which is to include a narrative summary and 
analysis of the information of all FDA reports within the reporting interval, a summary report of adverse 
drug experiences, and history of actions taken since the last report because of adverse drug experiences. 
15.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate hazard(s) 
for the protection, safety, and well-being of a research participant. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. All protocol deviations and 
planned protocol deviations will be reported in accordance with the City of Hope Clinical Research 
Protocol Deviation policy. 
16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, & DATA AND SAFETY MONITORING 
16.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
16.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities are executed in accordance with federal regulations.  
16.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, 
research nurse, clinical research associate/coordinator, and the study biostatistician, is responsible for 
ongoing monitoring of the data and safety of this study, including implementation of the stopping rules 
for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations, and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed.  
16.4 Quality Assurance  
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained. Monitoring for this study will be 
performed by the City of Hope Office of Clinical Trials Monitoring (OCTM), within City of Hope’s Office for 
Safety and Data Quality.  
Details of clinical site monitoring are documented in the OCTM SOP and the Risk Based Monitoring (RBM) 
plan. These documents specify the frequency of monitoring, monitoring procedures, the amount of 
subject data to be reviewed, and the distribution of monitoring reports to the study team and the COH 
DSMC.  

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16.5 Risk Determination  
This is a high risk study, as defined in the City of Hope Institutional DSMP. This determination was made 
because the study involves a COH IND. 
16.6 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study progress, 
compliance, toxicity, safety, and accrual data from this trial via the PMT Progress Report (submitted by 
the Study Principal Investigator according to the frequency outlined in the City of Hope Institutional 
DSMP). The DSMC is composed of clinical specialists who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Protocol 
Management Team.  
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 Title 21 Part 11 – Electronic Records; Electronic Signatures  
 Title 21 Part 50 – Protection of Human Subjects  
 Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 Title 21 Part 56 – Institutional Review Boards  
 Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 Title 21 Part 312 – Investigational New Drug Application  
 Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 Health Insurance Portability and Accountability Act of 1996  
 Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not limited 
to State of California Health and Safety Code, Title 17 
o Applicable NIH policies and procedures 
o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 
56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study. Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 

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The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
All participating sites must follow the lead institution’s IRB-approved protocol.  
17.4 Informed Consent 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document. In addition, they will review the experimental subject’s bill of rights if 
applicable, and the HIPAA research authorization form. Prospective participants will be informed that they 
may withdraw from the study at any time and for any reason without prejudice, including as applicable, 
their current or future care or employment at City of Hope or any relationship they have with City of Hope. 
Prospective participants will be afforded sufficient time to consider whether or not to participate in the 
research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
Children will provide assent when appropriate and indicated per institutional policy. Participants who are 
minors, who attain the age of majority while the study is still underway, must consent to continue taking 
part in the research. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form. Once the PI and site PI is notified 

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of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations 
17.6.1 Women and Minorities 
The study is open to anyone regardless of gender, race or ethnicity. Efforts will be made to extend the 
accrual to a representative population. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
Pregnant women are excluded because90Y-DOTA-anti-CD25 is an agent with the potential for teratogenic 
or abortifacient effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with Name of Agent, breastfeeding should be discontinued 
if the mother is treated with 90Y-DOTA-anti-CD25.   
17.6.2 Pediatric Population 
Pediatric participants (< 18 years of age) are excluded from this study because safety and effectiveness of 
protocol therapy has not yet been defined for the study population. Additional studies may be performed 
in the pediatric population once safety and effectiveness of protocol therapy is defined in the adult study 
population. 
17.6.3 HIV Positive Individuals 
Participants with HIV are excluded due to concerns about inadvertent augmentation of infectious and/or 
inflammatory activity. 
Participants with HIV are included based on specifications outlined in inclusion criteria. 
17.6.4 Vulnerable Populations 
Per 45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, and economically or educationally disadvantaged persons as vulnerable 
populations. 
17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, and the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 

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Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements. Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The Investigator/Institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities. The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject (accession) ID, date and time point of collection. 
The key to the code will be maintained in the COH clinical trials management system which is a secure 
environment.  
17.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will either be: (a) placed in a COH IRB approved biorepository with some clinical information and 
potentially PHI attached or (b) discarded. 
17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study. All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.10 
Financial Obligations, Compensation, and Reimbursement of 
Participants 
Drug 111 In /90 Y-DOTA-Anti-CD25 MAB and scans will be provided free of charge to participants.  
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier. The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope to the injured participant. There are no plans for City of Hope 
to provide financial compensation in the event of physical injury to a participant.  

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The research participant will not receive reimbursement or payment for taking part in this study. 
17.11 
Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the City of Hope PI. Any investigator involved 
with this study is obligated to provide City of Hope with complete test results and all data derived from 
the study. 
The publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov; it is City of Hope policy 
to register the trial prior to enrollment of the first patient. Results will be reported on ClinicalTrials.gov 
generally within 12 months after the primary completion date unless criteria to delay submission are met 
per the final rule. 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 

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18.0 REFERENCES 
 
 
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Blood 1988 Apr;71(4):888-93. 
 
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 (12)  Dinsmore R, Kirkpatrick D, Flomenberg N, Gulati S, Kapoor N, Brochstein J, et al. Allogeneic bone 
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or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute 
myeloblastic leukemia in first complete remission. Blood 2001 Jun 1;97(11):3669-71. 
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comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide 
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Radiat Oncol Biol Phys 1995 Jan 1;31(1):119-28. 
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body irradiation containing conditioning regimens for children with acute lymphoblastic 
leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 
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 (22)  Thomas ED, Lochte HL, Cannon JH, Sahler OD, Ferrebee JW. Supralethal whole body irradiation 
and isologous marrow transplantation in man. J Clin Invest 1959;38:11009-16. 
 (23)  Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP, et al. Allogeneic bone 
marrow transplantation for acute myeloid leukemia in first remission:  A randomized trial of 
busulfan-cytoxan versus cytoxan-total body irradiation as a preparative regimen:  A report from 
the Groupe d'Etudes de la Greffe de Moelle Osseuse. Blood 1992 May 15;79(10):2578-82. 

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 (24)  Dusenbery KE, Daniels KA, McClure JS, McGlave PB, Ramsay NK, Blazar BR, et al. Randomized 
comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide 
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comment]. International Journal of Radiation Oncology, Biology, Physics 1995;31(1):119-28. 
 (25)  Ringden O, Labopin M, Tura S, Arcese W, Iriondo A, Zittoun R, et al. A comparison of busulphan 
versus total body irradiation combined with cyclophosphamide as conditioning for autograft or 
allograft bone marrow transplantation in patients with acute leukaemia. Acute Leukaemia 
Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J 
Haematol 1996;93(3):637-45. 
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 (35)  Han C, Schultheiss T, Wong JY. Dosimetric study of volumetric modulated arc therapy fields for 
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 (48)  Bearman S, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related 
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 (51)  Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood 2010 Dec 
2;116(23):4762-70. 
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randomized, multicenter study of allogeneic stem cell transplantation after high versus reduced 
intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid 
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reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and 
myelodysplastic syndromes. J Clin Oncol 2017 Apr 10;35(11):1154-61. 
 (54)  Chen GL, Hahn T, Wilding GE, Groman A, Hutson A, Zhang Y, et al. Reduced-intensity 
conditioning with Fludarabine, Melphalan, and total body irradiation for allogeneic 
hematopopietic cell transplantation:  The effect of increasing Melphalan dose on underlying 
disease and toxicity. Biol Blood Marrow Transplant 2018;25:689-98. 
 (55)  Rosenthal J, Wong J, Stein A, Qian D, Hitt D, Naeem H, et al. Phase 1/2 trial of total marrow and 
lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic 
malignancies. Blood 2011 Jan 6;117(1):309-15. 
 (56)  Jensen LJ, Stiller T, Wong JYC, Palmer J, Stein A, Rosenthal J. Total marrow lymphoid 
irradiation/Fludarabine/Melphalan conditioning for allogeneic hematopoietic cell 
transplantation. Biol Blood Marrow Transplant 2018;24:301-7. 
 (57)  Speer TW. Radioimmunotherapy and unsealed radionuclide therapy. In: Halpern EC, Wazer DE, 
Perez CA, Brady LW, editors. Principles and Practic of Radiation Oncology. 6th ed. Philadelphia: 
Lippincott,Williams & Wilkins; 2013. p. 525-39. 
 (58)  Jurcic JG, Wong JYC, Knox SJ, Wahl DR, Rosenblat TL, Meredith RF. Targeted radionuclide 
therapy. In: Gunderson LL, Tepper JE, editors. Clinical Radiation Oncology. 4th ed. Philadelphia: 
Elsevier; 2016. p. 399-418. 

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 (59)  Burke JM, Caron PC, Papadopoulos EB, Divgi CR, Sgouros G, Panageas KS, et al. Cytoreduction 
with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced 
myeloid leukemias. Bone Marrow Transplant 2003;32:549-56. 
 (60)  Rosenblat TL, McDevitt MR FAU - Mulford D, Mulford DA FAU - Pandit-Taskar N, Pandit-Taskar 
NF, Divgi CR FAU - Panageas K, Panageas KS FAU - Heaney M, et al. Sequential cytarabine and 
alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid 
leukemia. Clin Cancer Res 2010;16(21):5303-11. 
 (61)  Jurcic JG, Ravandi F, Pagel JM, Park JH, Smith BD, Levy MY, et al. Phase I trial of targeted alpha-
particle immunotherapy with Actinium-225 (225 Ac)-Lintuzumab (Anti-CD33) and low-dose 
Cytarabine (LDAC) in older patients with untreated acute myeloid leukemia (AML). Blood 126, 
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 (62)  Pagel JM, Appelbaum F.R., Eary JF, Rajendran J, Fisher DR, Gooley T, et al. 131I-anti-CD45 
antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell 
transplantation for treatment of acute myeloid leukemia in first remission. Blood 2006 Mar 
1;107(5):2184-91. 
 (63)  Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, et al. Allogeneic 
hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibodyplus 
fludarabine and low-dose total body irradiation for elderly patients with advanced acute 
myeloid leukemia or high-risk myelodysplastic syndrome. Blood 2009;114(27):5444-53. 
 (64)  Mawad R, Gooley TA, Rajendran JG, Fisher DR, Gopal AK, Shields AT, et al. Radiolabeled anti-
CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger 
patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood 
Marrow Transplant 2014 Sep;20(9):1363-8. 
 (65)  Koenecke C, Hofmann M, Bolte O, Gielow P, Dammann E, Stadler M, et al. Radioimmunotherapy 
with [188Re]-labelled anti-CD66 antibody int he conditioning for allogeneic stem cell 
transplantation for high-risk acute myeloid leukemia. Int J Hematol 2008;87:414-21. 
 (66)  Ringhoffer M, Blumstein N, Neumaier B, Glatting G, von Harsdorf S, Buchmann I, et al. 188Re or 
90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with 
acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br 
J Haematol 2005 Aug;130(4):604-13. 
 (67)  Lauter A, Strumpf A, Platzbecker U, Schetelig J, Wermke M, Radke J, et al. 188Re anti-CD66 
radioimmunotherapy combined with reduced-intensity conditioning and in-vivo T cell depletion 
in elderly patients undergoing allogeneic haematopoietic cell transplantation. Br J Haematol 
2009;148:910-7. 
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Anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute 
leukemia and myelodysplastic syndrome. Blood 1999 Aug 15;94(4):1237-47. 

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 (69)  Bunjes D. 188Re-labeled anti-CD66 monoclonal antibody in stem cell transplantation for 
patients with high-risk acute myeloid leukemia. Leukemia & Lymphoma 2002;43(11):2125-31. 
 (70)  Zenz T, Glatting G, Schlenk RF, Buchmann I, Dohner H, Reske SN, et al. Targeted marrow 
irradiation with radioactively labeled anti-CD66 monoclonal antibody prior to allogeneic stem 
cell transplantation for patients with leukemia:  Results of a phase I-II study. Haematologica 
2006;91(2):285-6. 
 (71)  Appelbaum FR, Matthews DC, Eary JF, Badger CC, Kellogg M, Press OW, et al. The use of 
radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow 
transplantation for acute myelogenous leukemia. Transplantation 1992;54:829-33. 
 (72)  Waldmann TA, White JD, Carrasquillo JA, Reynolds JC, Paik CH, Gansow OA, et al. 
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labeled anti-Tac. Blood 1995;86(11):4063-75. 
 (73)  Dancey G, Violet J, Malaroda A, Green AJ, Sharma SK, Francis R, et al. A Phase I Clinical Trial of 
CHT-25 a 131I-Labeled Chimeric Anti-CD25 Antibody Showing Efficacy in Patients with 
Refractory Lymphoma. Clin Cancer Res 2009 Dec 15;15(24):7701-10. 
 (74)  Janik JE, Morris JC, O'Mahony D, Pittaluga S, Jaffe ES, Redon CE, et al. 90Y-daclizumab, an anti-
CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's 
lymphoma. Proc Natl Acad Sci U S A 2015 Oct 20;112(42):13045-50. 
 (75)  Conlon KC, Sportes C, Brechbiel MW, Fowler DH, Gress R, Miljkovic MD, et al. 90Y-Daclizumab 
(Anti-CD25), high-dose Carmustine, Etoposide, Cytarabine, and Melphalan chemotherapy and 
autologous hematopoietic stem cell transplant yielded sustained complete remissions in 4 
patients with recurrent Hodgkin's lymphoma. Cancer Biotherapy & Radiopharmaceuticals 
2020;35(4):249-61. 
 (76)  Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification 
of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci 
Transl Med 2010 Feb 3;2(17):1-22. 
 (77)  Terwijn M, Feller N, van Rhenen A, Kelder A, Westra G, Zweegman S, et al. Interleukin-2 
receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level 
of residual disease in AML. European Journal of Cancer 2009;45:1692-9. 
 (78)  Chen P, Chu A, Zia H, Koduru P, Collins R, Winick N, et al. CD25 expression in B lymphoblastic 
leukemia/lymphoma predicts t(9;22)(q34;q11)/Philadelphia chromosome translocation (Ph) and 
is associated with residual disease in Ph-negative patients. Am J Clin Pathol 2016;146:632-8. 
 
 
 
 

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APPENDIX A: PERFORMANCE STATUS SCALES 
 
ECOG Performance Scale [13] 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
 
 
Karnofsky 
Scale % 
Karnofsky 
Description 
ECOG 
Scale* 
ECOG 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
0 
Fully active, able to carry on all 
pre-disease activities without 
restriction 
90 
Able to carry on normal activity, minor 
symptoms or signs of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory and able 
to carry out work of a light or 
sedentary nature e.g. light house 
work, office work. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
Ambulatory and capable of all self 
care but unable to carry out any 
work activities. Up and about 
more than 50% of waking hours  
60 
Requires occasional assistance, but is able to 
care for most of own needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
Capable of only limited self care, 
confined to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization is indicated 
although death is not imminent. 
4 
Completely disabled. Cannot 
carry on any self care. Totally 
confined to bed or chair 
20 
Hospitalization necessary, very sick, active 
supportive treatment necessary. 
10 
Moribund, fatal processes 
Dead 
 
5 
Dead 
*also known as Zubrod, SWOG or WHO scale 
 
 

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APPENDIX B: TOXICITY SCALES 
Modified Bearman Scale [14] 
HCT Regimen-related toxicity by organ system 
Organ 
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 
congestive heart 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 ascites or 
image documented ascites > 100 mL; 
or weight gain > 5% from baseline of 
non-cardiac origin  
Severe hepatic dysfunction 
with bilirubin > 20 mg/dL; or 
hepatic encephalopathy; or 
ascites 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  
Note: Grade IV regimen-related toxicity is defined as fatal toxicity 

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Common Terminology Criteria for Adverse Events (Version 5): 
A copy of the CTCAE version 5 can be downloaded from the CTEP web site: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_
5x7.pdf 
 
 

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APPENDIX C: RESPONSE CRITERIA/GRADING/STAGING CRITERIA 
1. GvHD scoring criteria per Jagasia et.al., 2015[15] 
 
Score 0 
Score 1 
Score 2 
Score 3 
Performance score:______ 
 
KPS  ECOG  LPS 
 Asymptomatic 
and fully active 
(ECOG 0; KPS 
or LPS 100%) 
 Symptomatic, 
fully ambulatory,  
restricted only in 
physically 
strenuous activity 
(ECOG 1, KPS or 
LPS 80-90%) 
 Symptomatic, 
ambulatory, capable 
of self-care, >50% 
of waking hours out 
of bed (ECOG 2, 
KPS or LPS 60-
70%) 
 Symptomatic, 
limited self-care,  
>50% of waking 
hours in bed 
(ECOG 3-4, KPS or 
LPS <60%) 
SKIN† 
Score % BSA:______ 
GVHD features to be scored by 
BSA: 
Check all that apply: 
 Maculopapular 
rash/erythema 
 Lichen planus-like features 
 Sclerotic features 
 Papulosquamous lesions or 
ichthyosis 
Keratosis pilaris-like GVHD 
 No BSA 
involved 
 1-18% BSA 
 19-50% BSA 
 >50% BSA 
SKIN FEATURES SCORE: 
 No sclerotic 
features 
 
 Superficial 
sclerotic features 
“not hidebound” 
(able to pinch)  
Check all that 
apply: 
 Deep sclerotic 
features 
 “Hidebound” 
(unable to pinch) 
 Impaired mobility 
 Ulceration 
Other skin GVHD features (NOT scored by BSA) 
Check all that apply: 
 Hyperpigmentation 
 Hypopigmentation 
 Poikiloderma 
 Severe or generalized pruritus 
 Hair involvement 
 Nail Involvement 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_____________________________ 
† Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When 
a discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, OR if 
superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level 
should be used for the final skin scoring. 

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Score 0 
Score 1 
Score 2 
Score 3 
MOUTH 
Lichen planus-like features 
present: 
 Yes 
 No 
 No symptoms 
 Mild symptoms 
with disease 
signs but not 
limiting oral intake 
significantly  
 Moderate 
symptoms with 
disease signs with 
partial limitation of 
oral intake 
 Severe 
symptoms with 
disease signs on 
examination with 
major limitation of 
oral intake   
 
 
 
 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):______________________________ 
EYES 
 
Keratoconjunctivitis sicca (KCS) 
confirmed by ophthalmologist: 
 
 Yes 
 No 
 Not Examined  
 No symptoms 
 Mild dry eye 
symptoms not 
affecting ADL 
(requirement of 
lubricant eye 
drops ≤ 3 x per 
day) 
 Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring lubricant 
eye drops > 3 x per 
day or punctal 
plugs), 
WITHOUT new 
vision impairment 
due to KCS 
 Severe dry eye 
Symptoms 
significantly 
affecting ADL 
(special eyeware to 
relieve pain) OR 
unable to work 
because of ocular 
symptoms OR loss 
of vision due to 
KCS 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________________ 
GI Tract 
Check all that apply: 
 Esophageal web/ proximal 
stricture or ring 
 Dysphagia 
 Anorexia 
 Nausea 
 Vomiting 
 Diarrhea 
 Weight loss ≥5% within 3 
months 
 Failure to thrive 
 No symptoms 
 Symptoms 
without significant 
weight loss within 
3 months (<5%) 
 Symptoms 
associated with mild 
to moderate weight 
loss within 3 months 
(5-15%) OR 
moderate diarrhea 
without significant 
interference with 
daily living 
 Symptoms 
associated with 
significant weight 
loss within 3 months 
>15%, requires 
nutritional 
supplement for 
most calorie needs 
OR esophageal 
dilation OR severe 
diarrhea with 
significant 
interference with 
daily living 
 
 
 
 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):________________________________ 
LIVER 
 Normal total 
bilirubin and 
ALT or AP <3 x 
ULN 
 Normal total 
bilirubin with ALT 
≥3 to 5 x ULN or  
AP ≥3 x ULN 
 Elevated total 
bilirubin but ≤3 
mg/dL or ALT >5x 
ULN 
 Elevated total 
bilirubin >3 mg/dL  
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):________________________________ 

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Score 0 
Score 1 
Score 2 
Score 3 
LUNGS** 
 
Symptom score: 
 No symptoms 
 Mild symptoms 
(shortness of 
breath after 
climbing one flight 
of steps) 
 Moderate 
symptoms 
(shortness of breath 
at after walking on 
flat ground) 
 Severe 
symptoms 
(shortness of breath 
at rest; requiring O2) 
Lung score: 
% FEV1  ________ 
 FEV1≥80% 
 FEV1 60-79% 
 EFV1 40-59% 
 FEV1 ≤39% 
Pulmonary function tests 
 Not performed  
 
 
 
 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):________________________________ 
**Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be 
used in the final lung scoring where there is discrepancy between symptoms and FEV1 scores. 
JOINTS AND FASCIA 
P-ROM score 
(see below) 
Shoulder (1-7):___ 
Elbow (1-7):___ 
Wrist/finger (1-7):___ 
Ankle (1-4)___ 
 No symptoms 
 Mild tightness 
of arms or legs, 
normal or mild 
decreased range 
of motion (ROM) 
AND not affecting 
ADL 
 Tightness of 
arms OR legs or 
joint contractures, 
erythema thought 
due to fasciitis, 
moderate 
decreased ROM 
AND mild to 
moderate limitation 
of ADL 
 Contractures 
WITH significant 
decrease of ROM 
AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress 
self etc.)  
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________________ 
 
Photographic Range of Motion (P-ROM) 
 

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Score 0 
Score 1 
Score 2 
Score 3 
GENITAL TRACT 
(see Appendix-XXD‡) 
 Not examined 
Currently sexually active 
 Yes 
 No 
 No signs 
 Mild signs‡ and 
females with or 
without discomfort 
on exam 
 Moderate signs‡ 
and may have 
symptoms with 
discomfort on exam 
 Severe signs‡  
with or without 
symptoms 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________________ 
 
‡ To be completed by specialist or trained medical providers (see Appendix-XXD: GENITAL GVHD AND SCORING 
FORM) 
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and assign a  
score to severity (0-3) based on functional impact where applicable none — 0,mild -1, moderate -2, severe — 3) 
 Ascites (serositis) _____ 
 Pericardial Effusion_____ 
 Pleural Effusion(s) _____ 
 Nephrotic syndrome 
 Myasthenia Gravis_____ 
 Peripheral Neuropathy_____ 
 Polymyositis_____ 
 Weight loss > 5% within 3 months 
without GI symptoms___ 
 Eosinophilia > 500/μl_____ 
 Platelets <100,000/ μl_____ 
 Others (specify): _____ 
Overall GVHD Severity 
(Opinion of the evaluator)  
 No GVHD 
 Mild 
 Moderate 
 Severe  
 
 

This document is confidential and for research purposes only. Distribute and use ONLY as authorized.  
 
2.  Physician-Reported Global cGVHD Activity Assessment Form A 
 

This document is confidential and for research purposes only. Distribute and use ONLY as authorized.  
 
3. Chronic GVHD Activity Assessment-Patient Self Report 
Abstracted from: 
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host 
Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-
versus-Host Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant 2015; 
21:984 – 999

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4. Lee cGVHD Symptom Scale 
Abstracted from: 
Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure symptoms of 
chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002; 8:444-452. 
 
 
 

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APPENDIX D: ANTIBODY PREPERATION, RADIOLABELING, AND QUALITY CONTROL 
Simulect (basiliximab) is a chimeric IgGl monoclonal antibody produced by recombinant DNA technology that 
binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity interleukin-2 
(IL-2) receptor that is expressed on the surface of activated lymphocytes.  Basiliximab is a composite of human 
and murine antibody sequences.  The human sequences were derived from the constant domains of human IgGl 
and the variable framework regions of the Eu myeloma antibody.  The murine sequences were derived from the 
complementarity-determining regions of a murine anti-Tac antibody.  The molecular weight predicted from the 
DNA sequence is 144 kilodaltons.  
The anti-CD25 MAb is supplied by Novartis as a clear, sterile, colorless concentrate for further dilution and 
intravenous administration.  Each 20-mg vial contains 20 mg basiliximab, 7.21 mg monobasic potassium 
phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium chloride, 20 mg sucrose, 80 mg 
mannitol and 40 mg glycine, to be reconstituted in 5 mL of Sterile Water for Injection, USP.  No preservatives are 
added.  The anti-CD25 MAb was obtained from the City of Hope Pharmacy and then concentrated, dialyzed and 
conjugated with a macrocyclic chelate, DOTA, and then vialed in The City of Hope (COH) Center for Biomedicine 
and Genetics (CBG) Pilot Manufacturing Facility under cGMP.  The purified conjugated product was tested 
according to Quality Assurance Safety Guidelines of the US Code of Federal Regulations for Biologicals, CFR Section 
21 Part 610, FDA Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human 
Use (1997) and Points to Consider in the Characterization of Cells Lines used to Produce Biologicals (1993).  Each 
lot of anti-CD25-DOTA undergoes testing for sterility, identity, purity, lack of pyrogenicity, immunologic specificity, 
potency, and protein concentration. 
This study will use 111In– and 90Y–DOTA–anti-CD25 monoclonal antibody (MAb) radiolabeled in the Research 
Radiopharmacy and then purified by size exclusion chromatography immediately prior to patient infusion, 
assuring that the radiopharmaceutical is of highest purity, having eliminated any free radionuclide or radiolytically 
damaged protein.  In addition, the product will be tested for the presence of endotoxin prior to administration 
and will then be tested for sterility, purity and immunoreactivity. 
 
 

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APPENDIX E: IMAGING PROTOCOLS 
IMAGING PROTOCOL FOR 111In-basiliximab/DOTA 
BACKGROUND 
Scans are acquired with an in-line SPECT-CT scanner  comprising a dual-headed gamma camera and single-slice x-
ray CT scanner.  Internal standards, i.e., one or more known In-111 sources, are placed within the field of view in 
order to calibrate the scanner sensitivity. A total of three planar conjugate-view whole-body scans are performed 
beginning at the approximately 0-2 hours post start of 111In-basiliximab/DOTA infusion and again at approximately 
1 day, and 5/6 days post infusion.  Following the planar scans at 1 day, SPECT scans will also be obtained at Day 1.  
Blood samples (1 EDTA purple top tube and 1 red top tube) will be obtained  at 1-2 hours and 3-4 hours post start 
of infusion of 111In-/90Y-basiliximab/DOTA, and scan times of 1 day, and 5/6 days post infusion of the radiolabeled 
antibody.   
The method for image processing, extraction of pharmacokinetic data and dose estimation is as follows.  
Conjugate-view, geometric mean images and a standard program for calculating radionuclide radiation absorbed 
dose (Stabin et al., 2005) are used for estimating tissue activity concentrations and absorbed doses.  Attenuation 
corrections are based on body thickness and organ depth measurements made from CT scans. Regions of interest 
are defined on the radionuclear images.  Tissue time-activity curves derived from the image sets are corrected for 
the difference in half life between 111In and 90Y. Time extrapolation is achieved for blood and liver by fitting a 5-
compartment systemic model to the time-activity data obtained for those regions plus residual body, urine and 
feces. The time-activity curve for red marrow is assumed proportional to that for blood. Time-activity curves for 
other normal tissue regions (heart, kidneys, spleen, residual body), and for tumor if available, are assumed to 
follow the physical decay of 90Y after the final time of observation.  The extrapolated time-activity curves are 
numerically integrated to estimate cumulated activities, which are used in conjunction with OLINDA to calculate 
absorbed doses to various organs, tissues and whole body. Results are adjusted to better reflect the actual 
anatomy of the individual patient based on organ size measurements made from CT images.  
The current image processing software for SPECT scans obtained with the camera includes CT-based attenuation 
correction.  We also have access to advanced software for quantitative SPECT developed by Frey et al., at Johns 
Hopkins.  This includes iterative reconstruction-based corrections for scatter and collimator-detector response.  
We expect the fully-corrected SPECT images to provide estimates of In-111 concentration in normal organs that 
are accurate to within 20%.  (He et al., 2005).  Furthermore, the availability of coregistered CT will greatly facilitate 
region-of-interest definitions for SPECT quantitation for organs.   
 
REFERENCES 
He B, Du Y, Song X, Segars WP, Frey EC. A Monte Carlo and Physical Phantom Evaluation of Quantitative In-111 
SPECT. Phys Med Biol 2005; 50(17):4169-4185. 
Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: The Second-Generation Personal Computer Software for Internal 
Dose Assessment in Nuclear Medicine. J Nucl Med 2005; 46(6):1023-1027. 
 
PROTOCOL:  Indium–111 (111In)–basiliximab Data Acquisition 
I. 
Equipment and Materials 
1. SPECT-CT:  camera using medium energy collimators 

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2. 111In standards are to be included in the whole body γ–camera scans. 
II. 
Patient 111In–basiliximab Injection, Post–Injection Imaging and Fluid Collection 
A. 
Injected Activity 
1.   Intended radioactive dose is 5 mCi. 
2.   Just prior to infusion, verify and record the dose using a dose calibrator.  Record the time and date. 
3.   Count the empty syringe after injection using the dose calibrator to determine residual activity to 
calculate and record the total activity injected. 
B. 
 Image Acquisition and Fluid Sampling 
1. Beginning immediately after infusion of the 111In–basiliximab and prior to urination, perform a whole 
body scan acquiring both anterior and posterior images (160 s/pixel) using a medium energy 
collimator(MEGP-M2), a 256 x 1024 computer acquisition matrix and acquisition photo peak settings of 
172 and 247 keV with 20% windows. 
2. Repeat whole body images at 1 day and 5/6 days post–111In– basiliximab injection.   
3. After the 111-In/90-Y-basiliximab administration, blood samples (1 EDTA purple top tube and 1 red top 
tube) will be obtained  at 1-2 hours, 3-4 hours, 1 day, and 5/6 days post start of infusion of the 
radiolabeled antibody.   
4. For the Day 1 time point, acquire SPECT-CT scans (2 bed positions beginning at top of head) following 
the whole-body scans.  Collimators and energy windows are the same as for the whole-body scans.  The 
SPECT acquisition technique is 60 steps (120 views), 3o and 30 s/step, planar image matrix 128x128. 
5. Record the start times of the whole-body and SPECT acquisitions as well as the times of blood sampling. 
Each set of whole-body images should include a standard of 111In in a small plastic vial (such as a γ–counting 
vial).  A standard of ~ 50 µCi in 10 ml water should be made up prior to the 0 hr image and the same standard 
used with each planar image acquisition beginning after the dose is infused.  Measure the exact standard 
activity in a dose calibrator and record the time and activity.  This should correspond to the time of the start 
of the first scan.  Place the standard on the imaging table ~ 10 cm from the body, lateral to the feet.  Place 
standard on the same side of the body for each scan.   
B. 
SPECT Image Reconstruction 
1.  Perform standard OSEM reconstructions (image matrix 64x64x64) without and with CT-based 
attenuation correction. 
2.  Imaging Physicists will also perform image reconstruction that includes scatter and collimator-detector 
response corrections. 
 
 

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APPENDIX F. IMMUNOHISTOCHEMISTRY 
CD25 (IL2RA) is expressed in activated B-cells, T-cells, as well as myeloid precursors.  It is also expressed in cases 
of acute myeloid leukemia (AML) and in some instances associated with poor survival1.  CD25 expression will be 
determined by immunohistochemistry at the City of Hope Laboratories and evaluated for positivity in the myeloid 
blasts in formalin-fixed paraffin-embedded tissue sections by a pathologist.  Cases will be deemed positive if there 
is greater than 20% positivity in the blasts.     
 
1. 
Li J, Ran Q, Xu B, et al. Role of CD25 expression on prognosis of acute myeloid leukemia: A literature review 
and meta-analysis. PLoS One. 2020;15(7):e0236124. 
 
1. 
Pasquini, M.C., et al., Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-
Hodgkin lymphoma. Blood Adv, 2020. 4(21): p. 5414-5424. 
2. 
Tesch, H., et al., Expression of interleukin-2R alpha and interleukin-2R beta in Hodgkin's disease. Am J Pathol, 1993. 
142(6): p. 1714-20. 
3. 
Waldmann, T.A., Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the 
prevention of allograft rejection: a 25-year personal odyssey. J Clin Immunol, 2007. 27(1): p. 1-18. 
4. 
Flynn, M.J. and J.A. Hartley, The emerging role of anti-CD25 directed therapies as both immune modulators and 
targeted agents in cancer. Br J Haematol, 2017. 179(1): p. 20-35. 
5. 
Network, N.C.C., NCCN Clinical Practice Guideline in Oncology Acute Meloid Leukeumia, Version 2.2014. Available 
at nccn.org, 2014. 
6. 
National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology for Acute Lymphoblastic 
Lymphoma, Version 1.2014. Available at nccn.org, 2014. 
7. 
Moorman, A.V., et al., Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute 
lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet 
Oncology, 2010. 11(5): p. 429-38. 
8. 
Greenberg, P.L., et al., Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012. 
120(12): p. 2454-65. 
9. 
Alaggio, R., et al., The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: 
Lymphoid Neoplasms. Leukemia, 2022. 36(7): p. 1720-1748. 
10. 
Dohner, H., et al., Diagnosis and management of AML in adults: 2017 ELN recommendations from an international 
expert panel. Blood, 2017. 129(4): p. 424-447. 
11. 
Savona, M.R., et al., An international consortium proposal of uniform response criteria for 
myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood, 2015. 125(12): p. 1857-65. 
12. 
Cheson, B.D., et al., Refinement of the Lugano Classification lymphoma response criteria in the era of 
immunomodulatory therapy. Blood, 2016. 128(21): p. 2489-2496. 
13. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 
1982. 5(6): p. 649-55. 
14. 
Bearman, S.I., et al., Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol, 
1988. 6(10): p. 1562-8. 
15. 
Jagasia, M.H., et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow 
Transplant, 2015. 21(3): p. 389-401.e1. 

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APPENDIX G: HCT-CI INDEX 

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