Conditions: Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
To determine engraftment of neutrophils and platelets at 28 days following alpha/beta T-cell and CD19 cell depletion using Human Leukocyte Antigen (HLA) haploidentical donors for peripheral blood stem cell transplant in relapsed lymphoma.

Assess incidence of acute Graft Versus Host Disease (GVHD), chronic GVHD, graft failure rate, treatment related mortality rate, progression free survival and overall survival of patients.

The stem cell product will be processed using an investigational Miltenyi cell selection device/system that removes the alpha/beta T-cells and CD19+ cells, immune system cells that are more likely to cause GVHD.

Detailed description:

Arms:
arm 1: PREPARATIVE REGIMEN: Participants receive fludarabine phosphate IV over approximately 30 minutes on days -5 to -2, and mesna IV over 24 hours and cyclophosphamide IV over approximately 2 hours on days -5 and -4. Participants also undergo total nodal irradiation on day -1.

TRANSPLANT: Participants undergo T-Cell Receptor (TCR) alpha-beta/CD19 depleted hematopoietic stem cell transplant on day 0. If the graft contains less than 4 x 10\^6 CD34+ cells/kg participant body weight (BW), patients may receive a second graft on day 1.

GVHD PROPHYLAXIS: Participants receive mycophenolate mofetil orally twice a day (PO BID) on days -1 to 30, tacrolimus PO or IV on days 2-180 with a taper beginning on day 90 (given only if graft TCR alpha-beta+ cell content is over 1 x 10\^5 cells/kg ideal BW of the patient), and rituximab IV on day 2 (given only if graft B cell content exceeds 1 x 10\^5 cells/kg ideal BW of the participant).

Interventions: intervention 1: Fludarabine Phosphate intervention 2: Mesna intervention 3: Cyclophosphamide intervention 4: Total nodal irradiation intervention 5: T Cell-Depleted Hematopoietic Stem Cell Transplantation intervention 6: Allogeneic Hematopoietic Stem Cell Transplantation intervention 7: Peripheral Blood Stem Cell Transplantation intervention 8: Mycophenolate Mofetil intervention 9: Tacrolimus intervention 10: Rituximab
Intervention descriptions: intervention 1: Fludarabine will be administered by IV over approximately 30 minutes for 4 days. intervention 2: Given IV over 24 hours starting prior to cyclophosphamide intervention 3: Given IV for 2 days intervention 4: Undergo total lymphoid irradiation intervention 5: Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant intervention 6: Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant intervention 7: Undergo TCR alpha-beta/CD19-depleted hematopoietic stem cell transplant intervention 8: Given PO intervention 9: Given PO or IV ONLY if graft cell content is over 1 x 10\^5 cells/kg ideal BW of the patient intervention 10: Given IV ONLY if graft B cell content exceeds 1 x 10\^5 cells/kg ideal BW of the patient

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
A pilot study to assess engraftment using CliniMACS TCR-α/
β and CD19 depleted stem cell grafts from haploidentical 
donors for hematopoietic progenitor cell transplantation in 
patients with relapsed lymphoma 
 
 
 
 
Principal Investigator 
Vaishalee P Kenkre, MD 
University of Wisconsin SMPH  
Department of Medicine, Division of 
Hematology/Oncology, Blood and 
Marrow Transplant Program 
4037 WIMR 
1111 Highland Avenue 
Madison, WI  53705 
Phone: (608) 263-1699 
Fax: (608) 265-6905 
Email: vpkenkre@medicine.wisc.edu 
Co-Investigator 
Peiman Hematti, MD 
University of Wisconsin SMPH 
Department of Medicine, Division of 
Hematology/Oncology, Blood and 
Marrow Transplant Program 
4033 WIMR 
1111 Highland Avenue 
Madison, WI  53705 
Phone: (608) 265-0106 
Fax: (608) 262-4598 
Email: pxh@medicine.wisc.edu 
 
Co-Investigator 
Mark Juckett, MD 
University of Wisconsin SMPH  
Department of Medicine, Division of 
Hematology/Oncology, Blood and 
Marrow Transplant Program 
4051 WIMR 
1111 Highland Avenue 
Madison, WI  53705 
Phone: (608) 263-0338 
Fax: (608) 262-4598 
Email: mbj@medicine.wisc.edu 
Co-Investigator 
Aric Hall, MD 
University of Wisconsin SMPH  
Department of Medicine, Division of 
Hematology/Oncology, Blood and 
Marrow Transplant Program 
K6/548 CSC 600 Highland Avenue 
Madison, WI  53792 
Phone: (608) 262-1604 
Fax: (608) 265-8133 
Email: achall@medicine.wisc.edu 
Co-Investigator 
Natalie Callander, MD 
University of Wisconsin SMPH  
Department of Medicine, Division of 
Hematology/Oncology, Blood and 
Marrow Transplant Program 
4059 WIMR 
1111 Highland Avenue 
Madison, WI  53705 
Phone: (608) 265-8554 
Fax: (608) 265-8133 
Email: nsc@medicine.wisc.edu 
Clinical Team Manager 
Whitney Walters, BS 
University of Wisconsin 
Carbone Cancer Center 
K4/613 CSC 
600 Highland Avenue 
Madison, WI 53792-6164 
Phone: (608) 263-1974 
Fax: (608) 237-2469 
Email: wwalters2@wisc.edu 
 


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Co-Investigator 
Kristin Bradley, MD 
University of Wisconsin 
Department of Oncology Radiation 
University of Wisconsin SMPH  
Department of Medicine, Division of 
Human Oncology 
K4/B100 CSC 
600 Highland Avenue 
Madison, WI  53792 
Phone: (608) 263-8500 
Fax: (608) 263-9167 
Email: Kabradley@humonc.wisc.edu 
Protocol Activation Coordinator 
Monika Stankiewicz PhD, MSRC 
University of Wisconsin 
Carbone Cancer Center 
K4/613 CSC 
600 Highland Avenue 
Madison, WI 53792-6164 
Phone: (608) 262-6873 
Fax: (608) 263-4511 
Email: monika.stankiewicz@.wisc.edu 
 
Study Statistician 
KyungMann Kim, PhD 
University of Wisconsin SMPH 
Biostatistics and Medical Informatics 
K6/438 CSC 
600 Highland Avenue 
Madison, WI  53792 
Phone: (608) 265-6380 
Fax: (608) 265-5579 
Email: kmkim@biostat.wisc.edu 
Lead Cinical Research Coordinator 
Arissa Milton, BS 
University of Wisconsin 
Carbone Cancer Center 
K4/613 CSC 
600 Highland Avenue 
Madison, WI 53792-6164 
Phone: (608) 262-6873 
Fax: (608) 263-4511 
 
 
 
 
 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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Revision History 
 
 
Version 
Date 
 
Detail of Changes 
Consent 
Change 
(Y/N) 
 
Consent 
Date 
01/26/2016 
Expedited Change: Editorial and clarifications: 
--Updated protocol version date 
--Updated study personnel 
--Clarified Recipient Inclusion Criteria Section 3.1.2, 
current disease status and timeframe allowed 
between patient meeting the disease criteria and 
registration 
--Revised Donor Inclusion Criteria Section 3.3.2, age 
--No changes to consent documents were made 
N 
Recipient 
ICF: 
10/19/2015 
Donor ICF: 
10/19/2015 
08/15/2016 
Full Change 
--Updated protocol version date 
--Updated study personnel and roles 
--Updated revision history 
--Added Recipient Inclusion Criteria Section 3.1.2.9 to 
include all subtypes of non-Hodgkin Lymphoma 
--Further defined incurable indolent histologies in 
background Section 1.4 
--Updated Luminex Exclusion Criteria 3.4.1  
--Extended window for obtaining informed consent to 
42 days in Section 9 
--Removed ‘by RPR’ from Section 9, footnote 5  
--Added Section 9, Footnote 8 to clarify that the 
Panorex scan can be obtained through the CT sinus 
--Re-numbered footnotes in Section 9 
--Updated Section 9, Footnote 12 to indicate WBC 
count required starting Day +7 
 
Donor ICF Changes: 
--Are there risks? -Corrected number of days may 
need to donate from three to two 
--Are there any costs? -Removed the reference to the 
cell depletion being considered research 
Y (donor 
ICF 
corrections 
only) 
Recipient 
ICF: 
10/19/2015 
Donor ICF: 
8/15/2016 
10/23/2017 
Full Change 
--Updated protocol version date 
--Updated study personnel and roles 
--Updated revision history 
--Synopsis: updated disease status inclusion criteria 
to restrict DLBCL patients to those who are in 
complete or partial remission to salvage therapy after 
relapse 
--Synopsis: updated cardiac inclusion criteria to 
mandate against significant heart failure symptoms or 
severe valvular abnormalities 
--Synopsis: added exclusion criteria for history of prior 
mediastinal radiation and reported illicit drug use 
--Updated DLBCL inclusion criteria 3.1.2.3 and 
3.1.2.4 to restrict DLBCL patients to those who are in 
 
 


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complete or partial remission to salvage therapy after 
relapse 
--Updated cardiac inclusion criteria 3.1.5 to mandate 
against significant heart failure symptoms or severe 
valvular abnormalities 
--Added exclusion criteria 3.2.6 to exclude patients 
who have had mediastinal radiation 
--Added exclusion criteria 3.2.7 to exclude patients 
who report illicit drug use 
--Renumbered exclusion criteria 3.2.8 (previously was 
3.2.6) 
--Clarified section 6.5 rituximab dosing may be 
adjusted per UW SOP to nearest 50mg dose as long 
as within 10% of original dose 
--Section 9 Schedule of Evaluations modified to 
include asking and documenting illicit drug history, 
added footnote 1 
--Section 9 Schedule of Evaluations, subsequent 
footnotes re-numbered 
 
Recipient ICF Changes: 
--Updated version date 
--Unknown or Unexpected Side Effects: moved 
location for consistency, updated language for clarity 
--What if I have questions? Updated the first sentence 
for clarity 
04/24/2020 
Full change 
 
 
 
--Update to title page to remove former staff and add 
new staff 
--Updated protocol version date 
--Updated revision history 
--Updated Signature page  
--updated Protocol Synopsis: removed former co-
investigator, Study Procedures updated to include 
extended monitoring 
--Table of Contents updated for page numbers and 
addition of section 7.4.4 with this Amendment 
--List of Abbreviations and Definition of Terms has 
been updated to remove DOWG and include DOT as 
described  
--Section 7.2 has been updated for extending 
monitoring 
--Section 7.4 Table 1 has been revised to describe 
updated reporting timelines and to reference section 
7.4.4 
--Section 7.4.1 was updated for change in “DOWG” to 
“DOT” 
--Section 7.4.3 updated language for clarity 
--Section 7.4.4 added section for Extended Safety 
Monitoring out to 2 years post-transplant 
--Section 9.0 Schedule of Evaluations updated for 
extended monitoring, footnote 16 
-- minor spelling and grammar corrections throughout 
document 
 
 


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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the 
attachments, and provides the necessary assurances that this trial will be 
conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines. 
 
Principal Investigator 
 
Signed: 
 
 
 
 
 
 
     Date: 
 
 
________________________________________                          __________________ 
 
 
Vaishalee P Kenkre, MD 
Associate Professor 
University of Wisconsin SMPH 
Department of Medicine, Division of Hematology/Oncology, Blood and 
Marrow Transplant Program 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
 
 
Title 
A pilot study to assess engraftment using CliniMACS TCR-α/β and 
CD19 depleted stem cell grafts from haploidentical donors for 
hematopoietic progenitor cell transplantation in patients with relapsed 
lymphoma 
 
Short Title 
α/β depleted Haplo-HSCT for patients with relapsed lymphoma 
IDE Sponsor 
Peiman Hematti MD 
Principal 
Investigator 
Vaishalee Kenkre, MD 
Co-
Investigators 
Kristin Bradley, MD, Natalie Callander, MD, Aric Hall, MD, Peiman 
Hematti, MD, Mark Juckett, MD 
Participating 
Site 
University of Wisconsin-Madison  
Accrual 
Objective 
14 transplant recipients 
14 donors  
Study Design 
Single center, open label, single-arm, pilot trial 
Study Duration 
The estimated accrual period is two years. 
Primary 
Objectives 
To determine engraftment of neutrophils and platelets at 28 days 
following alpha/beta T-cell depletion using HLA haploidentical donors 
for stem cell transplant in relapsed lymphoma.  
 
Secondary 
Objectives 
Acute GVHD – The cumulative incidence of grade III – IV acute GVHD 
by Day +100 will be determined.  The GVHD grade will be determined 
by the IBMTR Severity Index criteria (Appendix A).   
 
Chronic GVHD – The cumulative incidence of severe chronic GVHD 
by Day +180 will be recorded and defined according to the NIH 
consensus criteria (Appendix B). 
 
Graft failure rate – defined as < 5% donor chimerism in the CD3 and/or 
CD33 selected cell populations at any time in the study follow up 
period once initial engraftment has been achieved.  
 
Treatment-related mortality rate – defined as death from any cause 
other than disease progression 
 
Progression-free survival – defined as time before any progression by 
either PET/CT or bone marrow (Appendix C) 
 


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Overall survival – after enrollment on study 
Exploratory 
Objectives 
• Evaluation of immune cell recovery 
 
Inclusion 
Criteria 
• Age 18 to 75 years  
 
• Patients must meet one of the following disease criteria within 24 
months of registration.  Salvage therapy is allowed between the 
patient meeting one of the below criterion and registration.  
Patients will be considered eligible regardless of their current 
disease status (i.e. complete remission, partial remission, stable 
disease, progressive disease) unless otherwise noted below as 
long as one of the below criterion has been met within the 
previous 24 months: 
 
o Relapsed/refractory Hodgkin lymphoma after autologous 
stem cell transplantation 
 
o Relapsed/refractory Hodgkin lymphoma, deemed ineligible 
for autologous stem cell transplantation due to refractory 
disease 
 
o Relapsed/refractory diffuse large B cell lymphoma after 
autologous stem cell transplantation (history of 
transformed lymphoma is acceptable). Disease must be in 
at least complete remission or partial remission with the 
use of salvage therapy before study treatment 
commences. 
 
o Relapsed/refractory diffuse large B cell lymphoma, 
deemed ineligible for autologous stem cell transplantation 
due to refractory disease (history of transformed 
lymphoma is acceptable). Disease must be in at least 
complete remission or partial remission with the use of 
salvage therapy before study treatment commences. 
 
o Relapsed/refractory T cell lymphoma relapsed after at 
least 1 prior line of therapy 
 
o Relapsed/refractory follicular lymphoma relapsed after at 
least 1 prior line of therapy 
 
o Relapsed/refractory mantle cell lymphoma relapsed after 
at least 1 prior line of therapy 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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o Relapsed/refractory small lymphocytic lymphoma/chronic 
lymphocytic leukemia relapsed after at least 1 prior line of 
therapy 
 
o Relapsed/refractory non-Hodgkin lymphoma, if not 
specified above, relapsed after at least 1 prior line of 
therapy 
 
• Karnofsky score of 60% or better (“Requires occasional 
assistance, but is able to care for most of his/her needs”). 
 
• Pulmonary: DLCO (corrected for hemoglobin) > 40%; and FEV1 > 
50% 
 
• Cardiac: EF ≥ 50%. No uncontrolled angina or active cardiac 
symptoms consistent with congestive heart failure (class III or IV), 
by the New York Heart Association criteria. No symptomatic 
ventricular arrhythmias or ECG evidence of active ischemia. No 
evidence by echocardiography of severe valvular stenosis or 
regurgitation. 
 
• Renal: estimated GFR by MDRD formula  > 40 mL/min/1.73m2 
 
• Women of child bearing potential must have a negative serum or 
urine pregnancy test within 14 days prior to study registration and 
agree to use adequate birth control during study treatment. A 
female of childbearing potential (FCBP) is a sexually mature 
female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for 
at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
 
• Voluntary written consent 
 
Exclusion 
Criteria 
• Active CNS lymphoma within two weeks of registration.  Patients 
with a history of CNS involvement must have adequate treatment 
as defined by at least two negative spinal fluid assessments 
separated by at least one week. (Otherwise LP is not required if 
no clinical suspicion or evidence of CNS involvement.) Patients 
who have received cranial radiation therapy must still be eligible 
to receive total lymphoid irradiation to 7 Gy.  
 
• New or active infection as determined by fever, unexplained 
pulmonary infiltrate or sinusitis on radiographic assessment.  


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Infections diagnosed within 4 weeks of registration must be 
determined to be controlled or resolving prior to treatment.   
 
• Presence of HIV, or active hepatitis A, B, or C infection 
 
• Allergy or hypersensitivity to agents used within the treatment 
protocol. 
 
• For an indolent lymphoma histology (follicular lymphoma, 
SLL/CLL) or mantle cell lymphoma, the patient should not have 
an HLA-matched sibling, who would be an eligible donor, 
available.  
 
• History of prior mediastinal radiation 
 
• Reported illicit drug use 
 
• Vulnerable population groups, i.e., prisoners, those lacking 
consent capacity, non-English speaking, illiterate, pregnant 
females.  
 
Treatment 
Description 
Patients will undergo a conditioning regimen prior to Peripheral Blood 
Stem Cell graft from a haploidentical donor depleted of TCR α/β+ 
and CD19+ cells.  
Study 
Procedures 
• Following screening and enrollment, the haploidentical family 
donor will receive stem cell mobilization therapy with 
subcutaneous G-CSF prior to PBSC collection by leukapheresis.   
 
• Patients will undergo a conditioning regimen consisting of 
Cyclophosphamide 60 mg/kg IV daily Days -5 and -4, 
      Fludarabine 40 mg/m2 IV daily, Days -5 to -2, Total lymphoid           
     irradiation (TLI) 7Gy, Day -1 prior to transplant with a    
     haploidentical donor Peripheral Blood Stem Cell graft depleted of    
     TCR α/β+ and CD19+ cells. GVHD prophylaxis will consist of  
     Mycophenolate mofetil (MMF) at a targeted dose of 20 mg/kg  
     orally BID beginning Day -1 until Day +30. Tacrolimus will be     
     administered starting Day +2 (through day +180) if TCRα/β+ cell     
     content exceeds 1 × 105 cells/kg  ideal BW of the patient.   
     Rituximab will be administered on Day +2 if B cell content  
     exceeds 1 x 105 cells/kg ideal BW of the patient.  
• Follow-up assessments will occur until 1 year post-
transplantation. Per Amendment version 04/24/2020, follow-up 
assessments will occur until 2 years post-transplantation.  


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Statistical 
Considerations 
• Fourteen transplant recipients (subjects) will be enrolled into the 
trial.  With 14 subjects, the trial will have 0.86 power to reject the 
null hypothesis that the probability of 28-day engraftment p ≤ 0.7 
in favor of the alternative hypothesis that p ≥ 0.9 according to a 
one-tailed test at a significance level of 0.2.   
 
 


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Treatment Schema: 
 
 
 


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Table of Contents 
 
1. 
Introduction ............................................................................................................................. 18 
1.1 
CD34+ Enriched Stem Cell Grafts ................................................................................. 19 
1.2 
CD3+ and CD19+ Depleted Stem Cell Grafts ............................................................... 19 
1.3 
TCRα/β+ and CD19+ Depleted Stem Cell Grafts ......................................................... 21 
1.4 
Relevance of haploidentical stem cell transplantation in lymphoma ............................. 22 
1.5 
Purpose of this protocol ................................................................................................. 24 
2. 
Study Aims / Study Objectives ............................................................................................... 26 
2.1 
Primary Hypothesis ........................................................................................................ 26 
2.2 
Secondary Hypotheses ................................................................................................. 26 
2.3 
Primary Objective: ......................................................................................................... 26 
2.4 
Secondary Objectives: ................................................................................................... 26 
3. 
Selection of Study Patients .................................................................................................... 27 
3.1 
Recipient Inclusion Criteria ............................................................................................ 27 
3.2 
Recipient Exclusion Criteria ........................................................................................... 29 
3.3 
Donor Inclusion Criteria ................................................................................................. 30 
3.4 
Donor Exclusion Criteria ................................................................................................ 30 
4. 
Research Design and Methods .............................................................................................. 30 
4.1 
Study Data Collection and Monitoring ........................................................................... 31 
4.2 
Privacy and confidentiality ............................................................................................. 31 
5. 
Registration Procedures ......................................................................................................... 32 
5.1 
Patients cannot begin protocol treatment prior to registration ....................................... 32 
5.2 
Removal from study ....................................................................................................... 32 
6. 
Treatment / Intervention Plan ................................................................................................. 32 
6.1 
Dose Calculations .......................................................................................................... 33 
6.2 
Preparative Regimen ..................................................................................................... 33 
6.3 
Preparation of the Hematopoietic Stem Cell Graft ........................................................ 33 
6.4 
Stem Cell Transplant ..................................................................................................... 35 
6.5 
Graft-vs-Host Disease Prophylaxis ................................................................................ 36 
6.6 
Indwelling Central Venous Catheter .............................................................................. 37 
6.7 
Supportive Care ............................................................................................................. 37 
7. 
Adverse Event Reporting Requirements ................................................................................ 37 
7.1 
Purpose ......................................................................................................................... 37 
7.2 
General AE reporting requirements ............................................................................... 37 
7.3 
Serious Adverse Events (SAE) Review and Oversight Requirements .......................... 38 
7.3.1 
Serious Adverse Event – Reported Within 24 Hours ................................................ 38 


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7.3.2 
Serious Adverse Event – Reported within 10 Days ................................................... 38 
7.3.3 
Sponsor-Investigator Responsibilities for SAE Review ............................................. 39 
7.3.4 
Study Progress Review ............................................................................................. 39 
7.4 
Expedited Reporting of Serious Adverse Events .......................................................... 40 
7.4.1 
SAE Requiring 24 Hour Reporting Occurs at UWCCC: ............................................ 43 
7.4.2 
SAE Requiring 10 Day Reporting Occurs at UWCCC: .............................................. 43 
7.4.3 
Other Reporting Requirements .................................................................................. 44 
7.5 
Risks and Toxicities ....................................................................................................... 45 
8. 
Study Endpoints ..................................................................................................................... 49 
8.1 
Primary Endpoint ........................................................................................................... 49 
8.2 
Secondary Endpoints..................................................................................................... 49 
9. 
Schedule of Evaluations ......................................................................................................... 50 
10. 
Correlative Assays ............................................................................................................. 52 
11. 
Statistical Considerations .................................................................................................. 52 
11.1 
Objectives ...................................................................................................................... 52 
11.2 
Endpoints ....................................................................................................................... 52 
11.3 
Analysis plan .................................................................................................................. 53 
11.4 
Sample size justification ................................................................................................ 53 
11.5 
Sequential monitoring of engraftment failure and GVHD .............................................. 53 
11.6 
Correlative analysis ....................................................................................................... 54 
12. 
Record Retention ............................................................................................................... 54 
13. 
Patient Consent and Peer Judgment ................................................................................. 54 
14. 
Data and Safety Monitoring ............................................................................................... 55 
15. 
References ........................................................................................................................ 56 
Appendices .................................................................................................................................... 61 
Appendix A ................................................................................................................................. 61 
Appendix B ................................................................................................................................. 62 
Appendix C ................................................................................................................................. 64 
 
 


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List of Abbreviations and Definition of Terms 
 
AABB 
American Association of Blood Banks 
ABG 
Arterial Blood Gas 
AER 
Adverse Event Reporting 
aGVHD 
Acute Graft Versus Host Disease 
ANC 
Absolute Neutrophil Count 
APC 
Antigen Presenting Cell 
ASCT 
Autologous Stem Cell Transplantation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATG 
Anti-Thymocyte Globulin 
Bid 
Twice daily 
BMT 
Bone Marrow Transplant 
BMTCTN 
Bone Marrow Transplant Clinical Trials Network 
BM 
Bone Marrow 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CAEPR 
Comprehensive Adverse Events and Potential Risks 
CBC 
Complete Blood Count 
CD 
Cluster of Differentiation 
cGVHD 
Chronic Graft Versus Host Disease 
CLL 
Chronic Lymphocytic Leukemia 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CRC 
Clinical Research Committee 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLBCL 
Diffuse Large B Cell Lymphoma 
DLCO 
Carbon Monoxide Diffusion Capacity 
DOT 
Disease Oriented Team 
DSMB/DSMC 
Data Safety Monitoring Board/Committee 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiography 
ECHO  
Echocardiography 
FACT 
Foundation for the Accreditation of Cell Therapy 
FCBP 
Female of Child Bearing Potential 
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GVHD 
Graft-versus-Host Disease 


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GVL 
Graft Versus Lymphoma 
HCT 
Hematopoietic cell transplantation 
HHCT 
Haploidentical Hematopoietic Cell Transplantation 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HCT 
Hematopoietic Cell Transplantation 
IDE 
Investigational Device Exemption 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
KIR 
Killer cell Immunoglobulin-like Receptor 
KM 
Kaplan-Meier 
LDH 
Lactate Dehydrogenase 
LP 
Lumbar Puncture 
LVEF 
Left Ventricular Ejection Fraction 
MDRD 
Modification of Diet in Renal Disease 
MFI 
Mean Fluorescence Intensity 
MMF 
Mycophenolate Mofetil 
MRD 
Matched Related Donor 
NCI 
National Cancer Institute 
NK 
Natural Killer (cell) 
NHL 
Non-Hodgkin lymphoma 
OS 
Overall Survival 
PB 
Peripheral Blood 
PBSC 
Peripheral Blood Stem Cell 
PCR 
Polymerase Chain Reaction 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PFT 
Pulmonary Function Test 
PI 
Primary Investigator 
PO 
Per Os (by mouth) 
PSR 
Protocol Summary Report 
PTLD 
Post-Transplant Lymphoproliferative Disease 
RBC 
Red Blood Cell 
RIC 
Reduced Intensity Conditioning 
RPR 
Rapid Plasma Regain 
SAE 
Serious Adverse Event 
SLL 
Small Lymphocytic Lymphoma 
SOP 
Standard Operating Procedure 
SPRT 
Sequence Probability Ratio Tests 
STR 
Short Tandem Repeat 
Sub-I 
SubInvestigator 


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T cells  
Thymus-derived white blood cells 
TCR 
T-Cell Receptor 
TID 
Three Times Daily 
TLI 
Total Lymphoid Irradiation 
TNI 
Total Nodal Irradiation 
TPN 
Total Parenteral Nutrition 
Treg 
T regulatory cell 
TRM 
Treatment Related Mortality 
TSH 
Thyroid Stimulating Hormone 
UWBMT 
University of Wisconsin Bone Marrow Transplant 
UWCCC 
University of Wisconsin Carbone Cancer Center 
VOD 
Veno-Occlusive Disease 
WBC 
White Blood Cell 
 
 
 


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1. Introduction 
 
Patients with aggressive lymphoma (e.g., Hodgkin lymphoma, DLBCL) 
have a potentially curative option in frontline therapy. However, up to 50% 
of patients will relapse.[1-3] At relapse, if disease remains chemo-sensitive, 
there is still a curative option with high-dose chemotherapy consolidation 
and autologous stem cell transplant (ASCT).[4-9] However, many patients 
are ineligible for ASCT due to chemo-refractory disease, or will relapse 
after ASCT. There is no good standard alternative for such patients and 
often treatment options going forward are palliative, at best, in nature.  
 
Patients with incurable lymphoma (e.g., follicular lymphoma, SLL, mantle 
cell lymphoma) can sometimes have an indolent course. A typical disease 
course, however, can include progressively briefer responses to treatment, 
leading ultimately to refractory and uncontrollable disease. 
 
In both of these patient populations, there is a need for novel (and ideally 
curative) options. Allogeneic hematopoietic cell transplantation has been 
studied in lymphoma, both in aggressive histologies (typically after ASCT 
or for those refractory to chemotherapy and thus ineligible for ASCT) [10-
18] and indolent histologies in relapse.[19-23] Studies support a potential 
for graft-versus-lymphoma (GVL) effect, though often at the cost of 
significant treatment related morbidity and mortality. Complications often 
arise as a result of graft-versus-host disease (GVHD). While rates of acute 
GVHD with reduced-intensity conditioning regimens may range relatively 
lower (10-20%), rates of extensive chronic GVHD range from 45-60% even 
with HLA matched donors.[22, 23] The optimal scenario would be one in 
which GVL could be optimized while minimizing GVHD.  
 
To avoid serious GVHD and graft rejection in allogeneic hematopoietic cell 
transplantation, it has long been inevitable to find donors with the highest 
possible human leukocyte antigen (HLA) match to the recipient. The 
therapeutic use of hematopoietic cell transplantation (HCT) thus is limited 
by the availability of a suitable HLA-matched donor. A matched related 
donor can be found for only 30% of patients, thus 70% of patients have to 
rely on finding a matched unrelated donor.[24] Though donors can be 
identified for most of these patients, the search takes at least several 
weeks, if not months. If the aggressive course of the disease requires the 
fast identification of a suitable donor, this is too long for a significant 
number of patients. And in some instances, a donor ultimately cannot be 
found. 
 
In order to find a solution, haploidentical hematopoietic cell transplantation 
(HHCT) using closely related, but only partially matched family donors has 
been exploited in several therapeutic settings, recently. In theory, virtually 


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every patient has a potentially suitable haploidentical related donor—
parent, sibling, or child—and thus a successful strategy for HHCT may 
clearly be the solution for the ‘lacking donor’ problem. Yet, once again in 
only partially matched donors and recipients, the difficulties of resulting 
GVHD and graft failure arise, and initially trials of HHCT were complicated 
by a high incidence of GVHD, engraftment failure, and infectious 
complications resulting in an unacceptably high treatment related morbidity 
and mortality.[25] Recent efforts have therefore been directed on 
developing therapeutic strategies to minimize these complications. GVHD 
and graft rejection are primarily mediated by T cells of host and donor. 
Therefore, attempts to overcome the HLA-barrier have focused on 
strategies for effective host and graft T cell depletion. 
 
1.1 CD34+ Enriched Stem Cell Grafts 
An approach pioneered by the groups of Bachar-Lustig et al [26] and 
Aversa et al [27] was to overcome the rejection of T cell depleted bone 
marrow cells by using a ‘megadose’ of CD34+ (stem) cells (i.e. >10 × 106 
CD34+ cells/kg) for transplantation. The harvesting of such megadoses 
was achieved by treating donors with hematopoietic growth factors prior to 
graft recovery. Using this setting, Aversa et al treated patients with 
advanced acute leukemia in different trials with haploidentical donors.[28] 
To avoid graft failure, intensive and highly straining patient conditioning 
regimens with total-body irradiation, thiotepa, fludarabine, and anti-
thymocyte globulin (ATG) had to be used. Fast engraftment rates of 
neutrophils and platelets were observed together with a low rate of GVHD 
(<10%) and a promising disease-free survival.  
 
Treatment-related mortality (TRM), however, was very high in these 
settings due to the intensive myeloablative conditioning regimens needed 
and a delayed immune reconstitution (due to T cell depletion) which 
resulted in a high number of serious infections or regimen related toxicities. 
Another major obstacle to this approach is achieving the ‘megadose’ of 
CD34+ stem cells necessary for overcoming major HLA-barriers. At doses 
below 10 × 106 CD34+ cells/kg BW of the recipient, rejection rates 
increased and engraftment and immune reconstitution were delayed (most 
pronounced in patients receiving less than 8 × 106 CD34+ cells/kg BW). 
[29] 
 
1.2 CD3+ and CD19+ Depleted Stem Cell Grafts 
The aim of another therapeutic approach therefore was to develop a 
strategy to improve engraftment independent from the infused stem cell 
doses, utilizing CD3 and CD19 depletion. A reduced intensity conditioning 
regimen (RIC) was developed to reduce TRM.[30, 31] The first promising 


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experiences were published for a pediatric population.[32-35] Here, the 
Miltenyi CliniMACS cell sorting system was used for CD3+/CD19+ 
depletion of the grafts using selective immunomagnetic beads. As 
discussed, profound T cell depletion is a fundamental prerequisite for 
successful HHCT to avoid severe GVHD. Meanwhile B cell depletion is 
obligatory to avoid EBV-related post-transplant lymphoproliferative disease 
(PTLD). 
 
On the other hand, earlier investigations had demonstrated the important 
therapeutic potential of alloreactive natural killer (NK)-cells in the graft [36] 
(increased disease-free survival [37, 38], engraftment facilitating and graft-
versus-tumor effects [39] and a smaller number of relapses and better 
survival [36]). NK-cells are also involved in the immune response against 
bacterial, viral and fungal infections. For example, in transplantation 
settings with KIR mismatched donors (thus more reactive NK cells), 
patients show lower incidences of CMV-reactivation.[40, 41] 
 
It was therefore expected that grafts selectively depleted of T and B cells, 
which still contain not only CD34+ stem cells but also a significant number 
of graft facilitating cells such as NK-cells, monocytes and granulocytes, 
would lead to improved engraftment and better disease control as well as 
immune reconstitution. 
 
Two phase I/II trials were initiated (adult patients with high risk myeloid and 
lymphoid malignancies and pediatric patients myeloid and lymphoid 
malignancies, solid tumors and non-malignant diseases).[27, 33] No G-
CSF was administered post-transplantation and mycophenolate mofetil 
(MMF, 15 mg/kg bid) was used only if the T-cell content in the graft 
exceeded 5 × 104 CD3+ cells/kg. The conditioning regimen was well 
tolerated and engraftment was rapid (median time to >500 neutrophils/mcl 
was 13 days and to >20,000 platelets/mcl was 11 days). Furthermore, all 
but one patient engrafted with full donor chimerism by day 14–28 post-
transplantation. In the trial with pediatric patients, graft rejection occurred in 
13%. Engraftment kinetics thus were similar to those reported by Aversa et 
al after HHCT with CD34+- megadoses [27] although patients received a 
clearly lower dose of CD34+ cells/kg. After total nodal irradiation (TNI) 
based reconditioning and second haploidentical stem cell donation, final 
engraftment in pediatric patients was achieved in 100%.[33]  
 
However, in adult patients, immune reconstitution was delayed due to the 
profoundly T-cell depleted grafts. NK-cell reconstitution was fast, probably 
due to the high NK-cell content of the CD3+/CD19+ depleted grafts. In this 
setting, 9 of 36 (25%) adult patients died due to transplant-related causes 
within the first 100 days and incidence of grade II–IV GVHD was 36%. 
Thus, incidence and degree of GVHD in adult patients after HHCT with 


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CD3+/CD19+ depleted grafts was higher than that reported for patients 
receiving HHCT with CD34+ selected grafts.[27]  
 
Thus, this methodology allowed HHCT in an older or heavily 
pre-treated patient population even without megadoses of CD34+ stem 
cells. However, several factors still needed to be improved: the 
reconstitution of T cells, engraftment, and prevention of significant 
transplant-related morbidity/mortality. 
 
1.3 TCRα/β+ and CD19+ Depleted Stem Cell Grafts 
The significant impact of graft composition and conditioning regimen on 
engraftment has already been demonstrated by the fast engraftment 
kinetics observed in patients receiving CD3+/CD19+ depleted grafts 
compared to merely CD34+ enriched grafts. Cell species endangering 
transplantation outcome have meanwhile been identified in even more 
detail. Mainly the subsets of CD3+ cells with TCRα/β receptors mediate 
graft-versus-host activity while, on the contrary, CD3+ cells with 
TCRγ/δ receptors show the highly interesting graft-versus-tumor 
activity.[42-48] The beneficial effects of NK cells in the graft have already 
been discussed above. Furthermore, recent studies have revealed the 
existence of CD34-negative stem cells, which are probably precursors of 
CD34+ stem cells with a high repopulating capacity.[49] Additional graft 
facilitating cells have also been defined, such as CD8-positive T-cells, 
monocytes and antigen-presenting cells (APCs). [39, 50-54] 
 
Thus, an efficient depletion of GVHD-mediating T cells presenting CD3 and 
TCRα/β as surface markers is imperative to prevent acute graft-versus-
host disease, while leaving in the product a high number of CD34+ 
hematopoietic stem cells, as well as other important cells including NK 
cells, monocytes and TCRγ/δ cells that provide graft-versus tumor and anti-
infectious activity. Further improvement of the cell product would be 
achieved by the depletion of CD19+ B cells because this reduces the risk 
for EBV-related PTLD. PTLD has previously been a major risk in 
transplantation settings.[55] In addition, there is growing evidence 
implicating B cells in the pathogenesis of acute and chronic GVHD [56], 
and rituximab used as prophylaxis against GVHD has been used 
successfully to minimize GVHD. [57, 58] Thus, CD19 depletion will serve 
both purposes, reducing the risk of PTLD as well as GVHD prophylaxis. 
 
To facilitate this, a new cell sorting strategy for processing of the cell grafts 
has been developed using again the Miltenyi CliniMACS cell sorting 
system. The stem cell grafts are selectively depleted of TCRα/β+ and 
CD19+ cells by using paramagnetic microbeads in a single processing step 


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and the resulting cell grafts are rich in a variety of blood cells with diverse 
immunological properties.[59] 
 
First clinical experiences in HHCT using TCRα/β- and CD19-depleted 
PBSC grafts have been obtained with pediatric patients in Tübingen.[60, 
61] All were at extremely high risk and had poor prognosis. They were 
pretreated with a reduced-intensity conditioning (RIC) regimen and 
received no post-transplantation immunosuppression. In these pilot 
patients, engraftment and immune reconstitution were rapid. No acute side-
effects were noted. By now, treatment of 23 pediatric patients with 
hematologic malignancies has been reported in Tübingen and Rome.[62]  
 
No post-transplantation GVHD prophylactic immunosuppression was given. 
In all cases, engraftment was rapid, and immune recovery was markedly 
improved compared to patients after CD3+/CD19+ depletion. TCRγ/δ cells 
expanded faster than TCRα/β cells early after transplantation, though at 
day 100, TCRα/β cells were predominant. Only 7 of 23 patients 
experienced grade 1 and 2 acute GVHD and only 1 patient experienced 
transient grade 3 acute GVHD of the skin. There was no chronic GVHD. 
 
In 23 children with nonmalignant disorders who received HHCT after 
TCRα/β/CD19 depletion, all but 4 patients engrafted and the latter were 
rescued by a second allograft.[63] Only 3 patients experienced skin-only 
grade 1 to 2 acute GVHD. No patient achieved visceral acute or chronic 
GVHD. With a median follow up of 18 months, 21 of 23 children are alive 
and disease free.  
 
In summary, in all pilot patients treated so far, rapid and sustained 
engraftment, rapid immune reconstitution, and a low incidence of GVHD 
were observed. Cell sorting using the CliniMACS device proved to be 
efficient since a high TCRα/β log depletion was achieved and the 
TCRα/β/CD19 depletion was demonstrated to be effective and feasible 
while good recovery rates for stem cells and innate effector cells were 
observed with a high viability of the resulting cells in the transplant. 
 
1.4 Relevance of haploidentical stem cell transplantation in lymphoma 
Allogeneic HCT and especially the transplantation of a haploidentical cell 
graft, carries substantial, well known risks that have to be weighed against 
the risk of the malignancy as well as the consideration of other treatment 
options. For patients entering this study, an allogeneic HCT has been 
deemed necessary by the treating physician.  
 
For patients with follicular lymphoma, small lymphocytic lymphoma/chronic 
lymphocytic leukemia, and mantle cell lymphoma), outcomes after matched 


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related donor (MRD) HCT are reasonable with progression-free survival 
(PFS) and overall survival (OS) after transplant ranging from 40-80% at 3-5 
years.[22, 23, 64] Thus, for these patients, the unavailability of a matched 
related donor will be a requirement prior to consideration on this trial for 
haploidentical donor transplantation, which would be meant to provide a 
transplantation alternative that would otherwise not be available. It is 
important to consider that the reasonable outcomes with MRD HCT in 
these disease histologies do not incorporate the significant amount of 
GVHD seen in these patients that can be a life altering problem even in the 
setting of their initial hematologic disease being cured. Ultimately, if this 
trial and subsequent study reveals that TCRα/β/CD19 depletion does 
indeed result in lower rates of GVHD (as hypothesized), it will be important 
to compare the efficacy of MRD HCT with HHCT in patients with these 
lymphomas and/or consider testing this method of cell processing 
(TCRα/β/CD19 depletion) with MRD HCT. 
 
For the patients with aggressive histologies, outcomes with MRD HCT are 
not as favorable, and with rarer NHLs, not as well studied. Typically, PFS 
and OS at 3-5 years after transplantation for aggressive lymphomas ranges 
20-40%. [65-67] It remains to be seen whether HHCT may actually be a 
more favorable alternative compared to MRD HCT. It can be hypothesized 
that there may be a stronger immune effect (GVL) against the disease in 
the setting of a partial mismatch. Interestingly, in a multi-center 
retrospective analysis evaluating alternative donors in transplantation of 
patients with relapsed/refractory Hodgkin lymphoma, haploidentical 
transplantation was associated with improved outcomes when compared to 
MRD HCT, including improved progression-free survival, lower relapse 
rates, and lower rates of GVHD.[68] In this study, however, T cell depletion 
was employed through post-transplant cyclophosphamide. Nonetheless, it 
still suggested a benefit of HHCT over MRD HCT in aggressive lymphoma. 
 
Thus, we would not prioritize a haploidentical donor over a matched related 
donor for follicular lymphoma, CLL/SLL, and mantle cell lymphoma, where 
disease control is reasonable with MRD HCT. However, for all of the other 
histologies, we feel using a haploidentical donor may improve disease 
control and is reasonable to consider as the first option even if a MRD is 
available. This is reflected in the eligibility criteria for this protocol. 
 
Patients eligible for this trial have severe disease and have a poor long-
term outcome if transplantation is not performed. The transplantation of 
TCRα/β and CD19 depleted haploidentical stem cell grafts offers 
considerable potential benefits. Due to the efficient TCRα/β cell depletion, 
similar GVHD rates are expected as observed with CD34+-selected or 
CD3/19-depleted grafts. However, GVHD as the most severe potential risk 
is addressed in this trial through the institution of statistical stopping 


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guidelines and continuous monitoring of the patient with the possibility to 
intervene if engraftment failure is too frequent or GVHD ensues (see 
Section 11.5 Sequential monitoring of engraftment failure and GVHD). 
 
Benefits of this cell processing plan are expected to be mediated by 
beneficial effector cells which are retained in the graft during the depletion 
procedure. These cells are expected to facilitate engraftment, exert GVL 
effects, reduce the risk of infections, and improve immune reconstitution. 
Especially the latter is currently one of the major challenges after stem cell 
transplantation. Additionally, these beneficial cells offer the advantage of 
using dose- and toxicity-reduced conditioning regimens and the efficient 
and selective depletion of TCRα/β+ cells allows the reduction of 
immunosuppression post-transplantation for GVHD prophylaxis. In 
summary, this is expected to translate into a reduced treatment-related 
toxicity.  
 
Preliminary data from transplantation of single patients with TCRα/β- and 
CD19-depleted haploidentical stem cell grafts show a low rate of acute and 
chronic GVHD as well as high engraftment rates and a fast recovery of the 
immune system compared to data published for patients transplanted with 
CD34-selected or CD3/CD19-depleted hematopoietic stem cell grafts. 
Therefore, overall, the available information suggests that the present 
study has a favorable risk-benefit ratio. 
 
1.5 Purpose of this protocol 
There are few efficacious treatment options for patients with Hodgkin 
lymphoma and aggressive non-Hodgkin lymphoma who have previously 
failed ASCT or who are ineligible for ASCT due to progressive disease. 
There are also limited options for patients with indolent lymphomas who 
have suffered multiple relapses. We propose to conduct a pilot study that 
will provide a potentially curative option for patients who do not otherwise 
have a viable transplant option with high-risk lymphoid malignancies, based 
on the hypotheses mentioned above.  We have chosen a conditioning 
regimen that should be myelosuppressive enough to allow engraftment of a 
haploidentical stem cell graft, without being fully myeloablative. This 
regimen also includes chemotherapy drugs and radiation techniques that 
are effective against lymphoma. The primary purpose of this study is to 
establish that this conditioning regimen along with this novel stem cell 
processing method is sufficient to lead to engraftment of donor cells in a 
reasonable period of time. The secondary purpose of this study is to 
confirm that rates of GVHD are comparable to prior published data of 
allogeneic stem cell transplant in this patient population. The hope is that 
engraftment will be achieved in all patients, and that rates of GVHD will, if 
anything, be lower than prior observed rates due to the selective depletion 


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25 
of TCRα/β+ cells, and that other secondary endpoints of this trial will be 
hypothesis-generating to evolve into a larger study of similar patients in 
which efficacy of this treatment can be better understood.    
 
 


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2. Study Aims / Study Objectives 
 
Patients with relapsed/refractory aggressive lymphoma have a high relapse 
rate and mortality following standard transplant protocols. Patients with 
indolent lymphoma have better outcomes following standard transplant, 
however, a matched related donor is often not available and rates of GVHD 
leave room for improvement. We hope to improve on the outcome of these 
patients by TCRα/β+ cell depletion using peripheral blood stem cells from a 
HLA-haploidentical to provide a suitable donor, optimize a GVL effect, and 
minimize GVHD.   
 
2.1 Primary Hypothesis 
• The rate of engraftment (defined as ANC >500/mcl and platelets > 
20K/mcl without transfusion in the prior 7 days) at Day +28 after 
transplantation is no less than 90% 
2.2 Secondary Hypotheses 
• Acute GVHD grade III/IV by Day +100 is below 30% 
• Chronic GVHD (severe) by Day+ 180 is below 40% 
 
 
 
 
To study these hypotheses, we propose to conduct a clinical trial with the 
following objectives: 
 
 
2.3 Primary Objective:   
To determine engraftment at 28 days after transplantation following 
TCRα/β and CD19 cell depletion using peripheral blood stem cells from a 
HLA-haploidentical donor.  
 
2.4 Secondary Objectives:  
Acute GVHD – The cumulative incidence of grade III – IV acute GVHD by 
Day +100 will be determined.  The GVHD grade will be determined by the 
IBMTR Severity Index criteria (Appendix A).   
 
Chronic GVHD – The cumulative incidence of severe chronic GVHD by Day 
+180 will be recorded and defined according to the NIH consensus criteria 
(Appendix B). 
 
Graft failure rate – defined as < 5% donor chimerism in the CD3 and/or 
CD33 selected cell populations at any time in the study follow up period 
once initial engraftment has been achieved.   
 


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27 
Treatment-related mortality rate – defined as death from any cause other 
than disease progression 
 
Progression-free survival – defined as time before any progression by either 
PET/CT or bone marrow (Appendix C). 
 
Overall survival – after enrollment on study 
 
3. 
Selection of Study Patients 
 
Study entry is open to adult patients regardless of gender, race or ethnic 
background.  
 
 
3.1 Recipient Inclusion Criteria 
 
3.1.1 Age 18 to 75 years  
 
3.1.2 Patients must meet one of the following disease criteria within 24 
months of registration. Salvage therapy is allowed between the 
patient meeting one of the below criterion and registration.  Patients 
will be considered eligible regardless of their current disease status 
(i.e. complete remission, partial remission, stable disease, 
progressive disease) unless otherwise noted below as long as one 
of the below criterion has been met within the previous 24 months: 
 
3.1.2.1 
Relapsed/refractory Hodgkin lymphoma after ASCT 
 
3.1.2.2 
Relapsed/refractory Hodgkin lymphoma, deemed 
ineligible for ASCT due to refractory disease 
 
3.1.2.3 
Relapsed/refractory diffuse large B cell lymphoma after 
ASCT (history of transformed lymphoma is acceptable). 
Disease must be in at least complete remission or partial 
remission with the use of salvage therapy before study 
treatment commences. 
 
3.1.2.4 
Relapsed/refractory diffuse large B cell lymphoma, 
deemed ineligible for ASCT due to refractory disease 
(history of transformed lymphoma is acceptable). 
Disease must be in at least complete remission or partial 
remission with the use of salvage therapy before study 
treatment commences. 


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3.1.2.5 
Relapsed/refractory T cell lymphoma relapsed after at 
least 1 prior line of therapy 
 
3.1.2.6 
Relapsed/refractory follicular lymphoma relapsed after at 
least 1 prior line of therapy 
 
3.1.2.7 
Relapsed/refractory mantle cell lymphoma relapsed after 
at least 1 prior line of therapy 
 
3.1.2.8 
Relapsed/refractory small lymphocytic  
lymphoma/chronic lymphocytic leukemia relapsed after at 
least 1 prior line of therapy 
 
3.1.2.9 
Relapsed/refractory non-Hodgkin Lymphoma, if not 
specified above, relapsed after at least 1 prior line of 
therapy 
 
3.1.3 Karnofsky score of 60% or better (“Requires occasional assistance, 
but is able to care for most of his/her needs”). 
 
3.1.4 Pulmonary: DLCO (corrected for hemoglobin) > 40%; and FEV1 > 
50% 
 
3.1.5 Cardiac: EF ≥ 50%. No uncontrolled angina or active cardiac 
symptoms consistent with congestive heart failure (class III or IV), 
by the New York Heart Association criteria. No symptomatic 
ventricular arrhythmias or ECG evidence of active ischemia. No 
evidence by echocardiography of severe valvular stenosis or 
regurgitation.   
 
3.1.6 Renal: estimated GFR by MDRD formula > 40 mL/min/1.73m2 
 
3.1.7 Women of child bearing potential must have a negative serum or 
urine pregnancy test within 14 days prior to study registration and 
agree to use adequate birth control during study treatment. A 
female of childbearing potential (FCBP) is a sexually mature female 
who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
 
3.1.8 Voluntary written consent 
 
 
 


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3.2 Recipient Exclusion Criteria 
 
3.2.1 Active CNS lymphoma within two weeks of registration.  Patients 
with a history of CNS involvement must have adequate treatment 
as defined by at least two negative spinal fluid assessments 
separated by at least one week. (Otherwise LP is not required if no 
clinical suspicion or evidence of CNS involvement.) Patients who 
have received cranial radiation therapy must still be eligible to 
receive total lymphoid irradiation to 7 Gy. 
 
3.2.2 New or active infection as determined by fever, unexplained 
pulmonary infiltrate or sinusitis on radiographic assessment.  
Infections diagnosed within 4 weeks of registration must be 
determined to be controlled or resolving prior to treatment.   
 
3.2.3 Presence of HIV (Ab positivity), or active hepatitis A, B or C 
infection (active infection will be defined as hepatitis A IgM Ab 
positivity, hepatitis B surface Ag positivity, or hepatitis C PCR 
positivity, respectively) 
 
3.2.4 Allergy or hypersensitivity to agents used within the treatment 
protocol. 
 
3.2.5 For an indolent lymphoma histology (follicular lymphoma, SLL/CLL) 
or mantle cell lymphoma, the patient should not have an HLA-
matched sibling, who would be an eligible donor, available. 
 
3.2.6 History of prior mediastinal radiation 
 
3.2.7 Reported illicit drug use 
 
3.2.8 Vulnerable population in groups, i.e., prisoners, those lacking 
consent capacity, non-English speaking, illiterate, pregnant 
females. 
 
 


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3.3 Donor Inclusion Criteria 
 
3.3.1 Donors must match at least one allele of HLA-A, B, C, DR and DP 
(or permissive mismatch in the case of DP) by high resolution 
typing.  An HLA-matched family member is ineligible to serve as a 
donor. Eligible donors include biological parents, siblings, half-
siblings or children.  
 
3.3.2 Age ≥ 18 and ≤ 70 years. 
 
3.3.3 Donors must meet the selection criteria prior to the start of the 
recipient’s pre-transplant conditioning regimen as defined by the 
Foundation for the Accreditation of Cell Therapy (FACT) and will be 
screened according to the American Association of Blood Banks 
(AABB) guidelines and UW BMT program SOP.   
 
3.4 Donor Exclusion Criteria 
3.4.1 Recipient derived anti-donor HLA antibodies identified as 
“unacceptable" by Luminex assay.  Exceptions may be made by the 
Director of the Histocompatibility Laboratory in conjunction with the 
recipient’s physician and a plan for desensitization. 
3.4.2 Not suitable for donation according to UW BMT program donor 
selection SOP. 
3.4.3  Vulnerable population groups, i.e., prisoners, those lacking consent 
capacity, non-English speaking, illiterate, pregnant females.   
 
4. Research Design and Methods 
 
Allogeneic HCT is a potentially curative option for patients with relapsed 
aggressive lymphoma and relapsed indolent lymphoma. This study is a pilot 
study intended to study clinical outcome and toxicity of a novel transplant 
approach for patients with high-risk lymphomas.  Research subjects will be 
identified among patients referred to the UWCCC for treatment of advanced 
lymphomas.  The patients will be treated and followed within the UW BMT 
program according to our approved standard-operating-procedures for 
clinical management of patients undergoing HSCT.  All clinical care will be 
provided by the UW BMT program and follow-up thereafter according to the 
clinical needs of the patients and what is considered standard of care.  
There will be no scheduled visits or evaluation on dates that do not 
correspond to those indicated by best practice.  


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4.1 Study Data Collection and Monitoring 
The study will report clinical data using the OnCore database using 
electronic case report forms.  These case report forms will be designed to 
collect specific information, including lab values, analysis of GVHD, 
chimerism data, staging evaluation, and survival data, in order to collect 
appropriate data to achieve the specific objectives of the study. Key study 
personnel are trained on the use of OnCore and will comply with protocol 
specific instructions and all measures to maintain confidentiality.  In 
addition, specific transplant related information will be collected and 
recorded in the UW BMT program database according to the program 
standard operating procedures, which will assure confidentiality according 
to HIPAA regulations.  Essential study documents will be retained in 
accordance with the University of Wisconsin record retention policy and all 
regulatory agencies that govern and oversee clinical trials.  
 
4.2 Privacy and confidentiality 
The collection of sensitive patient (study subject) information will be limited 
to the amount necessary to achieve the aims of the study.  Records 
identifying subjects will be kept confidential and to the extent permitted by 
applicable laws and/or regulations will not be made public.  If the results of 
the trial are published, subject identity will remain confidential. 
 
 
 
 


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5. Registration Procedures  
5.1 Patients cannot begin protocol treatment prior to registration 
Registration will occur in OnCore after the patient has signed the subject 
consent and eligibility is confirmed, but before any protocol treatment has 
been administered.  Any patient signing consent, but not enrolled in the 
study, will be recorded as a screen failure.  To be eligible for registration to 
this study, the patient must meet each criteria listed on the eligibility 
checklist based on the eligibility assessment documented in the patient’s 
medical record.   
5.2 Removal from study 
 
Eligibility criteria will be verified and ineligible patients will proceed off 
study (i.e. will not be registered). No further follow up will be obtained in 
that situation. Patients may withdraw fully from the study at any point, 
however, given the nature of this trial, once the initial registration and 
intervention with conditioning followed by transplantation occurs, it is not 
advisable for a patient to withdraw from close follow up and management 
as is dictated in the protocol for their own well-being. However, if a patient 
still wishes to withdraw, they will be allowed to do so and advised to 
continue at least off protocol care per the BMT program standard 
operating procedures. If they choose this, no further follow up will be 
obtained for purposes of the study. Similarly, the investigator may remove 
a patient from study, however, in the best interest of the patient, this 
should only be done if the patient is not able to comply with follow up as 
dictated in the protocol and in that situation, it would be advised to follow 
at least off protocol care per the BMT program standard operating 
procedures. If this happens, no further follow up will be obtained for 
purposes of the study. 
6. Treatment / Intervention Plan 
 
 
Day -5 to -2 
Fludarabine 40 mg/m2 IV daily  
Day -5 to -4 
Cyclophosphamide 60 mg/kg IV daily, Mesna 60 mg/kg 
IV over 24 hours starting prior to cyclophosphamide 
Day -1 
Total Lymphoid Irradiation 7 Gy (in one fraction) 
Day -1 
Begin MMF (through Day +30)  
Day 0 
Peripheral Blood Stem Cell Transplant 
Day +1 
Second day of PBSC infusion (if needed, see Section 
6.3) 
Day +2 
Begin Tacrolimus (through Day +180) ONLY if graft 
TCRα/β+ cell content is over 1 × 105 cells/kg ideal BW 
of the patient 


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Day +2 
Rituximab 375 mg/m2 IV once ONLY if graft B cell 
content exceeds 1 x 105 cells/kg ideal BW of the patient. 
 
6.1 Dose Calculations  
 
 Dosing of all medications will be according to actual body weight. 
 
6.2 Preparative Regimen 
 
Fludarabine 40 mg/m2/day will be administered by intravenous infusion 
over approximately 30 minutes on Days -5 through -2 for a total dose of 
160 mg/m2. For patients who have an estimated or measured GFR < 
70 mL/min/1.73 m2, the fludarabine dose should be reduced by 20%. 
Fludarabine dosing is based on the last calculated GFR prior to the start 
of conditioning. The fludarabine dose should be the same on Days -5 to -
2, even if the patient’s creatinine changes. 
 
Cyclophosphamide 60 mg/kg/day will be administered by intravenous 
infusion over approximately 2 hours on Days -5 and -4 for a total dose of 
120 mg/kg.  Mesna 60 mg/kg will be administered IV over 24 hours on 
Days -5 and -4, starting prior to cyclophosphamide. Cyclophosphamide 
should be given following fludarabine.  
 
Total Lymphoid Irradiation (TLI) is to be administered on Day -1.  A 
single dose of 7 Gy is to be administered using 3D conformal radiation 
therapy or intensity-modulated radiation therapy as per standard UW 
techniques.  TLI will encompass the cervical, supraclavicular, 
infraclavicular, axillary, hilar, mediastinal, para-aortic, iliac, and inguinal 
lymph node regions.  In addition, the spleen will be included if present. 
 
6.3   Preparation of the Hematopoietic Stem Cell Graft  
 
Mobilization and Collection of Donor PBSC 
Donors will self-administer G-CSF subcutaneously per UW SOP. 
Appropriate teaching will be provided. The morning of the stem cell 
blood product collection after subcutaneous injection of G-CSF, the 
donor will report to UW Hospital Infusion Center for laboratory work to 
include: WBC, Differential, Platelets, Hematocrit, and CD 34+ analysis.  
The donor will then undergo a 2-3 blood volume apheresis at the 
University of Wisconsin Hospital and Clinics Infusion Center.  
 
Cell Processing 


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The manufacturing process of TCRα/β- and CD19-depleted cell grafts 
and quality control will be performed according to validated procedures 
and documented according to institutional guidelines. The graft will be 
depleted of α/β+T cells and CD19+ B cells using the CliniMACS 
magnetic cell separation system, anti-CD19 microbeads and the anti-
TCR α/β microbead kit containing biotinylated monoclonal anti-TCR α/β 
antibody and anti-biotin microbeads (Miltenyi Biotec) as described in the 
IDE, and the CliniMACS user manual (version 2.40, manual publication 
date: July 2011).  Labeling and graft processing will be performed in 
accordance with the manufacturer’s guidelines and SOPs developed by 
the Stem Cell Processing facility at University of Wisconsin.  A median 
log >4 depletion of α/β T cells and log > 3 depletion of B cells is 
expected using this system, per published performance data provided by 
the manufacturer.  The cellular composition of the graft will be evaluated 
by flow cytometry before and after the processing steps using extensive, 
lineage specific antibody panels.  For further details on the mechanism 
of function of the CliniMACS device see the CMC section of the IDE. 
 
The specification for the final formulation of the cell product has been set 
according to findings from previous studies [41, 42, 48, 50].  For 
transplantation, the following graft composition is targeted: 
 
• Number of viable CD34+ cells ≥4 × 106 cells/kg ideal BW of the 
patient 
• Number of CD3+ TCRα/β+ cells ≤1.5 × 105 cells/kg ideal BW of the 
patient 
• Number of B cells ≤1 × 105 cells/kg ideal BW of the patient 
 
The graft must contain ≥4 × 106 CD34+ cells/kg ideal BW of the 
patient. This will be prioritized in graft composition with the actions 
listed below if this or other targets cannot be jointly achieved. 
 
• If after one day of stem cell collection and TCRα/β- and CD19-
depletion, a minimum cell dose of 4 × 106 CD34+ cells/kg ideal BW 
of the patient is not reached, a second day of collection is allowed 
(on Day 0) and stem cells will be infused on Day +1, following initial 
infusion on Day 0.  
 
• If after one day of stem cell collection and TCRα/β- and CD19-
depletion, the number of CD3+ TCRα/β+ cells exceeds 1.5 × 105 
cells/kg ideal BW of the patient, product will be reduced to bring the 
CD3+ TCRα/β+ cell count to ≤1.5 × 105 cells/kg ideal BW of the 


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patient. If in doing this, the CD34+ cell content falls below the 
above goal, a second day of collection is allowed (on Day 0) and 
stem cells will be infused on Day +1, following initial infusion on 
Day 0.  
 
• For any graft with TCRα/β+ cell content greater than 1 × 105 
cells/kg ideal BW of the patient, the patient will be placed on 
tacrolimus starting Day +2, in addition to MMF for 
immunosuppression.  Specifications for tacrolimus dosing included 
in Section 6.5. 
 
• If B cell content exceeds 1 x 105 cells/kg ideal BW of the patient, 
rituximab (375 mg/m2) will be administered post-transplant Day +2. 
 
If a second apheresis of the same donor needs to be performed, 
this would be known and performed on Day 0 and the second 
infusion administered on Day+1. A CD34 selection will be 
performed if a second day of collection is needed, rather than a 
TCRα/β- and CD19 cell depletion. The rationale and algorithm for 
cell processing based on graft content is further detailed in the 
CMC section of the IDE.  
 
 
Packaging and Labeling 
Labeling of final HSC graft product will be performed in accordance with 
the SOPs developed by the Stem Cell Processing facility at the 
University of Wisconsin.  The graft is intended for direct administration 
after completion of the preparation process.  However, if administration 
must be delayed for medical reasons, the product has a shelf-life of 72 
hours, calculated from the end of apheresis with storage at 5 ± 3°C.  The 
graft product will be delivered to the UW BMT Unit in sterile bags. 
 
6.4  
Stem Cell Transplant 
 
On Day 0, patients will receive the HSC graft product.  A sample of the 
product to be infused will be sent for flow cytometry to determine the 
content of CD34+, CD19 +, CD56+, TCRα/β, and TCRγ/δ cells.  
 
Administration of stem cell product 
For transplantation, patients will receive the TCRα/β- and CD19-
depleted HSC graft intravenously on Day 0 after the appropriate 
premedication. Resuscitation equipment and emergency medications 
will be on hand in case of infusion reaction. If the graft contains less 


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than 4 x 106 CD34+ cells/kg patient BW, a second graft may be 
administered to boost the number of hematopoietic stem cells that the 
patient receives on Day +1.   
 
Nursing staff will remain at the patient’s bedside during the entire stem    
cell graft infusion.  Patients will be monitored for adverse effects of the 
infusion such as rash, acute allergic reaction, bronchospasm, 
respiratory distress, and hemodynamic instability.  If severe acute 
reactions occur (defined as CTCAE grade 4 - life-threatening 
consequences; urgent intervention indicated), the infusion will be 
stopped until the patient is stabilized. Monitoring and supportive care 
will be provided during the cell infusion according to institutional 
guidelines. 
 
6.5 
Graft-vs-Host Disease Prophylaxis 
 
 
 
Alpha-beta T cell depletion will be performed on the stem cell 
product prior to infusion – as detailed above in Section 6.3. This in 
and of itself serves as a prevention of GVHD. 
 
Mycophenolate Mofetil (MMF) will be given at a targeted dose of 20 
mg/kg PO BID (based upon actual body weight and rounded up to the 
nearest pill size) with the maximum total daily dose not to exceed 3 
grams (1.5g PO BID).  MMF prophylaxis will be started on Day -1 and 
discontinued after the last dose on Day +30.   
 
Tacrolimus (if applicable) will be given at a dose of 0.12 mg/kg/day oral 
in two divided doses (or 0.04 mg/kg/day IV if unable to tolerate oral) 
rounded to the nearest 0.5 mg with dose adjusted to maintain a trough 
level of 5-15 ng/mL beginning Day +2 until Day +180. Taper can be 
started at any point after day +90, as seen fit by the treating physician 
and in accordance with the BMT SOP, with a goal of the medication 
being completely discontinued by day 180, in the absence of GVHD.  
Tacrolimus will ONLY be given if graft TCRα/β+ cell content is over 
1 × 105 cells/kg ideal BW of the patient 
 
Rituximab (if applicable) will be administered at a dose of 375 mg/m2 
by intravenous infusion per standard protocol for rituximab infusion on 
Day +2 ONLY if graft B cell content exceeds 1 x 105 cells/kg ideal 
BW of the patient. Per UW institutional practice, rituximab may be 
rounded to the nearest 50mg dose as long as within 10% of original 
calculated dose. 
 


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6.6  
Indwelling Central Venous Catheter 
 
Patients will have a central venous catheter for the administration of IV 
medications and transfusion of blood products.   
 
6.7  Supportive Care 
Patients will receive the standard supportive care provided to HCT 
patients according to the UW BMT SOPs. 
 
7. Adverse Event Reporting Requirements  
 
7.1 Purpose 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation subject that is enrolled in a clinical trial.  An AE may be any 
unfavorable or unintended sign, symptom, or disease temporally 
associated with participation in a clinical trial. While some events may not 
initially appear to be associated with the use of the study treatment, a 
relationship may not emerge until sufficient numbers of reports 
accumulate over the course of the study. Adverse event data collection 
and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, 
certain adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following sections 
provide information about expedited reporting.  
 
7.2 General AE reporting requirements 
The study period during which all AEs and SAEs must be reported    
begins upon initiation of study treatment and ends at the 12 month post-
transplant follow-up visit; Please note that with this Amendment version 
04/24/2020, study follow-up has been extended to 24 months as specified 
in section 7.4.4.  Both AEs and SAEs will be reported using Common 
Terminology Criteria for Adverse Events (CTCAE Version 4.0).  In 
general, HSCT is performed by first administrating myelotoxic and 
immunosuppressive medications followed by infusion of allogeneic stem 
cells.  There is a predictable and expected period of severe hematologic 
toxicity followed by recovery as the allogeneic stem cells engraft (grow) 
and produce blood cells.  This early post-transplant toxicity is predictable, 
expected and typically resolved by one month after transplantation.  
Consequently, reporting requirements for expected AEs and SAEs until 
Day +30 will follow exceptions to SAE reporting guidelines outlined in 


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Table 2.  Beyond Day +30 (Day 31 to 365), the AE and SAE reporting will 
be determined according to Table 1 below. In addition, section 7.4.4 has 
additional follow-up monitoring as delineated by protocol Amendment 
version 04/24/2020. 
 
 
 
7.3 Serious Adverse Events (SAE) Review and Oversight Requirements 
7.3.1 Serious Adverse Event – Reported Within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as 
described in the protocol) must also be reported to the Data and Safety 
Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day.  The OnCore 
SAE Details Report must be submitted along with other report materials 
as appropriate (NCI CTEP-AERs form or FDA Medwatch Form #3500 
and/or any other documentation available at that time of initial reporting). 
The DSMC Chair will review the information and determine if immediate 
action is required. Within 10 working days, all available subsequent SAE 
documentation must be submitted electronically along with a 24 hour 
follow-up SAE Details Report and a completed UWCCC SAE Routing 
Form to saenotify@uwcarbone.wisc.edu. All information is entered and 
tracked in the UWCCC database. 
The Principal Investigator notifies all investigators involved with the study 
at the UWCCC, the IRB, the sponsor, and the funding agency (all as 
applicable) and provides documentation of these notifications to the 
DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the 
sponsor-investigator, the PI reviews the event to determine whether the 
SAE requires reporting to the FDA and other participating investigators.   
 
See Section 7.4 for detailed instructions on SAE reporting. 
7.3.2 Serious Adverse Event – Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described 
in the protocol) must also be reported to the Data and Safety Monitoring 
Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu.  The OnCore SAE Details Report must 
be submitted along with other report materials as appropriate (NCI 
CTEP-AERs form or FDA Medwatch Form #3500 and/or any other 
documentation available at that time of initial reporting). The DSMC 
Chair will review the information and determine if further action is 
required. All information is entered and tracked in the UWCCC database. 


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The Principal Investigator notifies all investigators involved with the study 
at the UWCCC, the IRB, the sponsor, and the funding agency and 
provides documentation of these notifications to the DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the 
sponsor-investigator, the PI reviews the event to determine whether the 
SAE requires reporting to the FDA and other participating investigators.   
For a multiple-institutional clinical trial the PI is responsible for ensuring 
SAEs are reported to the FDA as well as to all participating investigators. 
 
See Section 7.4 for detailed instructions on SAE reporting. 
 
7.3.3 Sponsor-Investigator Responsibilities for SAE Review 
 The UWCCC Principal Investigator is acting as a Principle Investigator 
and Sponsor-Investigator. The IDE Holder assumes responsibilities of 
the study sponsor in accordance with FDA 21 CFR 312.32.  In this 
capacity, the UWCCC PI reviews all reports of serious adverse events 
occurring on the study at the UWCCC and participating external sites 
and makes a determination of 1) suspectedness (i.e., whether there is 
a reasonable possibility that the device caused the AE); and 2) 
unexpectedness (the event is not listed in the Investigator’s Brochure 
or is not listed at the specificity or severity that has been observed) in 
the context of this study.  SAE with suspected causality to study device 
and deemed unexpected are reported as IDE Safety Reports by the 
UWCCC PI to the FDA, all participating investigators on the study, and 
the external global sponsor (if applicable) within 15 calendar days. All 
fatal or life-threatening SAE that are unexpected and have suspected 
causality to the study device will be reported by the UWCCC PI to the 
FDA, all participating investigators on the study, and the external global 
sponsor (if applicable) within 7 calendar days. 
 
Refer to Section 7.4.3 for UWCCC PI instructions for reporting to the 
FDA. 
 
7.3.4 Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the 
DSMC in the timeframe determined by the risk level of the study 
(quarterly; semi-annually; or annually). The PSR provides a cumulative 
report of SAEs, as well as instances of non-compliance, protocol 
deviations, and unanticipated problems, toxicities and responses that 
have occurred on the protocol in the timeframe specified.  PSRs for 
those protocols scheduled for review are reviewed at each DSMC 
meeting. 


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Protocol Summary Reports enable DSMC committee members to 
assess whether significant benefits or risks are occurring that would 
warrant study suspension or closure. This information is evaluated by 
the DSMC in conjunction with other reports of quality assurance 
activities (e.g., reports from Internal Audits, Quality Assurance Reviews, 
etc.) occurring since the prior review of the protocol by the DSMC.  
Additionally, the DSMC requires the study team to submit external 
DSMB or DSMC reports, external monitoring findings for industry-
sponsored studies, and any other pertinent study-related information.  
In the event that there is significant risk warranting study suspension or 
closure, the DSMC will notify the PI of the DSMC findings and ensure the 
appropriate action is taken for the protocol (e.g., suspension or closure).  
The DSMC ensures that the PI reports any temporary or permanent 
suspension of a clinical trial to the sponsor (e.g., NCI Program Director, 
Industry Sponsor Medical Monitor, Cooperative Group Study Chair, etc.) 
and other appropriate agencies. DSMC findings and requirements for 
follow-up action are submitted to the CRC. 
 
7.4 Expedited Reporting of Serious Adverse Events 
 
Depending on the nature, severity, and attribution of the serious adverse 
event an SAE report will be phoned in, submitted in writing, or both 
according to Table 1 below. All serious adverse events must also be 
reported to the UWCCC Data and Safety Monitoring Committee Chair.  All 
serious adverse events must also be reported to the UW IRB (if 
applicable), and any sponsor/funding agency not already included in the 
list. 
 
Determine the reporting time line for the SAE in question by using the 
following tables.  Then refer to following sections A, B and C. 
 
 


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Table 1 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to  Peiman Hematti, IDE holder, and any other 
parties outlined in the protocol ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to 
the UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
10 Calendar 
Days 
* Exceptions to SAE Reporting: Table 1 applies to events that occur 31 to 365 days after 
HSCT.  Refer to Table 2 for SAE expedited reporting requirements within 30 days after HSCT.  
Specific protocol exceptions to expedited reporting (SPEER) are listed in the CAEPR Table 
below.  Per Amendment version 04/24/2020, see section 7.4.4 below. Reporting 
timelines do not apply because these events were not collected in real time. 
They will be collected and reported as they are reviewed by the study team 
with approval of this Amendment. 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE 
 
Table 2: SAE reporting requirements for events that occur within 30 days after 
HSCT 
 
Grade 1 – 
3 
Grade 4 
Grade 4 
Grade 5 
Grade 5 
 
 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
Not 
required 
Not required 
Not 
required 
10 
Calendar 
days 
10 
Calendar 
days 


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Possible 
Probable 
Definite 
Not 
required 
10 
Calendar 
days 
Not 
required 
24-Hrs;  
5 
Calendar 
Days 
10 
Calendar 
days 
 
 
 


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7.4.1 
SAE Requiring 24 Hour Reporting Occurs at UWCCC: 
 
1. Report to the UWCCC: 
 
Reference the SAE SOP (Standard Operating Procedure) and the 
SAE Reporting Workflow on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal) for specific instructions on how and 
what to report to the UWCCC for 24 hour initial and follow-up 
reports.  A follow-up report is required to be submitted within 10 
days of the initial 24 hour report. 
 
For this protocol, the following UWCCC entities are required to be 
notified: 
a) saenotify@uwcarbone.wisc.edu 
b) UWCCC PI, Vaishalee P Kenkre, MD: 
vpkenkre@medicine.wisc.edu 
c) Hematology DOT Program Manager 
d) Any other appropriate parties listed on the SAE Routing Form (for 
follow-up reports only) 
 
2. Report to the IRB: 
Consult the UW-IRB website for reporting guidelines 
(https://kb.wisc.edu/hsirbs) 
 
7.4.2 
SAE Requiring 10 Day Reporting Occurs at UWCCC: 
 
1. Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow on the 
UWCCC website (https://kb.wisc.edu/uwccc/internal) for specific 
instructions on how and what to report to the UWCCC for 10 day 
reports. 
 
For this protocol, the following UWCCC entities are required to be 
notified: 
a) saenotify@uwcarbone.wisc.edu 
b) Any appropriate parties listed on the SAE Routing Form 
 
2. Report to the IRB: 
Consult the UW-IRB website for reporting guidelines 
(https://kb.wisc.edu/hsirbs) 
 
 


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7.4.3 
Other Reporting Requirements 
Reporting to the FDA: 
The FDA does not need to be automatically notified of every SAE 
that occurs during the clinical trial.  For every SAE, the PI (or Sub-I 
in absence of the PI) must complete the UWCCC Sponsor-
Investigator Determination of FDA Reporting for Institutional Trials.  
The PI or Sub-I will evaluate the SAE to determine if reporting to the 
FDA is necessary. 
 
SAE with suspected causality to study device and deemed 
unexpected are reported as IDE Safety Reports by the UWCCC PI 
to the FDA, all participating investigators on the study, and the 
external global sponsor (if applicable) within 15 calendar days. All 
fatal or life-threatening SAE that are unexpected and have 
suspected causality to the study device will be reported by the 
UWCCC PI to the FDA, all participating investigators on the study, 
and the external global sponsor (if applicable) within 7 calendar 
days. 
 
Reportable Serious Adverse Events occurring on studies on which a 
UW PI is acting as sponsor-investigator must be reported to the FDA 
within the appropriate time frame.  Mandatory and voluntary 
reporting guidelines and instructions are outlined on the FDA 
website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
 
7.4.4 Extended Safety Monitoring 
 
Per Amendment version 04/24/2020, study follow-up is being 
retroactively extended to 2 years post-transplant. Reporting timelines 
listed above for UWCCC, IRB, and FDA cannot be applied, because 
these data points are being collected retrospectively. They will be 
collected and reported as they are reviewed by the study team 
following the approval of the amendment. In the additional year of 
follow up that is being added, data on the following will be specifically 
collected and entered at 18 months and 24 months post-transplant: 
 
Survival (alive/dead) 
Disease status (progression or stable) 
Start of any further disease directed therapy 


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Grade 2-3 infections in the prior 6 month period 
Hospitalizations in the prior 6 month period 
Non protocol specified transplant 
Secondary graft failure 
Reportable adverse events (what was previously defined in Table 1 
as SAEs reportable to DSMC) 
Unanticipated problems reportable to IRB 
Secondary cancers 
7.5 Risks and Toxicities 
 
Fludarabine – myelosuppression (dose limiting toxicity), fever, nausea, 
vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, 
skin rashes, myalgia, headache, agitation, hearing loss, transient episodes 
of somnolence and fatigue, autoimmune hemolytic anemia, autoimmune 
thrombocytopenia, paresthesias, peripheral neuropathy, renal and 
pulmonary toxicity (interstitial pneumonitis). Severe fatal CNS toxicity 
presenting with loss of vision and progressive deterioration of mental status 
were encountered almost exclusively after very high doses of fludarabine 
monophosphate. 
Tumor 
lysis 
syndrome, 
complicating 
fludarabine 
monophosphate therapy has been observed, especially in patients with 
advanced bulky disease. Opportunistic infections (protozoan, viral, fungal, 
and bacterial) have been observed in both pre-treated patients receiving 
fludarabine and in individuals receiving fludarabine combined with other 
agents.  
 
 
 


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Cyclophosphamide – cardiomyopathy, skin rash, mucositis, sterility, fluid 
weight gain/edema, alopecia and hemolytic/anemia. Hematologic including 
leukopenia, thrombocytopenia, anemia, pancytopenia; gingivitis, glossitis, 
pharyngitis, stomatitis, enteritis; nausea/vomiting, anorexia, diarrhea; 
hematemesis, melena; photosensitivity; nephropathy: hemorrhagic cystitis, 
dysuria, azotemia, hematuria, renal failure.  
 
Total Lymphoid Irradiation – acute - fatigue, nausea & vomiting, 
diarrhea, mild skin redness, dry mouth; late – secondary malignancy, early 
cardiac disease, infertility, azoospermia, menopause induction 
 
Mycophenolate Mofetil – pancytopenia, nausea, vomiting, diarrhea, 
hypertension, headache, dizziness, insomnia, hyperglycemia, electrolyte 
imbalances, rash, and leg cramps/bone pain, reversible renal insufficiency, 
hypertension, 
hyperglycemia, 
hypomagnesemia, 
hypokalemia, 
and 
neurologic toxicity. 
 
Tacrolimus – reversible renal insufficiency, hypertension, hyperglycemia, 
hypomagnesemia, hyperkalemia, and neurological toxicity (tremor and 
headache)  
 
 
Rituximab – Immediate: Fever, chills, rigors (especially with first dose), 
nausea, asthenia, lethargy, malaise, vomiting, headache, throat irritation, 
abdominal pain, back pain, hypotension, hypertension, arrhythmias, 
diarrhea, rash during infusion, cough, bronchospasm, dyspnea, rhinitis, 
dizziness, night sweats, myalgia, arthralgia, pruritis, urticarial, anxiety, 
flushing, syncope, anaphylactic reactions, fatal infusion reaction complex 
(including hypoxia, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, ventricular fib or cardiogenic shock), fatal 
cardiovascular events (in rheumatoid arthritis patients), tumor lysis 
syndrome (especially with > 25,000/mm circulating malignant cells or high 
tumor burden) and associated renal failure, serum sickness, 
hypocalcemia, seizure; Prompt: Lymphopenia, infectious events (bacterial, 
viral, fungal), Leukopenia, neutropenia, angioedema, peripheral edema, 
hyperglycemia, elevated LDH, sinusitis, Thrombocytopenia, anemia, 
transient red cell aplasia (1 case), hemolytic anemia (2 cases), 
mucocutaneous reactions including paraneoplastic pemphigus, Stevens- 
Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, toxic 
epidermal necrolysis, Delayed to late: Bowel obstruction and/or 
perforation, late onset neutropenia, fatal cardiac failure, bronchiolitis 
obliterans, interstitial pneumonitis, hepatitis B virus reactivation with 
fulminant hepatitis, hepatic failure, and death, (new, reactivated, or 
exacerbated) viral infections (including JC virus, CMV, herpes simplex, 
parvovirus B19, VZV, West Nile virus [WNV], hepatitis C), Waldenstrom’s 
(hyperviscosity), progressive multifocal leukoencephalopathy (PML) 
caused by activation of the JC virus. 


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47 
 
 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for BMT. 
Adverse Events with at least possible relationship to 
allogeneic stem cell transplantation 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (> 20%) 
Less Likely (<20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Pancytopenia 
 
 
Anemia, 
thrombocytopenia, 
neutropenia (gr.3)  
Febrile neutropenia 
 
 
Febrile neutropenia (gr. 
3,4 before day 30) 
 
Immune 
Hemolytic 
anemia 
 
 
 
 
Microangiopathic 
hemolytic anemia 
 
CARDIAC DISORDERS 
 
 
Atrial fibrillation 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Diarrhea (gr. 3) 
 
Constipation 
 
Nausea/vomiting (gr.3) 
Diarrhea 
 
 
 
Oral mucositis 
 
 
 
Nausea 
and 
vomiting 
 
 
 
Anorexia 
 
 
Anorexia (gr. 4 before day 
30) 
Colitis 
 
 
 
GENERAL DISORDERS  
 
Edema 
 
 
 
Fever 
 
 
 
 
 
Multi-organ failure 
 
Pain 
 
 
 
 
Non-cardiac chest 
pain 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatic failure 
 
 
 
Veno-occlusive 
disease 
 
IMMUNE SYSTEM DISORDERS 
 
Graft-vs-host 
disease 
 
 
 
 
 
Cytokine 
release 
syndrome 
 
INFECTIONS AND INFESTTIONS 
 
 
Bladder infection 
 
 
 
Catheter 
related 
infection 
 
 
 
Bacteremia 
 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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48 
Adverse Events with at least possible relationship to 
allogeneic stem cell transplantation 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
 
 
Sepsis 
 
 
Lung infection 
 
 
 
Pustular rash 
 
 
 
Sinusitis 
 
 
INVESTIGATIONS 
 
 
AST, ALT, bili, 
Alkaline 
phosphatase 
increased 
 
 
 
Creatinine increased 
 
 
 
Lymphocytes 
decreased 
 
Lymphocytosis (gr. 3) 
 
Weight gain/loss 
 
 
 
WBC, HGB, PLTs 
decreased 
 
Anemia, 
thrombocytopenia, 
neutropenia (gr.3) 
METABOLISM AND NUTRITIONAL DISORDERS 
 
 
Multiple 
electrolyte 
abnormalities 
 
Dehydration (gr.3), 
Hyponatremia 
(gr.3), 
hypokalemia (gr.3) 
 
Iron overload 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
 
Avascular necrosis 
 
 
 
Fibrosis 
deep 
connective tissue 
 
 
Muscle weakness 
 
 
 
Osteoporosis 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
Proteinuria 
 
 
REPRODUCTIVE SYSTEM 
 
Azoospermia 
 
 
 
Dysmenorrhea 
 
 
 
Infertility 
 
 
 
RESPIRATORY 
DISORDERS 
 
 
 
 
 
ARDS 
 
 
 
Bronchiolitis 
obliterans (bronchial 
obstruction) 
 
 
 
Pneumonitis 
 
 
 
Pulmonary edema 
 
 
 
Pulmonary fibrosis 
 
 
 
Respiratory failure 
 
SKIN AND SUBCUTANEOUS DISORDERS 
 
 
Erythroderma 
 
 
 
Skin induration 
 
 
 
Rash maculo-
papular 
 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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49 
Adverse Events with at least possible relationship to 
allogeneic stem cell transplantation 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
VASCULAR DISORDERS 
 
 
Capillary leak 
syndrome 
 
 
 
Hypertension 
 
 
 
Thromboembolic 
event 
 
 
 
8. Study Endpoints 
8.1 Primary Endpoint 
The primary endpoint is engraftment at 28 days from the time of 
transplantation. Neutrophil engraftment is defined as ANC ≥ 500/mcl for 
three consecutive measurements on different days.  The first of the three 
days will be designated the day of recovery.  The only competing event for 
neutrophil recovery is death without neutrophil recovery. Platelet 
engraftment is defined as the first day of a platelet count > 20,000/mm3 with 
no platelet transfusions in the preceding 7 days 
 
8.2 Secondary Endpoints  
Acute GVHD – The cumulative incidence of grade III – IV acute GVHD by 
Day +100 will be determined.  The GVHD grade will be determined by the 
IBMTR Severity Index criteria (Appendix A).   
 
Chronic GVHD – The cumulative incidence of severe chronic GVHD by Day 
+180 will be recorded and defined according to the NIH consensus criteria 
(Appendix B). 
 
Graft failure – defined as < 5% donor chimerism in the CD3 and/or CD33 
selected cell populations at any time during the study follow up period once 
initial engraftment has been achieved. 
 
Treatment-related mortality – defined as death from any cause other than 
disease progression 
 
Progression-free survival – defined as time before any progression by either 
PET/CT or bone marrow (Appendix C). 
 
Overall survival – after enrollment on study 
 
 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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50 
9. Schedule of Evaluations  
 
All evaluations are considered part of the standard of care evaluation of a 
patient for allogeneic stem cell transplantation, except the TCRα/β and 
TCRγ/δ portion of the lymphocyte subset analysis, which is considered for 
research purposes.  Informed consent must be obtained within 42 days of 
registration, all other pre-transplant evaluations must be completed within 28 
days of registration unless otherwise stated below.  Scheduled evaluations 
post-transplant may be performed within 3 days from the targeted date prior 
to Day +28 and within 7 days thereafter.  
 
 
Pre-BMT 
Evaluation 
Weekly –  
Day +1 to 
engraftment12 
Day 28 
Restaging 
Weekly 
Day +28 
to Day 
+84 
3 month 
restaging 
(Day +91 
– Day 
+105) 
Months 
6, 9, 1216 
Informed Consent 
X 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Performance 
Status 
X 
 
X 
At 
month 2 
X 
X 
GVHD evaluation2 
 
Twice weekly 
X 
X 
X 
X 
CMV PCR3 
 
X 
X 
X 
X 
X 
EBV PCR 
 
 
X 
Every 2 
weeks 
X 
X 
CBC 
X 
Twice 
weekly13 
X 
X 
X 
X 
Magnesium 
X 
Twice weekly  
 
X 
X 
X 
Total bilirubin 
X 
X 
X 
X 
X 
X 
AST 
X 
X 
X 
X 
X 
X 
ALT 
X 
X 
X 
X 
X 
X 
Alkaline 
phosphatase 
X 
 
 
 
 
 
Electrolytes, 
Creatinine, BUN 
X 
Twice weekly 
 
X 
X 
X 
Quantitative 
Immunoglobulins 
X 
 
 
 
X 
 
Uric acid, INR, 
Ferritin4, Calcium, 
Phosphate 
X 
 
 
 
 
 
Lymphocyte 
subset analysis5 
 
 
X 
 
X 
X5 
Tacrolimus level (if 
on this 
medication) 
 
X 
X 
X 
X 
X14 
Pre-transplant 
viral panel6 
X 
 
 
 
 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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51 
 
Pre-BMT 
Evaluation 
Weekly –  
Day +1 to 
engraftment12 
Day 28 
Restaging 
Weekly 
Day +28 
to Day 
+84 
3 month 
restaging 
(Day +91 
– Day 
+105) 
Months 
6, 9, 1216 
Urinalysis with 
microscopy and 
culture if indicated 
X 
 
 
 
 
 
Pregnancy test7 
X 
 
 
 
 
 
Luminex screen8 
X 
 
 
 
 
 
CD3, CD33 STR 
(PB) 
X 
 
X 
At 
month 2 
X 
X 
Panorex9 
X 
 
 
 
 
 
CT sinuses 
X 
 
 
 
 
 
Disease 
Restaging by PET 
or CT scan10 
X 
 
 
 
X 
X15 
BM aspirate and 
biopsy 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
Cardiac ECHO 
X 
 
 
 
 
 
PFTs with ABG 
X 
 
 
 
 
 
LP11 
X 
 
 
 
 
 
 
1. Patients should be specifically asked if they engage in illicit drug use and their answer 
should be documented in the medical chart.  
2. Refer to Appendix A for acute GVHD grading scales 
3. Weekly CMV PCR starting Day +14 for those at risk for CMV infection (CMV positive 
donor or recipient) until Day +100 and then at 6, 9 and 12 months 
4. Ferritin is only required if recipient has a prior history of RBC transfusions. 
5. Lymphocyte subset analysis includes by flow cytometry the cell counts/percentages of: 
CD3+, TCRα/β, TCRγ/δ, CD4, CD8, CD19 +, CD16/CD56.  Testing to be completed by 1 
month, 3 months, 6 months, and 12 months post HCT.  
6. Viral panel to include:  HIV 1 and 2 antibody; HTLV I/II antibody screen; Hepatitis A total 
antibody, if positive IgM Ab; Hepatitis B surface antigen, surface antibody and core 
antibody; Hepatitis C antibody, if positive Hepatitis C PCR; Syphilis testing, if positive 
repeat to confirm; Toxoplasma antibody IgM. For patients negative for CMV or not 
previously tested, order CMV IgG/IgM.  For patients who have been previously tested 
and positive, order CMV PCR.  For Hodgkin’s patients only, order EBV IgG and IgM 
antibodies.  
7. Urine or serum pregnancy test within 14 days of registration ONLY for females of 
childbearing potential. A female of childbearing potential (FCBP) is a sexually mature 
female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has 
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
 
8. Consider ordering luminex upon identification of donors to help facilitate donor selection. 
May then need to be repeated within 28 days of protocol registration.  
9. Separate Panorex scan not required if CT sinus includes an evaluation of teeth. 
10. Pre-transplant disease restaging by PET, rather than CT, is suggested for all disease 
types other than SLL/CLL, but is not required. A CT is acceptable if PET cannot be 
attained.  Post-transplant disease restaging for all disease types may be performed by 
CT, but (for all disease types except SLL/CLL) is preferable by PET until complete 
remission has been attained.  At all time points the type of imaging used for disease 
restaging is left to physician discretion.   


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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52 
11. LP to be performed within 14 days of registration ONLY for those patients who meet 
criteria described in Exclusion Criteria 3.3.1 (i.e., if clinical suspicion of CNS involvement, 
then LP needed to rule out. If patient previously had involvement, but 2 negative LPs as 
stated, and no further suspicion of recurrence, no need to repeat LP at this time.) 
12. Twice weekly assessments should be performed until patient meets criteria for both 
neutrophil and platelet engraftment. 
13. During the transplant admission, it is permissible to obtain a wbc, hemoglobin and 
platelet count twice weekly in lieu of a full CBC until the patient shows signs of cell 
recovery (to be determined by clinical staff), at which point a full CBC will be ordered to 
monitor for neutrophil engraftment.  WBC count not required until Day +7. 
14. Tacrolimus level only required (if applicable) at month 6. 
15. Disease restaging by PET or CT only required at months 6 and 12.   
16. Data to be collected at months 18 and 24 as described in section 7.4.4 
 
10. Correlative Assays 
 
Reconstitution of T, B and NK cell subsets (lymphocyte subset analysis) 
will be assessed by immune cell phenotyping. Cell counts/percentages of 
CD3+, TCRα/β, TCRγ/δ, CD4, CD8, CD19+, CD16//CD56 will be 
evaluated using samples collected at 1 month, 3 months, 6 months, and 
12 months post-transplant (see Section 11.6 Correlative Analysis). 
 
11. Statistical Considerations 
 
11.1 Objectives 
 
As a pilot trial, the objective is to generate preliminary data on engraftment 
after TCRα/β cell depletion from a haploidentical cell product, and also 
observe clinical outcome such as acute GVHD, chronic GVHD, graft failure, 
treatment-related mortality, progression-free survival, overall survival and 
immune markers listed in Section 10.0. 
 
11.2 Endpoints 
 
 
The primary endpoint of the study is engraftment at 28 days after transplant.  
Any patient who is enrolled and receives HHCT will be accounted for in the 
final assessment. Secondary endpoints include aGVHD grade III-IV by Day 
+100, cGVHD (severe) at Day +180, graft failure at any point during study 
follow up and after initial engraftment, treatment-related mortality, 
progression-free survival, and overall survival.  Immune markers as 
measured by cell counts of CD3+, TCRα/β, TCRγ/δ, CD4, CD8, CD19+, 
CD16, and CD56 will be obtained 1 month, 3 months, 6 months, and 12 
months post-transplant. 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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53 
11.3 Analysis plan 
 
Times to event such acute and chronic GVHD, graft failure, treatment-
related mortality, PFS, and OS will be analyzed using Kaplan-Meier 
(KM) method, and the incidence rates of Day +28 engraftment, Day 
+100 aGVHD grade III-IV, Day +180 cGVHD (severe), and Day +100 
OS will be obtained from the KM estimates along with 95% confidence 
intervals.  Binary outcome variables such as grade 3 or worse non-
hematologic toxicity, will be summarized with a proportion and a 95% 
confidence interval.   
 
11.4 Sample size justification 
 
The sample size is limited by the feasibility over 2 years.  Fourteen 
transplant subjects and 14 donor subjects will be enrolled into the trial.  
With 14 transplant subjects, the trial will have 0.86 power to reject the 
null hypothesis that the probability of 28-day engraftment p is ≤ 0.7 in 
favor of the alternative hypothesis that p is ≥ 0.9 according to a one-
tailed test at a significance level of 0.2.  Considering this being a limited 
pilot study, it was felt important to have a reasonably high power at the 
expense of a significance level much higher than typical. 
 
Given the sample size of 14, the study has 0.93 power to reject the null 
hypothesis that the probability of 100-day aGVHD grade III-IV p is ≥ 0.6 
in favor of the alternative hypothesis p is ≤ 0.3 according to a one-tailed 
test at a significance level of 0.2.  Similarly, the study has 0.93 power to 
reject the null hypothesis that the probability of 180-day cGVHD p is ≥ 
0.7 in favor of the alternative hypothesis p is ≤ 0.4 according to a one-
tailed test at a significance level of 0.2.  
 
11.5 Sequential monitoring of engraftment failure and GVHD 
 
In order to ensure that patients are not subject to treatment with higher 
engraftment failure and higher acute or chronic GVHD, engraftment 
failure and GVHD will be monitored continuously based on sequential 
probability ratio tests (SPRTs).  If the engraftment failure rate or acute 
or chronic GvHD rate appears high by crossing the SPRT boundary for 
the null hypothesis for any of the three outcome measures, the study 
will be suspended and the UWCCC Data and Safety Monitoring 
Committee (DSMC) will be notified. After investigation of the outcome 
as of the SPRT boundary crossing, the PI in consultation with other 
investigators, study statistician, and the UWCCC DSMC will make the 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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54 
decision whether to continue the trial or to terminate for patient safety 
concern.  
 
The following three tables give the SPRT boundaries for suspension of 
the study for 28 day engraftment failure, 100 day aGVHD grade III-IV 
and 180 day severe cGVHD.  No adjustment for multiplicity for three 
outcome measures has been made as being anti-conservative is 
desirable to ensure adequate treatment and safety of patients. 
 
Number of  
SPRT boundaries* for 28-day engraftment failure 
Patients 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Events 
 
2 
2 
3 
3 
3 
3 
3 
3 
4 
4 
4 
4 
4 
 
Number of  
SPRT boundaries for 100-day aGVHD grade III-IV 
Patients 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Events 
 
 
 
4 
5 
5 
6 
6 
6 
7 
7 
8 
8 
9 
 
Number of  
SPRT boundaries for 180-day severe cGVHD  
Patients 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Events 
 
 
 
 
5 
6 
6 
7 
7 
8 
9 
9 
10 
10 
 
* If the number patients with event is equal to boundary, suspend the study. 
Blank entries imply no decision can be made due to insufficient data. 
  
11.6 Correlative analysis 
 
Longitudinal analysis will be performed on the immune markers using 
repeated measures generalized mixed linear models.  Also analysis of 
association between immune markers and clinical outcomes be 
performed to evaluate whether the trajectory of the immune markers 
predict clinical outcome.  These correlative analyses will be exploratory 
in nature. 
 
12. Record Retention 
 
The UW BMT Program maintains a HIPAA compliant clinical database that is 
used to comply with FACT and Center for International Blood and Marrow 
Transplant Research (CIBMTR) reporting requirements.  Patient, disease, 
treatment and outcome data are collected and reported as required by 
regulatory and quality reporting requirements.  Patients will also be 
registered in the OnCore database within the UWCCC. 
 
13. Patient Consent and Peer Judgment 
 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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55 
Current FDA, NCI, state, federal and institutional regulations concerning 
informed consent will be followed. 
 
14. Data and Safety Monitoring 
Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible 
for the regular review and monitoring of all ongoing clinical research in the 
UWCCC.  A summary of DSMC activities are as follows: 
• Reviews all clinical trials conducted at the UWCCC for subject safety, 
protocol compliance, and data integrity. 
• Reviews all Serious Adverse Events (SAE) requiring expedited 
reporting, as defined in the protocol, for all clinical trials conducted at 
the UWCCC, and studies conducted at external sites for which 
UWCCC acts as an oversight body. 
• Reviews all reports generated through the UWCCC DSMS elements 
(Internal Audits, Quality Assurance Reviews, Response Reviews, 
Compliance Reviews, and Protocol Summary Reports) 
• Notifies the protocol Principal Investigator of DSMC decisions and, if 
applicable, any requirements for corrective action related to data or 
safety issues. 
• Notifies the CRC of DSMC decisions and any correspondence from the 
DSMC to the protocol Principal Investigator. 
• Works in conjunction with the UW Health Sciences IRB in the review of 
relevant safety information as well as protocol deviations, non-
compliance, and unanticipated problems reported by the UWCCC 
research staff.  
• Ensures that notification of SAEs requiring expedited reporting is 
provided to external sites participating in multi-institutional clinical trials 
coordinated by the UWCCC. 
 
Monitoring And Reporting Guidelines 
Data related to these trials undergo review of subject safety at regularly 
scheduled DOT meetings where the results of each subject’s treatment are 
discussed and the discussion is documented in the DOT meeting minutes. 
The discussion includes the number of subjects enrolled, significant 
toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted by the study team for review by the DSMC. Any 
unanticipated problems, complications, and adverse events will be reported 
to the investigator upon occurrence, and reported to the IRB in accordance 
with posted guidance. 


TCR-α/β and CD19 depletion with HHCT in aggressive lymphoma 
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56 
UWCCC quality assurance and monitoring activities are determined by study 
sponsorship and risk level of the protocol as determined by the PRMC.  All 
protocols (including Intervention Trials, Non-Intervention Trials, Behavioral 
and Nutritional Studies, and trials conducted under a Training Grant) are 
evaluated by the PRMC at the time of committee review.  UWCC monitoring 
requirements for trials without an acceptable external DSMB are as follows: 
 
a) Intensive Monitoring 
Protocols subject to intensive monitoring generally include UW 
Institutional Phase I and Institutional Trials of any phase involving 
recombinant DNA/gene transfer.  These protocols undergo continuous 
review of data and subject safety at weekly Phase I/Disease Oriented 
Team (DOT) meetings where the results of each subject’s treatment 
are discussed and the discussion is documented in the DOT meeting 
minutes. The discussion includes the number of subjects enrolled, 
significant toxicities, dose adjustments, and responses observed. 
Protocol Summary Reports are submitted on a quarterly basis by the 
study team for review by the DSMC. 
 
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from related donors with one fully mismatched HLA haplotype. N Engl J Med, 1998. 
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Bethge, W.A., et al., Haploidentical allogeneic hematopoietic cell transplantation in adults 
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Bethge, W.A., et al., Haploidentical allogeneic hematopoietic cell transplantation in adults 
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Barfield, R.C., et al., A one-step large-scale method for T- and B-cell depletion of 
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Appendices 
Appendix A 
 
ACUTE GRAFT VERSUS HOST DISEASE 
 
Investigators should document on a weekly basis (beginning with the day of 
transplant) the raw data for the GVHD target organs either in the medical record 
directly or on a trial-specific worksheet.  This should include the extent of skin rash, 
if any; the bilirubin; the daily stool output; or number of stools per day for an 
outpatient.  The weekly record should reflect the worst representative days of the 
preceding week for each target organ involvement.  Biopsy confirmation of target 
organs is recommended in most circumstances to confirm the diagnosis acute 
GVHD. Grading will be determined by the International Bone Marrow Transplant 
Registry (IBMTR) Severity Index grading system (A, B, C, D corresponding to I, II, 
III, and IV, respectively).[69]  
 
 
Stage 
Skin 
GI 
Liver 
1 
< 25% rash 
Diarrhea > 500mL/d 
or persistent 
nausea 
Bilirubin 2-3mg/dl 
2 
25-50% 
> 1000 mL/d 
Bilirubin 3-6 mg/dl 
3 
Generalized 
erythroderma 
> 1500 mL/d 
Bilirubin 6-15 mg/dl 
4 
Generalized 
erythroderma with 
bullae 
> 2000 mL/d and 
severe abdominal 
pain ± ileus 
Bilirubin > 15 mg/dl 
 
 
 
 
Grade 
Skin 
GI 
Liver 
A 
Stage 1 
none 
none 
B 
Stage 2    
Stage 1-2     
Stage 1-2 
C 
Stage 3 
Stage 3 
Stage 3 


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D 
Stage 4 
Stage 4 
Stage 4 
 
Appendix B 
 
CHRONIC GRAFT VERSUS HOST DISEASE 
 
The diagnosis of chronic GVHD is based on both clinical and histopathologic 
findings for each organ system.  Examples of pathognomonic and possible 
manifestations of chronic GVHD are outlined below; possible manifestations 
should be further evaluated to rule out other potential non-chronic GVHD 
etiologies.  For example, pancreatic enzyme insufficiency may cause 
malabsorption and weight loss independent of chronic GVHD.  
 
Time since transplant will not be used to distinguish acute from chronic GVHD 
(e.g., chronic GVHD may occur before Day 100, and acute GVHD may occur after 
Day 100).  If acute GVHD is suspected after Day 60 or chronic GVHD is suspected 
before Day 100, biopsies are strongly encouraged to confirm the diagnosis.  
Additionally, biopsies are encouraged to confirm the diagnosis of chronic GVHD in 
patients with “possible” manifestations. 
 
Definite and Possible Manifestations of Chronic GVHD 
Organ System 
Definite manifestations of chronic 
GVHD 
Possible manifestations of chronic 
GVHD 
Skin 
Scleroderma (superficial or fasciitis), 
lichen planus, vitiligo, scarring alopecia, 
hyperkeratosis pilaris, contractures from 
skin immobility, nail bed dysplasia 
Eczematoid rash, dry skin, 
maculopapular rash, 
hyperpigmentation, hair loss 
Mucous 
membranes 
Lichen planus, non-infectious ulcers, 
corneal erosions/non-infectious 
conjunctivitis 
Xerostomia, keratoconjunctivitis sicca  
GI tract 
Esophageal strictures, steatorrhea 
Anorexia, malabsorption, weight loss, 
diarrhea, abdominal pain 
Liver 
None 
Elevation of alkaline phosphatase, 
transaminitis, cholangitis, 
hyperbilirubinemia 
GU 
Vaginal stricture, lichen planus 
Non-infectious vaginitis, vaginal atrophy 
Musculoskeletal/ 
Serosa 
Non-septic arthritis, myositis,  
myasthenia, polyserositis, contractures 
from joint immobilization 
Arthralgia 
Hematologic 
None 
Thrombocytopenia, eosinophilia, 
autoimmune cytopenias 
Lung 
Bronchiolitis obliterans  
Bronchiolitis obliterans with organizing 
pneumonia, interstitial pneumonitis 
 
 


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Clinical scoring and assessment of severity will be determined by the NIH 
consensus criteria (severity briefly detailed below) and the treatment algorithm will 
be according to the UW BMT program SOP regarding chronic GVHD.[70]  
 
 
 
 
  
 
Mild cGVHD 
1 or 2 organs involved with no more 
than score 1, plus lung score 0  
Moderate cGVHD 
3 or more organs involved with no more 
than score 1 OR 
at least 1 organ (not lung) with score of 
2 OR 
lung score 1 
Severe cGVHD 
At least 1 organ with score of 3 OR 
lung score of 2 or 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C 
 
DISEASE RESPONSE CRITERIA AND EVALUATION 
 
Criteria for response assessment and evaluation for progression for Hodgkin and 
non-Hodgkin lymphoma (not CLL) will be according to the Lugano classification 
briefly outlined below and further outlined in the referenced publication.[71] 
 
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 of 1, 2, or 3 with or without 
residual mass on 5 point scale. It is 
recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic 
uptake or with activation  within 
spleen or marrow (eg, 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 
Target nodes/nodal masses must 
regress to < 1.5 cm in longest 
transverse diameter of a lesion. 
 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminant, IHC negative 
Partial Response 
Partial metabolic response 
Partial remission (all of the 
following): 
 
Lymph nodes and extralymphatic 
sites 
Score 4 or 5 with reduced uptake 
compared with baseline and residual 
mass(es) of any size. 
>50% decrease in sum of the product 
of the perpendicular diameters (SPD) 
for multiple lesions of up to 6 target 
measurable nodes and extranodal 
sites. 
 
When a lesion is too small to 
measure on CT, assign 5mmx5mm 
as the default value. 
 
When no longer visible, 0x0mm. 
 
For a node > 5mmx5mm, but smaller 
than normal, use actual 
measurement for calculation 
Nonmeasured lesion 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by 
>50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake 
in normal marrow but reduced 
Not applicable 


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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 
No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score of 4 or 5 with no significant 
change in FDG uptake from baseline 
<50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 
Nonmeasured lesion 
Not applicable 
No increase consistent with 
progression 
Organ enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic 
disease 
Progressive disease requires 
at least one of the following: 
Individual target nodes/nodal 
masses 
Score of 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
Progression of cross product of 
largest transverse diameter and 
perpendicular diameter (PPD): 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma 
An individual node/lesion must be 
abnormal with: 
 
Longest transverse diameter > 1.5 
cm and 
 
Increase by > 50% from PPD nadir 
and 
 
An increase in largest transverse 
diameter (or shortest axis 
perpendicular to the largest 
transverse diameter) from nadir 
0.5 cm for lesions < 2cm 
1.0 cm for lesions > 2cm 
 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of pre-
existing nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma. If uncertain, biopsy or 
interval scan may be considered 
Regrowth of previously resolved 
lesions 
 
A new node > 1.5 cm in any axis 
 
A new extranodal 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 
 


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Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
 
 
 
 
 
Criteria for response assessment and evaluation for progression for CLL will be 
according to the International Workshop on Chronic Lymphocytic Leukemia 
briefly outlined below and further outlined in the referenced publication.[72] 
 
 
 
 
Parameter 
CR* 
PR* 
PD* 
Group A 
 
 
 
Lymphadenopathy+ 
None > 1.5cm 
Decrease > 50% 
Increase > 50% 
Hepatomegaly 
None 
Decrease > 50% 
Increase > 50% 
Splenomegaly 
None 
Decrease > 50% 
Increase > 50% 
Blood lymphocytes 
< 4000/mcl 
Decrease > 50% from 
baseline 
Increase > 50% over 
baseline 
Marrow 
Normocellular, < 30% 
lymphocytes, no B-
lymphoid nodules.  
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules 
 
Group B 
 
 
 
Platelet count 
>100, 000/mcl 
>100, 000/mcl or increase 
> 50% over baseline 
Decrease of > 50% from 
baseline secondary to 
CLL 
Hemoglobin 
>11g/dl 
>11g/dl or increase > 50% 
over baseline 
Decrease of > 2g/dl from 
baseline secondary to 
CLL 
Neutrophils 
>1500/mcl 
>1500/mcl or > 50% 
improvement over 
baseline 
 
 
*CR (complete remission): all of the criteria have to be met, and patients have to lack disease-related constitutional 
symptoms; PR (partial remission): at least two of the above criteria of group A plus one of the criteria of group B have to 
be met; SD is absence of progressive disease (PD) and failure to achieve at least a PR; PD: at least one of the above 
criteria of group A or group B has to be met. 
 
+Sum of the products of multiple lymph nodes (as evaluated by CT scans at visits scheduled to have imaging or by 
physical exam that can be confirmed by CT if needed).