Conditions: Post-Transplant Lymphoproliferative Disorder Recurrent Adult Diffuse Large Cell Lymphoma Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Burkitt Lymphoma Refractory B-Cell Non-Hodgkin Lymphoma Refractory Burkitt Lymphoma Refractory Diffuse Large B-Cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects and how well high-dose yttrium-90 (Y-90)-ibritumomab tiuxetan (anti-cluster of differentiation \[CD\]20) followed by fludarabine phosphate, low-dose total body irradiation (TBI), and donor peripheral blood stem cell transplant (PBSCT) work in treating patients with aggressive B-cell lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Radiolabeled monoclonal antibodies, such as Y-90-ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them with less effect on normal cells. Giving chemotherapy, such as fludarabine phosphate, and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. However, high-dose radiolabeled antibodies also destroy healthy blood cells in the patient's body. When healthy stem cells from a donor are infused into the patient (stem cell transplant), they may help the patient's body replace these blood cells. Giving high-dose Y-90-ibritumomab tiuxetan followed by fludarabine phosphate, TBI, and donor PBSCT may be an effective treatment for patients with B-cell lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety and efficacy of 1.5 mCi/kg (max 120 mCi) 90Y-Ibritumomab tiuxetan (yttrium Y 90 ibritumomab tiuxetan) (anti-CD20) combined with fludarabine (fludarabine phosphate) (30 mg/m\^2 x 3) and 2 gray (Gy) total body irradiation followed by human leukocyte antigens (HLA) matched allogeneic hematopoietic transplantation for patients with relapsed or refractory aggressive B-cell lymphoma.

OUTLINE:

Beginning 24-48 hours prior to therapy infusion, patients receive rituximab intravenously (IV) over 4-6 hours and then receive a therapy-dose of high-dose yttrium Y 90 ibritumomab tiuxetan IV over 30 minutes on day -14 prior to transplant. Patients also receive fludarabine phosphate IV on days -4 to -2 and undergo TBI followed by allogeneic PBSCT on day 0. Patients also receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56 with taper to day 180 (related donor) or -3 to 100 with taper over 11 weeks (unrelated donor) and mycophenolate mofetil PO BID on days 0-27 (related donor) or PO thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donor).

After completion of study treatment and assessments through \~day 100 following transplant, patients are followed up at 1, 3, 6, and 12 months and then annually up to 2 years thereafter.

Arms:
arm 1: Beginning 24-48 hours prior to therapy infusion, patients receive rituximab IV over 4-6 hours and then receive a therapy-dose of high-dose yttrium Y 90 ibritumomab tiuxetan IV over 30 minutes on day -14 prior to transplant. Patients also receive fludarabine phosphate IV on days -4 to -2 and undergo TBI followed by allogeneic PBSCT on day 0. Patients also receive cyclosporine PO BID on days -3 to 56 with taper to day 180 (related donor) or -3 to 100 with taper over 11 weeks (unrelated donor) and mycophenolate mofetil PO BID on days 0-27 (related donor) or PO TID on days 0-40 with taper to day 96 (unrelated donor).

Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Cyclosporine intervention 3: Fludarabine Phosphate intervention 4: Indium In-111 Ibritumomab Tiuxetan intervention 5: Mycophenolate Mofetil intervention 6: Pharmacological Study intervention 7: Rituximab intervention 8: Total-Body Irradiation intervention 9: Yttrium Y-90 Ibritumomab Tiuxetan intervention 10: Fludarabine
Intervention descriptions: intervention 1: Undergo allogeneic PBSCT (infusion of donor stem cells via central catheter) intervention 2: Given PO intervention 3: Given IV intervention 4: Given IV intervention 5: Given PO intervention 6: Correlative studies intervention 7: Given IV prior to yttrium Y 90 ibritumomab tiuxetan intervention 8: Undergo TBI intervention 9: Given IV intervention 10: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2398.00 
Page 1 of 34 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
  Current version:  08/27/2019  
Previous Version:  06/26/2019  
Title of Protocol:  A phase II trial of high-dose 90Y-Ibritumomab tiuxetan (anti-
CD20) followed by fludarabine and low-dose total body irradiation and HLA-
matched allogeneic hematopoietic transplantation for patients with relapsed or 
refractory aggressive B-cell lymphoma 
Investigator 
Professional Title 
Phone 
Ajay Gopal, MD 
Member, FHCRC; Professor of Medicine, UW 
206-606-2037
Ryan Cassaday, MD 
Assistant Member FHCRC;  
Assistant Professor of Medicine, UW 
206-606-1202
Brenda Sandmaier, MD 
Member FHCRC; Professor UW 
206-667-4961
Damian Green, MD 
Assistant Member, FHCRC; Associate Professor 
of Medicine, UW 
206-667-5398
Johnnie J. Orozco, MD, PhD Assistant Member, FHCRC 
206-667-4102
Manuela Matesan, MD, PhD Assistant Professor, Nuclear Medicine, UW 
206-598-7200
Statistician:     TBN 
Research RN:    Robyn Haaf, RN 
(206) 667-5974 
Emergency Phone: 206-598-8902, 206-598-6190; FAX 206-598-4034 
IRO REC'D APR 16 2020
FHCRC IRB Approval  
MAY 07 2020 
Document Released Date


Protocol 2398.00 
Page 2 of 34 
TABLE OF CONTENTS 
 
1 
INTRODUCTION 
 
2 
BACKGROUND 
 
3 
OBJECTIVE 
 
4 
ENDPOINTS 
A. 
Primary Endpoint 
B. 
Secondary Endpoints 
 
5 
PATIENT SELECTION 
A. 
Inclusions 
B. 
Exclusions 
 
6 
DONOR SELECTION 
 
7 
INFORMED CONSENT 
 
8 
PROTOCOL REGISTRATION  
 
9 
PLAN OF TREATMENT  
A. 
Outline of Treatment Plan (Table 4) 
B. 
Treatment Regimen Overview 
C. 
Rituximab 
E. 
90Y-ibritumomab tiuxetan 
F. 
Fludarabine 
G. 
Total Body Irradiation (TBI) 
H. 
Collection of donor stem cells 
I. 
Hematopoietic stem cell transplant 
J. 
Immunosuppression 
K. 
ABO incompatibility 
L. 
Post-transplant growth factors 
M. 
Infection prophylaxis 
N. 
Post-transplant donor lymphocyte infusion (DLI) 
O. 
Criteria for removal of individual patients 
 
10 
PATIENT AND DONOR EVALUATIONS 
A. 
Patient pretransplant baseline evaluation 
B. 
Patient post-transplant evaluations 
C. 
GVHD evaluation 
D. 
Evaluation of MRD and chimerism 
E. 
Donor evaluations 
 
11 
DEFINITIONS 
 
12 
TOXICITIES AND COMPLICATIONS 
A. 
Rituximab 
B. 
90Y-ibritumomab tiuxetan 
C. 
Fludarabine 


Protocol 2398.00 
Page 3 of 34 
D. 
Total body irradiation (TBI) 
E. 
Stem cell transplant 
F. 
Cyclosporine (CSP) 
G. 
Mycophenolate mofetil (MMF) 
 
 
13 
GUIDELINES FOR SERIOUS ADVERSE EVENT REPORTING 
A. 
Definitions 
B. 
Monitoring and Recording AEs 
C. 
Reporting AEs 
D. 
SAEs Associated with Hematopoietic Stem Cell Transplant 
 
14 
DATA AND SAFETY MONITORING PLAN 
 
15 
RECORDS 
 
16 
STATISTICAL CONSIDERATIONS 
 
17 
TERMINATION OF THE STUDY 
 
18 
ETHNIC AND GENDER DISTRIBUTION CHART 
 
19 
REFERENCES 
 
 
 
APPENDICES 
 
Appendix A: 
SWOG/ECOG PERFORMANCE STATUS 
 
Appendix B: 
ACUTE GVHD ASSESSMENT 
 
Appendix C: 
CHRONIC GVHD GRADING 
 


Protocol 2398.00 
Page 4 of 34 
1. 
Introduction 
Nearly 60,000 cases of non-Hodgkin’s lymphoma (NHL) are diagnosed each year in the USA and 
two-thirds of these die of this disease (SEER data). At the time of relapse, only a minority of 
affected patients with chemotherapy-responsive disease achieve long-term disease-free survival 
with high-dose therapy and autologous stem cell transplantation (ASCT)1-4.  Relapses in the 
setting of ASCT likely occur due to the inability of the treatment regimen to eradicate lymphoma 
from the patient and/or the re-infusion of a tumor-contaminated stem cell product. In addition, 
high-dose therapy and ASCT is of limited utility in the setting of refractory disease, relapse 
following autologous transplantation or relapse in the setting of a poor stem cell reserve5. There 
are few potentially curative options for such patients. Likewise, the utility of standard allogeneic 
transplantation and non-ablative allogeneic transplantation is limited in these settings by their 
excessive toxicity and limited ability to eradicate rapidly progressive disease, respectively. This 
study will address this clinical challenge by evaluating a novel method to both limit toxicity and 
maximize direct anti-lymphoma effects in patients with relapsed B-cell NHL. 
 
2. 
Background 
Reduced intensity allogeneic conditioning regimens  
One approach that has been studied in patients with relapsed B-cell NHL has been the use of 
high-dose therapy followed by allogeneic hematopoietic stem cell grafting, an approach which 
affords both an uncontaminated stem cell source and a potential graft versus lymphoma (GVL) 
effect.  Allogeneic transplant trials for lymphoma have documented much lower relapse rates than 
comparable autologous transplantation studies6. Despite the potential advantages of allogeneic 
transplantation, this approach is infrequently employed in patients with relapsed lymphomas 
because of the high rate of treatment-related mortality (TRM) stemming from the toxicity of 
myeloablative conditioning regimens, and from graft versus host disease (GHVD) and infections. 
6,7  
 
A strategy has recently been developed to mitigate the toxicity of high-dose therapy prior to 
allogeneic transplantation by employing reduced intensity conditioning regimens that provide 
sufficient immunosuppression to facilitate allogeneic engraftment while simultaneously limiting 
TRM 8,9-11.  This approach, relying on the immunologic GVL effect to eradicate disease, has 
proven to both reduce TRM and induce remissions in pilot studies12. Early observations, however, 
have suggested that patients with rapidly progressive or excessively bulky disease rarely benefit 
from this approach, presumably because the rate of the disease progression outpaces the GVL 
effect 11,13,14. These findings support the need for identifying an approach to safely cytoreduce 
bulky tumors or control rapidly progressive disease in order to allow sufficient time for the allograft 
to mediate a GVL effect and maintain long-term remissions.  
 
Radioimmunotherapy for NHL 
Over the last 10 years radioimmunotherapy (RIT) has been developed as a novel, reduced-toxicity 
approach for the treatment of B-cell NHL. RIT, based on the exquisite radiosensitivity of NHL, 
involves delivering targeted therapy directly to tumor sites with the use of monoclonal antibodies. 
Studies have demonstrated that non-myeloablative doses of anti-CD20 RIT in patients with 
relapsed lymphomas can be safely delivered using either 131I or 90Y as the therapeutic 
radionuclide15-18. This “low-dose” RIT approach with agents such as Bexxar® (131I-tositumomab) 
or Zevalin® (90Y-ibritumomab tiuxetan) has resulted in response rates of 40-70% with moderate 
hematologic and minimal non-hematologic toxicity in patients with indolent NHL (Figures 1 and 
2). The highest complete response rates (>80%) and longest response durations in all histologic 
subtypes of B-cell NHL, however, were seen with escalated doses of radioisotope when 


Protocol 2398.00 
Page 5 of 34 
hematopoietic progenitor support is used to offset the hematopoietic toxicity 19. Studies performed 
by our group demonstrated that targeted radiation doses of 27 Gy to normal organs when given 
alone and doses of 25 Gy to normal organs along with high doses of chemotherapy were well 
tolerated in these patients with relapsed lymphomas19,20. The same patients that received these 
optimal doses (27 Gy) of RIT had surprisingly low rates (<10%) of grade 3-4 non-hematological 
toxicity. Other groups using 90Y-ibritumomab tiuxetan as a single agent have safely delivered 
doses up to 18.56 Gy to liver without non-hematologic toxicity 21(and Zevalin BLA/IND). Note that 
the median radiation exposure of red marrow with standard dose (32 mCi) 90Y-ibritumomab 
tiuxetan is 1.5 Gy (range 0.8-2.1)22.  Despite the tolerability, favorable response rates and 
remission durations, the majority of patients in these studies eventually experienced progression 
of their disease. Thus, though cytoreduction with minimal toxicity is possible for patients with B-
cell NHL, additional measures are needed to maintain these remissions.  
 
 
Fig 1: Response rates observed in selected clinical 
trials using radiolabeled anti-CD20 mAb to treat 
relapsed or refractory B-NHL (PR, hatched bars; CR, 
black). 
Fig. 2: Overall and Relapse-Free Survival of the first 37 
Patients with Relapsed B cell Lymphomas treated in 
Seattle with Iodine-131-labeled anti-B cell mAb 
  
High-dose radioimmunotherapy prior to autologous transplantation 
Our group has pioneered the use of high-dose 131I-labeled anti-B cell antibodies prior to 
autologous transplantation. These studies have indicated that up to 27Gy can be delivered to 
normal organs with 131I as a single agent and up to 25Gy when combined with high dose 
chemotherapy19,20. Toxicity profiles are considerably lower than traditional high-dose conditioning 
when the single agent regimen is used, and comparable to TBI-based regimens when high-dose 
chemotherapy is added 20,23. Notably, comparisons with non-randomized controls suggest that 
RIT improves both overall and progression-free survival 20,24. Other groups have evaluated high-
dose 90Y-anti-CD20-containing regimens with similar results. Flinn et al have utilized high-dose 
90Y-Ibritumomab Tiuxetan with a dosimetry based strategy and reported that doses of up to 28 
Gy to critical normal organs were tolerated25. Both Ferrucci and Devizzi and colleagues have 
treated patients with dose escalated 90Y-Ibritumomab Tiuxetan prior to ASCT and were able to 
safely deliver doses up to 1.2-1.5 mCi/kg. 26,27 Devizzi, using 1.2 mCi/kg, demonstrated no TRM 
and complete remissions in 7 of 10 DLBCL patients. In the Ferucci study the normal organ with 
the greatest exposure (liver) received a median of 13 Gy (range 9.5-25.3 Gy) at the highest dose 
level of 1.5 mCi/kg, but only one of 5 patients experienced transient grade 3 hepatotoxicity. 
Importantly, these studies confirmed the feasibility, efficacy, and tolerability of using a high-dose 
mCi/kg dosing strategy of 90Y-Ibritumomab Tiuxetan prior to autologous stem cell transplantation. 
Finally, other groups have combined high-dose 90Y-Ibritumomab Tiuxetan with high-dose 
chemotherapy, demonstrating that an absorbed dose of 10 Gy can be combined with 100 mg/kg 
cyclophosphamide and 60 mg/kg etoposide or 15 Gy with BEAM conditioning was safe and 
0%
20%
40%
60%
80%
100%
CR
PR
Kaminski 
(pivotal) 
Witzig 
Phase II 
Knox Kaminski 
(relapsed) 
Press 
Witzig 
Phase III 
Non-Myeloablative
Myelo- 
Ablative
Refractory
Relapsed B-NHL
I-131-B1
Y-90-B28
I-131-B1
I-131-B1
Y-90-B28
Y-90-B28
Cum. Survival
0
.2
.4
.6
.8
1
0
20
40
60
80
Months
Overall Survival
Relapse-Free Survival


Protocol 2398.00 
Page 6 of 34 
effective 28,29. Table 1 reviews many of the key trials using 90Y-Ibritumomab Tiuxetan and ASCT.  
In summary, studies from a variety of centers conclude that high-dose 90Y-Ibritumomab Tiuxetan 
prior to autologous transplantation is feasible, reproducible, and efficacious. 
 
Table 1 Selected trials using high-dose 90Y-Ibritumomab Tiuxetan as part of autologous stem cell 
transplant conditioning regimens for B-cell lymphomas 
Author (Year) 
Maximum  90Y dose/other 
therapy  
n 
Outcomes 
Nademanee (2005)30 
10 Gy (105 mCi)/high dose 
CY/VP-16 
31 
2-year estimated RFS 78% 
Winter (2009)28 
17 Gy (104 mCi)/ high dose BEAM 33 
3-year PFS 43% 
Flinn (2006)25 
28 Gy (143.1 mCi)/none 
16 
80%(62.5% CR)  
Ferrucci (2007)26 
1.5 mCi/kg (150 mCi)/none 
13 
NRM=7.6% 
Divizzi (2008)27 
1.2 mCi/kg (not reported)/none 
30 
69% EFS at 30 mo. 
 
 
Impact of CD20 blocking on anti-CD20 tumor targeting.  
Initial studies of anti-CD20 RIT indicated that the addition of unlabeled anti-CD20 MoAb was 
required to clear circulating B-cells, block sites of splenic sequestration, yield improved radiation 
delivery to nodal sites 15,31. However, with the widespread use of rituximab, most B-NHL patients 
maintain persistent levels of anti-CD20 antibodies and few circulating B-cells. Preclinical data 
suggest that excess anti-CD20 antibody may impair CD20 directed tumor targeting 18,32. Based 
on these observations, we will only use rituximab prior to the radiolabeled infusions in patients 
with serum rituximab levels potentially insufficient to optimize delivery isotope to nodal sites 
(<10µg/ml).   
 
Synergy of radioimmunotherapy and nucleoside analogs 
A potential method of optimizing anti-lymphoma RIT involves combining synergistic 
chemotherapeutic agents with RIT.  Studies performed by our group evaluating co-incubation of 
various anti-lymphoma drugs and 131I-anti-CD20 antibodies along with B-cell lymphoma lines in 
vitro showed maximal supra-additive levels of cell killing with nucleoside analogues cytarabine 
and fludarabine (Table 2)33. Though pilot studies looking at sequential fludarabine followed by 
low dose RIT have suggested feasibility 34, clinical data are limited regarding the concurrent or 
rapidly sequenced use of RIT followed by such drugs.  A schema administering RIT in close 
proximity to drugs like fludarabine would more closely mirror the in vitro findings of synergy and 
may lead to improved outcomes. 
 


Protocol 2398.00 
Page 7 of 34 
Table 2 Dose modification factors (degree of synergy) of chemotherapeutic agents combined with 
a fixed low dose of 131I-anti-CD20 antibody in human NHL cell lines 
Drug 
Dose Modification Factor 
(Degree of Synergy) 
p value 
Cytarabine 
5.21+/- 0.47 
<0.001 
Fludarabine 
4.00+/-0.25 
<0.0001 
Etoposide 
2.35+/-0.07 
0.0024 
Doxorubicin 
2.03+/-0.21 
0.013 
Cisplatin 
1.10+/-0.07 
0.12 
4-HC 
1.01+/-0.04 
0.93 
(A DMF of 1 represents additive effects, <1 represents antagonistic effects, and >1 represents 
synergistic/supra-additive effects.)  
 
Safety of combining RIT, TBI, and chemotherapy 
We and others have extensive experience combining RIT, high-dose TBI and high-dose 
chemotherapy in a single transplant conditioning regimen35,36. Selected studies are summarized 
in Table 3. Matthews et al reported that the delivery of 12.25 Gy to normal organs using 
radioimmunotherapy along with 12 Gy of TBI and 120 mg/kg of cyclophosphamide has acceptable 
toxicities and appeared to efficacious in preliminary analyses35,37. Similar studies were carried out 
by groups from Memorial Sloan Kettering combining high-dose anti-CD33 RIT with 12 Gy of TBI 
and 120 mg/kg of cyclophosphamide38. Based on the tolerability of studies combining high-dose 
RIT with high-dose TBI and high-dose chemotherapy, we anticipate that the proposed 
combination of RIT with low-dose TBI and low dose chemotherapy will be extremely well tolerated.  
 
Table 3. Selected published trials that combine high-dose radioimmunotherapy with high-
dose chemotherapy and ablative total body irradiation (TBI). 
Author (Year) 
Isotope 
Dose 
Target Additional 
therapy 
Leukemia type/ 
Setting 
n 
Appelbaum(1992)36 I-131 
110-330 mCi 
CD33 
Cy/TBI 
AML 
4 
Jurcic (1995)39 
I-131 
50-70 mCi/m2 
CD33 
Bu/Cy 
AML 
19 
Matthews (1999)40  
I-131 
3.5-12.25 Gy 
CD45 
Cy/TBI 
AML/MDS/ALL 
34 
Bunjes (2001)38  
Re-188 
7.4 Gy 
CD66 
CY/TBI or 
Bu/Cy 
AML/MDS 
36 
Burke (2003)41  
I-131 
122-437 mCi 
CD33 
Bu/Cy 
AML/CML/MDS 31 
Pagel (2005)42 
I-131 
12-24 Gy 
CD45 
Flu, TBI 
(2Gy) 
AML/AML 
33 
Ringhoffer (2005)43  Re-188/ 
Y-90 
9.7+/-5.3 Gy 
CD66 
Flu/ATG 
+/-Mel 
AML/MDS 
20 
Pagel (2006)44  
I-131 
5.25 Gy 
CD45 
Bu/CY 
AML- CR1 
46 


Protocol 2398.00 
Page 8 of 34 
 
 
Use of low dose 90Y-anti-CD20 RIT prior to reduced intensity allogeneic transplantation. 
Despite the potential for long term remissions in B-NHL and CLL with the use of reduced intensity 
allogeneic transplantation, patients with adverse pre-transplant features are at high-risk of 
relapse. For example, MCL patients with ≥ 5 cm disease bulk pre transplant had a 47% chance 
of relapse as compared to 14% in those with < 5 cm disease 45. Similar findings were seen in 
other histologies and in settings of chemoresistant disease and aggressive/transformed histology 
11,13,14,46. Presumably, relapse in this setting is based both on early disease control (as imparted 
by pretransplant salvage chemotherapy or the conditioning regimen) as well as long-term disease 
control via the graft-versus-lymphoma (GVL) effect. Data from the European Group for Blood and 
Marrow Transplantation (EBMT) support the importance of intensified conditioning to reduce 
relapse with patients receiving the least intensive regimen (Flu/TBI) experiencing a 2.7-fold higher 
relapse rate compared to those receiving other more intensive regimens47. Unfortunately, the non-
targeted nature of more intensified regimens may increase toxicity and exclude patients with 
comorbidities.  
 
To address this problem, we recently completed a phase II trial adding standard (0.4 mCi/kg) 90Y-
Ibritumomab Tiuxetan to a Flu/2 Gy TBI preparative regimen in B-NHL patients not in CR prior to 
matched related or matched unrelated allogeneic transplantation 48(and unpublished data). Forty 
patients were treated on this trial evaluating the primary endpoint of 100 day TRM. Despite over 
half of the patients carrying comorbidity indexes of ≥3 and a median tumor bulk of 4.2 cm, there 
was only one (3%) non-relapse death (MRSA sepsis) prior to day 100 with the RIT adding little 
apparent non-hematologic toxicity. Furthermore, responses were observed in half of patients at 
post transplant day 28 with 83% of patients experiencing some degree of tumor reduction (Figure 
3).  Poorer outcomes were associated with aggressive B-NHL and mantle cell lymphoma, 
whereas the best long-term disease-free survival was associated with early objective responses, 
even in patients with aggressive B-NHL or MCL (Figures 4 and 5). These data would suggest 
that improved early disease control could translate into prolonged disease-free survival mediated 
by the GVL effect, but improvements in early disease control and ultimately PFS are required for 
patients with aggressive and mantle cell histologies. 
 


Protocol 2398.00 
Page 9 of 34 
 


Protocol 2398.00 
Page 10 of 34 
Figure 4: Progression free survival of B-NHL patients undergoing 90Y-ibritumomab tiuxetan (0.4 
mCi/kg) based transplantation, grouped by histology.  
 
Figure 5: Landmark analysis of OS based on response at 3 months post transplant 
 
Proposed use of escalated dose RIT and allografting  
The goal of this protocol is to assess the safety and efficacy of delivering high-dose 90Y-
Ibritumomab tiuxetan (anti-CD20) prior to fludarabine (30 mg/m2 x 3) and 2 Gy total body 
irradiation (TBI) followed by HLA matched allogeneic hematopoietic transplantation for patients 
with relapsed or refractory aggressive B-NHL. This work builds on prior data from our center and 
others, and complements data using I-131 anti-CD45 RIT in AML 70. We posit that the high-dose 
targeted cytoreductive effect of RIT will confer prolonged remissions with minimal non-
hematologic toxicity and that the immunologic GVL effect will prevent relapses. We anticipate that 
this novel strategy will reduce TRM as compared with standard ablative allogeneic transplantation 
regimens, while affording better cytoreduction and long-term disease control than current non-
myeloablative conditioning regimens for patients with the highest-risk disease.   
 
3. 
Objective 
To assess the safety and efficacy of 1.5 mCi/kg (max 120 mCi) 90Y-Ibritumomab tiuxetan (anti-
CD20) combined with fludarabine (30 mg/m2 x 3) and 2 Gy total body irradiation followed by HLA 
matched allogeneic hematopoietic transplantation for patients with relapsed or refractory 
aggressive B-cell lymphoma. 
 
4. 
Endpoints   
A. Primary Endpoint 
1. 1-year progression-free survival 


Protocol 2398.00 
Page 11 of 34 
B. Secondary Endpoints 
1. 100 day treatment-related mortality  
2. Overall survival  
3. Response rates at day 100 
4. Engraftment and hematopoietic toxicity 
 
5. 
Patient Selection 
 
Results of tests and/or procedures conducted as per standard of care may be used for 
eligibility determination. 
 
A. Inclusions 
1. Patients must have a histologically confirmed diagnosis of aggressive B-cell 
lymphoma (DLBCL, BL, etc.) expressing the CD20 antigen and have failed at least 
one prior standard systemic therapy. 
Patients must have relapsed after high-dose therapy and autologous 
transplantation or be ineligible for high-dose therapy and autologous 
transplantation. Patients that have failed autologous transplantation are those with 
persistent disease >30 days after transplant. Those ineligible for autologous 
transplant include those with chemoresistant disease (i.e., patients who have not 
achieved a partial response or better with their most recent chemotherapy 
regimen), are expected to have a poor outcome from autologous transplant (e.g., 
DLBCL relapsing within one year of R-CHOP-like chemotherapy, double hit 
lymphoma, MYC+ lymphoma, persistent PET positivity after chemotherapy), are 
unable to collect sufficient or tumor-free autologous stem cells per Seattle Cancer 
Care Alliance (SCCA) standard practice, are unable to tolerate the high-dose 
autologous conditioning regimens, or who refuse a high-dose autologous 
transplant regimen.  
2. Patients must have acceptable renal (Cr <2.0) and hepatic function (bilirubin 
<1.5mg/dL, and AST/ALT <3 x ULN), with the exception of patients thought to have 
Gilbert’s syndrome, who may have a total bilirubin above 1.5mg/dL.  
3. Patients must have an expected survival without treatment of >60 days and must 
be free of major infection including HIV. 
4. Patients must have an HLA-identical related or HLA-matched unrelated donor. 
5. Patients must be ≥ 18 years old. 
 
B. Exclusions. 
1. Receipt of systemic anti-lymphoma therapy within the following intervals prior to 
the therapeutic 90Y-ibritumomab tiuxetan dose: 
a. < 30 days for intravenously-administered cytotoxic chemotherapy and/or 
monoclonal antibodies 
b. < 5 half-lives for all other anti-cancer agents (e.g., targeted therapies, 
corticosteroids, immunomodulatory agents, etc.) 
2. Inability to understand or give an informed consent. 
3. Active central nervous system lymphoma. 
4. Pregnancy. 
5. Fertile men or women unwilling to use contraceptive techniques during and for 12 
months following treatment. 


Protocol 2398.00 
Page 12 of 34 
6. SWOG/ECOG performance score ≥2. 
7. High-dose chemotherapy or external beam radiation therapy to lung, liver, or 
kidneys >20 Gy within the previous 100 days prior to therapeutic 90Y-ibritumomab 
tiuxetan dose. 
8. Medical condition that would contraindicate allogeneic transplantation as per 
standard practice guidelines (e.g., impaired cardiopulmonary function, hepatitis, 
etc). 
 
6. 
Donor Selection 
HLA-identical related donor or HLA-matched unrelated donor who meets standard Seattle Cancer 
Care Alliance (SCCA) and/or NMDP criteria for PBSC donation.  Related donors should be 
matched by molecular methods at the intermediate resolution level at HLA-A, B, C, and DRB1 
according to FHCRC Standard Practice Guidelines and to the allele level at DQB1.  Unrelated 
donors should be identified using matching criteria that follows the FHCRC Standard Practice 
Guidelines limiting the study to eligible donors that are allele matched for HLA-A, B, C, DRB1, 
and DQB1 (Grade 1), and accepting up to one allele mismatch as per Standard Practice Grade 
2.1 for HLA-A, B, or C.  Participants with HLA-matched, related, non-sibling donors will be treated 
according to regimen for participants with HLA-matched unrelated donors. PBSC is the only 
permitted stem cell source. 
 
 
7. 
Informed Consent 
Subjects will be referred to SCCA/UW for consideration of a PBSC transplant. Both subject and 
donor will be completely evaluated. The protocol will be discussed thoroughly with subject, donor 
and other significant individuals by the attending physician and/or investigators. All known risks 
to the subject and donor will be described. The study procedures and available alternative forms 
of therapy will be reviewed as objectively as possible, and the risks and hazards of the procedures 
explained.  Consent will be obtained using forms approved by the Institutional Review Board of 
the Fred Hutchinson Cancer Research Center. A summary of the conference will be dictated for 
the medical record detailing what was covered. 
 
Related donors will be counseled and consented in accordance with standard SCCA procedures 
and using the standard donor consent form.  Unrelated donors will be counseled and consented 
according to the guidelines of the NMDP and other donor centers. 
 
 
8. 
Protocol Registration 
Patients will be assigned to the protocol by the Clinical Coordinator, who will register the patient 
with the Registration Office, (206) 667-4728, between 8:30 a.m. and 4:00 p.m., Monday through 
Friday.  After hours, the Registration Office can be reached by paging (206) 995-7437.  Eligibility 
criteria will be verified by the research coordinator and the investigator before any patient is 
registered on study. 
 
 
9. 
Plan of Treatment 
Treatment will be initiated in the outpatient department and patients will be admitted only as 
medically necessary for control of transplant complications.  
 


Protocol 2398.00 
Page 13 of 34 
A. Outline of treatment plan (Table 4).  The day of treatment is listed in order to give a 
loose time-frame.  An individual study calendar is created for each patient, with 
modifications permitted in consideration of clinical and logistical needs.   
Time Point 
Event 
<4 weeks pre 
therapy 
Staging studies (CT, bone marrow, flow, PCR) and organ function 
assessment as detailed under Section 10.A.  
 
24 to 48 hours 
prior to therapy 
infusion 
Administer 250 mg/m2 of rituximab per product labeling and 
institutional guidelines. 
 
Day -14 (± 2 days 
relative to 
transplant) 
Therapy infusion: 
90Y-ibritumomab tiuxetan infusion (1.5 mCi/kg 90Y-ibritumomab 
tiuxetan mCi/kg actual body weight, maximum of 120 mCi) 
 
Day -4 to -2 
Fludarabine 30 mg/m2 IV QD x 3 
 
Day -3 
Cyclosporine (CSP) initiated 
 
Day 0 
2 Gy total body irradiation (TBI) 
Allogeneic Stem Cell Infusion 
Mycophenolate mofetil (MMF) initiated 
Post therapy  
Assessments: 
Staging studies/disease assessment: ~1 and 3 months after 
transplant per protocol.  Six months and 12 months after transplant 
patient will be followed for disease progression and survival. 
Thereafter, patients will be followed for survival for up to 2 years after 
transplant. 
  
Immunosuppression: 
CSP: Related Donors- to day +56, then taper off by day +180 
Unrelated Donors- +100, then taper off by day +180. 
MMF: Related Donors-to +27 and then discontinue   
Unrelated Donors- to +40, taper off by + 96 
TBI=total body irradiation, CSP= cyclosporine, MMF= mycophenolate mofetil. 
 
B. Treatment regimen overview 
1. 24 – 48 hours prior to therapy dose:  
250 mg/m2 of rituximab administered IV per product labeling and institutional 
guidelines.  
2. Day -14 (± 2 days), therapy dose:  
90Y-ibritumomab tiuxetan administered IV. Dose: 1.5 mCi/kg actual body weight 
(maximum of 120 mCi).  See statistical section. 
3. Days –4 to –2: Fludarabine 30 mg/m2/day i.v. (3 doses total) 
4. Day -3: Begin immunosuppression with CSP 4 mg/kg p.o. b.i.d. 
5. Day 0: TBI 2.0 Gy at 6-7 cGy/min from a linear accelerator.   


Protocol 2398.00 
Page 14 of 34 
6. Day 0: Hematopoietic cell infusion from HLA-identical donor per standard practice 
guidelines. 
7. Day 0: Begin immunosuppression with MMF (15 mg/kg p.o. b.i.d. [patients with 
related donors] or t.i.d. [patients with unrelated donors]) 5-10 hours following PBSC 
infusion. 
 
C. Rituximab 
Dose: Rituximab is given 24 – 48 hours prior to therapy infusion at a dose of 250 
mg/m2. Premedications include: Dexamethasone 10mg po/IV, Diphenhydramine 50 
mg po/iv and acetaminophen 650 mg po. 
 
Infusion rate: In general, initiate infusion at a rate of approximately 50 milligrams/hour 
(mg/hr). If no infusion reactions occur, the rate will be escalated by 50 mg/hr 
increments every 30 minutes to a maximum of 400 mg/hr. If infusion reactions 
occurred during the infusion, follow guidelines as per product labeling and institutional 
guidelines (e.g., the infusion may be slowed, temporarily interrupted and re-started at 
one-half the previous rate, or discontinued depending on severity of symptoms). 
 
D. 90Y-ibritumomab tiuxetan 
Dose:  The target 90Y dose will be 1.5 mCi/kg actual body weight (maximum of 120 
mCi). The antibody dose (ibritumomab tiuxetan) will be determined based on the 
volume required for radiolabeling with the desired number of millicuries 90Y, per 
radiolabeling processes used with standard Zevalin.  This is expected to require up to 
approximately 8 mg of antibody. 90Y-ibritumomab tiuxetan will be provided by the 
manufacturer (Acrotech Biopharma, LLC) and radiolabeling pharmacy (Cardinal 
Health). The product will be provided in a volume and packaging format agreed upon 
by Cardinal Health and SCCA. Premedications for the therapeutic infusion include 
Dexamethasone 10mg po/IV, Diphenhydramine 25-50 mg po/iv, and acetaminophen 
650 mg po. 
 
Infusion rate: 90Y-ibritumomab tiuxetan should be infused over 30 minutes via a central 
line within 24 - 48 hours of the completion of rituximab dose. Patients will receive one 
liter of normal saline over 2-4 hours following the therapy infusion. Following this, 
patient will be encouraged to increase oral fluid intake. Additional IVF will be given at 
the discretion of the treating physician.  
 
E. Fludarabine 
Fludarabine will be administered on days –4 to –2. Dose: 30 mg/m2 IV administered 
per routine pharmacy guidelines. 
 
F. Total Body Irradiation (TBI) 
Day 0: TBI 2.0 Gy administered per SCCA standard practice. TBI to be administered 
prior to peripheral blood stem cell (PBSC) infusion, in general between 10:00 a.m. and 
1:00 p.m. if possible to avoid proximity to CSP/MMF administration.  
 
G. Collection of donor stem cells 
Donor PBSC will be collected as per institutional or NMDP standard practice. 
 


Protocol 2398.00 
Page 15 of 34 
H. Hematopoietic stem cell transplant 
Patients will receive unmodified G-CSF mobilized PBSC from an HLA-identical related 
or unrelated donor on day 0 of the treatment regimen, infused per standard practice 
guidelines.   
 
Cryopreservation of DLI will not be covered in this protocol. 
 
I. Immunosuppression 
Day –3:  Related Donors: Commence CSP at 4.0 mg/kg p.o. b.i.d. from day -3 to day 
+56, then if no GVHD taper off by day +180. Unrelated Donors: For patients with 
matched unrelated donors, CSP at 4.0 mg/kg p.o. b.i.d. is given from day –3 to day 
+100, then is tapered to day 180.  If GVHD is present immunosuppression will follow 
standard practice guidelines and/or the direction of the primary treating physician. CSP 
whole blood "trough" levels (i.e., just prior to the next dose) will be evaluated starting 
on day 0 post-transplant. Routine patient monitoring and dose adjustments will in 
general follow the guidelines of the standard practice manual. In general, CSP trough 
levels will be targeted to 400 ng/mL through day +28, then 120-360 ng/mL thereafter, 
but these goals can be adjusted at the discretion of the attending physician. Equivalent 
i.v. doses of CSP may be utilized at the discretion of the attending physician.  
 
Day 0: Related Donors: MMF will be given at 15 mg/kg p.o. b.i.d. (30 mg/kg/day), with 
the first dose administered 5-10 hours after the PBSC infusion is complete. MMF will 
continue at full dose through day +27 and then be discontinued without a taper. 
Unrelated Donors: MMF will be given at 15 mg/kg p.o. t.i.d. (45 mg/kb/day), with the 
first dose administered 5-10 hours after the PBSC infusion is complete. MMF will 
continue at full dose through day +40, at which point it will be tapered to be stopped 
by day +96.  Equivalent i.v doses of MMF may be utilized at the discretion of the 
attending physician. MMF dose adjustment may occur at the discretion of the attending 
physician or PI (for reasons such as toxicity, impending graft rejection, etc.).  
 
J. ABO incompatibility 
All patients with ABO incompatibility should be evaluated and treated according to 
standard practice.  
 
K. Post-transplant growth factors 
Given the theoretical risk of driving myeloid cell production during exposure to an 
antimetabolite, patients should not receive post-transplant growth factors while 
receiving MMF.  Growth factors should not be given unless severe persistent 
neutropenia develops or persists past day +27 post-transplant (ANC ≤ 100/ul for > 5 
days). As MMF may cause myelosuppression, consideration should be given to 
reducing the dose of MMF prior to the start of growth factor. 
 
L. Infection prophylaxis 
Patients will receive prophylaxis for PCP, fungus, VZV, and HSV as per standard 
practice. The start of the conditioning regimen will in general be considered the date 
of treatment dose. 
 
M. Post-transplant Donor Lymphocyte Infusion (DLI) 
DLI will not be a component of this trial.  Patients requiring DLI for chimerism or 
disease progression will be treated on alternate protocols or as standard practice. 
Complete responses may require 6 months or more to evolve in NHL patients treated 


Protocol 2398.00 
Page 16 of 34 
with RIT. Thus, patients on this protocol will not be considered a treatment failure/DLI 
candidate for stable disease alone. Patients will require objective evidence of disease 
progression to be considered treatment failures. 
 
N. Criteria for removal of individual patients 
Individual patients may be removed from the trial for the following reasons: 
• 
patient request,  
• 
patient no longer meets eligibility criteria at the time of therapy dose,  
• 
serious infusion reaction or other toxicity preventing further administration of 
treatment regimen.  
 
Patients removed from the study due to toxicities will be monitored for continuing 
toxicities until resolution. 
 
10. 
Patient and Donor Evaluations 
A. Patient Pretransplant Baseline Evaluation 
Pre transplant work up will occur as per standard practice for patients undergoing 
myeloablative allogeneic transplantation, including standard clinical staging 
assessments for lymphoma (e.g., CT scans of chest, abdomen, and pelvis, and neck 
at the discretion of treating MD or investigator; bone marrow biopsy if indicated; etc.), 
PET-CT scan within 21 days prior to 90Y-ibritumomab tiuxetan dose is strongly 
recommended but not required and standard clinical workup for transplant including 
pulmonary function testing. In addition, the following assessments will be performed:  
1. Echocardiogram or MUGA scan in all patients to assess cardiac ejection fraction 
(common in clinical workup per standard practice, but not required in all instances). 
 
B. Patient Post-transplant Evaluations 
The primary endpoint of this study is 1-year progression-free survival, with secondary 
endpoints including 100-day response and mortality rates, and overall survival.  Timing 
of all post-transplant evaluations, including those identified as protocol-specific, may 
vary based on each patient’s individual course of clinical care.  Patients typically 
remain under the care of the SCCA Outpatient Service for approximately 100 days 
post-transplant, but the actual time frame will vary for individual patients.  Similarly, 
certain response evaluations that may be described as occurring at “day +28 and day 
+84,” “four and twelve weeks,” or “one and three months” post- transplant are expected 
to be conducted within these general time frames. 
 
Appropriate post-transplant evaluations are consistent with standard practice for 
patients undergoing myeloablative allogeneic transplantation. Common follow-up 
guidelines used when patients are followed on an outpatient basis are summarized in 
Table 5 below. All hospitalized patients have daily clinical assessments.  
 
Table 5: General Post-Transplant Outpatient Monitoring Guidelines 
Assessment 
Interval 
 
When ANC<500 or PLT<20K 
When ANC≥500 and PLT≥20K 
CBC 
Daily 
Weekly 
Electrolytes 
Weekly 
Weekly 
Liver Function Tests 
Weekly 
Weekly 
Clinical assessment 
Weekly 
Weekly 
 


Protocol 2398.00 
Page 17 of 34 
In addition, the following protocol-specific assessments will be performed at the 
approximate timepoints indicated:   
 
1. CT scan of chest abdomen and pelvis with bi-dimensional measurement of disease 
for staging of lymphoma at day +~28 and +~84. Neck CT will be requested for 
patients with neck involvement. PET-CT is required at day ~+84 (or sooner to 
confirm CR). Note that patients who are in complete remission (CR) pre-transplant 
do not need a follow up PET-CT. 
2. On or near day +84 post-transplant, patients with baseline marrow involvement will 
have bone marrow done to confirm CR as per standard criteria.71 Patients with a 
negative marrow at an earlier post-transplant time point do not need to have the 
marrow repeated. Additional bone marrow studies will be at the discretion of the 
attending physician.  
3. GVHD evaluations will be performed as per standard of care.  
 
Following day +100 or discharge from the SCCA, patients will typically return to their 
primary care physicians under the guidance of the FHCRC/SCCA Long-Term Follow-
Up After Hematopoietic Stem Cell Transplant General Guidelines for Referring 
Physicians.  Patient follow-up will be performed according to institutional standards by 
the FHCRC Long-Term Follow-Up (LTFU) Department under the FHCRC/SCCA 
Master Protocol for Collection of Clinical Data and Storage of Leftover Specimens from 
Patients Treated According to FHCRC Protocols (Protocol #0999.209).  We will 
monitor survival and progression reported under the standard long-term follow-up 
protocol, and will record this data at 6 and 12 months, and annually thereafter for 2 
years for long-term analysis and reporting, until 2 years after transplant or patient 
request to withdraw from study follow-up. If there is not sufficient LTFU data available 
at 12 months after transplant to assess both survival and disease status (e.g., 
radiologic imaging reports; blood and bone marrow assessments as needed), we will 
request records from the patient’s primary care physician. 
 
C. GVHD Evaluation  
GVHD evaluations should in general follow standard practice guidelines and a full 
evaluation should be performed before departure from the center. 
 
D. Donor Evaluations 
Donor evaluations will follow the standard practice guidelines. 
 
 
11. 
Definitions 
A. Disease and Response Criteria:  Response will be interpreted by investigator review 
of radiographic findings along with MD assessed physical findings and bone marrow 
or blood reports and will follow the revised response criteria.71   
B. Graft rejection is defined as < 1% peripheral blood donor T cells on day +28 and/or 
later.  
C. Treatment Failure:  Disease progression as defined by the revised response criteria 
71 at any time after Day 0 will be considered a treatment failure. Because complete 
responses may require 6 months or more to evolve in NHL patients treated with RIT, 
stable disease alone will not be considered a treatment failure for patients on this 


Protocol 2398.00 
Page 18 of 34 
protocol. Patients will require objective evidence of disease progression to be 
considered treatment failures. 
 
 
12. 
Toxicities and Complications 
A. Rituximab 
Rituximab can cause severe, including fatal, infusion reactions associated with 
hypersensitivity and anaphylaxis.  All patients receiving rituximab will be given 
premedications as described under section 9.C.  Some patients treated with rituximab 
have experienced tumor lysis syndrome, severe (including fatal) mucocutaneous 
reactions, and progressive multifocal leukoencephalopathy (PML) resulting in death.  
Other significant toxicities may include Hepatitis B virus reactivation with fulminant 
hepatitis, increased risk of infection, cardiac arrhythmia, renal toxicity, and bowel 
obstruction or perforation.  The most common adverse reactions associated with 
rituximab infusion include infusion reactions, fever, chills/rigors, infection, asthenia, 
lymphopenia, nausea, vomiting, pruritus, angioedema, hypotension, headache, 
bronchospasm, urticaria, rash, myalgia, dizziness, and hypertension. 
 
B. 90Y-ibritumomab tiuxetan 
The most serious toxicities observed following radiolabeled ibritumomab tiuxetan are 
prolonged and severe cytopenias, and secondary malignancies including 
myelodysplastic syndrome and/or acute myeloid leukemia.  Severe cutaneous and 
mucocutaneous reactions, some fatal, have been reported following a therapeutic 
regimen using rituximab and 90Y-ibritumomab tiuxetan.  The most common adverse 
reactions include cytopenias, fatigue, abdominal pain, nausea, nasopharyngitis, 
asthenia, diarrhea, cough, and pyrexia.   
 
C. Fludarabine 
Clinical toxicities of fludarabine include: myelosuppression, primarily lymphopenia and 
granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, stomatitis, 
diarrhea, somnolence, fatigue, peripheral neuropathy, mental status changes, cortical 
blindness, hepatocellular toxicity with elevation in serum transaminases, and 
interstitial pneumonitis. These effects are reversible when the drug is discontinued.  
Immunosuppression observed with the use of fludarabine increases the risk of 
infection which can be life-threatening. 
 
D. Total body irradiation (TBI) 
See Standard Practice Manual for information on associated toxicities. 
 
E. Stem cell transplant 
See Standard Practice Manual for information on associated toxicities. 
 
F. Cyclosporine (CSP) 
See Standard Practice Manual for information on associated toxicities. 
 
G. Mycophenolate mofetil (MMF) 
See Standard Practice Manual for information on associated toxicities. 
 
 


Protocol 2398.00 
Page 19 of 34 
13. 
Guidelines for Serious Adverse Event Reporting 
A. 
DEFINITIONS 
Adverse Event (AE) – Any side effect or untoward medical occurrence in a subject enrolled 
in a clinical trial, which does not necessarily have to have a causal relationship with the 
treatment.  An AE can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with study 
participation. 
Serious Adverse Event (SAE) – An adverse event that results in any of the following 
outcomes:   
• 
Death. 
• 
Life-threatening AE (placing the patient, in view of the investigator, at immediate 
risk of death from the reaction). 
• 
Inpatient hospitalization or prolongation of hospitalization.   
• 
Persistent or significant disability/incapacity. 
• 
Congenital anomaly or birth defect. 
• 
An important medical event that requires intervention to prevent one of the above 
outcomes. 
Unexpected Adverse Event – An AE that is not consistent in nature or severity with the 
product information documented in the protocol, consent form, and/or prior reports.   
B. 
MONITORING AND RECORDING AES 
B.1 
Responsibility for AE monitoring 
As noted under section 14, the PI meets regularly with the study coordinator, during which 
time any adverse events that have not already been reported to the PI are discussed.   
B.2 
Time frame for monitoring AEs 
AEs will be monitored and recorded in study-specific case report forms (CRFs) from the 
time of first exposure to a study intervention (i.e., the start of the rituximab infusion 
associated with the therapy dose) through day +100 post-transplant or through discharge 
prior to that date from the SCCA system to care of the patient’s primary physician.  AEs 
with an onset date prior to the first exposure to an investigational product will not be 
recorded, except in the event of clinically significant worsening of the AE during the 
specified monitoring time frame. 
B.3 
AE grading 
All AEs will be graded in severity according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).   
All patients undergoing allogeneic transplantation using any investigational or standard 
myeloablative approach are expected to experience multiple grade 1-3 adverse events.  
These events will be reviewed and captured in the source documentation.  Through day 
100 (or through discharge prior to that date from the SCCA system), non-hematologic 
adverse events of ≥ grade 3, possibly related events of grade 2 that have not previously 
been observed with components of the study regimen, and all serious adverse events will 
be captured in protocol-specific case report forms.  Grade ≤4 hematologic toxicity is 
expected and will only be recorded as time to engraftment.  After day 100 patients will be 
tracked only for progression and survival. 


Protocol 2398.00 
Page 20 of 34 
The following events are not identified as AEs in this study: 
• 
Disease progression or relapse.  However, clinical events associated with 
progression/relapse may be reportable as AEs. 
• 
Hospitalization for the purpose of facilitating stem cell transplant is not considered 
an AE.  Any AE requiring prolongation of this hospitalization will be recorded and 
subject to applicable SAE reporting. 
• 
Medical or surgical procedures in and of themselves, including those that require 
hospitalization (e.g., surgery, endoscopy, biopsy procedures) are not considered 
AEs.  However, an event or condition requiring such procedures may be an AE. 
• 
All patients undergoing hematopoietic stem cell transplant are expected to have ≤ 
Grade 4 pancytopenia as an intended therapeutic effect.  These hematologic AEs 
will therefore be tracked and recorded only as time to recovery of blood 
counts/engraftment. 
• 
Abnormal laboratory values will be identified and recorded as AEs only if clinical 
intervention is required as a result. 
B.4 
AE attribution 
Association or relatedness to the study agent will be assessed by the investigator as 
follows: 
• 
Definite:  The event follows a reasonable temporal sequence from exposure to the 
investigational agent, has been previously described in association with the 
investigational agent, and cannot reasonably be attributed to other factors such as 
the patient’s clinical state, other therapeutic interventions or concomitant 
medications; AND the event disappears or improves with withdrawal of the 
investigational agent and/or re-appears on re-exposure (e.g., in the event of an 
infusion reaction). 
• 
Probable:  The event follows a reasonable temporal sequence from exposure to 
the investigational agent and has been previously been described in association 
with the investigational agent OR cannot reasonably be attributed to other factors 
such as the patient’s clinical state, other therapeutic interventions or concomitant 
medications. 
• 
Possible:  The event follows a reasonable temporal sequence from exposure to 
the investigational agent, but could be attributable to other factors such as the 
patient’s clinical state, other therapeutic interventions or concomitant medications. 
• 
Unlikely:  Toxicity is doubtfully related to the investigational agent(s).  The event 
may be attributable to other factors such as the patient’s clinical state, other 
therapeutic interventions or concomitant medications. 
• 
Unrelated:  The event is clearly related to other factors such as the patient’s clinical 
state, other therapeutic interventions or concomitant medications. 
An AE is considered related if it is assessed as definitely, probably, or possibly related; 
unrelated if it is assessed as unlikely related or unrelated. 
C. 
REPORTING AES 
Adverse event reporting to the Institutional Review Board will occur in accordance with 
FHCRC IRB policies.  All unexpected and serious adverse events that may be due to study 
treatment or intervention, and other unanticipated problems that involve risk to research 


Protocol 2398.00 
Page 21 of 34 
participants or others, will be reported to the FHCRC Institutional Review Office as soon 
as possible and within the IRB’s required time frame from the investigator learning of the 
event.  The FHCRC Adverse Event Reporting Form, Unanticipated Problem Reporting 
Form, or appropriate equivalent will be completed for this reporting.  If necessary due to 
limited information available, an incomplete report form will be faxed at the initial report, 
followed by a completed report within the time frame dictated by IRB policy.  SAEs that do 
not meet the requirement for expedited reporting will be reported to the IRB as part of the 
annual renewal of the protocol. 
All deaths except those from relapse of malignancy, but otherwise regardless of 
attribution, that occur within the first 100 days following transplant will undergo expedited 
reporting to the FHCRC IRB.  If the patient has returned to the care of the referring 
physician prior to day 100 post-transplant, the death will be subject to expedited reporting 
based on the time we learn of the death.  Deaths occurring after 100 days will not undergo 
expedited reporting although they will be included in annual reports and publications of 
the study.   
In the event of study closure due to toxicities, or activation of any other 
stopping/suspension rule, the FHCRC IRB would be notified promptly within 7 days of the 
determination. 
D. 
SAES ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT 
Certain events that are commonly observed as SAEs following stem cell transplant are 
described here in order to facilitate assessments of attribution.  SAEs that are identified 
as routinely experienced in the allogeneic transplant setting would typically be assessed 
as unrelated to elements of the RIT regimen used in this protocol.  The following list 
represents some of the most frequent SAEs expected in this setting and is not intended 
to be comprehensive.  Symptoms associated with graft versus host disease are described 
under Appendices C and D.   
 
CTCAE Category 
Toxicity 
Blood and lymphatic 
system disorders 
As noted above, all patients undergoing stem cell transplant are 
expected to have ≤ Grade 4 pancytopenia as an intended 
therapeutic effect.  These hematologic adverse events will be 
tracked and recorded only as time to recovery of blood 
counts/engraftment.  
 
Febrile neutropenia 
General disorders and 
administration site 
conditions 
Fatigue 
Fever 
Rigors, chills 
Gastrointestinal 
Diarrhea 
Dysphagia 
Esophagitis 
Mucositis/Stomatitis 
Nausea 
Vomiting 
Hemorrhage/Bleeding 
Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia 
Infections and 
infestations 
Infections may be associated with neutropenia following HCT 


Protocol 2398.00 
Page 22 of 34 
CTCAE Category 
Toxicity 
Metabolism and 
nutrition disorders 
Anorexia 
Dehydration 
Hypokalemia (e.g., potassium < 2.5 can result from wasting induced 
by transplant-related medications) 
Reproductive system 
and breast disorders 
Reproductive system and breast disorders – Other: Sterility/infertility 
 
 
 
14. 
Data and Safety Monitoring Plan 
Ongoing trial oversight is carried out by the principal investigator, Dr. Gopal, and the study 
coordinator.  These individuals will meet at least monthly to review recently acquired data, 
stopping rules, and adverse events.  The data recorded within the research charts and protocol 
database is compared with the actual data that is available from the medical record and/or clinical 
histories.  Data detailed in the research case report forms includes the nature and severity of all 
toxicities, which are also reported as described above.  All investigators on the protocol have 
received formal training in the ethical conduct of human research. 
 
Institutional support of trial monitoring is provided in accordance with the FHCRC Institutional 
Data and Safety Monitoring Plan.  Under the provisions of this plan, the FHCRC Research Trials 
Office coordinates monitoring for data accuracy and compliance by consultants, contract research 
organizations, or FHCRC employees unaffiliated with the conduct of the study.  Independent 
monitoring visits occur at specified intervals determined by the assessed risk level of the study 
and the findings of previous visits. In addition, protocols are reviewed at least annually by the 
Protocol and Data Monitoring Committee (PDMC) and the Institutional Review Board (IRB).  The 
PDMC reviews accrual, adverse events, stopping rules, and adherence to the data and safety 
monitoring plan.  The FHCRC IRB reviews the study progress and safety information to assess 
continued acceptability of the risk-benefit ratio for human subjects.  Approval of both committees 
is necessary to continue the study.   
 
This protocol is a single institution phase II trial that does not employ gene therapy and, thus, 
does not require a separate data safety monitoring board. The trial will comply with the standard 
guidelines set forth by the regulatory committees of the FHCRC (Scientific Review Committee, 
IRB, PDMC) and other state and federal guidelines. 
 
15. 
Records 
Research staff under the supervision of the investigators will maintain case report forms and 
secured databases on the relevant clinical and laboratory data.  Records maintained in 
investigators' offices will be secured with access limited to study personnel. Radiologic data from 
scanning will be stored in the Division of Nuclear Medicine. Authorization for access to medical 
records will be obtained from all patients in accordance with provisions of the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
16. 
Statistical considerations  
A Primary endpoint: The primary objective of this protocol is to examine the efficacy of 
this approach in patients with aggressive B-NHL. Prior data from FHCRC1726 using 
standard dose Zevalin prior to NMAT indicated that approximately 30% of patients 
were estimated to be alive and progression-free at 1 year.  This study will be deemed 
successful if the 1 year PFS of this highest-risk group of patients is 54% or greater.  If 
the true rate of 1 year PFS using the proposed approach is 54%, then 24 patients will 


Protocol 2398.00 
Page 23 of 34 
provide 80% power to detect a statistically significantly increased rate of PFS from the 
fixed rate of 30%, based on a one-sample chi-square test with one-sided significance 
level of five percent.   
 
B Stopping rule for safety: This trial will be paused prematurely due to toxicity if there 
is sufficient evidence suggesting that the true incidence of TRM within 100 days of 
transplant exceeds 20%. TRM will be defined for this purpose as death in the absence 
of progressive lymphoma that can be possibly, probably, or definitely attributed to the 
radioimmunotherapy. Sufficient evidence will be taken to be an observed rate of TRM 
within 100 days of transplant that corresponds to a one-sided 80% confidence interval 
with a lower limit greater than 20%.  For this rule, patients will be stratified into 2 arms 
and evaluated separately, (1) those that have received >20 Gy prior radiation therapy 
and (2) all others. These limits will be examined after every 5th enrolled patient within 
each arm becomes eligible for evaluation.  Operationally, the given arm will be 
suspended if we observe the following numbers of events out of sequentially treated 
patients in a given arm within the first 100 days of transplant: 3/5, 4/10, 5/15, 6/20, or 
8/25. If an arm of the study is halted, we will assemble an independent data safety 
monitoring committee to advise us as to how to proceed. Table 6 summarizes the 
operating characteristics of this stopping rule, where the probability of stopping the trial 
is estimated from 10,000 Monte Carlo simulations. 
 
Table 6. Probability of stopping the trial for excess treatment-related deaths. 
Number of 
patients 
 
True rate of TRM 
Probability of 
stopping 
10 
10% 
0.02 
15 
10% 
0.02 
20 
10% 
0.03 
 
 
 
10 
30% 
0.38 
15 
30% 
0.53 
20 
30% 
0.64 
 
 
 
10 
40% 
0.64 
15 
40% 
0.81 
20 
40% 
0.91 
 
 
17. 
Termination of the Study 
Study enrollment will be terminated upon complete accrual of patients or when stopping rules 
described above have been met. The study will remain open throughout patient survival in order 
to continue data collection from long-term evaluations.  
 
 


Protocol 2398.00 
Page 24 of 34 
18. 
Ethnic and Gender Distribution Chart (based on prior accrual) 
 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
9 
13 
22 
Ethnic Category Total of All 
Subjects* 
10 
14 
24 
Racial Categories 
American Indian / Alaska Native 
0 
0 
0 
Asian 
0 
1 
1 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
Black or African American 
1 
0 
1 
White 
9 
13 
22 
Racial Categories:  Total of All 
Subjects* 
10 
14 
24 
 
19. 
References 
 
1. 
Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as 
compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's 
lymphoma. N Engl J Med 1995;333:1540-5. 
2. 
Weaver CH, Appelbaum FR, Petersen FB, et al. High-dose cyclophosphamide, 
carmustine, and etoposide followed by autologous bone marrow transplantation in patients with 
lymphoid malignancies who have received dose-limiting radiation therapy. J Clin Oncol 
1993;11:1329-35. 
3. 
Pavletic ZS, Bierman PJ, Vose JM, et al. High incidence of relapse after autologous 
stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic 
lymphoma. Ann Oncol 1998;9:1023-6. 
4. 
Freedman AS, Neuberg D, Mauch P, et al. Long-term follow-up of autologous bone 
marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999;94:3325-33. 
5. 
Shipp MA, Abeloff MD, Antman KH, et al. International Consensus Conference on High-
Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's 
Lymphomas: report of the jury. J Clin Oncol 1999;17:423-9. 
6. 
Golden J, Gooley T, Gopal A, et al. Allogeneic or Autologous Bone Marrow or Peripheral 
Blood Transplantation for Follicular Lymphoma: A Cohort Analysis from the Fred Hutchinson Cancer 
Research Center. Blood 1999.;94:164a. 
7. 
Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic bone marrow 
transplantation for non- Hodgkin's lymphoma: a case-controlled analysis of the European Bone 
Marrow Transplant Group Registry data. J Clin Oncol 1992;10:1690-5. 
8. 
McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in 
older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-
versus- tumor effects. Blood 2001;97:3390-400. 
9. 
Bertz H, Illerhaus G, Veelken H, Finke J. Allogeneic hematopoetic stem-cell 
transplantation for patients with relapsed or refractory lymphomas: comparison of high-dose 


Protocol 2398.00 
Page 25 of 34 
conventional conditioning versus fludarabine-based reduced-intensity regimens. Ann Oncol 
2002;13:135-9. 
10. 
Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation 
after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell 
lymphoma. Blood 2004;104:3535-42. 
11. 
Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after 
nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 
2005;23:3819-29. 
12. 
Kogel KE, McSweeney PA. Reduced-intensity allogeneic transplantation for lymphoma. 
Curr Opin Oncol 2002;14:475-83. 
13. 
Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative allogeneic 
haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre 
experience. Br J Haematol 2008;143:395-403. 
14. 
Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell 
transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma. J 
Clin Oncol 2008;26:211-7. 
15. 
Kaminski MS, Zasadny KR, Francis IR, et al. Radioimmunotherapy of B-cell lymphoma 
with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med 1993;329:459-65. 
16. 
Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with iodine (131)I 
tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-
term follow-up of the University of Michigan experience. Blood 2000;96:1259-66. 
17. 
Witzig TE, White CA, Wiseman GA, et al. Phase I/II trial of IDEC-Y2B8 
radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's 
lymphoma. J Clin Oncol 1999;17:3793-803. 
18. 
Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-
labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients 
with relapsed or refractory low-grade, follicular, or transformed B-cell non- Hodgkin's lymphoma. 
J Clin Oncol 2002;20:2453-63. 
19. 
Press OW, Eary JF, Appelbaum FR, et al. Radiolabeled-antibody therapy of B-cell 
lymphoma with autologous bone marrow support [see comments]. N Engl J Med 
1993;329:1219-24. 
20. 
Press OW, Eary JF, Gooley T, et al. A phase I/II trial of iodine-131-tositumomab (anti-
CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-
cell lymphomas. Blood 2000;96:2934-42. 
21. 
Wiseman GA, Kornmehl E, Leigh B, et al. Radiation dosimetry results and safety 
correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-
Hodgkin's lymphoma: combined data from 4 clinical trials. J Nucl Med 2003;44:465-74. 
22. 
Wiseman GA, Leigh BR, Dunn WL, Stabin MG, White CA. Additional radiation absorbed 
dose estimates for Zevalin radioimmunotherapy. Cancer Biother Radiopharm 2003;18:253-8. 
23. 
Gopal AK, Rajendran JG, Gooley TA, et al. High-dose [131I]tositumomab (anti-CD20) 
radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 
years old with relapsed or refractory B-cell lymphoma. J Clin Oncol 2007;25:1396-402. 
24. 
Gopal AK, Gooley TA, Maloney DG, et al. High-dose radioimmunotherapy versus 
conventional high-dose therapy and autologous hematopoietic stem cell transplantation for 
relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis. Blood 
2003;102:2351-7. 
25. 
Flinn IW FE, Bianco JA, Hammes RJ, Webb J, Swinnen LJ, Sgouros G, Wahl RL. Dose 
finding trial of Yttrium 90 ibritumomab tiuxetan (90YIT) with autologous stem cell transplantation 
(ASCT) in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Proc Am 
Soc Clin Oncol 2006;24(18S):7535. 


Protocol 2398.00 
Page 26 of 34 
26. 
Ferrucci PF, Vanazzi A, Grana CM, et al. High activity 90Y-ibritumomab tiuxetan 
(Zevalin) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell 
non-Hodgkin lymphomas. Br J Haematol 2007;139:590-9. 
27. 
Devizzi L, Guidetti A, Tarella C, et al. High-dose yttrium-90-ibritumomab tiuxetan with 
tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic 
cell transplantation. J Clin Oncol 2008;26:5175-82. 
28. 
Winter JN, Inwards DJ, Spies S, et al. Yttrium-90 ibritumomab tiuxetan doses calculated 
to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and 
autologous transplantation in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin 
Oncol 2009;27:1653-9. 
29. 
Nademanee A, Molina, A,  Forman, S,  Kogut, N, Yamauchi, D, Liu, An, White, C,  
Raubitschek, A. A Phase I/II Trial of High-Dose Radioimmunotherapy (RIT) with Zevalin in 
Combination with High-Dose Etoposide (VP-16) and Cyclophosphamide (CY) Followed by 
Autologous Stem Cell Transplant (ASCT) in Patients with Poor-Risk or Relapsed B-Cell Non-
Hodgkin's Lymphoma (NHL). American Society of Hematology Annual Meeting 2002;Abstract # 
679. 
30. 
Nademanee A, Forman S, Molina A, et al. A phase 1/2 trial of high-dose yttrium-90-
ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed 
by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin 
lymphoma. Blood 2005;106:2896-902. 
31. 
Knox SJ, Goris ML, Trisler K, et al. Yttrium-90-labeled anti-CD20 monoclonal antibody 
therapy of recurrent B- cell lymphoma. Clin Cancer Res 1996;2:457-70. 
32. 
Gopal AK, Press OW, Wilbur SM, Maloney DG, Pagel JM. Rituximab Blocks Binding of 
Radiolabeled Anti-CD20 Antibodies (Ab) but not Radiolabeled Anti-CD45-Ab. American Society 
of Hematology 2007;110: 525. 
33. 
Johnson TA, Press OW. Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal 
antibodies and chemotherapy for treatment of B-cell lymphomas. Int J Cancer 2000;85:104-12. 
34. 
Leonard J, Coleman M, Kostakoglu L, et al. Bexxar (Iodine I-131 Tositumomab and 
Tositumomab) Can be Administered Safely in Sequential Combination with Chemotherapy in 
Initial Treatment of Non-Hodgkin's Lymphoma (NHL). Proceeding of the American Society of 
Oncology 2001; 
35. 
Matthews DC, Appelbaum FR, Eary JF, et al. Phase I study of (131)I-anti-CD45 antibody 
plus cyclophosphamide and total body irradiation for advanced acute leukemia and 
myelodysplastic syndrome. Blood 1999;94:1237-47. 
36. 
Appelbaum FR, Matthews DC, Eary JF, et al. The use of radiolabeled anti-CD33 
antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous 
leukemia. Transplantation 1992;54:829-33. 
37. 
Matthews DC, Appelbaum FR, Eary JF, et al. Development of a marrow transplant 
regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled 
anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood 
1995;85:1122-31. 
38. 
Bunjes D, Buchmann I, Duncker C, et al. Rhenium 188-labeled anti-CD66 (a, b, c, e) 
monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for 
patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase 
I-II study. Blood 2001;98:565-72. 
39. 
Jurcic JG, Caron PC, Nikula TK, et al. Radiolabeled anti-CD33 monoclonal antibody 
M195 for myeloid leukemias. Cancer Res 1995;55:5908s-10s. 
40. 
Matthews DC, Martin PJ, Nourigat C, Appelbaum FR, Fisher DR, Bernstein ID. Marrow 
ablative and immunosuppressive effects of 131I-anti-CD45 antibody in congenic and H2-
mismatched murine transplant models. Blood 1999;93:737-45. 


Protocol 2398.00 
Page 27 of 34 
41. 
Burke JM, Caron PC, Papadopoulos EB, et al. Cytoreduction with iodine-131-anti-CD33 
antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow 
Transplant 2003;32:549-56. 
42. 
Pagel J, Appelbaum F, Rajendran J, et al. 131I-anti-CD45 Antibody Plus Fludarabine, 
Low-Dose TBI and PBSC Infusion for Elderly Patients with Advanced Acute Myeloid Leukemia 
or High-Risk Myelodysplastic Syndrome. Blood 2005;106:119a. 
43. 
Ringhoffer M, Blumstein N, Neumaier B, et al. 188Re or 90Y-labelled anti-CD66 
antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or 
myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol 
2005;130:604-13. 
44. 
Pagel JM, Appelbaum FR, Eary JF, et al. 131I-anti-CD45 antibody plus busulfan and 
cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute 
myeloid leukemia in first remission. Blood 2006;107:2184-91. 
45. 
Sorror M, Storer B, Sandmaier, et al. Sustained Graft-Versus-Lymphoma Effect among 
Patients (pts) with Mantle Cell Lymphoma (MCL) Given Nonmyeloablative Allogeneic 
Hematopoietic Cell Transplantation (HCT). Blood 8 November 16, 2008. 
46. 
Robinson SP, Goldstone AH, Mackinnon S, et al. Chemoresistant or aggressive 
lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell 
transplantation: an analysis from the Lymphoma Working Party of the European Group for 
Blood and Bone Marrow Transplantation. Blood 2002;100:4310-6. 
47. 
Robinson SP, Sureda A, Canals C, et al. Identification of Prognostic Factors Predicting 
the Outcome of Reduced Intensity Allogeneic Stem Cell Transplantation in Mantle Cell 
Lymphoma. An Analysis from the Lymphoma Working Party of the EBMT. Blood 
2008;November 16. 
48. 
Gopal AK, Pagel JM, Rajendran JG, et al. Improving the Efficacy of Reduced Intensity 
Allogeneic Transplantation for Lymphoma using Radioimmunotherapy. Biol Blood Marrow 
Transplant 2006;12:697-702. 
49. 
Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host 
disease. N Engl J Med 2005;353:1321-31. 
50. 
Messina G, Giaccone L, Festuccia M, et al. Multicenter experience using total lymphoid 
irradiation and antithymocyte globulin as conditioning for allografting in hematological 
malignancies. Biol Blood Marrow Transplant 2012;18:1600-7. 
51. 
Kohrt HE, Turnbull BB, Heydari K, et al. TLI and ATG conditioning with low risk of graft-
versus-host disease retains antitumor reactions after allogeneic hematopoietic cell 
transplantation from related and unrelated donors. Blood 2009;114:1099-109. 
52. 
Press OW, Eary JF, Appelbaum FR, et al. Radiolabeled-antibody therapy of B-cell 
lymphoma with autologous bone marrow support. N Engl J Med 1993;329:1219-24. 
53. 
Chen YB, Cutler CS. Biomarkers for acute GVHD: can we predict the unpredictable? 
Bone Marrow Transplant. E-pub: 2012 Aug 6. 10.1038/bmt.2012.143. 
54. 
Lan F, Zeng D, Higuchi M, Higgins JP, Strober S. Host conditioning with total lymphoid 
irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-
reactive natural killer T cells. Biol Blood Marrow Transplant 2003;9:355-63. 
55. 
Liu YP, Li Z, Nador RG, Strober S. Simultaneous protection against allograft rejection 
and graft-versus-host disease after total lymphoid irradiation: role of natural killer T cells. 
Transplantation 2008;85:607-14. 
56. 
Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-versus-host disease 
prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol 2012;30:3202-8. 
57. 
Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell 
(Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. 
Blood 2006;108:1291-7. 


Protocol 2398.00 
Page 28 of 34 
58. 
Zorn E, Kim HT, Lee SJ, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T 
cells in patients with chronic graft-versus-host disease. Blood 2005;106:2903-11. 
59. 
Holler E, Kolb HJ, Moller A, et al. Increased serum levels of tumor necrosis factor alpha 
precede major complications of bone marrow transplantation. Blood 1990;75:1011-6. 
60. 
Imamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels in bone marrow 
transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis 
factor-alpha in graft-versus-host disease. Bone Marrow Transplant 1994;13:745-51. 
61. 
Or R, Kalinkovich A, Nagler A, et al. Soluble tumor necrosis factor (sTNF) receptors: a 
possible prognostic marker for bone marrow transplantation-related complications. Cytokines 
and molecular therapy 1996;2:243-50. 
62. 
Fujimori Y, Takatsuka H, Takemoto Y, et al. Elevated interleukin (IL)-18 levels during 
acute graft-versus-host disease after allogeneic bone marrow transplantation. Br J Haematol 
2000;109:652-7. 
63. 
Nakamura H, Komatsu K, Ayaki M, et al. Serum levels of soluble IL-2 receptor, IL-12, IL-
18, and IFN-gamma in patients with acute graft-versus-host disease after allogeneic bone 
marrow transplantation. The Journal of allergy and clinical immunology 2000;106:S45-50. 
64. 
Schots R, Kaufman L, Van Riet I, et al. Proinflammatory cytokines and their role in the 
development of major transplant-related complications in the early phase after allogeneic bone 
marrow transplantation. Leukemia : official journal of the Leukemia Society of America, 
Leukemia Research Fund, UK 2003;17:1150-6. 
65. 
Visentainer JE, Lieber SR, Persoli LB, et al. Serum cytokine levels and acute graft-
versus-host disease after HLA-identical hematopoietic stem cell transplantation. Experimental 
hematology 2003;31:1044-50. 
66. 
Paczesny S, Krijanovski OI, Braun TM, et al. A biomarker panel for acute graft-versus-
host disease. Blood 2009;113:273-8. 
67. 
Paczesny S, Braun TM, Levine JE, et al. Elafin is a biomarker of graft-versus-host 
disease of the skin. Science translational medicine 2010;2:13ra2. 
68. 
Cho BS, Min CK, Kim HJ, et al. High levels of B cell activating factor during the 
peritransplantation period are associated with a reduced incidence of acute graft-versus-host 
disease following myeloablative allogeneic stem cell transplantation. Biol Blood Marrow 
Transplant 2010;16:629-38. 
69. 
Thiant S, Yakoub-Agha I, Magro L, et al. Plasma levels of IL-7 and IL-15 in the first 
month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. 
Bone Marrow Transplant 2010;45:1546-52. 
70. 
Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation 
after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body 
irradiation for elderly patients with advanced acute myeloid leukemia or high-risk 
myelodysplastic syndrome. Blood 2009. 
71. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579-86. 
 


Protocol 2398.00 
Page 29 of 34 
APPENDIX A 
SWOG/ECOG Performance Status 
 
PERFORMANCE STATUS SCALE 
 
STATUS1,2 
(Karnofsky) 
SCALE 
"WHO" - STATUS3,4 
(Zubrod-ECOG) 
 
 
 
 
Normal, no complaints 
 100 
0 
Normal activity 
 
 
 
 
Able to carry on normal activity 
 90 
1 
Symptoms, but 
Minor signs or symptoms of disease 
 
 
ambulatory 
 
 
 
 
Normal activities for effort 
 80 
 
 
 
 
 
 
Cares for self, unable to carry on 
 70 
2 
Some bed time, but in  
normal activity or to do active 
 
 
bed less than 50% of 
work 
 
 
normal daytime 
 
 
 
 
Requires occasional assistance, but 
 60 
 
 
able to care for most of own needs 
 
 
 
 
 
 
 
Requires considerable assistance and 
 50 
3 
Needs to be in bed 
frequent medical care 
 
 
more than 50% of 
 
 
 
normal daytime 
 
 
 
 
Disabled, requires special care and  
 40 
 
 
assistance 
 
 
 
 
 
 
 
Severely disabled, hospitalization 
 30 
4 
Unable to get out of 
indicated though death not 
 
 
bed 
imminent 
 
 
 
 
 
 
 
Very sick, hospitalization necessary, 
 20 
 
 
active supportive treatment 
 
 
 
necessary 
 
 
 
 
 
 
 
Moribund 
 10 
 
 
 
 
 
 
Dead 
 
0 
 
 
 
1. Karnofsky,D.A., Abelmann,W.H., Craver,L.F., and Burchenal,J.H.,  The use of the 
nitrogen mustards in the palliative treatment of carcinoma.  Cancer (Philad.) 1: 634, 
1948. 
2. Schag,C.C., Heinrich,R.L., Ganz,P.A., Karnofsky Performance Status Revisited: 
Reliability, Validity, and Guidelines,  Clinical Oncology.  2, 187-193, 1984 
3. Zubrod,C.G., et.al. Appraisal of Methods for the Study of Chemotherapy of Cancer in 
Man.  Journal of Chronic Diseases.  11: 7-33, 1960 
4. WHO Handbook for Reporting Results of Cancer Treatment.  WHO Offset Publication 
No.48.  World Health Organization,  Geneva,  1979 


Protocol 2398.00 
Page 30 of 34 
 
 


Protocol 2398.00 
Page 31 of 34 
APPENDIX B: 
ACUTE GVHD ASSESSMENT 
 
Staging by Individual Organ Involvement 
 
SKIN: 
measured by rash first appearing generally between 10 and 70 days after transplant. 
(excludes rashes of known viral or other origin) 
 
Stage 
Description 
1 
Maculopapular rash <25% BSA 
2 
Maculopapular rash 25 – 50% BSA 
3 
Generalized erythroderma  
4 
Generalized erythroderma with 
bullous formation and desquamation 
 
LIVER*: 
measured by total serum bilirubin 
 
Stage 
Description 
1 
2.0 – 2.9 mg/dL 
2 
3.0 – 5.9 mg/dL 
3 
6.0 – 14.9 mg/dL 
4 
> 15.0 mg/dL 
 
GUT**: 
includes only diarrhea occurring after Day +21 
 
Score 
Adult 
Pediatric*** 
1 
upper GI (anorexia, nausea, vomiting) 
with diarrhea of <1000 mL/day 
upper GI (anorexia, nausea, vomiting) 
with diarrhea of <555 mL/m2/day 
2 
1000 – 1499 mL/day diarrhea 
556-833 mL/m2/day diarrhea 
3 
> 1500 mL/day diarrhea 
>833 mL/m2/day diarrhea 
4 
severe abdominal cramping, bleeding or ileus caused by GVHD 
 
* 
In cases where another cause of hyperbilirubinemia antedated the onset of rash, the liver score 
should be decreased by one stage. 
** In cases where peak GI symptoms are exacerbated by a cause other than GVHD, the gut score 
should be decreased by one stage. 
*** Pediatric patients <17 years of age 
 
 
 


Protocol 2398.00 
Page 32 of 34 
Overall Grade 
 
The determination of an overall GVHD grade should be based on the organ stage, response to treatment 
and whether GVHD was a major cause of death. 
 
Overall 
Grade 
 Organ Stage 
Qualifying Conditions 
Additional Qualifying Conditions 
I 
Stage 1 -2 skin  
No liver or gut 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD. 
II 
Stage 3 skin  
 
or  
Stage 1 liver  
 
or  
Stage 1 gut 
N/A 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD, but glucocorticoid treatment after 
the onset of GVHD was generally sufficient 
to control the disease. 
III 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
without GVHD as a major 
contributing cause of death 
 
 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD and that additional treatment after 
the onset of GVHD did not readily control 
the disease. 
IV 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
with GVHD as a major 
contributing cause of death 
 
 
GVHD was resistant to both the 
prophylactic immunosuppressive regimen 
and any additional treatment after the onset 
of the disease. 
 


Protocol 2398.00 
Page 33 of 34 
APPENDIX C: 
CHRONIC GVHD GRADING* 
In all cases, concomitant processes (i.e. infections or drug reactions) must be ruled out. Karnofsky or 
Lansky Clinical Performance scores, 60%, > 15% weight loss, and recurrent infections are usually signs of 
clinical extensive chronic GVHD. Abnormalities that could indicate chronic GVHD are categorized by organ 
systems as listed below. 
 
Skin 
Erythema, dryness, pruritus, pigmentary changes (i.e. hyperpigmentation, vitiligo), 
mottling, papulosquamous plaques, nodules, exfoliation, macular-papular or 
urticarial rash, scleroderma, morphea (one or several circumscribed, indurated and 
shiny lesions) 
Nails 
Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying, (scalp hair, eyelashes, eyebrows), thinning scalp hair, alopecia, 
decreased body hair 
Mouth 
Dryness, burning, gingivitis, mucositis, striae, atrophy, erythema, lichenoid changes, 
ulcers, labial atrophy or pigmentary changes, tooth decay, tightness around the 
mouth 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vulva 
Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid changes 
not included 
Liver 
Elevated liver function tests not due to other causes (alkaline phosphatase ≥ 3x 
upper limit of normal, AST or ALT ≥4x upper limit of normal or total serum bilirubin ≥ 
2.5; in the absence of chronic GVHD involving other organs, liver biopsy is required 
to confirm diagnosis) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on 
exertion, history of recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, weight loss, dysphasia, odynophagia, malabsorption 
Fasciitis 
Stiffness and tightness with restriction of movement, occasionally with swelling pain, 
cramping, erythema and induration, most commonly affecting forearms, wrists and 
hands, ankles, legs, and feet, inability to extend wrists without flexing the fingers or 
the elbows, contractures 
Serositis 
Chest pain or cardiopulmonary comprise due to pericarditis or pleuritis 
Muscle 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 
 


Protocol 2398.00 
Page 34 of 34 
Laboratory testing and diagnostic indicators of chronic GVHD* 
Eye 
Schirmer’s test with a mean value ≤ 5mm at 5 minutes, or symptomatic with 
values of 6-10mm or keratitis detected by slit lamp examination 
Liver 
Elevated liver function tests not due to other causes (see definition of clinical 
limited and extensive chronic GVHD) 
Lung 
New obstructive lung defect defined as FEV1 < 80% of predicted with either an 
FEF 25-75 <65% of predicted or RV >120% of predicted, or a decrease of 
FEV1/FVC by > 12% within a period of less than 1 year. A diagnosis of 
bronchiolitis 
obliterans 
requires 
negative 
microbiological 
tests 
from 
bronchoalveolar lavage and evidence of air trapping by high resolution end-
expiratory and end-inspiratory CAT scans o the chest. A thoracoscopic lung 
biopsy may be necessary in order to confirm the diagnosis of bronchiolitis 
obliterans in patients who have obstructive lung disease without air trapping when 
chronic GVHD involving other organs is absent 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by barium 
swallow, endoscopy or manometry 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis 
Blood 
Thrombocytopenia (usually 20,000-100,000/µl), eosinophilia, hypogamma-
globulinemia, hypergammaglobulinemia, and autoantibodies occur in some 
cases 
________________ 
* From Standard Practice Guidelines for “Chronic Graft-versus-Host Disease Classification at the time of 
presentation” developed by Long Term Follow-Up at the FHCRC