A Phase II Study of Non-myeloablative Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) In Patients With Cutaneous T Cell Lymphoma
Phase: PHASE2
Conditions: Mycoses, Sezary Syndrome, Lymphoma, T-Cell, Cutaneous, Bone Marrow Transplant Failure, Lymphoma, Non-Hodgkin, Cutaneous T-cell Lymphoma
Sponsor: Stanford University

 
 
 
 
A Phase II Study of Non-myeloablative Allogeneic Transplantation Using 
Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) In 
Patients with Cutaneous T Cell Lymphoma 
Study Protocol and Statistical Analysis Plan 
NCT00896493 
January 7, 2019 

Page 1 of 42 
BMT 206 
 
January 7, 2019 
 
 
BMT 206:  A Phase II Study of Non-myeloablative Allogeneic Transplantation 
Using Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) In 
Patients with Cutaneous T Cell Lymphoma 
 
 
 
 
Coordinating Center: 
 
Stanford Cancer Center 
 
 
875 Blake Wilbur Drive  
 
 
Stanford, CA 94305 
 
Principal Investigator: 
 
Wen-Kai Weng, MD, PhD 
BMT Program, 300 Pasteur Drive 
 
Stanford, CA 94305 
Telephone 650-723-7689 
Fax 
 
wkweng@stanford.edu 
 
 
Co-Principal Investigator:  
 
Youn Kim, MD 
 
Co-Investigators: 
 
Richard Hoppe, MD 
 
 
David Miklos, MD, PhD 
Robert Negrin, MD 
Robert Lowsky, MD 
Judith Shizuru, MD, PhD 
Laura Johnson, MD 
Sally Arai, MD 
BMT Program 
Lynn Million, MD 
Sunil Reddy, MD 
Everett Meyer, MD,PhD 
Andrew Rezvani, MD 
Lori Muffly, MD 
 
 
 
 
 
 
 
 
Study Coordinator: 
 
 
Clinical Research Coordinator 
800 Welch Rd, 
 
 
Palo Alto, CA 94304 
Telephone 
 
@stanford.edu 
 

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January 7, 2019 
Biostatistician: 
, PhD 
  
Professor of Biostatistics 
  
Health Research and Policy   
Redwood Bldg, 
   
Telephone 
 
  
 
 
 
 
 
Fax 
   
 
 
 
 
  
 
 
 
 
@stanford.edu 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
Administrative Contact:           
, RN, PhD 
Oncology Clinical Nurse Specialist
300 Pasteur Drive, 
 
Stanford, CA 94305
Telephone 
 
Fax 
 
@stanfordmed.org 
 
 
 
 
 
 
Protocol Type: 
       Original: March 11, 2009 
Revision 1: April 29, 2009 
Revision 2: June 29, 2009 
Revision 3: March 30, 2010 
Revision 4: October 27, 2010 
Revision 5: October 5, 2011 
Revision 6: February 24, 2012 
Revision 7: May 31, 2012 
Revision 8: February 27, 2013 
Revision 9: February 25, 2014 
Revision 10: November 18, 2014 
Revision 11: September 16, 2015 
Revision 12: February 17, 2017 
Revision 13: January 7, 2019 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
 
Page 
PROTOCOL SYNOPSIS ..............................................................................................................5 
SCHEMA ........................................................................................................................................6 
LIST OF ABBREVIATIONS .......................................................................................................7 
 
1. OBJECTIVES ..........................................................................................................................8 
1.1. Primary Objectives..............................................................................................................8 
1.2. Secondary Objectives ..........................................................................................................8 
2. BACKGROUND ......................................................................................................................8 
2.1. Study Disease ......................................................................................................................8 
2.2. Investigational Agent or Device .......................................................................................11 
2.3. Rationale ...........................................................................................................................12 
2.4. Correlative Studies Background .......................................................................................12 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .........................13 
3.1. Inclusion Criteria ..............................................................................................................13 
3.2. Exclusion Criteria .............................................................................................................13 
3.3. Donor Inclusion Screening Guideline…...………………………………………………14 
3.4. Donor Exclusion Screening Guideline…………………………………………………..14 
3.5. Enrollment………...……………………………………………………………………..14 
3.6. Informed Consent Process ................................................................................................14 
3.7. Randomization Procedures ...............................................................................................15 
4. TREATMENT PLAN ............................................................................................................15 
4.1. Investigational Agent or Device Administration ..............................................................15 
4.2. General Concomitant Medication and Supportive Care Guidelines .................................17 
4.3. Duration of Therapy ..........................................................................................................17 
4.4. Duration of Follow Up ......................................................................................................18 
4.5. Criteria for Removal from Study ......................................................................................18 
4.6. Alternatives .......................................................................................................................18 
4.7. Compensation ...................................................................................................................18 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ..................18 
5.1. Investigational Agent/Device/Procedure ..........................................................................18 
5.2. Availability .......................................................................................................................19 
5.3. Agent Ordering .................................................................................................................19 
5.4. Agent Accountability ........................................................................................................19 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................19 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ..............................................19 
7.1. Potential Adverse Events ..................................................................................................19 
7.2. Adverse Event Reporting ..................................................................................................21 
8. CORRELATIVE/SPECIAL STUDIES ...............................................................................21 
8.1. Laboratory Correlative Studies .........................................................................................21 
9. STUDY CALENDAR ............................................................................................................22 
10. MEASUREMENT OF EFFECT ..........................................................................................24 
10.1. Anti-tumor Effect ............................................................................................................24 
10.2. Other Response Parameters ............................................................................................24 
11. DATA REPORTING/REGULATORY CONSIDERATIONS ..........................................24 
11.1. Monitoring Plan ..............................................................................................................24 
11.2. Stopping Rules ................................................................................................................25 
11.3. Data Management ...........................................................................................................25 

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11.4. Confidentiality ................................................................................................................25 
12. STATISTICAL CONSIDERATIONS .................................................................................25 
12.1. Endpoints ........................................................................................................................25 
12.2. Analysis Populations .......................................................................................................26 
12.3. Plan of Analysis ..............................................................................................................26 
12.4. Sample Size .....................................................................................................................26 
12.5. Interim analyses ..............................................................................................................27 
 
REFERENCES .............................................................................................................................26 
 
APPENDICES 
 
A. Participant Eligibility Checklist 
 
B. AE and SAE Reporting Guidelines 
 
C. Response Criteria in Mycosis Fungoides and Sezary Syndrome  

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January 7, 2019 
PROTOCOL SYNOPSIS 
 
TITLE 
A Phase II Study of Non-myeloablative 
Allogeneic Transplantation Using Total 
Lymphoid Irradiation (TLI) and Antithymocyte 
Globulin (ATG) In Patients with Cutaneous T 
Cell Lymphoma 
STUDY PHASE 
II 
INDICATION 
Advanced Stage Cutaneous T Cell 
Lymphoma 
PRIMARY OBJECTVES 
Clinical Response 
SECONDARY OBJECTIVES 
Engraftment and GVHD 
HYPOTHESES 
Graft versus Lymphoma effect provided by 
Non-myeloablative Allogeneic 
Transplantation will provide disease control 
STUDY DESIGN 
Single arm phase II 
PRIMARY ENDPOINTS AND 
SECONDARY ENDPOINTS 
Clinical response 
Incidence of GVHD, EFS, OS 
SAMPLE SIZE BY TREATMENT 
GROUP 
40 patients 
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Advanced stage cutaneous T cell lymphoma 
patients with HLA-matched related or 
unrelated donor 
INVESTIGATIONAL PRODUCTS 
DOSAGE AND ADMINISTRATION 
Total lymphoid irradiation (TLI) 800 cGy and 
anti-thymocyte immunoglobulin 
CONTROL GROUP 
Not applicable 
PROCEDURES 
Not applicable 
STATISTICAL CONSIDERATIONS 
Clinical response and incidence of GVHD will 
be reported as percentage. EFS and OS will 
be determined using Kaplan-Meier 
estimation. 
 
 

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January 7, 2019 
SCHEMA 
 
 
ENROLLMENT 
• 
Advanced stage cutaneous T cell lymphoma 
• 
Relapse or refractory to conventional therapy 
• 
HLA matched donor 
• 
Signed Informed Consent 
 
TLI/ATG CONDITIONING AND ALLOGENEIC TRANSPLANTATION 
Day -35 to Day -2 
TSEBT for extensive skin involvement 
Length of treatment and dose of TSEBT 
will be determined by the radiation 
oncologist 
     
Day -11 to Day -7 
TLI 800 cGy 
ATG 1.5 mg/kg & solumedrol 1 mg/kg 
    
Day -4 to Day -2 
TLI 800 cGy 
Day -3 
Start oral tacrolimus 
Day -1 
 
TLI 800 cGy x2 
Day 0 
Infusion of mobilized peripheral blood 
cells from donor, start oral MMF 
    
Day +28 
ECP weekly x4, then every two week x4, 
then monthly x4 in patients with persistent 
Sezary cells 
    
 

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January 7, 2019 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADL 
Activity of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EFS 
Event Free Survival 
GVHD 
Graft versus Host Disease 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IRB 
Institutional Review Board 
IV 
Intravenous 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TSEBT 
Total skin electron beam therapy 
TTP 
Time to progression 
UNK 
Unknown 
WBC 
White blood cell 
 
 

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1. OBJECTIVES 
 
1.1  
Primary Objectives  
 
To evaluate the graft versus lymphoma effect by monitoring rate of clinical response, event-free and overall 
survival. 
 
1.2  
Secondary Objectives 
 
 
To evaluate the incidence and extent of acute and chronic GVHD and time to engraftment. 
 
2. BACKGROUND 
 
2.1  
 Study Disease 
 
Mycosis Fungoides/Sezary Syndrome 
MF is a mature T cell lymphoma that arises primarily from the skin. It is the major subtype of cutaneous T 
cell lymphoma (CTCL). Patients usually present initially with patch, plaque, tumor or erythrodermic 
involvement of their skin. MF has a long natural history (2). Many patients have non-specific skin 
manifestations for several years before a diagnosis is made. Although the initial lesions are usually limited 
skin patches or plaque, generalized plaques involving large body surface area and tumor lesions are 
common by the time patients seek medical attention. Extra-cutaneous dissemination may occur to lymph 
nodes, liver, spleen, lungs and blood (Sezary cells). SS is a leukemic form of MF in which patients have 
significant blood involvement with Sezary cells and diffuse erythroderma (3). 
 
After the diagnosis is established, appropriate staging is important. Initial staging should include 
comprehensive skin examination, peripheral blood evaluation for Sezary cells, and appropriate imaging 
such as CT scan. The International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous 
Lymphoma Task Force of the EORTC has recently published a revised TNM staging for MF/SS (4). 
Several large studies have shown that overall clinical stage determines long-term outcome. Patients with 
limited stage IA disease have a very favorable outcome with life expectancy comparable to matched 
control population. Patients with IB/IIA disease have a median survival of 11-12 years after diagnosis, 
with fewer than 20% experiencing progression to higher stage. However, stage IIB/III disease carried a 
worse outcome with median survival of 4-5 years and higher chance to have large cell transformation. 
Patients with stage IV disease have the worst, <2 year median survival (Figure 1) (2). 
 
 
 
Figure 1  Actuarial overall survival of 525 patients at Stanford with MF/SS according to TNM stage at 
diagnosis. 
 
 
Therapy for Mycosis Fungoides/Sezary Syndrome 

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Choosing appropriate treatment for individual patients is not easy. The most important consideration is 
the T (tumor) classification and overall clinical stage, with specific concerns for large cell transformation, 
acuity or severity of associated symptoms, and potential treatment related toxicities (5). In general, step-
wise approach with first skin-directed therapy, then mild biological systemic therapy, and then systemic 
chemotherapy is the current strategy. Skin-directed therapies should be the first step to control skin 
lesions, which include topical steroids, topical nitrogen mustard, topical retinoids and phototherapy. 
Narrow-band UVB and Psoralen plus UVA are highly effective for thicker plaques. Total skin electron 
beam therapy, considered the most intensive skin-directed therapy, is reserved for patients with extensive 
generalized disease and severe skin symptoms (6). While clinical response is greater with more intensive 
skin-directed therapies, no improved progression free or overall survival has been shown. 
 
For patients with refractory disease to skin-directed therapies or with advanced stage of MF (IIB-IV) and 
Sezary syndrome, systemic treatments should be included in the primary therapy strategy, with or without 
skin-directed treatments. The first category of systemic therapy is mild immunomodulating agents 
(biologics), such as systemic retinoids (bexarotene) (7), interferons (8,9), low dose methotrexate and 
newer reagents, histone deacetylase inhibitors (10), and denileukin diftitox (11). While these treatments 
have a slow time to response and generally provide partial response rates no greater than 50%, their lack 
of cumulative toxicity allows them to be used as maintenance treatment for long periods. Extracorporeal 
photopheresis (ECP) has been used as monotherapy or in combination with other systemic therapy and 
has been shown to be a very effective treatment, especially for disease control of SS (12). The next 
category of systemic therapy is more traditional cytotoxic chemotherapy. The most common reagents are 
liposomal doxorubicin, gemcitabine, chlorambucil and high dose methotrexate. Pegylated liposomal 
doxorubicin is effective as a single agent. In a prospective study, every 4 week infusions gave an overall 
response rate of 84% with 42% of the patients achieving complete response (13). However, these 
responses are usually short-lived and patients move from one agent to another agent, then proceed to 
combination chemotherapies, and eventually progress after multiple therapies.  
 
Treatment with Hematopoietic Stem Cell Transplantation 
Emerging data on allogeneic HSCT, particularly using non-myeloablative conditioning, suggest the 
existence of a graft-versus-T cell lymphoma effect. Allogeneic transplant should be considered in patients 
with advanced disease who fail to respond to all primary therapies or do not have durable response with 
salvage treatments. 
 
Recently, we have performed a meta-analysis of studies treating MF/SS patients with HSCT in an attempt 
to understand its utility. In this analysis, 15 published reports with a total of 38 cases and 5 unpublished 
cases were included (14-28). Twenty three cases had high dose therapy followed by autologous HSCT 
and twenty cases had allogeneic transplant. The median age was relatively young of 42 years with an 
equal male/female distribution. All but one case had advanced stage (>IIB) disease at time of transplant. 
The median follow-up was 21 and 29 months for autologous and allogeneic transplant group, 
respectively. For autologous group, 12 cases received total body irradiation (TBI) and chemotherapy and 
11 cases had only high dose chemotherapy. For allogeneic group, half of them received myeloablative 
preparative regimen with TBI plus chemotherapy; and the other half had non-myeloablative preparative 
regimen. As a whole group, the allogeneic transplant had a significantly longer event-free survival (EFS) 
than the autologous HSCT (Figure 2). In the autologous transplant group, 19 of 23 cases 
progressed/relapsed after transplant with median time to progression of 3 months. In contrast, only 5 of 
20 cases progressed/relapsed with median time to progression not reached in allogeneic group.  
 
The overall survival (OS) was also longer in allogeneic group than in autologous group (Figure 3). The 
estimated OS was 85% vs 65% at 1 year, 79% vs 56% at 2 year and 79% vs 36% at 5 year for the two 
groups. One hundred day post transplant mortality was 5% and 13% in allogeneic and autologous groups 
respectively. One year mortality was 15% and 35% for the two groups. While progressive disease caused 
11 deaths in autologous group, none of the death in allogeneic cases was due to disease progression. 
The most interesting finding was that there was no difference in clinical outcome between the cases 
receiving myeloablative regimen and the cases having non-myeloablative approach in the allogeneic 
group. 
 

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Figure 2  Post transplant event-free survival of MF/SS patients according to the type of transplant  
(p < 0.0005). 
 
 
 
Figure 3  Post transplant overall survival (OS) of MF/SS patients according to the type of transplant  
(p = 0.028). 
 
Although this is a very small sample size with many limitations, this meta-analysis suggests several 
important points related to the use of HSCT to manage MF/SS: 
1) High dose therapy with either TBI or chemotherapy has not provided significant clinical benefit 
given the extremely short time to progression (3 months) in autologous transplant experience. 

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January 7, 2019 
2) A significant fraction of cases remained in progression free status after allogeneic transplant, 
suggesting an effective graft-versus-MF/SS effect. 
3) Non-myeloablative approach for allogeneic transplant is a reasonable option, especially given 
that the median age at diagnosis is 55-60 years and compromised skin is frequently present in 
these patients, which increases the risk of infection. Therefore, we propose a clinical study with 
allogeneic HSCT using a unique non-myeloablative preparative regimen, TLI/ATG, to treat 
advanced MF/SS. 
 
2.2  
Investigational Agent/Device/Procedure 
 
Total lymphoid irradiation (TLI)/antithymocyte globulin (ATG) preparative regimen 
One of the concerns using allogeneic HSCT is the toxicity related to transplantation process. While graft-
versus-lymphoma is highly desired for a long-term disease control, the mortality and morbidity from 
preparative regimen, infections and graft versus host disease (GVHD) makes allogeneic transplant 
difficult to apply to patients with indolent lymphoma. To overcome this, preparative regimens of non-
myeloablative radiotherapy, chemotherapy, or both to decrease early toxicity have been used (29-32). 
However, acute GVHD remains a major problem after non-myeloablative transplantation and is 
responsible for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm (31-
33). 
 
A new approach to the prevention of acute GVHD takes advantage of the immune system's regulatory T 
cells. Two types of regulatory T (Treg) cells in mice, natural killer T cells and CD4+CD25+ T cells, can 
prevent acute GVHD (34-37). These Treg cells inhibit the proliferation of and cytokine secretion by CD4+ 
and CD8+ donor T cells that injure the intestines, liver, and skin in acute GVHD (34,37). Nevertheless, the 
direct tumor-killing activity mediated by donor CD8+ T cells remains unaffected (35). Thus, Treg cells can 
separate GVHD from the antitumor activity of the graft. Regulatory natural killer T cells of either donor or 
host origin have the unique capacity to prevent acute GVHD by secreting interleukin-4 (36-38). In a mice 
models, after repeated treatment with low-dose irradiation targeted to the spleen, thymus, and lymph 
nodes (total lymphoid irradiation, TLI), the proportion of these cells progressively increases until ultimately 
they constitute the majority of T cells in the spleen and bone marrow (37, 38). In preclinical studies, 
murine recipients of allogeneic bone marrow that underwent conditioning with anti–T-cell antibodies and 
TLI were fully protected from GVHD, whereas mice that underwent conditioning with anti–T-cell 
antibodies and a single dose of total-body irradiation were not protected (37, 38). Studies of the pattern of 
cytokine secretion by donor T cells in protected hosts showed a polarization toward a pattern of type 2 
helper T (Th2) cells, with increased secretion of interleukin-4 (38). The Th2 cells assist B cells to produce 
antibodies and reduce the inflammation promoted by type 1 helper T cells. 
 
To apply this novel non-myeloablative regimen of TLI and ATG for allogeneic HSCT, a clinical trial has 
been conducted in patients with hematological malignancies other than myelodysplasia or 
myeloproliferative disorders since December 2001. Analysis of the first 37 patients (last patient enrolled in 
2004), 19 of whom had NHL, appeared in the New England Journal of Medicine (39). The regimen 
consisted of 800 cGy in 10 fractions over 11 days with ATG administered at 1.5 mg/kg/d from day -11 to -
7. The median age was 56 (28-65) years and 35% had failed prior autologous HSCT. Multi-lineage 
chimerism was achieved within 56 days and sustained in 31 of 37 patients. Of the 6 who lost their grafts, 
4 were in the setting of progressive disease. Minimal neutropenia was observed and more than half of 
patients did not require hospitalization. Remarkably and in agreement with the preclinical studies, 35 of 
37 patients developed no acute GVHD. Among the 18 patients in partial remission at transplant, 10 
achieved complete remission, strongly suggestive of retained graft versus tumor effect. Among the 17 
patients in complete remission at transplant, 11 continued to be disease-free at 1.5 years. Transplant-
related mortality in this study was just 5% at 180 days. To date, 4 deaths due to disease progression and 
4 deaths related to the procedure have been recorded. Overall, these results indicate that preparation 
with TLI/ATG and allogeneic HSCT is well tolerated, associated with prompt multi-lineage engraftment 
and a markedly low incidence of acute GVHD, with a strong suggestion of retained graft versus tumor 
effect. 
 
Update on experience in B cell lymphoma patients 
Since the initial report, we continue to accumulate the experience using this novel non-myeloablative 
preparative regimen. To date, we have performed allogeneic HSCT using TLI/ATG preparative regimen in 
111 patients. Sixty four of the patients had malignant lymphoma. The majority of the patients (83%) 
achieved full donor chimerism (> 95% donor cells) and the transplant was well tolerated.  
 

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January 7, 2019 
The one-year non-relapse mortality was 2% for patients receiving HLA-matched sibling donor graft and 
8% for patients having HLA-matched unrelated donor graft. Acute GVHD only occurred in 4% of the 
patients, while the incidence of chronic GVHD is estimated to be around 35-45% at 2 years. For patients 
with lymphoma, the disease control was significantly better in patients who responded to salvage 
chemotherapy prior to transplantation than those who had refractory disease (Figure 4). One possibility is 
that graft-versus-lymphoma effect is a slow process after non-myeloablative allogeneic transplant and is 
unable to control high tumor burden or fast growing tumor in time. Therefore, we propose in this project to 
use non-myeloablative allogeneic HSCT in MF/SS patients after they achieve some degree of disease 
control with salvage therapy. One important observation was that patients who failed to achieve full donor 
chimerism had significant chance to relapse after transplant.  
 
 
 
Figure 4  Actuarial event-free survival among patients with lymphoid malignancies (non-skin) stratified by 
disease status at transplant (N=64). 
 
 
2.3  
Rationale 
 
Mycosis Fungoides (MF) and its leukemic variant, Sezary Syndrome (SS) is the most common type of 
cutaneous non-Hodgkin's lymphoma (NHL) in North America. Though most of the patients have an 
indolent course with median survival of 12-15 years, those with advanced diseases have a survival of 1-3 
years after diagnosis, and there is no curative therapy (1). While localized skin treatment, novel biological 
therapies such as histone deacetylase inhibitors, or systemic chemotherapy can temperately control the 
diseases, none of these provide a long-term remission. Graft-versus-lymphoma effects after allogeneic 
hematopoietic stem cell transplantation (HSCT) have been demonstrated to provide a long-term disease 
control in B cell lymphoma, including low-grade B cell lymphoma and chronic lymphocytic leukemia. We 
propose a clinical trial using non-myeloablative allogeneic HSCT to treat patients with advanced stage 
MF/SS. The rationale is that graft-versus-lymphoma provided by this non-myeloablative approach will 
result in a clinical response and a prolonged progression free survival in these patients. The patient 
population enrolled in this clinical trial will be those with MF/SS who still have persistent or progressive 
disease after being treated with multiple lines of local and systemic therapies. When MF/SS reached this 
stage of their disease, the conventional chemotherapies will no longer provide any clinical benefit. 
Therefore, we proposed using this low toxicity allogeneic HSCT protocol to these patients. 
 
2.4  
Correlative Studies Background 
 
2.4.1  Donor Cell Chimerism: The standard definition for full engraftment is that the percentage of 
donor cells in CD3 population rises above 95%. While most of our patients (83%) having undergone 
TLI/ATG preparative regimen reached full donor chimerism, the timing to achieving full chimerism varied 
significantly. It is of great interest to determine whether the full donor chimerism correlates to clinical 
response. In addition, donor chimerism of different cell populations may also have a significant impact on 

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January 7, 2019 
clinical outcome. We will attempt to correlate the kinetics of donor chimerism of different cell populations 
to tumor response, disease progression, and GVHD. One prediction is that rising donor CD3/CD4/CD8 
cells correlate to tumor response. 
 
2.4.2 
Profile of Grafting Immune Cells: To assess the T cells immune profile, intracellular cytokines 
with monoclonal antibodies against IL-2, IFN-g (Th1 pattern), IL-4 and IL-10 (Th2 pattern) will be 
assayed. In mouse models, TLI/ATG polarized T cells to a Th2 pattern, which has been thought to be 
critical for graft-versus-tumor effect. Therefore, it is of great interest to see whether this Th2 polarization 
can be recapitulated in humans and whether Th2 polarization may affect tumor response. In the case of 
MF/SS, it is more complicated as most of the tumor T cells express Th2 phenotype (44). Whether this 
will facilitate or hamper the graft-versus-tumor effect by the donor T cells is unknown. 
 
 
2.4.3 
Donor T Cell Trafficking: Engrafted donor T cells have to be in close contact with the tumor cells 
to help antigen-presenting cells (APC) to cross-prime cytotoxic CD8 T cells. Recently, chemokine 
receptors, CCR4, CCR10 and cutaneous lymphocyte antigen (CLA) have been shown to play a critical 
role in mediating CD4 T cell trafficking to skin in both mice and humans (45-49). We will first test whether 
the peripheral blood T cells express these skin homing receptors by using multi-color flow cytometry. In 
addition, CCR7 has been shown to mediate the homing of T or B lymphocytes to lymph nodes (50), 
which is an essential step after T cells being primed in the tumor sites. In addition, examining the skin 
tumor site after transplant will be extremely informative to determine whether donor T cells reach the 
tumor sites. 
 
2.4.4 
Regulatory T cell (Treg): Treg cells have been implicated in many important aspects of 
allogeneic transplant, such as modulating graft-versus-tumor effect and damping GVHD. Recent studies 
have also pointed a role for Treg in the progression of MF/SS and in immunomodulation in the skin 
(52,53). Therefore, monitoring the number and function of Treg will be performed. We will monitor the 
number of Treg in blood and their function using a mixed-lymphocyte-reaction (MLR) inhibition assay 
(39). 
 
We will specifically monitor the number and function of Treg cells in patients who undergo ECP or 
TSEBT. The status of Treg cells in these patients becomes even more interesting because these 
treatments have been proposed to mediate their therapeutic effects via modulating Treg (54). 
 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
3.1  
Inclusion Criteria 
 
3.1.1 
Stage IIB-IV mycosis fungoides or Sezary syndrome, who have failed at least 1 standard 
systemic therapy or are not candidates for standard therapy. 
 
3.1.2 
Pathology reviewed and the diagnosis confirmed at Stanford University Medical Center.  
 
3.1.3 
Age > 18 years and < 75 years. 
 
3.1.4 
Karnofsky Performance Status > 70%.  
 
3.1.5 
Corrected DLCO > 40%. 
 
3.1.6 
Left ventricle ejection fraction (LVEF) > 30%. 
 
3.1.7 
ALT and AST must be < 3x normal.  
 
3.1.8 
Total bilirubin < 2 mg/dL unless hemolysis or Gilbert’s disease. 
 
If AST and ALT are > 3  <5 x ULN, patient may be eligible if: 
1) Liver biopsy performed within 60 days of HCT excludes active cirrhosis grade greater 
than 2/4 and bridging fibrosis. 
2) No clinically evident ascites. 
3) Patient with Hepatitis B or C are excluded if AST or ALT > 3 x UL. 

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January 7, 2019 
 
3.1.9 
Estimated creatinine clearance > 50 ml/min. 
 
3.1.10 
Have a related or unrelated HLA-identical donor, or one antigen/allele mismatched in HLA-
A, B, C or DRB1. 
 
3.1.11     Signed Informed Consent. 
 
3.1.12 
Patients with prior malignancies diagnosed > 5 years ago without evidence of disease are 
eligible.   
 
3.1.13 
Patients with a prior malignancy treated < 5 years ago but have a life expectancy of > 5 
years for that malignancy are eligible. 
 
 
3.2  
Exclusion Criteria 
 
3.2.1 
Uncontrolled active infection. 
 
3.2.2 
Uncontrolled congestive heart failure or angina. 
 
3.2.3 
Pregnant or nursing patients will be excluded from the study.  
 
3.2.4 
Those who are HIV-positive will be excluded from the study due to high risk of lethal 
infection after hematopoietic cell transplantation.   
 
 
3.3  
Donor Inclusion Screening Guideline 
 
3.3.1 
Age ≥17. 
 
3.3.2 
HIV seronegative. 
 
3.3.3 
No contraindication to the administration of G-CSF. 
 
3.3.4 
Willing to have a central venous catheter placed for apheresis if peripheral veins are 
inadequate. 
 
3.4 
Donor Exclusion  Screening Guideline 
 
3.4.1 
Serious medical or psychological illness. 
 
3.4.2 
Pregnant or lactating women are not eligible. 
 
3.4.3 
Prior malignancies within the last 5 years, except for non-melanoma skin cancers. 
 
3.5 
Enrollment 
 
Enrollment occurs when all eligibility criteria are met. 
 
3.6 
Informed Consent Process 
 
A conference will be held with the patient and family to discuss this study and alternative treatments 
available for treatment of the underlying disease. The attending physician will conduct the conference. All 
potential risks associated with the use of TLI, ATG, immunosuppressive drugs, and allogeneic 
hematopoietic cell infusions will be discussed as objectively as possible. It will be explained that patients 
offered this protocol have an underlying malignancy that render them at high risk of relapse or that will 
result in a significant decrease in life expectancies with conventional treatments. Informed consent from 

Page 15 of 42 
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January 7, 2019 
the patient will be obtained using a form approved by the Administrative Panel on Human Subjects in 
Medical Research of the Stanford University Medical Center. 
 
 
3.7       Randomization Procedures 
 
No randomization process will be performed in this study. 
 
 
 
4. TREATMENT PLAN 
 
4.1  
Investigational Agent or Device Administration 
 
4.1.1 
Pre-transplant Evaluation 
 
a) Prior to initiating therapy, patients will have a complete history and physical examination performed.  
In addition, a bone marrow specimen and bone marrow aspirate will be obtained for the evaluation. 
b) Patients will have the following laboratory tests performed: CBC with differential, HLA typing, 
comprehensive metabolic panel, urinalysis, hepatitis panel, HIV antibody, HIV p24 antigen, herpes 
simplex titer, herpes zoster titer, and CMV titer.  Additional evaluation will include a chest radiograph, 
EKG and pulmonary function testing with spirometry and diffusing capacity.  Other testing may be 
needed and will be determined based on the patients history and physical examination. 
c) HLA typing of the donor will be confirmed at Stanford before beginning treatment. 
 
4.1.2 
Allogeneic Transplant: Preparative Regimen 
 
d) Total Lymphoid Irradiation (TLI) Administration: TLI is administered ten times in 80c- 120c Gy 
fractions on day –11 through day –7 and day –4 through day –1 according to the above delineated 
schedule. TLI is administered from a 6 MeV linear accelerator (photon beam). The radiation field (four 
fields—two anterior and two posterior) will include all major lymphoid organs including the thymus, 
spleen and lymph nodes. A radiation oncologist will evaluate patients prior to conditioning to 
determine blocks and radiation ports. TLI will generally be administered between 10 a.m. and 1 p.m. 
Since TLI can cause nausea, premedication with antiemetic therapy is needed. TLI schedule may be 
adjusted based on schedule of radiation therapy department. 
e) Anti-thymocyte Globulin (ATG) Administration: ATG will be administered five times intravenously at 
1.5 mg/kg/day from day –11 through day –7 for a total dose of 7.5 mg/kg. ATG doses will be based 
on the adjusted ideal body weight. Premedication for ATG will include benadryl 25-50 mg, Tylenol 
650 mg and solumedrol 1.0 mg/kg. 
f) 
Total skin electron beam therapy (TSEBT) Administration: TSEBT will be given to patients who have 
extensive skin involvement such as wide spread plaques, tumors, or erythroderma with significant 
tumor infiltration, as part of cytoreduction prior to transplant. The length of therapy and dose of 
TSEBT will be determined by the radiation oncologist and individualized based on the patient’s 
presentation and treatment history.  In patients receiving TSEBT, TLI will begin during the last two 
week of TSEBT. 
g) Extracorporeal Photopheresis (ECP) Administration:  Extracorporeal photopheresis (ECP) is a 
leukapheresis-based immunomodulatory therapy that has been approved by the US Food and Drug 
Administration for the treatment of cutaneous T cell lymphoma (CTCL) since 1988. ECP will be 
performed using the UVAR XTS Photopheresis System developed by Therakos, Inc (Exton, Pa). 
Blood (225 mL) will be passed through 3 cycles of leukapheresis, or 125 mL of blood will be passed 
through 6 cycles, depending on the patient's hematocrit value and body size. At the end of each 
leukapheresis cycle, the red blood cells and plasma are returned to the patient. The collected WBCs 
will be mixed with heparin, saline, and 8-methoxypsoralen (8-MOP), which intercalates into the DNA 
of the lymphocytes upon exposure to UVA light and makes them more susceptible to apoptosis when 
exposed to UVA radiation. The treated WBC mixture is returned to the patient. 
 
4.1.3 
Donor PBPC 
 
h) Donors will receive G-CSF injections daily from day -5 to day 0.  G-CSF will be administered 

Page 16 of 42 
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January 7, 2019 
subcutaneously at a dose of 16 µg/kg/day.  Collection of peripheral blood progenitor cells (PBPC’s) 
will be performed by apheresis.  Collections generally occur on day –1 and day 0 if needed. CD34+ 
proportion will be evaluated by flow cytometry. Patients will receive all cells collected.  The ideal cell 
doses (based on recipient body weight) for MRD and MUD transplants are > 5x106 CD34+ cells/kg. 
Cells collected on days –1 and 0 will be processed for infusion on day 0. Fresh cells (not frozen) are 
to be infused whenever possible. Patients will receive premedication approximately 1 hour prior to 
infusion using current standard of care or as recommended: 
i) 
Acetaminophen:  650 mg p.o., Diphenhydramine:  50 mg i.v., Hydrocortisone:  100 mg i.v.,1 hour 
prior to infusion. 
j) 
For MRD transplants, if the target cell dose is not achieved then a third apheresis procedure may be 
performed on day +1 and the cells infused on the same day. If after a third apheresis procedure the 
CD34 dose is <3x106/kg and the total CD3 cell dose does not exceed 5x108/CD3+ cells per kg, then a 
fourth apheresis procedure may be performed on day +2 and the cells infused on the same day. Total 
CD3+ cell dose should not exceed 7x108 CD3+ cells/kg. Grafts that contain >7x108 CD3+ cells/kg must 
first be evaluated by the Principal Investigator before infusion.  Administration and premedication prior 
to cell infusion will be identical to those specified for day 0. 
k) Collection of cells for the MUD transplants will be coordinated through the National Marrow Donor 
Program and subject to the rules of that Program, thus MUD collections will be limited to days –1 and 
0 only. If mobilized PBPC is not available through certain NMDP collection centers then bone marrow 
will be considered. 
l) 
ABO incompatibility: ABO incompatibility between donor and host will require red cell depletion only if 
bone marrow is used as the hematopoietic source. Red cell depletion is performed by Hetastarch 
sedimentation according to standard procedure. 
m) Post-Transplant Growth Factors: Patients should not receive post-transplant growth factors while 
receiving MMF, particularly during the first month off MMF taper. Growth factors should not be given 
unless severe neutropenia develops or persists past day 27 post-transplant (ANC < 100/ml for > five 
days). 
 
4.1.4 
Immunosuppression for GVHD prophylaxis 
 
n) Immunosuppression will include tacrolimus (Prograf) and mycophenolate mofetil (MMF) ).  Tacrolimus 
will be administered orally at a dose of 0.03 mg/kg/day bid from day -3 through day +56.  MMF will 
begin at 15 mg/kg p.o. bid for MRD and Q 8 hours for MUD from the evening of day 0 to day +27 for 
MRD or day + 40 with a taper for MUD.  Prograf dose adjustments will be made as clinically indicated.  
Trough levels will be monitored to keep the Tacrolimus level in the range of 8-10 ng/ml.  MMF dose 
adjustments will be made if there is evidence of MMF-related GI toxicity or myelosuppression. 
o) Tacrolimus (Prograf): Tacrolimus is given at 0.03 mg/kg p.o. b.i.d (9 am and 9 pm) from day –3 until 
after the day +56 chimerism studies have been obtained. Doses should be adjusted to maintain a 
high therapeutic Tacrolimus level to between 8-10 ng/mlng/ml, unless there is renal insufficiency 
(creatinine >2.0) or hyperbilirubinemia (bilirubin >2.0) in which case the Tacrolimus should be 
reduced to normalize these parameters. If there is nausea and vomiting at any time during FK506 
treatment, Tacrolimus should be administered intravenously by continuous infusion at 3 mg/kg over 
20 hours, and adjusted for the Tacrolimus blood level. Tacrolimus will be tapered per standard 
guideline of Stanford BMT program after the day +56 chimerism studies are obtained. If patient does 
not tolerate Tacrolimus, tacrolimus may be used and administered per standard guideline of Stanford 
BMT program. 
p) Mycophenylate mofetil (MMF): Administration of MMF will begin at 15 mg/kg po on day 0, at 5-10 
hours after mobilized PBPC infusion is complete. Thereafter, beginning on day +1 MMF is taken at 15 
mg/kg po b.i.d. (30 mg/kg/day) if transplantation was using a matched related donor, and 15 mg/kg po 
Q8 hours if from a matched unrelated donor or a one antigen mismatched donor.  Doses will be 
rounded up to the nearest 250 mg (capsules are 250 mg). MMF will be stopped on day +28 for 
matched related donors and for one antigen mismatched or unrelated donors beginning day +40. 
MMF will be tapered by 10% weekly till off, typically by day +96.  If there is nausea and vomiting at 
any time preventing the oral administration of MMF, MMF should be administered intravenously. 
q) Guidelines for MMF dose adjustment: If in the clinical judgment of the investigator, there is 
documented toxicity related to MMF administration, a dose adjustment will occur.  Based on previous 
solid organ transplantation studies, dose adjustments are likely to occur because of hematopoietic or 
gastrointestinal adverse effects.  Dose adjustments will not be made for hematopoietic toxicities 
unless severe neutropenia develops or persists until day +21 post-transplantation (ANC <100/ml for 
>5 days).  In the event of gastrointestinal toxicity that requires medical intervention including 

Page 17 of 42 
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January 7, 2019 
medication for control of persistent vomiting or diarrhea that is considered to be due to MMF, a 20% 
dose reduction or the drug will be given i.v.  For severe gastrointestinal toxicity related to MMF 
(severe refractory diarrhea or overt gastrointestinal bleeding), MMF may be temporarily stopped. 
 
4.1.5 
Infection Prophylaxis 
 
r) It is expected that patients on this protocol will be susceptible to opportunistic infections in the post-
transplant period for at least 6 months.  These expectations are based upon prior experiences with 
patients that have undergone treatment with TLI and/or ATG, as well as other non-myeloablative 
allogeneic transplantation procedures.  Infectious disease prophylaxis will be according to the current 
standards of care of Stanford BMT program. 
 
4.1.6 
Engraftment and Disease Status Monitoring 
 
s) Patients will be followed in the ITA for signs of infection or GVHD.  Monitoring for engraftment and 
infection will be according to current standard of care of Stanford BMT program. 
t) 
Chimerism:  Microsatellite analysis (VNTR) of CD3, CD19, CD15, and CD56 peripheral blood cell 
subsets will be performed on days +28 (+ 5 days), +56 (+ 5 days), +90 (+ 14 days),+180 (+ 14 days), 
+270 (+ 14 days), and yearly (+ 4 weeks) to evaluate the degree of donor hematopoietic cell 
engraftment (donor chimerism), and on bone marrow on day +90 (+ 14 days), and yearly per 
physician’s discretion. 
u) Clinical response will be determined at 3, 6, 9, 12, 18, 24 months or until relapse or progression after 
transplant. The disease status and clinical response will be scored on a rigorous and multifactorial 
approach described before (41, appendix). This approach takes tumor burden in skin, lymph nodes 
and blood into consideration. To achieve this, patients will be evaluated at Cutaneous Lymphoma 
Clinic before transplant and at specified time points after transplant. 
 
4.1.7 
Therapeutic Interventions for Disease Progression 
 
v) Early discontinuation of immunosupression (< day +120) should be considered the first therapeutic 
maneuver. However, neither MMF nor Tacrolimus should be stopped prior to reviewing chimerism 
results. If the donor T cell chimerism in blood is > 50% and there is < grade II GVHD, MMF is to be 
stopped if still being taken, and Tacrolimus tapered over two weeks. Bone marrow aspirate and blood 
chimerism studies will be performed two weeks after discontinuation of immunosuppression. 
w) For Sezary Syndrome patients, lymphoma cells in the blood (Sezary cells) will be monitored by flow 
cytometry on days +28, and then 3, 6, 9, 12, 18, 24 months after transplant as described for clinical 
response determination. Patients with persistent Sezary cells on day +28 will have the option to start 
extracorporeal photopheresis (ECP) on day +30 + 5. The recommendation is to administrate four 
weekly treatments at the discretion of the investigator, followed by additional four monthly treatments, 
and to be re-evaulated. 
 
4.2 
General Concomitant Medication and Supportive Care Guidelines 
 
4.2.1 
Supportive care measures will be consistent with standard practice of the Stanford BMT Program.  
Standard care measures are included by not limited to measures for skin care, mucositis, nausea, 
diarrhea, constipation, pain control, infection prevention and patient and family education. 
4.2.2 
Transfusion support for red blood cells and platelets will be consistent with standard practice of 
the Stanford BMT Program. 
 
 
4.3 
Duration of Therapy 
4.3.1 
See table below for time lines. 
 
 
Non-Myeloablative Allogeneic Transplant 
 
Day – 11 
Day - 10 
Day - 9 
Day -8 
Day - 7 

Page 18 of 42 
BMT 206 
 
January 7, 2019 
TLI 
ATG 
TLI 
ATG 
TLI 
ATG 
TLI 
ATG 
TLI 
ATG 
 
Day - 4 
Day - 3 
Day - 2 
Day - 1 
Day 0 
TLI 
TLI 
Begin 
Tacrolimus 
TLI 
TLI x 2 
Allogeneic 
Transplant 
 
4.3.2 
Active treatment continues post-allogeneic transplant for approximately 3 – 4 months and then 
care is transitioned back to the BMT clinic for ongoing monitoring and care. 
 
4.4  
Duration of Follow Up 
 
Patients will be followed for 2 years after transplant. Subsequent follow-up will be consistent with 
standard practice of the Stanford BMT program. 
 
4.5 
Criteria for Removal from Study 
 
4.5.1 
Patients who develop severe adverse reaction to ATG infusion, such as serum sickness that 
result end-organ damage will be removed from study. 
 
4.6 
Alternatives 
 
4.6.1 
Alternatives may include continued standard therapies, other investigational therapies or no 
therapy. 
 
4.7 
Compensation 
 
Subjects will not be paid for their participation in the study.  
 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
 
5.1 
 Investigational Agent/Device/Procedure   
 
5.1.1 
Non-myeloablative allogeneic transplant using total lymphoid irradiation (TLI) and anti-
thymocyte globulin (ATG): 
 
As discussed earlier, using a non-myeloablative preparation regimen for allogeneic transplant preserves 
the benefit of graft versus tumor effect but decreases the toxicity. However, one major complication found 
in our previous approach using TBI/fludarabine regimen is GVHD. Recently, Lowsky et al. (32) have 
extended the preclinical model of Strober and colleagues to the clinic using a novel conditioning strategy 
of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) prior to allogeneic HCT. In this recent 
report, the incidence of acute GVHD was just 5%, prompt multi-lineage engraftment was demonstrated, 
and promising efficacy was reported in hematologic malignancies, including mantle cell lymphoma and 
DLBCL(32).  Since this report, we have performed allogeneic transplant with both related and unrelated 
donors using TLI/ATG in over 150 patients who have a variety of hematological malignancies including 
mantle cell lymphoma, transformed lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute 
myelobalstic leukemia, myelodysplastic syndrome and myelofibrosis. The overall experience has re-
demonstrated the low incidence of acute GVHD and preserved graft versus tumor effect. 
 
5.2 
Availability 
 
All agents used in this study are commercially available. Total lymphoid irradiation is part of 
standard care provided by Stanford Radiation Oncology department. 
 

Page 19 of 42 
BMT 206 
 
January 7, 2019 
5.3 
Agent Ordering 
 
All agents used in this study are commercially available and will be ordered accordingly. 
 
5.4 
Agent Accountability 
 
The agents will be kept and monitored by Stanford central pharmacy. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
No dose modifications will be made. 
 
7. ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1 
Potential Adverse Events 
 
Tacrolimus 
 
• 
Human Toxicology: Nephrotoxicity is the most frequent side effect of tacrolimus.  Other frequently 
observed side effects include hypertension, hirsutism, tremors, paresthesias, hepatotoxicity, 
hypomagnesemia, and hyperkalemia.  Transient gastrointestinal symptoms have also occurred, to 
include anorexia, nausea and ileus.  The drug has demonstrated a relative lack of myelotoxicity. 
 
• 
Pharmaceutical Data Formulation: Tacrolimus is available for oral and intravenous administration.  
The intravenous solution is available as 1 ml ampules containing 5 mg/ml.  Tacrolimus should be 
administered intravenously over 2-6 hours. Longer infusion times are acceptable and sometimes 
better tolerated.  The contents of the ampules should be diluted 0.9% NaCl injection or 5% dextrose 
injection 
 
• 
Supplier:  This drug is commercially available. 
 
Mycophenolate Mofetil 
 
• 
Human Toxicology: The principal side effects include diarrhea, leukopenia, vomiting and infection.  
The drug is also associated with abdominal pain, nausea, hypertension and anemia. 
 
• 
Pharmaceutical Data: Mycophenolate Mofetil is available in 250 mg capsules and 500 mg tablets.  
Mycopenolate Mofetil should be taken on an empty stomach. 
 
• 
Supplier:  Mycophenolate Mofetil is commercially available. 
 
Granulocyte-Colony Stimulating Factor 
 
• 
Human Toxicology: The primary side effect of G-CSF is bone pain and is more common with higher 
doses of G-CSF. 
 
• 
Pharmaceutical Data: G-CSF is available in vials containing 300µg or 480µg at a concentration of 
300µg/ml.  G-CSF should be refrigerated.  G-CSF is given as a daily subcutaneous injection. 
 
• 
Supplier:  G-CSF is commercially available. 
 
Anti-thymocyte Globulin (ATG) 
 
• 
Thymoglobulin is a rabbit-thymocyte globulin. It is the purified, sterile, IgG fraction of immune serum 
of rabbits immunized with human thymus lymphocytes. ATG is a lymphocyte-selective 
immunosuppressant. It is believed to act by modifying the number and function of lymphocytes. 
 
• 
Administration: Thymoglobulin is diluted in 0.9% NaCl. Thymoglobulin is given intravenously as a 4-

Page 20 of 42 
BMT 206 
 
January 7, 2019 
6 hour infusion into a central vein. 
 
• 
Potential Toxicities: Thymoglobulin may cause: 
Cytopenia of any cell line 
Pyrogenic action (ATG causes chills and fever in a high proportion of patients treated) 
Fluid retention 
Allergic reactions (rash, pruritus, urticaria, wheal and flare reactions are reported, as well as 
bronchospasm and anaphylactic shock) 
A serum sickness-like syndrome may develop.  This is best prevented by steroid co-administration. 
EBV lymphoproliferative disorders have been associated with administration of anti-thymocyte 
globulin in highly immunosuppressed patients. 
 
• 
Because of the potential for anaphylaxis, resuscitation equipment should be available during 
administration.  After an anaphylactic reaction, infusion should not be resumed. A central line should 
be established and oxygen, as well as resuscitation equipment should be available. 
 
Total Lymphoid Irraditaion (TLI) 
 
• 
TLI may cause nausea, vomiting, diarrhea, temporary hair loss and painful swelling of the salivary 
glands for a few days. The TLI in this protocol is approximately one-fifth of that used in standard NHL 
treatments. Therefore, these side effects most likely will be milder and severe acute side effects are 
not expected. The risk of secondary malignancies after the low dose TLI is yet to be determined. 
 
Total Skin Electron Beam Therapy (TSEBT) 
 
Acute side effects can include a skin burn that is much like a moderate to severe sun burn (worse in 
patients who burn but do not tan when exposed to sun), deep tanning (in those who tan after sun 
exposure), itching and fatigue. Although these acute side effects are occasionally severe, they are self-
limited if appropriate supportive therapy is administered in a timely fashion. 
 
Long-term side effects can include generalized dry skin and permanently decreased secretion of sweat 
and oil on much but not all of the skin, scattered dilated blood vessels (telangectasias), pigmentation 
changes, and partial or complete scalp hair loss which is more severe in males with signs of thinning hair 
than in females. 
 
Extracorporeal photopheresis (ECP) 
 
ECP is a very well-tolerated procedure. Transient hypotension may occur in some patients during the 
collection phase of the treatment, but this is asymptomatic. Some patients may experience low-grade 
fevers a few hours after ECP. 
 
Some patients with CTCL may experience an increase in pruritus or redness during the course of ECP. 
 
In all of the various patient groups treated, no immunosuppression, opportunistic infections, or neoplasia 
has been associated with ECP. The risk of secondary malignancies after the low dose TLI is yet to be 
determined. 
 
Finally, although patients with hypertriglyceridemia do not experience further adverse events during ECP, 
they may have a less efficacious treatment because of the inability of the UVAR machine to separate the 
WBCs from the lipid-rich blood. Because of this, patients should have triglyceride levels of less than 300 
mg/dL and should eat a very low fat or non-fat diet starting the evening before the procedure. 
 
7.2 Adverse Event Reporting 
 
Appendix C outlines AE and SAE reporting Guidelines. 
 

Page 21 of 42 
BMT 206 
 
January 7, 2019 
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1 Laboratory Correlative Studies 
 
8.1.1 
Donor Cell Chimerism 
8.1.1.1 Collection of Specimens 
Peripheral blood will be drawn on day +28, +56, +90, and +180.  
Bone marrow biopsy will be performed on day +90. 
8.1.1.2 Handling and Shipping of Specimens 
 
Per standard BMT guidelines. 
 
8.1.1.3  Site(s) Performing Correlative Study 
Stanford HLA Typing Laboratory will be responsible for performing the donor chimerism 
study. 
 
8.1.1.4  Coding of specimens for privacy protection 
Specimens will be coded for privacy protection. 
 
8.1.2 
Profile of Grafting Immune Cells 
8.1.2.1 Collection of Specimens 
Peripheral blood will be drawn before preparative regimen and on day +30, +60, +90, and 
+180 post transplant. 
 
8.1.2.2 Handling and Shipping of Specimens 
Per standard BMT guidelines. 
 
8.1.2.3  Site(s) Performing Correlative Study 
Study of T cell cytokine and chemokine receptor profile will be performed in the Stanford 
Cellular Therapy Facility (CTF). 
 
8.1.2.4  Coding of specimens for privacy protection 
Specimens will be coded for privacy protection. 
 
8.1.3 
Donor T Cell Trafficking 
8.1.3.1 Collection of Specimens 
Two 5 mm punch skin biopsy of target lesions will be performed in Stanford Cutaneous 
Lymphoma Center on day +90 and at the time of tumor regression/progression. 
 
8.1.3.2 Handling and Shipping of Specimens 
 Per standard BMT guidelines. 
 
8.1.3.3  Site(s) Performing Correlative Study 
Stanford Cellular Therapy Facility (CTF)  
 
8.1.3.4  Coding of specimens for privacy protection 
Specimens will be coded for privacy protection. 
 
8.1.4 
Regulatory T Cell (Treg) 
8.1.4.1 Collection of Specimens 
Peripheral blood will be drawn on day +30, +60, +90, and +120 post transplant. 
 
8.1.4.2 Handling and Shipping of Specimens 
Per standard BMT guidelines. 
 
8.1.4.3  Site(s) Performing Correlative Study 
Study of Treg will be performed in the Cellular Therapy Facility (CTF). 
 
8.1.4.4  Coding of specimens for privacy protection 
Specimens will be coded for privacy protection. 
 

Page 22 of 42 
BMT 206 
 
January 7, 2019 
8.1.5 
Tumor Immune Response 
8.1.5.1 Collection of Specimens 
Peripheral blood will be drawn on day +60, +90, and +180. 
 
8.1.5.2 Handling and Shipping of Specimens 
Per standard BMT guidelines. 
 
8.1.5.3  Site(s) Performing Correlative Study 
Stanford Human Immune Monitoring Center (HIMC) Laboratory will be responsible for 
serum storage. The testing of antibody against patients’ tumor cells will be performed by 
Dr. Weng in HIMC laboratory. 
 
8.1.5.4  Coding of specimens for privacy protection 
Specimens will be coded for privacy protection. 
 
9. STUDY CALENDAR 
 
 
 
Post-Transplant Day 
 
BS 
±5 
days 
±5 
days 
±10 
days 
± 2 
wks 
± 2 
wks 
± 2 
wks 
± 4 
wks 
± 4 
wks 
 
 
d+30 
d+60 
d+90 
d+180 
d+270 
d+365 
d+540 
d+730 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Path Review 
X 
 
 
 
 
 
 
 
 
H&P/KPS 
X 
 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
 
Echo 
X 
 
 
 
 
 
 
 
 
CBC with diff 
X 
 
 
 
 
 
 
 
 
Chemistry: BMT I 
X 
 
 
 
 
 
 
 
 
HLA confirmed 
X 
 
 
 
 
 
 
 
 
BMT Panel 
(serologies) 
X 
 
 
 
 
 
 
 
 
CXR 
X 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
STR subsets: PB 
 
X 
X 
X 
X 
X 
X** 
 
X 
BM bx/asp** 
 
X 
 
 
X 
 
 
X 
 
X 
Research Samples 
 
X 
X 
X 
X 
 
 
 
 
Skin Biopsy 
X 
 
 
X 
 
 
 
 
 
Flowcytometry** 
(SS only) 
 
X 
 
X 
X 
X 
X 
X 
X 
Disease 
Status/Response** 
X 
 
 
X 
 
X 
X 
X 
X 
GVHD 
assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
** Per Attending Physician’s discretion 

Page 23 of 42 
BMT 206 
 
January 7, 2019 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Study Calendar 
 
Donor 
Chimerism 
Chemokine 
Receptor 
Profile 
Th1/Th2 
Phenotype 
Treg 
Cell 
Quantity 
Treg 
Cell 
Function 
Skin 
Biopsy 
Pathology 
Skin Biopsy 
T Cell 
Trafficking 
Derm 
Clinical 
Assessment 
Bone Marrow 
Biopsy 
CTL Assay 
Tumor Cell 
Banking 
Pre TSEBT 
 
X 
 
X 
 
X 
 
X 
X 
X 
Sezary only 
Pre TLI/ATG 
 
X 
 
X 
 
X 
First 5 pt 
X 
 
 
 
Pre Infusion 
 
X 
 
X 
 
 
 
 
 
 
 
 + 30 day 
X 
X 
X 
X 
First 5 pt 
 
 
X 
 
 
 
 + 60 day 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 + 90 day 
X 
X 
X 
X 
First 5 pt 
X 
First 5 pt 
X 
X 
X 
 
 + 180 day 
X 
X 
X 
X 
First 5 pt 
 
First 5 pt 
X 
X 
X 
 
 + 270 day 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 + 1 year 
X 
X 
X 
X 
First 5 pt 
 
First 5 pt 
X 
X 
X 
 
 + 2 year 
X 
 
 
 
 
 
 
X 
X 
 
 
Cell Product 
 
X 
X 
X 
 
 
 
 
 
 
 
Pre ECP 
 
X 
X 
X 
 
 
 
 
 
 
 
Post ECP 
 
X 
X 
X 
 
 
 
 
 
 
 
Disease 
Regression 
 
 
 
 
 
X 
 
X 
 
 
 
Disease 
Progression 
 
 
 
 
 
X 
 
X 
 
 
 
Sample 
 
Up to 5 
GGT 
 
 
 
5 mm 
punch 
5 mm punch 
 
Routine 
2 GTT for 
effector 
2 GTT 
Site 
HLA Lab 
HIMC 
CTF 
CTF 
CTF 
Path 
CTF 
Cut Lym 
Clinic 
 
HIMC 
HIMC 
Assay 
Chimerism:
CD3, CD19, 
CD56, 
CD15 
Skin: 
CCR4, 
CCR10, 
CLA;       
LN: CCR7 
Th1: IL-2, 
IFN γ;    
Th2: IL-4, 
IL-10 
FoxP3 
positive 
Inhibition 
of MLR 
Monitoring 
Residual 
Disease 
Lymphocyte 
Donor 
Chimerism, 
Chemokine 
receptor 
 
 
FAM-VAD 
Assay 
Use as 
Target Cell 
for CTL 

Page 24 of 42 
BMT 206 
 
January 7, 2019 
10.  
MEASUREMENT OF EFFECT 
 
The measurement of effect is determined by clinical response to non-myeloablative allogeneic 
HSCT. The clinical response will be assessed by a rigorous and multifactorial approach described 
before (41, appendix). This approach takes tumor burden in skin, lymph nodes and blood into 
consideration. To achieve this, patients will be evaluated at Cutaneous Lymphoma Clinic before 
transplant and at specified time points after transplant. 
 
10.1 
Anti-tumor Effect 
 
10.1.1 
Definitions 
Disease status will be evaluated right before non-myeloablative allogeneic transplants and  
at 3, 6, 9, 12, 18, 24 months after allogeneic transplant or up to 1st recurrence or 
progression. 
 
10.1.2 
Disease Parameters 
Measurable diseases include skin, lymph node, viscera and blood Sezary cells. 
 
10.1.3 
Methods for Evaluation of Measurable Disease 
Please refer to Appendix C. 
 
10.1.4 
Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
Please refer to appendix. 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
N/A 
 
10.1.4.3 
Evaluation of Best Overall Response 
Clinical response will be determined at different time points after allogeneic transplant. 
 
10.1.5 
Duration of Response 
Duration of overall response is time measurement between first compete response and the 
first recurrent documentation. 
 
10.1.6 
Progression-Free Survival (or other parameters) 
Event-free survival (EFS) is the time measurement between the day of allogeneic 
transplant and the first documented recurrence or death from any cause.  Overall survival 
(OS) is the time measurement between the day of allogeneic transplant and death from any 
cause. 
 
10.1.7 
Response Review 
No external review of clinical response is planned. 
 
10.2 
Other Response Parameters 
N/A 
 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 
Monitoring plan 
Research team will meet monthly to review the adverse events. Any severe adverse events will 
be reported to principal investigator immediately. The stopping rule is described below. 
 

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January 7, 2019 
11.2 
Stopping rules for the individual patient and for the study as a whole 
Individual patient:  
Patients who develop severe adverse reaction to the ATG infusion, such as serum sickness that 
result end-organ damage, will be removed from study. 
 
For the study as a whole: There is no interim analysis for efficacy (PFS), but the study may stop 
early for safety. The safety monitoring is by means of two rules, one for Grade II-IV acute GVHD 
and the other for 100 day mortality. The rules call for assessing observed counts after every 5 
patients and stopping as follows: 
 
For 100 day mortality 
 
after.pt            5    10    15    20    25    30    35    40 
stop.if.reach    2     3      3      4      5      5      6      7 
 
For Grade II-IV acute GVHD 
 
after.pt            5    10    15    20    25    30    35    40 
stop.if.reach    2     3      4      5      6      7      8      9 
 
For example, if there are 3 deaths in the first 15 patients, the study will stop at 15 patients or 
earlier, or if there are 3 Grade II-IV acute GVHD cases in the first 10 patients, the study will stop 
at 10 or earlier, and so on. The usual 'look ahead' principle will apply: as soon as it is known that 
a stopping boundary will surely be reached (such as 3 deaths in the first 9 patients) the study will 
stop. These rules guarantee stopping if the lower 80% one-sided confidence limit for the true rate 
exceeds 10% for 100 day mortality or 15% for Grade II-IV acute GVHD. 
 
11.3 
Data management  
All the clinical data from this study will be maintained by BMT data management team. 
 
11.4 
Confidentiality  
 
All patients undergoing hematopoietic cell transplantation at Stanford are assigned a SPN (Stanford 
Patient Number) and data is entered into a secure database.  Access to the database is limited to study 
personnel and password protected.  Research records are maintained in a secure office of the data 
management staff.   
 
12. STATISTICAL CONSIDERATIONS 
 
The primary goal of this study is to provide proof-of-concept evidence for the safety and efficacy of non-
myeloablative allogeneic transplant with TLI/ATG conditioning for patients with MF/SS as described 
above. Safety will be measured at the end of study by rates of GVHD, other measures of side effects, and 
overall survival (see above for safety monitoring methods). The primary efficacy endpoint is PFS at 180 
days. The historical control for safety is the acute GHVD and mortality rates of myeloablative allogeneic 
treatment. The rationale for this study is based on the expectation that the new non-myeloablative 
allogeneic transplant will achieve response rates (and subsequent disease control) that is comparable to 
myeloablative allogeneic transplant, but with a great reduction in GVHD and TRM.  
 
12.1 
Endpoints 
 
12.1.1 Primary endpoint 
The primary efficacy endpoint is PFS at 180 days (defined above). The safety endpoints 
include GVHD and other treatment related events, including mortality. 
 
12.1.2 Secondary endpoints 
We will report OS, EFS, cumulative incidence of cancer and treatment-related mortality. 

Page 26 of 42 
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January 7, 2019 
 
12.2 
Analysis Populations 
We will report outcomes on all patients who begin the preparative protocol (corresponding to 
the intent-to-treat principle) as the primary analysis, and also on those who actually receive 
transplant and those who successfully engraft (subset analyses). 
 
12.3 
Plan of Analysis 
 
12.3.1 Background and Demographic Characteristics 
Tabulate summary statistics with measures of variation. 
 
12.3.2 Evaluation of Efficacy 
Efficacy will be evaluated by calculating the Kaplan-Meier estimates of progression-free survival 
(PFS, i.e., probability of remaining alive and free of progression). We will also calculate the 
cumulative incidence estimate of the progression rate, using non-relapse mortality as a 
competing risk. 
 
12.3.3 Methods for handling missing data and non-adherence to protocol 
We do not expect to have missing data on key outcome variables, and non-adherence to 
protocol presumably is limited to failure to complete the entire process of preparation and 
transplant; this will be handled by subgroup analyses as described. 
 
12.3.4 Evaluation of Conduct of trial (including accrual rates, data quality) 
Accrual and progress of patients through the regimen will be monitored by the PI, and data 
quality will be monitored by the BMT data coordinators. 
 
12.3.5 Pharmacokinetics/Pharmacodynamics 
N/A 
 
12.3.6 Methods for Correlative Studies 
Analyses of the correlation of response and other outcomes with measures of chimerism and 
other markers will be done with standard methods, including fixed and time-varying Proportional 
Hazards models and graphical methods. Given the small sample size, we do not expect to have 
power to do more than explore such correlations. 
 
12.4 
Sample Size 
 
12.4.1 Accrual estimates 
12-15 patients per year over 3 years for a maximum of 40 patients, subject to stopping rules 
above. 
 
12.4.2 Sample size justification 
The study sample size is based on expected accrual of 12-15 patients per year, up to a 
maximum of 40 patients over 3 years, with at least 1 year of follow-up in all patients. With 180 
day PFS measure and assuming a target rate of 75%, the 95% confidence interval half-width 
(the precision estimate) will be 15% (e.g., from 58% to 88% if we observe 27/36 PFS). If the 
PFS is substantially closer to 50%, the results will not be considered encouraging, while if the 
PFS is even better than 75% the half-width is never greater than 17%. 
 
12.4.3 Criteria for future studies 
See above. 
 
12.5 
Interim analyses 
The trial may also stop early for safety at any time, based on unexpected high rates of acute 
GVHD or mortality. Specifically, the stopping rule (every 5 patients) will guarantee stopping if 

Page 27 of 42 
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January 7, 2019 
the lower one-sided confidence limit for the rate exceeds 10% for 100 day mortality or 15% for 
acute GVHD. 
 
 

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January 7, 2019 
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APPENDICIES  
 
A. Participant Eligibility Checklist  
B. AE and SAE reporting Guidelines 
C. Response Criteria in Mycosis Fungoides and Sezary Syndrome 
 
 
 

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January 7, 2019 
Appendix A 
I. Participant Eligibility Checklist  
 
Protocol Title: 
A Phase II Study of Non-myeloablative Allogeneic 
Transplantation Using Total Lymphoid Irradiation (TLI) 
and Antithymocyte Globulin (ATG) In Patients with 
Cutaneous T Cell Lymphoma 
Protocol Number: 
BMT 206 / IRB # 16213 
Principal Investigator: 
Dr. Wen-Kai Weng, MD PhD 
Study Coordinator: 
 
 
II. Subject Information: 
Subject Name/MRN: 
 
Gender:    
 Male     
 Female 
 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
 
IV. Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation 
1. Stage IIB-IV mycosis fungoides or 
Sezary syndrome, who have failed at least 
1 standard systemic therapy or are not 
candidates for standard therapy. 
 
 
 
2. Pathology reviewed and the diagnosis 
confirmed at Stanford University Medical 
Center. 
 
 
      
3. Age > 18 years and  < 75 years.  
 
 
      
4. Karnofsky Performance Status > 70%. 
 
 
      
5. Corrected DLCO > 40%.  
 
 
      
6. Left ventricle ejection fraction (LVEF)  
> 30%. 
 
 
      
7. Total bilirubin < 2 mg/dL unless 
hemolysis or Gilbert’s disease. 
 
 
 
8. ALT and AST must be < 3x ULN.  
 
 
 
9. If AST and ALT are > 3 < 5 x ULN,  
patient may be eligible if: 
1) Liver biopsy performed within 60 days    
of HCT excludes active cirrhosis grade 
greater than 2/4 and bridging fibrosis. 
2)   No clinically evident ascites. 
 3)   Patient with Hepatitis B or C are  
       excluded if AST or ALT > 3 x UL. 
 
 
 
10. Estimated creatinine clearance  
>  50 ml/min. 
 
 
 

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January 7, 2019 
11. Have a related or unrelated HLA-
identical donor or one antigen/allele 
mismatched in HLA-A, B, C or DRB1. 
 
 
 
12. Signed Informed Consent. 
 
 
 
13. Patients with prior malignancies 
diagnosed > 5 years ago without 
evidence of disease are eligible. 
 
 
      
14. Patients with a prior malignancy treated  
< 5 years ago but have a life  
expectancy of > 5 years for that 
malignancy are eligible. 
 
 
 
 
 
 
 
Exclusion Criteria 
(From IRB approved protocol)         
Yes 
No 
Supporting Documentation 
1. Uncontrolled active infection. 
 
 
 
2. Uncontrolled congestive heart failure or 
angina. 
 
 
      
3. Pregnancy or nursing patients will be 
excluded from the study.  
 
 
      
4. Those who are HIV-positive will be 
excluded from the study due to high risk 
of lethal infection after hematopoietic 
cell transplantation.   
 
 
      
 
 
IV.  Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [ 
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 

Page 34 of 42 
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January 7, 2019 
Appendix B 
AE and SAE Reporting Guidelines 
 
ADVERSE EVENT MONITORING AND REPORTING 
 
Definitions: 
 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product, medical treatment or procedure and which does not necessarily have 
to have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), a symptom, or 
disease temporally associated with the use of a medicinal product, medical treatment or 
procedure whether or not considered related to medicinal product or treatment. 
 
Life Threatening Adverse Event 
Any adverse event that places the subject, in the view of the investigator, at immediate risk of 
death from the reaction.   
 
Unexpected Adverse Event 
An adverse event, the nature or severity of which is not consistent with the applicable product 
information (Investigator’s Brochure, product insert).  For studies that do not involve 
investigational products or devices, an unexpected adverse event is an adverse event that is not 
described in the transplant medical literature or consent form. 
 
Serious Adverse Event (SAE) 
Any adverse event occurring that results in any of the following outcomes: death, a life 
threatening adverse event, a persistent or significant disability/incapacity, a congenital anomaly, 
requires intervention to prevent permanent impairment or damage.  Unless the Principal 
Investigator is using an investigational agent, s/he is not bound by the definition in Title 22 CFR 
312.32.  The PI is bound by Title 45 CFR 46, Subpart A which is the “Common Rule” for the 
Protection of Human Subjects, therefore, the Stanford IRB definition applies (report 
“unanticipated problems” involving risks to study participants or others). 
 
Distinction between Serious and Severe 
The term severe is used to describe the intensity (severity) of a specific event, for example mild, 
moderate or severe.  The event itself however, may be of relatively minor medical significance, 
for example a severe headache.  This is not the same as serious, which is based on the 
patient/event outcome and is usually associated with events that pose a threat to the patient’s 
life or functioning.  Seriousness, not severity, serves as a guide for defining regulatory 
obligations. 
 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a number 
of life threatening malignant and non-malignant disorders.  Individuals presenting for HCT 
generally have exhausted other avenues of therapy that will result in any lasting benefit.  The 
treatment related mortality (TRM) of autologous transplantation is approximately 5%.  The TRM 
of a sibling myeloablative allogeneic transplant is approximately 20% and the TRM for an 
unrelated myeloablative allogeneic transplant ranges from 20-50%.  In the setting of a non-
myeloabative allogeneic transplant from a sibling donor the TRM is approximately 10% and 
ranges from 20-50% for unrelated donors.   
 
As an aggressive therapy HCT is associated with a large number of AEs and SAEs.  The 
toxicities associated with HCT are related to the following: 1) the underlying disease, 2) therapy 
antecedent to HCT, 3) the health status of the transplant recipient including co-exiting 

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January 7, 2019 
conditions, 4) the high dose preparative regimen employed in preparation for transplant, 5) 
therapies directed at reducing transplant related complications (e.g. immunosuppressants for 
the prevention of GVHD), and 6) the treatment of complications of HCT.  
 
The use of toxicity grading scales such as the NCI CTC is a standard in the medical community 
for the reporting of AEs and SAEs in the investigation of new drugs or devices.  The use of this 
type of scale is less helpful in the evaluation of AEs and SAEs associated with a treatment, such 
as HCT.  In an effort to report to regulatory agencies the toxicities that are relevant and 
meaningful for the evaluation of risks and benefits to potential HCT recipients the following 
guidelines will serve to determine what is reported as AEs and SAEs. 
 
 
The following SAEs require reporting to the CCTO.  If the event is unexpected, it will also 
require reporting to the IRB: 
 
1) Deaths  
All deaths  
• 
while the patient is receiving treatment on a protocol  
• 
up to 60 days (autologous) or 90 days (allogeneic) after last dose of protocol treatment 
• 
or any death that occurs more than 60 days (autologous) or 90 days (allogeneic) after 
protocol treatment has ended that is felt to be treatment related. 
 
This includes deaths from the common and expected grade 4 toxicities noted below.  Deaths 
that occur outside of Stanford will be reported whenever possible.  It must be noted that 
obtaining detailed information on the cause and circumstances of a death occurring at another 
institution can be difficult.  This excludes deaths related to relapse of underlying disease, which 
will be reported at the time of protocol renewal.   
 
2) All serious and unexpected toxicities.   
Defined as those toxicities not identified in the transplant literature, product inserts or in the 
consent form. 
 
The following will generally not be reported as AEs or SAEs: 
 
1) Hospitalizations  
Approximately 70% of autologous transplants are readmitted to the hospital for management of 
HCT related events.  The most common indication for readmission of an autologous transplant 
recipient is neutropenic fever. Approximately 50% of allogeneic transplant recipients will be 
readmitted to the hospital.  The most common indications for readmission of an allogeneic HCT 
recipient are fever, failure to maintain nutritional status and graft versus host disease. 
 
2) Relapse of disease 
Relapse unfortunately remains a significant problem following both autologous and allogeneic 
transplantation.  The risk of relapse is influenced by both patient and disease variables.  In 
general, the risk of relapse following autologous transplant is approximately 50%.  The risk of 
relapse following allogeneic transplant is extremely dependent on the disease being treated but 
ranges from 10% (for patients with severe aplastic anemia) to 80% (for patients with refractory 
acute leukemia). 
 
3) Common and expected grade 4 toxicities of HCT that are well described in the transplant 
literature, the product inserts or stated in the consent form and do not result in death.   
This includes but is not limited to neutropenia, thrombocytopenia, anemia, thrombotic 
microangiopathy, bleeding requiring transfusions, edema, hypertension, hypotension, gastritis, 
mucositis, nausea, vomiting, diarrhea, hematuria, central venous catheter infections, febrile 

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January 7, 2019 
episodes, sepsis, mental status changes, infections, insomnia, mood alterations, seizures, 
tremor, pain, hypoxia, pleural effusion, pneumonitis, incontinence, infertility, laboratory 
abnormalities, veno-occlusive disease, graft failure, cardiac arrhythmias and graft versus host 
disease.  
 
4) Secondary Maligancies. 
The occurrence of secondary malignancies and associated mortality is a known risk of cancer 
therapies.  The occurrence of secondary malignancies will be reported at the time of the 
protocol annual review.  

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January 7, 2019 
Appendix C 
Response criteria for Mycosis fungoides and Sezary Syndrome 
 
Clinical Endpoints and Response Criteria in Mycosis Fungoides and Sezary Syndrome:  a Joint 
Consensus Statement of the International Society for Cutaneous Lymphomas (ISCL), the United 
States Consortium for Cutaneous Lymphomas (USCCL) and the Cutaneous Lymphoma Task 
Force of the European Organization for Research and Treatment of Cancer (EORTC) 
 
The global response criteria uses scoring system for the following four organ involvement systems: skin, 
lymph node, blood and viscera.  Based on the response score of individual systems, a global response 
score will be given for individual patient. The skin disease burden will be measured using the modified 
severity weighted assessment tool (mSWAT); the skin responses are recorded and assessed as changes of 
the mSWAT score.   
 
Response in Skin* 
Complete response (CR) 
100% clearance of skin lesions#   
Partial response (PR) 
50-99% clearance of skin disease from baseline without new tumors (T3) in 
patients with T1, T2 or T4 only skin disease 
Stable disease (SD) 
<25% increase to <50% clearance in skin disease from baseline without new 
tumors (T3) in patients with T1, T2 or T4 only skin disease 
Progressive disease (PD)♦ 
(1) >25% increase in skin disease from baseline or 
(2) New tumors (T3) in patients with T1, T2 or T4 only skin disease or 
(3) Loss of response: in those with CR or PR, increase of skin score of greater than 
the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with CR  
*Based on mSWAT score. 
# A biopsy of normal appearing skin is unnecessary to assign a CR.  However, a skin biopsy should be 
performed of a representative area of the skin if there is any question of residual disease where otherwise 
a CR would exist.  If histologic features are suspicious or suggestive of MF/SS (see histologic criteria for 
early MF7), the response should be considered a PR only. 
♦ Whichever criterion occurs first. 
 
Response in Lymph Nodes* 
CR 
All lymph nodes are now <1.5 cm in greatest transverse (long axis) diameter by method used to assess 
lymph nodes at baseline or biopsy negative for lymphoma.  In addition, lymph nodes that were N3 
classification and <1.5 cm in long axis diameter at baseline, must now be <1 cm in diameter of the 
short axis or biopsy negative for lymphoma.  
PR 
(1) Cumulative reduction >50% of the SPD sum of the maximum linear dimension (major axis) x 
longest perpendicular dimension (minor axis) of each abnormal lymph node at baseline and no new 
lymph node >1.5 cm or >1.0 cm in the short axis if long axis 1-1.5cm diameter.  
SD 
Fails to attain the criteria for CR, PR and PD 
PD ♦ 
(1) >50% increase in SPD from baseline of lymph nodes or 
(2) Any new node >1.5 cm in greatest transverse diameter or >1 cm in short axis diameter if 1-1.5 cm 
in long axis that is proven to be N3 histologically or  
(3) Loss of response:  in those with PR or CR, >50% increase from nadir in SPD of lymph nodes  
Relapse Any new lymph node >1.5cm in long axis diameter in those with CR  
* Peripheral and central lymph nodes. 
♦Whichever criterion occurs first. 
 

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January 7, 2019 
      Response in Blood* 
CR** 
B0 
PR# 
>50% decrease in quantitative measurements of blood tumor burden from baseline in those 
with high tumor burden at baseline (B2) 
SD 
Fails to attain criteria for CR, PR or PD 
PD♦ 
(1) B0 to B2 or  
(2) >50% increase from baseline and at least 5,000 neoplastic cells/μL42 or 
(3) Loss of response:  
1. in those with CR who were B1 or B2 at baseline, increase in neoplastic 
>1000 neoplastic cells/ μL or  
2. in those with PR who were originally B2 at baseline, >50% increase from 
nadir and at least 5,000 neoplastic cells/μL  
Relapse 
Increase of neoplastic blood lymphocytes to > B1 in those with CR 
 
* As determined by absolute numbers of neoplastic cells/uL. 
** If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative 
of lymphomatous involvement, then to confirm a global CR where blood assessment now meets 
criteria for B0, a repeat bone marrow biopsy must show no residual disease or the response should be 
considered a PR only.  
# There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic 
cells that define B1 is not considered significant and should not affect determination of global 
objective response. 
♦ Whichever occurs first. 
 
Response in Viscera 
CR 
Liver or spleen or any organ considered involved at baseline should not be enlarged on physical 
exam and should be considered normal by imaging. No nodules should be present on imaging of 
liver or spleen. Any post treatment mass must be determined to be biopsy to be negative for 
lymphoma. 
PR 
>50% regression in any splenic or liver nodules, or in measureable disease (SPD) in any organs 
abnormal at baseline.  No increase in size of liver or spleen and no new sites of involvement.   
SD 
Fails to attain the criteria for CR, PR or PD 
PD♦ 
(1) >50% increase in size (SPD) of any organs involved at baseline or 
(2) New organ involvement or 
(3) Loss of response:  in those with PR or CR, >50% increase from nadir in the size (SPD) of any 
previous organ involvement  
Relapse New organ involvement in those with CR 
 
*Use of FDG-PET scan in this instance is compatible with other NHLs but there is a paucity of data 
in clinical trials of MF/SS to document its utility. 
♦Whichever criterion occurs first. 
 
 
 
 
 
 
Global Response Score 

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BMT 206 
 
January 7, 2019 
Global 
Score* 
Definition 
Skin  
Nodes 
Blood 
Viscera 
CR 
Complete 
disappearance of all 
clinical evidence of 
disease 
CR 
All categories have CR/NI 
 
PR 
Regression of 
measurable disease  
CR 
All categories do not have a CR/NI and no category has a PD  
PR 
No category has a PD and if any other category involved at 
baseline, at least one has a CR or PR  
SD 
Failure to attain CR, 
PR or PD 
representative of all 
disease 
PR 
No category has a PD and if any other category involved at 
baseline, no CR or PR in any 
SD 
CR/NI, PR, SD in any category and no category has a PD  
PD 
Progressive disease 
PD in any category 
 
Relapse 
Recurrence disease 
in prior CR 
Relapse in any category  
 
NI = non-involved 
*It is recommended that not only the proportion of patients who achieve a response or an unfavorable 
outcome be calculated but a life table account for the length of the interval during which each patient 
is under observation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record of Changes 
 
Date 
Protocol Changes 
IRB 

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BMT 206 
 
January 7, 2019 
Approval 
Date 
March 11, 
2009 
Original protocol 
April 21, 2009 
April 29, 
2009 
Request of the SRC for clarifications in the statistical section 
May 19, 2009 
June 29, 
2009 
Changed eligibility criteria related to prior malignancies. 
Clarified collection goals and processing. Changed CSA taper to begin when chimerism 
studies obtained.  Added timeframes for chimerism evaluations.  Added tumor assessments 
to study calendar.  Updated study calendar.  Added research sample calendar.  Changed 
fasting before ECP to a low fat diet. 
July 14, 2009 
March 30, 
2010 
Decreased TLI from 1200 cGy to 800 cGY.  Length of treatment and dose of TSEBT will be 
determined by the radiation oncologist. 
April 20, 2010 
October 
27, 2010 
Clarified stopping rule for acute GVHD to Grade II-IV acute GVHD. Clarified minimum 
number of research GGT. 
November 
09, 2010 
October 5, 
2011 
Modified Study calendar for BM Bx 
October 18, 
2011 
February 
24, 2012 
Modified verbiage  
April 17, 2012 
May 31, 
2012 
Updated Investigators and  Appendix D (response criteria ) 
June 19, 
2102 
February 
28, 2013 
Modified eligibility criteria 3.1.8 ALT and AST must be < 3X ULN previously </= to 3X 
Normal. Total 
bilirubin </= 2 mg/dL previously <3 unless hemolysis or Gilbert's disease. 
If AST and ALT are <5 x ULN, patient may be eligible if: 
1 Liver biopsy performed within 60 days of HCT excludes active cirrhosis gradd greater 
than 2/4 and bridging 
fibrosis 
2 No clinically evident ascites 
3 Patientwith Hepatitis B or C are excluded if AST or ALT > 3 x ULN 
Deleted BM STR subset on section 9 of the study calendar. 
Deleted bone marrow biopsy on Day 90 for chimerism study in section 8.1.1.1 
March 19, 
2013 
March 7, 
2014 
Changed from cyclosporine to tacrolimus 
Section 3 PARTCIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria. Modified section 3.1.4 from Age > 18 years and < 75 years. to Age 
>18 
Section 4.1.4 Immunosuppression for GVHD prophylaxis. 
Modified Immunosuppresant from Cycloporine to Tacrolimus 
Section 4.3 Duration of Therapy: 
Day -3;Modified from Cyclosporine to Tacrolimus 
Section 7.ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 Potential Adverse Events: 
Human Toxicology section: from cyclosporine to tacrolimus 
Pharmaceutical Data: Formulation: from cyclosporine to tacrolimus 
March 18, 
2014 
June 13, 
2014 
Consent form: 
Modified the footer to add patient name and MRN  Medical Record Number 
Protocol body 
Updated Schema Page 6 to reflect: "Length of treatment and dose of TSEBT will be 
determined by the 
radiation oncologist". Has been approved in April 10,2010 but was not change in the 
protocol body. 
Moved the "Record of Revision" from page 38 to page 42 where all the list of revisions are 
located. 
Updated the list of revisions. 
June 17, 
2014 
November 
18, 2014 
Added Dr. Lori Muffly as listed personnel 
Protocol body: 
Modified  section 4.1.4 Immunosuppression for GVHD prophylaxis in section n and o: 
Tacrolimus dose from 0.12 to 0.05 mg/kg  
4.1.4 
Immunosuppression for GVHD prophylaxis 
June 21, 
2016  

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January 7, 2019 
n) Immunosuppression will include tacrolimus (Prografand mycophenolate mofetil (MMF).  
Tacrolimus will be administered orally at a dose of 0.05 mg/kg/day bid from day -3 through 
day +56.   
o) Tacrolimus (Prograf): Tacrolimus is given at 0.05 mg/kg p.o. b.i.d (9 a.m and 9 p.m.) from 
day –3 until after the day +56 chimerism studies have been obtained. 
Updated the verbiage to reflect the change previously submitted on March 7,2014 
from cyclosporine to Tacrolimus on section 4.1.1 section n and o: 
n) Trough levels will be monitored to keep the Tacrolimus level in the range of 8-10 ng/ml.  
MMF dose adjustments will be made if there is evidence of MMF-related GI toxicity or 
myelosuppression. 
o) Tacrolimus should be administered intravenously by continuous infusion at 3 mg/kg over 
20 hours 
February 
17, 2017  
Protocol edits 
Page 1 – adjusted version # in footer  
Page 1-  Added BMT # to protocol title  
Page 1 -  formatting- added spaces after Dr. Meyer and Dr. Rezvani names, added date to 
footer  
Page 1 - Removed italics from PIs name to make consistent with rest of document  
Page 2 - Adjusted alignment to match page 2  
Page 2 – updated study personnel to CJG as study coordinator, added revision #12 
Page 2 - Added missing space between February 6,2014  
Page 3- corrected page #s so reflected actual page #s in document  
Page 3-4 – added spaces after section numbers for formatting   
Page 5 – adjusted font to be consistent  
Page 5 - Added missing letter a to “GVHD will be reported as a percentage”  
Page 5 – removed bold lettering from subject titles  
Page 5 - Changed Non-Myeloablative hypothesis section to lowercase Non-myeloablative 
to match how it is lowercase in protocol title  
Page 6 – added missing space between Day-2  
Page 6 - Added missing space to Day-7  
Page 6 – added spaces between days for clarification, added border formatting to schema 
table  
Page 6 - Removed space to cGy x2 to be consistent with rest of schema  
Page 8  - removed dash between T-cell to be consistent with how written in protocol title  
Page 8 - Made arise plural so now reads “MF is a mature T cell lymphoma that arises 
primarily”  
Page 9 – added missing a to “is effective as a single agent”  
Page 9 – correct word “withour” to “without” 
Page 11 – added dash to non-myeloablative to reflect how it is written in protocol title  
Page 11 – changed “a effective” to “an effective,” bullet formatting unbolded, added missing 
word is to sentence “compromised skin is frequently present”  
Page 12 – changed year to years  
Page 12- added missing word “with” so now reads “The patient population enrolled in this 
clinical trial will be those with MF/SS who”  
Page 13- changed since to as  
Page 14 – added missing punctuation  
Page 15 - Added missing comma after “Since TLI can cause nausea, premedication” 
Page 15 - Added missing parenthesis in (ECP)  
Page 16 – removed space between – 5 so matches schema  
Page 16- Added missing period after day +40 
 
Page 16 – made font consistent 
Page 17- add windows to ECP treatments  (+/- 3 days)  
Page 17 – removed duplicate comma  
Page 18 – made footnote formatting consistent with rest of document, made font consistent   
Page 19 – corrected spacing, added punctuation  
Page 20 – correct on-fifth to one-fifth, added missing period  
Page 21 – spacing  
Page 21- changed name of Stanford Therapeutics and Transplantation (SCTT) Laboratory 
to new name of Stanford Cellular Therapy Facility (CTF) 
Page 22 – removed extraneous chart  
 

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January 7, 2019 
Page 34- made appendix B heading bold to match Appendix A 
Page 23 – adjusted table settings of Correlative Study Calendar so all fits on one page  
Page 24 – added missing word “to”  
Page 25 – added missing word “the,” changed “see below” to “see above,” removed 
unnecessary italics  
Page 27- added missing period  
Page 29 – spacing  
Page 34 – changed “patient or subject” to subject to be consistent with above paragraph 
Page 35 – added missing word be to “disease, which will be reported”  
Page 35 – adjusted spacing  
Page 36 – removed duplicate summary of changes log  
Page 37 - Adjusted spacing in Adverse Event Reporting, added missing period after 
lymphoma 
Page 41 – corrected spelling of revisions to revisions  
Page 42 – added above changes to summary of changes log, added last IRB approval date 
to Summary of Changes Log, adjusted spacing of table 
 
Informed Consent edits: 
Entire document- Added hyphen to Dr. Wen-Kai’s name  
Page 1- Added word have to “you were selected as a possible participant because you 
have a T cell”  
Page 8 – added comma after “If your donor is a sibling,”  
Page 9 – added missing word start to “cells will not start growing”  
Page 11- changed “Web site” to “website”  
Page 15 – tabbed final bullet point so in proper alignment with rest of experimental subjects 
bill of rights  
 
Eligibility Checklist edits 
Added period after UL in item #10  
Added date consent signed to footer  
Adjusted spacing in Exclusion criteria #1 from center to left alignment  
 
Donor Eligibility Checklist  
Changed Donor Screening criteria to CCTO eligibility checklist format  
 
January 7, 
2019  
Protocol edits