Conditions: Graft Versus Host Disease Leukemia Lymphoma
Keywords: graft versus host disease contiguous stage II grade 1 follicular lymphoma contiguous stage II grade 2 follicular lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma stage I grade 1 follicular lymphoma stage I grade 2 follicular lymphoma stage I grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma contiguous stage II adult diffuse large cell lymphoma noncontiguous stage II adult diffuse large cell lymphoma recurrent adult diffuse large cell lymphoma stage I adult diffuse large cell lymphoma stage III adult diffuse large cell lymphoma stage IV adult diffuse large cell lymphoma Waldenstrom macroglobulinemia contiguous stage II marginal zone lymphoma extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma noncontiguous stage II marginal zone lymphoma recurrent marginal zone lymphoma stage I marginal zone lymphoma stage III marginal zone lymphoma stage IV marginal zone lymphoma B-cell chronic lymphocytic leukemia refractory chronic lymphocytic leukemia stage I chronic lymphocytic leukemia stage II chronic lymphocytic leukemia stage III chronic lymphocytic leukemia stage IV chronic lymphocytic leukemia contiguous stage II mantle cell lymphoma noncontiguous stage II mantle cell lymphoma recurrent mantle cell lymphoma stage I mantle cell lymphoma stage III mantle cell lymphoma stage IV mantle cell lymphoma contiguous stage II adult diffuse mixed cell lymphoma noncontiguous stage II adult diffuse mixed cell lymphoma recurrent adult diffuse mixed cell lymphoma stage I adult diffuse mixed cell lymphoma stage III adult diffuse mixed cell lymphoma stage IV adult diffuse mixed cell lymphoma contiguous stage II small lymphocytic lymphoma noncontiguous stage II small lymphocytic lymphoma recurrent small lymphocytic lymphoma stage I small lymphocytic lymphoma stage III small lymphocytic lymphoma stage IV small lymphocytic lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
RATIONALE: Giving monoclonal antibody therapy, radioimmunotherapy, and chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related donor that do not exactly match the patient's blood, are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and sirolimus before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects and how well giving indium In 111 ibritumomab tiuxetan and yttrium y 90 ibritumomab tiuxetan together with rituximab, fludarabine, melphalan, and donor stem cell transplant works in treating patients with B-cell non-Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVES: I. To evaluate the safety and efficacy of a preparative regimen of Yttrium-90 (90\^Y)- labeled anti-cluster of differentiation (CD)20 monoclonal antibody (MAb) (yttrium Y 90 ibritumomab tiuxetan) in combination with fludarabine (fludarabine phosphate) and melphalan followed by allogeneic hematopoietic stem cell transplant (APBSCT) for treatment of patients with B-cell low-grade non-Hodgkin lymphoma (LG NHL), intermediate-grade non-Hodgkin lymphoma (IG NHL) and mantle cell lymphoma (MCL). II. To evaluate the short- and long-term complications of this new preparative regimen, including rates of engraftment, acute and chronic graft-versus-host-disease (GVHD) and infectious complications. III. To estimate the disease response rate, disease relapse (progression) rate, and non-relapse mortality rate. IV. To perform exploratory studies that seek to measure/characterize the expression of costimulatory molecules and impact of these molecules on the natural killer (NK) and T cells of a subset of lymphoma patients pre- post- allogeneic stem cell transplant (ASCT) and the stem cell product from a portion of sibling donors.

OUTLINE: REDUCED-INTENSITY CONDITIONING: Patients receive rituximab intravenously (IV) followed by indium In-111 ibritumomab tiuxetan IV over 10 minutes on day -21 and rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day -14. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4.

STEM CELL TRANSPLANTATION: Patients undergo APBSCT on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for up to 5 years.

Arms:
arm 1: REDUCED-INTENSITY CONDITIONING: Patients receive rituximab IV followed by indium In-111 ibritumomab tiuxetan IV over 10 minutes on day -21 and rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day -14. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. STEM CELL TRANSPLANTATION: Patients undergo APBSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.

Interventions: intervention 1: rituximab intervention 2: fludarabine phosphate intervention 3: melphalan intervention 4: sirolimus intervention 5: tacrolimus intervention 6: allogeneic hematopoietic stem cell transplantation intervention 7: indium In 111 ibritumomab tiuxetan intervention 8: yttrium Y 90 ibritumomab tiuxetan intervention 9: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given PO intervention 5: Given PO or IV intervention 6: Undergo APBSCT intervention 7: Given IV intervention 8: Given IV intervention 9: Correlative Studies

Protocol document:
Prot_SAP_000.pdf: 
 
IRB # 05149 
                                                                                            12/11/13 
Packet:  28 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 EAST DUARTE ROAD 
DUARTE CA 91010 
DIVISION OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
TITLE: 
A PHASE II STUDY OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT FOR B–CELL NON–
HODGKIN LYMPHOMA USING ZEVALIN®, FLUDARABINE AND MELPHALAN 
CITY OF HOPE PROTOCOL VERSION:    # 05149 
 
Protocol Date: 12/11/13 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
INITIAL REVIEW 
PROTOCOL DATED 08/15/2006 
VERSION 00 
AMENDMENT 01 
PROTOCOL DATED 03/09/2007 
VERSION 01 
AMENDMENT 02 
PROTOCOL DATED 09/07/2007 
VERSION 02 
AMENDMENT 03 
PROTOCOL DATED 11/14/2007 
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AMENDMENT 04 
PROTOCOL DATED 03/13/2008 
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AMENDMENT 05 
PROTOCOL DATED 05/09/2008 
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AMENDMENT 06 
PROTOCOL DATED 09/03/2008 
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AMENDMENT 07 
PROTOCOL DATED 02/04/2009 
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AMENDMENT 08 
PROTOCOL DATED 04/02/2009 
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AMENDMENT 09 
PROTOCOL DATED 07/17/2009 
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AMENDMENT 10 
PROTOCOL DATED 08/18/2009 
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AMENDMENT 11 
PROTOCOL DATED 04/19/2010 
VERSION 11 
AMENDMENT 12 
PROTOCOL DATED 10/04/2010 
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AMENDMENT 13 
PROTOCOL DATED 03/02/2011 
VERSION 13 
AMENDMENT 14 
PROTOCOL DATED 07/13/2011 
VERSION 14 
AMENDMENT 15 
PROTOCOL DATED 11/15/2011 
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AMENDMENT 16 
PROTOCOL DATED 02/13/2012 
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AMENDMENT 17 
PROTOCOL DATED 04/17/2012 
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AMENDMENT 18 
PROTOCOL DATED 05/30/2012 
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AMENDMENT 19 
PROTOCOL DATED 06/21/2012 
VERSION 19 
AMENDMENT  20 
TITLE PAGE DATED 01/17/2013 
VERSION 20 
AMENDMENT 21 
PROTOCOL DATED 08/13/2013 
VERSION 21 
AMENDMENT 22 
PROTOCOL DATED 12/11/2013 
VERSION 22 
AMENDMENT 23 
TITLE PAGE DATED 06/25/2014 
VERSION 23 
AMENDMENT 24 
TITLE PAGE DATED 09/15/2014 
VERSION 24 
AMENDMENT 25 
TITLE PAGE DATED 01/12/2015 
VERSION 25 
AMENDMENT 26 
TITLE PAGE DATED 01/13/2020 
VERSION 26 
AMENDMENT 27 AT CONTINUATION 
Protocol Dated 12/11/2013 (tp) 
Packet: 27 
AMENDMENT 28 AT CONTINUATION 
Protocol Dated 12/11/2013 (tp) 
Packet: 28 
 
SITE: 
Lymphoma 
HISTOLOGY: 
Relapsed/Refractory Low–Grade, Mantle Cell, Intermediate– 
 
Grade Non–Hodgkin Lymphoma 
STAGE (IF APPLICABLE): 
N/A 
MODALITY: 
Chemotherapy, Radioimmunotherapy, Allogeneic Stem Cell  
 
Transplantation 
TYPE: 
Phase II Study 
PRINCIPAL INVESTIGATOR: 
 
 
Matthew Mei, MD  
 
COLLABORATING INVESTIGATORS: 
Jeffrey Wong, M.D.  
 
Joycelynne Palmer, Ph.D.,  
PARTICIPATING CLINICIANS: 
 
 
Firoozeh Sahebi, MD 
Ibrahim Aldoss, MD  
 
Ahmed Aribi, MD  
Tanya Siddiqi, MD 
Ravi Bhatia, MD  
Amrita Krishnan, MD 
 
Eileen Smith, MD  
Ji-Lian Cai, MD 
 
Ryotaro Nakamura, MD 
Nitya Nathwani, MD 
 
Ricardo Spielberger, MD Anthony Stein, MD   
Len Farol, MD 
 
Jasmine Zain, MD 
 
Stephen J. Forman, MD 
Leslie Popplewell, MD                      
Myo Htut, MD                      Alex Herrera, MD  
 
Savita Dandapani, MD        Haris Ali, MD
Dave Yamauchi, MD 
Thai Cao, MD 
 
 
Monzr Al Malki, MD 
Vinod Pullarkat, MD 
 


 
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12/11/13 
TABLE OF CONTENTS 
 1.0 
PROPOSED STUDY ............................................................................................................................. 4 
 2.0 
OBJECTIVES ...................................................................................................................................... 4 
 3.0 
BACKGROUND AND RATIONALE .......................................................................................................... 4 
3.1 
INTRODUCTION .............................................................................................................................. 4 
3.2 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR 
NON–HODGKIN LYMPHOMA (NHL) ................................................................................................ 5 
3.3 
MANTLE CELL LYMPHOMA (MCL) .................................................................................................. 7 
3.4 
DIFFUSE LARGE–CELL B–CELL NON–HODGKIN LYMPHOMA (B–DLCL NHL) ................................. 8 
3.5 
LOW–GRADE NON–HODGKIN LYMPHOMA (LG NHL) ...................................................................... 9 
3.6 
RADIOIMMUNOTHERAPY (RIT) FOR B–CELL NON–HODGKIN LYMPHOMA (NHL) ............................ 10 
3.7 
PERIPHERAL BLOOD B-CELL DEPLETION WITH RITUXIMAB ............................................................ 14 
 4.0 
DRUG FORMULATION ........................................................................................................................ 15 
4.1 
RITUXAN® (IDEC–C2B8 OR RITUXIMAB) ...................................................................................... 15 
4.2 
ZEVALIN® (IDEC–2B8–MX–DTPA OR IBRITUMOMAB TIUXETAN) ................................................. 16 
4.3 
FLUDARA  (2–FLUORO–ARA–AMP, FLUDARABINE PHOSPHATE OR FLUDARABINE) ...................... 16 
4.4 
ALKERAN  (L–PHENYLALANINE MUSTARD, L–PAM OR MELPHALAN) ........................................... 17 
4.5 
PROGRAF® (FK–506 OR TACROLIMUS) ........................................................................................ 17 
4.6 
RAPAMUNE® (SIROLIMUS) ............................................................................................................ 18 
4.7 
METHOTREXATE .......................................................................................................................... 19 
4.8 
NEUPOGEN® (G–CSF, GRANULOCYTE–COLONY STIMULATING FACTOR OR 
FILGRASTIM) ............................................................................................................................... 19 
 5.0 
PATIENT SELECTION ......................................................................................................................... 20 
5.1 
INCLUSION CRITERIA ................................................................................................................... 20 
5.2 
EXCLUSION CRITERIA .................................................................................................................. 21 
5.3 
DONOR SELECTION ..................................................................................................................... 22 
5.4 
GENDER AND MINORITY INCLUSIONS AT CITY OF HOPE NATIONAL MEDICAL CENTER (COHNMC) . 22 
 6.0 
STUDY DESIGN ................................................................................................................................. 22 
6.1        TOXICITY GRADING AND REPORTING ............................................................................................ 23 


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TABLE OF CONTENTS (CONTINUED) 
 7.0 
TREATMENT PLAN ............................................................................................................................ 23 
7.1 
TREATMENT SCHEMA .................................................................................................................. 23 
7.2 
REDUCED INTENSITY CONDITIONING (RIC) REGIMEN .................................................................... 24 
7.3 
IMMUNOSUPPRESSION [GRAFT–VERSUS–HOST–DISEASE (GVHD) PROPHYLAXIS] ....................... 26 
7.4 
COLLECTION OF DONOR HEMATOPOIETIC STEM CELLS (PBSCS) ................................................. 29 
7.5 
HEMATOPOIETIC STEM CELL (PBSC) INFUSION ........................................................................... 30 
7.6 
DONOR LYMPHOCYTE INFUSION (DLI) .......................................................................................... 30 
7.7 
SUPPORTIVE CARE ...................................................................................................................... 30 
7.8 
GUIDELINES FOR TAPERING IMMUNOSUPPRESSION ....................................................................... 31 
 8.0 
PATIENT EVALUATIONS .................................................................................................................... 32 
8.1 
EVALUATION/TESTS DURING THE 111IN–ZEVALIN® IMAGING PERIOD .............................................. 31 
8.2 
EVALUATION/TESTS DURING THE 90Y–ZEVALIN® TREATMENT PERIOD UP TO MONTH 3................... 32 
 9.0 
STUDY CALENDAR ........................................................................................................................... 33 
9.1 
STUDY CALENDAR ― PRE–STUDY THROUGH DAY 0 (TRANSPLANT DAY) ...................................... 33 
9.2 
STUDY CALENDAR ― DAY 1 THROUGH DAY 84 POST–TRANSPLANT ............................................. 34 
9.3 
STUDY CALENDAR ― DAY 90 THROUGH YEAR 5 POST–TRANSPLANT FOLLOW–UP ....................... 35 
10.0 
MEASUREMENT OF EFFECT ............................................................................................................... 36 
10.1 
STAGING CRITERIA ...................................................................................................................... 36 
10.2 
CRITERIA FOR EVALUATIONS AND ENDPOINT DEFINITIONS ― REVISED RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMA ......................................................................................... 36 
10.3 
PERFORMANCE STATUS .............................................................................................................. 41 


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TABLE OF CONTENTS (CONTINUED) 
11.0 
INTERNAL REGULATORY REQUIREMENTS ............................................................................................ 41 
11.1 
INSTITUTIONAL REVIEW BOARD (IRB) .......................................................................................... 41 
11.2 
CANCER PROTOCOL REVIEW AND MONITORING COMMITTEE (CPRMC) ........................................ 41 
11.3 
DATA AND SAFETY MONITORING BOARD (DSMB) ........................................................................ 41 
12.0 
ETHICAL CONSIDERATIONS ............................................................................................................... 43 
12.1 
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPPA) ........................................ 43 
12.2 
MEASURES TO ASSURE PROTECTED HEALTH INFORMATION (PHI) CONFIDENTIALITY ..................... 43 
13.0 
FORMS AND DATA MANAGEMENT...................................................................................................... 43 
13.1 
INFORMED CONSENT ................................................................................................................... 44 
13.2 
REGISTRATION GUIDELINES ......................................................................................................... 44 
13.3 
PROCEDURES FOR WAIVERS OF ELIGIBILITY AND TREATMENT DEVIATIONS ................................... 44 
13.4 
DATA MANAGEMENT ................................................................................................................... 44 
13.5 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE ........................................................... 44 
14.0 
STATISTICAL CONSIDERATIONS .......................................................................................................... 44 
15.0 
REFERENCES ..................................................................................................................................... 47 
 
APPENDIX I   MODIFIED Bearman Toxicity Scale  
 
 
 
 
 
 
NOTE: This protocol was written in compliance with the policies and procedures of THE CITY OF HOPE 
NATIONAL MEDICAL CENTER HEMATOPOIETIC CELL TRANSPLANT PROGRAM; CLINICAL MANUAL; STANDARD 
OPERATING POLICIES AND PROCEDURES; SEPTEMBER 2004.  Sections in this protocol followed by Ω § [#] refer 
to information found in the HCT CLINICAL MANUAL. 
 
 
 


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1.0 
PROPOSED STUDY 
As a member of the West Coast Transplant Consortium (WCTC), City of Hope National Medical Center 
(COHNMC) has extensive experience with the use of Reduced Intensity Conditioning (RIC) regimens.  
Fludarabine, 125 mg/m2 and Melphalan, 140 mg/m2 followed by Allogeneic Hematopoietic Stem Cell 
Transplant (AHSCT) has been used effectively with limited toxicity in patients with hematologic 
malignancies.1, 30  However, relapse remains a significant cause of failure for patients with aggressive 
histologies.31 
Because of its relative safety and ability to target radiation directly to lymphoma cells, IDEC–2B8–MX–
DTPA [Ibritumomab Tiuxetan (Zevalin®)] will be combined with the RIC regimen of Fludarabine and 
Melphalan.  This preparative regimen will be used in selected patients with relapsed or refractory Low–
Grade Lymphoma (LGL), Mantle Cell Lymphoma (MCL) and Intermediate–Grade Non–Hodgkin 
Lymphoma (IG NHL).  The goal of this protocol is to use Zevalin® to increase the anti–lymphoma effect in 
these B–Cell lymphomas while at the same time preserving the adoptive immunotherapeutic Graft–
Versus–Lymphoma (GVL) effect and low Transplant–Related Mortality (TRM) associated with our current 
RIC regimen. 
This study will be a Phase II trial of 46 patients focusing on TRM, Relapse–Free Survival (RFS), Overall 
Survival (OS) and toxicity. Early stopping rules will be incorporated for safety outcomes.  However, there 
will be no early stopping based on efficacy.  For details on stages of accrual and sample size 
requirements, please refer to § 14.0 STATISTICAL CONSIDERATIONS. 
2.0 
OBJECTIVES 
2.1 
To evaluate the safety and efficacy of a preparative regimen of Yttrium–90 (90Y)–
Labeled Anti–CD20 Monoclonal Antibody (MAb) in combination with Fludarabine and 
Melphalan followed by Allogeneic Hematopoietic Stem Cell Transplant (APBSCT) for 
treatment of patients with B–Cell Low–Grade Non–Hodgkin Lymphoma (LG NHL), 
Intermediate–Grade Non–Hodgkin Lymphoma (IG NHL) and Mantle Cell Lymphoma 
(MCL). 
2.2 
To evaluate the short– and long–term complications of this new preparative regimen, 
including rates of engraftment, Acute and Chronic Graft–Versus–Host–Disease 
(GVHD) and infectious complications. 
2.3 
To estimate the disease response rate, disease relapse (progression) rate, and non-
relapse mortality rate. 
2.4 
To perform exploratory studies that seek to measure/characterize the expression of 
costimulatory molecules and impact of these molecules on the NK and T cells of a 
subset of lymphoma patients pre- post- ASCT and the stem cell product from a 
portion of sibling donors. 
3.0 
BACKGROUND AND RATIONALE 
3.1. 
INTRODUCTION 
Non–Hodgkin Lymphoma (NHL) is the fifth most common cancer in the United States.  According to 
the American Cancer Society (ACS), approximately 58,870 people in the United States will be 
diagnosed with Hodgkin Disease (HD) or NHL, and an estimated 18,840 will die from either disease 
in 2006.  These numbers include both adults and children.  But the incidence of most types of 
indolent and aggressive lymphomas increases with age.  It is estimated that a person‟s risk of 
developing the disease in his or her lifetime is approximately 1 in 50.  The risk of dying of the disease 
is about 1 in 100.  This cancer is somewhat more common in men than in women.  Men have a 1 in 
46 risk of developing NHL over his lifetime.  Women have a 1 in 55 risk of developing NHL over her 
lifetime.  Whites are affected more often than African Americans or Asian Americans.  Between 1973 
and 1996 the incidence of NHL increased by 80% in the United States.2 


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IRB # 05149, Version 22 
 
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Based on unique clinicopathologic features defined in the Revised European American Classification 
of Lymphoid Malignancies (REAL) and World Health Organization (WHO) classification system, 
Diffuse Large–Cell Lymphoma (DLCL), Follicular Lymphoma (FL) and MCL are diagnosed in 
approximately 31%, 22%, and 6%, respectively, of all new adult lymphoma diagnoses.3  
Approximately 30–40% of patients with DLCL can be cured with conventional chemotherapy,4 
whereas MCL and LGL are incurable with similar therapies.5 
High–Dose Therapy (HDT) with autologous Hematopoietic Stem Cell Transplantation (aHSCT) can 
rescue patients with DLCL who fail to achieve a remission or relapse after initial therapy, but 
treatment failure occurs in the majority of these patients, with Long–Term Survival (LTS) seen in 
approximately 30–40% of these patients.6, 7  Relapse is also common after aHSCT for MCL and FL.8 
Relapse after aHSCT may be the result of tumor contamination of the re–infused Stem Cells (SCs) or 
intrinsic resistance of malignant cells to HDT.  Moreover, many patients fail to collect adequate 
numbers of SCs due to Bone Marrow (BM) involvement with lymphoma or extensive prior 
chemoradiotherapy.  Patients who relapse after conventional therapy and cannot undergo aHSCT, or 
those relapsing after this procedure usually have short median survivals. 
Allogeneic donors can provide an alternative source of healthy Hematopoietic Stem Cells (HSCs) for 
these patients, with the added benefit of a potential GVL effect.  The GVL effect in lymphoma has 
been demonstrated by the efficacy of Donor Lymphocyte Infusions (DLIs) after relapse from all 
AHSCTs 9, 10, 11 and by the observation that relapses occur less frequently after AHSCT as compared 
to aHSCT.12, 13, 14  This effect is more pronounced in the LGLs.  The evidence for a GVL effect in MCL 
and DLCL is weaker, coming from studies reporting responses following withdrawal of 
immunosuppression or coincidental with the development of GVHD15, decreased relapse rates in 
patients with GVHD,16, 17 remissions after DLI and relapses in patients with graft rejection.18, 19  The 
potential benefit of the GVL effect from AHSCT has been offset in most cases by the increased 
toxicity of this procedure compared to aHSCT, resulting from Regimen–Related Toxicity (RRT) and 
GVHD.  To try to improve these results, RIC regimens have been successfully developed, allowing 
adequate engraftment in most cases and decreasing the RRT considerably.  These regimens rely 
predominantly on the GVL effect for their success.  As expected, patients with malignancies that are 
more vulnerable to this effect, such as LGLs and Chronic Lymphocytic Leukemia (CLL), have 
benefited more from this approach.20  Conversely, decreasing the power of the regimen may 
compromise disease control for patients with High(er)–Grade Lymphomas (HGLs) and other 
aggressive hematological malignancies.  This issue cannot be overstated given the observation that 
relapse contributes significantly to treatment failure and that chemosensitivity consistently appears 
predictive of outcome following AHSCTs for NHL and Acute Myelogenous Leukemia (AML).9, 21, 22, 30   
The study will also focus on costimulatory receptors, namely, PD-1, CTLA-4, CD28, ICOS, OX40 and 
4-1BB (CD137), and will be performed on blood samples collected at various time points before and 
after the AHSCT regimen, using either FACS analysis or mRNA Q-PCR.  The results may contribute 
to a better understanding of immune factors important in outcome.  To date, we have shown that the 
PD-1 molecule was up-regulated in HCT subjects before the development of CMV disease.  Similar 
techniques will be used for the expression of the other costimulatory receptors. 
Therefore, improving the potency of the conditioning regimen for lymphoma with targeted therapies, 
such as radioimmunoconjugates, would be a desirable goal in the AHSCT setting, by combining 
improved tumor control with a potential GVL effect, without significantly increasing RRT. 
3.2 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR NON–HODGKIN LYMPHOMA 
(NHL) 
The use of AHSCT in the treatment of NHL is increasing.  Although there are no large prospective 
randomized trials comparing the outcome of aHSCT versus AHSCT in NHL, most retrospective 
comparisons suggest that there is a lower risk of relapse following AHSCT, particularly in patients 
with LGL.  Unfortunately, AHSCT is also associated with a higher rate of early and late TRM, which 
tends to offset any potential advantage conferred by the reduced risk of relapse. 


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IRB # 05149, Version 22 
 
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We recently evaluated the long–term results in 55 patients who underwent a traditional myeloablative 
AHSCT at COHNMC between 1/91 and 5/99.23  All patients have had adequate follow–up to 
determine LTS and risk of relapse.  In this study the median age was 40.7 years (range 18–54).  
Fifteen patients (27%) had LGL, 16 patients (29%) had Intermediate–Grade Lymphoma (IGL), 8 
patients (15%) had MCL and 16 patients (29%) had HGL.  In this series, 93% of patients had 
advanced disease including relapse, PR after initial treatment or Progressive Disease (PD) during 
induction or multiple relapses.  The majority of patients received a Fractionated Total Body Irradiation 
(FTBI) containing regimen.  At the time of this analysis, 29 patients (53%) were alive.  Overall, the 
TRM was 29% and the relapse rate was 20%.  The Kaplan–Meier estimates for the 2 year OS and 
RFS rates for the entire group were 46% and 42% (see FIGURE 1A and FIGURE 1B).  The 2 year OS 
probability by histologic subtypes were: LGL 83%, IGL 33%, HGL 0%, and MCL 56%, with a 
statistically significant difference seen between LGL and HGL patients based on the log–rank test 
(p=0.0110) (see FIGURE 2). 
These results suggest that AHSCT is an effective therapeutic strategy in selected patients with poor 
risk or refractory lymphoma.  Compared to aHSCT, the relatively lower risk of relapse observed in this 
study is in agreement with other reported trials, which suggest that AHSCT introduces a GVL effect.24, 
25, 26  Although the median age of patients with LGL and MCL is about 60 years, the median age of 
patients in our study was 40–41 years because, as commonly is the case, older patients were 
excluded because of concerns over the higher TRM and mortality associated with conventional Total 
Body Irradiation (TBI) based allografting in older patients.  Thus, the use of non–myeloablative or RIC 
regimens and AHSCT as part of a clinical trial should be explored for an older, less robust patient 
population and for those patients who would not be candidates to receive an aHSCT. 
Recent studies conducted in the WCTC involving primarily the Fred Hutchinson Cancer Center 
(FHCC), COHNMC and Stanford University have explored the use of a potentially less toxic approach 
to allografting for older patients (≥ 50 years) with LG NHL, AML and multiple myeloma – diseases not 
readily cured by autografting.27, 28  These studies are based on the use of potent immunosuppression 
using Fludarabine, low dose TBI, Cyclosporine A (CSA) and Mycophenolate Mofetil (MMF) to limit the 
risk of graft rejection and GVHD and thereby establish mixed chimerism as identified in a preclinical 
canine model.  Updates of these trials have evaluated the efficacy of establishing mixed or full donor 
hematopoietic chimerism using a non–myeloablative and relatively non–toxic conditioning regimen for 
allogeneic engraftment and to obtain preliminary data on GVL or Graft–Versus–Tumor (GVT) effects 
in a variety of tumor types and clinical situations (remissions, relapse).  The results from treatment of 
lymphoma with this approach for 74 patients (29 DLCL, 16 MCL and 29 LGL) show a Progression–
Free Survival (PFS) of 48% at 1 year for the whole group.  When analyzed by histology, the more 
aggressive form of the disease showed a PFS of 35% with a relapse rate of 33% while those patients 
with LGL showed a RFS of 60% and relapse of 16% with a median follow–up of a little > 1 year.29 
Based on the idea that some component of anti–tumor activity, in addition to the anti–tumor 
allogeneic response would be necessary for patients with this disease to improve the overall 
outcome, without increasing the toxicity, at COHNMC we conducted a parallel study to those active in 
the consortium with a regimen of Fludarabine and Melphalan (140 mg/m2).  In this Phase I/II Trial of 
40 patients, all patients received Human Leukocyte Antigen (HLA) matched related or unrelated 
N = 55 
10 
9 
8 
7 
6 
5 
4 
3 
2 
1 
0 
FIGURE 2B 
Time Post-BMT (Years) 
ALLO HSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA: 
PROGRESSION FREE SURVIVAL (PFS) 
0.0 
0.2 
0.4 
0.6 
0.8 
1.0 
9 
8 
7 
6 
5 
4 
3 
2 
1 
0 
10 
FIGURE 2A 
Cumulative Survival Probability 
Time Post-BMT (Years) 
ALLO HSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA: 
OVERALL SURVIVAL (OS) 
N = 55 
High (n = 16) 
Intermediat e (n = 16) 
Low (n = 15) 
Mantle Cell (n = 8) 
ALLO HSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA 
OS: HISTOLOGIC GRADE 
Cumulative Survival Probability 
Time Post-BMT (Years) 
FIGURE 3 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1.0 
0.0 
0.4 
0.2 
0.8 
0.6 
FIGURE 1A 
FIGURE 1B 
FIGURE 2 
ALLOHSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA 
OVERALL SURVIVAL (OS) 
ALLOHSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA 
RELAPSE FREE SURVIVAL (RFS) 
ALLOHSCT FOR POOR RISK NON-HODGKIN‟S LYMPHOMA 
OS:  HISTOLOGIC GRADE 


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transplant and all engrafted with full chimerism.  Disease–Free Survival (DFS) was 54% at 1 year for 
all patients, 67% for LGL and 48% for DLCL.  Similar to the more RIC approach of our studies with 
Seattle, relapse was more common in those patients with advanced DLCL.30  
In summary, taken together, the 2 studies, along with data from MD Anderson Cancer Center 20, 21, 31 
suggest that the RIC AHSCT approach is very effective in some patients with lymphoma.  The 
therapy appears to be more successful in controlling disease for those patients with LGL and that 
relapse is higher in patients with more aggressive histology, despite the apparent GVL effect that is a 
major component of the treatment.  Thus, based on the clinical and toxicity observations we have to 
date concerning the incorporation of the radiolabeled anti CD20 antibody into the aHSCT regimen,32 
33 we hypothesize that we can augment the anti–tumor efficacy of the allogeneic RIC regimen by the 
addition of antigen specific RIT against the CD20 antigen on B–Cell lymphoma, without an increase in 
RRT for patients with advanced lymphoma who would not be good candidates to benefit from the 
autologous approach (BM/blood involvement, multiple relapsed LGL, MCL). 
3.3 
MANTLE CELL LYMPHOMA (MCL) 
3.3.1 
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR MANTLE CELL LYMPHOMA 
(MCL) 
MCL is associated with a poor prognosis and median OS of 3 years when treated with standard 
chemotherapy.  Advanced stage disease, including BM and Peripheral Blood (PB) involvement, is 
commonly seen at diagnosis.  Response to conventional treatment approaches such as CHOP 
chemotherapy tends to be poor and PD is usually seen within 12–18 months.1 
A recent update of the combined COHNMC/Stanford experience with 45 MCL patients undergoing 
aHSCT showed a higher OS and Event–Free Survival (EFS) rate for patients undergoing 
transplantation in first remission (CR1) (n=16) compared to patients beyond CR1 (n=29).34  In this 
analysis, the median follow–up was 2.6 months.  The OS and EFS were 94% and 87% for CR1 
patients compared to 61% and 38%, respectively, for patients beyond CR1.  Relapse rate was lower 
(8% vs 56%) in CR1 patients. 
Other studies have yielded conflicting results from aHSCT for MCL.  Some show inferior outcome 
compared with historical controls,35 and continued trend of relapse,8, 36 whereas others suggest 
apparent benefit.37, 38  Other studies support our observation that aHSCT may be more effective in 
CR1.39-42 
In summary, results from these studies have not clarified the role of aHSCT in the treatment of MCL 
due to lack of controlled studies; patients in CR1 appear to benefit most.  The routine use of this 
procedure cannot be routinely recommended outside of clinical protocols. 
3.3.2 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR MANTLE CELL LYMPHOMA 
(MCL):  CONVENTIONAL MYELOABLATIVE REGIMENS 
The literature is limited for allogeneic HSCT for MCL.  Few studies have examined conventional dose 
conditioning regimens for this histology; in heavily pre–treated patients, EFS and OS at 2–3 years 
were around 50%–60%, in registry and single institution studies.18, 43  This is in agreement with our 
experience with conventional myeloablative regimens in 10 patients with MCL with a 5 year 
probability of OS and PFS of 40–50%.23, 30 
3.3.3 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR MANTLE CELL LYMPHOMA 
(MCL):  REDUCED INTENSITY CONDITIONING (RIC) REGIMENS 
An appealing strategy for MCL is the use of RIC regimens, given that most patients are older and 
experience excessive toxicity from conventional myeloablative regimens. Conflicting results have 
been reported in this setting. 


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At COHNMC, 5 patients with relapsed MCL underwent sibling AHSCT utilizing Fludarabine and 
Melphalan as conditioning regimen, with CSA and MMF as GVHD prophylaxis.  Patients were heavily 
pre–treated with a median of 3 prior regimens.  Three patients had failed aHSCT.  Three patients had 
chemosensitive disease at the time of transplantation.  All patients engrafted.  At a median follow up 
of 13 months, 2 patients are alive without evidence of PD; 2 patients have relapsed and died of PD 
and 1 died of acute GVHD without evidence of disease.30 
The WCTC has transplanted 16 patients with MCL using a non–myeloablative regimen of Fludarabine 
and single dose TBI, with CSA and MMF as GVHD prophylaxis.  Nine patients are alive in remission 
at 8–36 months after HSCT.29 
A single institution study of 18 patients with advanced/relapsed MCL conditioned with Fludarabine, 
Cyclophosphamide (Cy) and Rituxan® or Cisplatin, Fludarabine and Cytarabine followed by matched 
sibling or unrelated HSCT, with Tacrolimus and Methotrexate for GVHD prophylaxis, was performed 
at MD Anderson.21  Patients were heavily pre–treated with a median of 3 prior regimens.  Four 
patients had relapsed after aHSCT.  All patients engrafted and none experienced > grade 2 acute 
GVHD.  Seventeen patients achieved a CR.  Three patients relapsed post–transplant.  One of these 
patients achieved a CR after DLI.  At a median 26 month follow up, the current EFS was 82%. 
In contrast to MD Anderson and WCTC studies, a retrospective analysis from the European Bone 
Marrow Transplantation (EBMT) Lymphoma Registry reported poor outcomes in this setting.9  
Twenty–two heavily pre–treated patients with advanced MCL, 36% of who had failed previous 
aHSCT, were conditioned with a Fludarabine based regimen in 84% and BEAM in 10% of patients.  
Sixteen patients had chemosensitive disease at the time of transplant.  The 2 year PFS, OS and TRM 
were of 0%, 13%, and 82%, respectively.  The TRM in this series is higher than most studies with RIC 
regimens. 
Overall, the experience with AHSCT for MCL is limited.  Relapse remains a significant cause of 
treatment failure, and may be more common after RIC regimens than with conventional myeloablative 
regimens.  This issue, coupled with the anecdotal evidence of a GVL effect in MCL, the exquisite 
radiosensitivity of MCL and the generally older age of these patients, provides the rationale for 
enhancing the efficacy of RIC regimens with radioimmunoconjugates prior to AHSCT. 
3.4 
DIFFUSE LARGE–CELL B–CELL NON–HODGKIN LYMPHOMA (B–DLCL NHL) 
3.4.1 
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR DIFFUSE LARGE–CELL B–
CELL NON–HODGKIN LYMPHOMA (B–DLCL NHL) 
The role of aHSCT for DLCL in chemosensitive relapse has been well established in a randomized 
study, with 46% of patients in the transplant arm enjoying durable remissions compared to 12% of 
patients salvaged with chemotherapy alone.6  Many patients considered for this approach, however, 
remain refractory to salvage therapy or may not collect adequate SCs due to tumor contamination or 
insufficient BM reserve from prior therapy. 
Convincing data has also emerged for the role of aHSCT in high risk DLCL patients in CR1, though 
this is not widely accepted.  More controversy exists regarding the role of this procedure for patients 
with chemorefractory disease, with few patients achieving long–term remissions.44 
3.4.2 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR DIFFUSE LARGE–CELL 
LYMPHOMA (DLCL):  CONVENTIONAL MYELOABLATIVE REGIMENS 
A multicenter study from France reported 5 year OS and DFS of 41% and 40% in 73 patients with 
aggressive lymphomas, excluding Burkitt‟s and lymphoblastic lymphoma.45  Similarly, a registry 
analysis from the EBMT including 147 patients with IG NHL found a 4 year PFS and OS of 35% and 
38%, respectively; in this study, Chronic GVHD was associated with a lower risk of relapse.13  Our 
results in 16 patients with IGL in this setting showed an actuarial 2 year OS and PFS of 50%, with a 
low relapse rate of 10%. 23, 30  


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3.4.3 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR DIFFUSE LARGE–CELL 
LYMPHOMA (DLCL):  REDUCED INTENSITY CONDITIONING (RIC) REGIMENS 
Low numbers of patients with DLCL treated with RIC regimens have been reported, with PFS rates of 
20–55%.  A registry analysis from the EBMT showed high rates of relapse for a heterogeneous group 
of HG NHL, including several with DLCL, with 1 year PFS of 32%. 
Similarly, our experience at COHNMC with Fludarabine and Melphalan in 12 patients with B–DLCL 
undergoing sibling (7) or unrelated donor (5) transplantation shows a low 2 year OS and PFS of 36% 
and 17% with a high relapse rate of 76%.30 
The WCTC transplanted 18 patients with DLCL with the non–myeloablative regimen of Fludarabine 
and TBI.  Eight patients are alive in remission, 4 have died of PD, 2 are alive in relapse, and 4 have 
died of non–relapse causes.29 
These results with AHSCT for DLCL suggest a higher relapse rate with RIC than with conventional 
regimens, and would provide the rationale for augmenting the preparative regimen with targeted 
therapies. 
3.5 
LOW–GRADE NON–HODGKIN LYMPHOMA (LG NHL) 
3.5.1 
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR LOW–GRADE LYMPHOMA 
(LGL) 
Current treatment approaches are generally not curative in patients with advanced stage LG NHL 
although many in this patient population have indolent clinical courses.  Standard treatments often 
produce high Response Rates (RRs), but CR1 duration ranges from 12–36 months.46-48  Relapsed 
LGL often responds to salvage therapy.  However, duration of subsequent remissions progressively 
decreases. 
HDT and aHSCT have been shown to improve PFS and increase the duration of remission in select 
patients with chemosensitive relapsed LG NHL.49-54  We have analyzed engraftment, toxicity, 
treatment outcome and prognostic factors in 58 patients with a history of LG FL who underwent HDT 
and aHSCT from 1991–1995 at COHNMC.53  Although prolonged OS (see FIGURE 3A) and PFS can 
be seen after aHSCT (see FIGURE 3B), long–term follow–up demonstrates a continuous risk of 
relapse.  Interventions aimed at decreasing the risk of relapse (ie, Rituximab for post–transplant 
consolidation and/or in vivo purging) are being investigated in this setting. 


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Studies from COHNMC53 and Stanford54 suggest that the use of a FTBI containing preparative 
regimen is associated with a higher OS and PFS rate, perhaps reflecting the exquisite sensitivity of 
LGLs to radiation therapy.  This observation supports the exploration of using intensified target doses 
of radiation such as radiolabeled antibodies in the conditioning regimen to maximize the anti–
lymphoma effect of the transplant.  However, because of the long natural history and continued 
pattern of relapse after aHSCT (see FIGURE 3B), the curative potential of autografting in patients with 
relapsed LGL has not been established.  Moreover, an increased risk of Myelodysplasia Syndrome 
(MDS) is observed in this patient population, indicating a need for close monitoring and reporting 
long–term follow–up of studies in this area.55 
New treatment modalities, including the use of MAbs, radioimmunoconjugates, lymphoma vaccines 
and antisense molecules, have been introduced into the treatment armamentarium for the various 
types of NHLs.  Some of these agents are being incorporated into aHSCT and AHSCT strategies, as 
discussed below. 
3.5.2 
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) FOR LOW–GRADE NON–
HODGKIN LYMPHOMA (LG NHL) 
Outcomes for LGLs after AHSCT are generally better than for more aggressive NHL, with PFS and 
EFS rates of 50%–80% and low relapse rates of 10–20%,56, 57 suggesting an important role for GVL in 
curing these malignancies.  As such, RIC regimens are particularly appealing in this setting.  A recent 
report from MD Anderson showed a 2 year DFS of 84%, with a TRM of 5% and no relapses in 18 
patients with chemosensitive FL (n=18), and CLL/Small Lymphocytic Lymphoma (SLL) (n=2), 
conditioned Fludarabine, Cy, with or without Rituximab.20  The EBMT reported a 2 year PFS, PD and 
TRM of 54%, 21% and 31%, respectively, in 52 patients with LG NHL receiving a RIC regimen.9 
Similarly, the outcome for 34 patients with B–Cell LG NHL transplanted at COHNMC with 
conventional dose regimens (n=18) and a RIC regimen of Fludarabine and Melphalan (n=16) was 
similar in terms of relapse rates (15% versus 17%), with 2 year OS/PFS rates of 56%/50% and 
74%/61%, (p–values of 0.45 and 0.78), suggesting that RIC regimens provide similar disease control 
to conventional dose regimens, with less TRM. 
3.6 
RADIOIMMUNOTHERAPY (RIT) FOR B–CELL NON–HODGKIN LYMPHOMA (NHL) 
Recently, Radioimmunotherapy (RIT) has emerged as a promising treatment for NHL.  Radioisotope 
labeled MAbs provide a mechanism for targeting radiation preferentially to tumor sites, while sparing 
normal tissues.  B–Cell lymphomas are an attractive target for RIT because of their radiosensitivity, 
their well defined surface antigens, and the availability of multiple MAbs to those antigens. 
1.0 
0.8 
0.4 
0.2 
0.0 
0.6 
FIGURE 1A 
Probability of Survival 
OVERALL SURVIVAL AFTER AHSCT 
FOR LOW GRADE LYMPHOMA — ALL PATIENTS (N = 58) 
6 
8 
7 
5 
4 
3 
0 
2 
1 
Marks (  ) indicate censored points 
Time in Years 
95% Confidence Inter val 
(12/01/99) 
PROGRESSION-FREE SURVIVAL AFTER AHSCT 
FOR LOW GRADE LYMPHOMA — ALL PATIENTS (N = 58) 
FIGURE 1B 
3 
4 
7 
6 
1 
2 
8 
5 
0 
95% Confidence Inter val 
Marks (  ) indicate censored points 
(12/01/99) 
Time in Years 
FIGURE 3A 
FIGURE 3B 


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Iodine–131 (131I) has been the gold standard for RIT due to its long track record in treating thyroid 
cancer, its well–defined radiochemistry, its clinical availability, and its potential for both 
Radioimmunoimaging (RII) and RIT.  However, there are disadvantages of 131I, including its long 8–
day half life, the risks of radiation exposure to health care providers and the non–specific irradiation to 
normal organs from the gamma (γ) components of 131I. 
Recent RIT trials for lymphoma have utilized 131I labeled anti–B1 (anti–CD20) antibody, with results 
suggesting that 131I labeled anti–B1 is safe and effective and may induce prolonged CR in heavily 
pre–treated LG and transformed LG NHL.58-60  Although additional studies are needed, 131I anti–B1 
antibody can be safely given in combination with HD chemotherapy in an aHSCT setting for NHL.60 
Yttrium–90 (90Y) may be an ideal radionuclide for RIT since it emits beta ( ) particles that are more 
potent than those delivered by 131I.  It is a pure  emitter, making it a safer reagent for medical 
personnel to administer than 131I.  In addition, the short half–life also facilitates the use of 90Y in 
combination with other agents, (ie, chemotherapy) and allows for high dose rates at localized sites.  
Unfortunately, 90Y cannot be used for RII due to its absence of  emissions.  Indium–111 (111In) has 
been substituted as an imaging reagent to show tumor localization in patients scheduled for 90Y 
therapy, on the assumption that its biodistribution closely mimics that of 90Y. 
3.6.1 
SINGLE–AGENT ZEVALIN® FOR RELAPSED LOW–GRADE NON–HODGKIN LYMPHOMA (LG NHL) 
The efficacy of the Zevalin® regimen was evaluated in 2 multicenter studies61, 62 enrolling a total of 
197 subjects: 
STUDY 1 was a single arm study of 54 patients with relapsed FL refractory to Rituxan® treatment.  
Patients were considered refractory if their last prior treatment with Rituxan® did not result in a CR or 
Partial Response (PR), or if Time–to–[Disease] Progression (TTP) was < 6 months.61  The primary 
efficacy endpoint of the study was the Overall Response Rate (ORR).  Secondary efficacy endpoints 
included TTP and Duration of Response (DR).  In a secondary analysis comparing objective 
response to the Zevalin® regimen with that observed with the most recent treatment with Rituxan®, 
the median DR following the Zevalin® regimen was 6 months vs 4 months.  TABLE 1 summarizes 
efficacy data from this study and STUDY 2. 
STUDY 2 was a randomized, controlled, multicenter study comparing the Zevalin® regimen to 
treatment with Rituxan®.62  The trial was conducted in 143 patients with relapsed or refractory LG or 
follicular NHL, or transformed B–Cell NHL.  A total of 73 patients received the Zevalin® regimen, and 
70 patients received Rituxan® given as an intravenous (iv) infusion at 375 mg/m2 weekly x 4 doses.  
The primary efficacy endpoint of the study was to determine the ORR.  The ORR was significantly 
higher (80% vs 56%, p=0.002) for patients treated with the Zevalin® regimen.  The secondary 
endpoints, DR and TTP, were not significantly different between the 2 treatment groups on this study. 


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TABLE 1: 
SUMMARY OF CLINICAL EFFICACY DATA† 
STUDY 1 
STUDY 2 
ZEVALIN® 
THERAPEUTIC REGIMEN 
n=54 
ZEVALIN® 
THERAPEUTIC REGIMEN 
n=73 
RITUXAN® 
n=70 
ORR £ (%) 
74 
80 
56 
CRR ф (%) 
15 
30 
16 
CRu Rate π (%) 
0 
4 
4 
Median DR ƒ,$ 
(Months) 
[Range*] 
64 
[0.5 – 24.9+] 
13.9 
[1.0 – 30.1+] 
11.8 
[1.2 – 24.5] 
Median TTP ƒ,¢ 
(Months) 
[Range*] 
6.8 
[1.1 – 25.9+] 
11.2 
[ 0.8 – 31.5+] 
10.1 
[0.7 – 26.1] 
† Efficacy Data Based on International Workshop Response Criteria (IWRC). 
£ Overall Response Rate 
ф Complete Response Rate 
π Complete Response Rate Unconfirmed 
ƒ Estimated with Observed Range 
$ Duration of Response:  Interval from Onset of Response to Progression of Disease (PD) 
* + Indicates an Ongoing Response 
¢ Time to Progression:  Interval from First Infusion to Progression of Disease (PD) 
Adverse Events (AEs) observed in previous trials of the Zevalin® regimen were primarily hematologic, 
transient, and reversible.  Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 32%, 
8.5%, and 4.3% of patients, respectively.  Hematologic levels recovered in all patients, except when 
patients went on to other therapy or had pre–existing cytopenias.  The severity of hematologic toxicity 
was related to baseline platelet count and percent BM involvement. 
The most frequent, non–hematologic AEs (asthenia, chills, fever, nausea, and headache) were 
related to accompanying Rituxan® infusions.  No major acute organ dysfunction was seen.  B–Cell 
depletion recovered 6–9 months after therapy.  Median serum immunoglobulins remained within the 
normal range and were relatively stable throughout the treatment period and follow–up.  The 
formation of Human Anti–Murine Antibodies (HAMA) or Human Anti–Chimeric Antibodies (HACA) 
occurred after the Zevalin® regimen in < 2% of patients.  T–cells were not depleted.  The incidence of 
severe infection was low (7.6% of patients hospitalized during the treatment period).  No observable 
age–dependent differences were seen in the safety profile.  Rare cases of MDS observed were within 
the expected rate for this heavily pretreated patient population. 
3.6.2 
SINGLE–AGENT ZEVALIN® FOR MANTLE CELL LYMPHOMA (MCL) 
Experience with Zevalin® as single agent for MCL is limited.  Younes reported 9 heavily pre–treated 
patients, 6 of whom were chemorefractory to their previous regimen.  The ORR was 33%, with 2 CRs 
and 1 PR, with the most common toxicity being hematological.63 
3.6.3 
ZEVALIN® AS PART OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT) 
Use of high–dose RIT with Zevalin® plus high–dose chemotherapy followed by aHSCT is being 
investigated at COHNMC and other centers for the treatment of poor risk NHL.32, 33, 64  Preliminary 
observations indicate that Zevalin® can be combined with high–dose chemotherapy followed by 
aHSCT. 
Investigators in Seattle have assessed biodistribution toxicities and efficacy of 131I anti–CD20 antibody 
in patients with B–Cell lymphoma undergoing aHSCT.  Patients were assessed with a test dose and 
those study subjects determined to have tumor doses > liver, lungs and kidney, were eligible for 
therapeutic infusion of 131I labeled antibody in this Phase I/II transplant trial.  Of 43 patients, 24 achieved 
favorable biodistributions and 19 subsequently received therapeutic infusions of approximately 232–777 
mCi of 131I labeled antibody at a dose of 58–1168 mg.  This was followed by autologous BM re–infusion.  


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Sixteen patients achieved a CR, 2 patients PR and 1 a minor response.  In their series 9 patients 
remain in continuous CR (PFS) between 3–53 months.  This study indicates a 95% RR in patients able 
to demonstrate favorable biodistribution, with manageable toxicity, particularly with provision for 
autologous BM support. 
Further studies from this group sought to determine the MTD of 131I anti–CD20 antibody that could be 
combined with Etoposide (VP–16) and Cy.  Fifty–two patients with relapsed lymphoma were studied 
who received a therapeutic dose of 1.3 mg/kg protein labeled with iodine calculated to deliver a 
targeted dose of radiation (20–27 Gy) to critical organs.  In this, the DFS after 2 years was 68%.  
Investigators in Nebraska have also combined 131I anti–CD20 antibody to a regimen of high–dose 
chemotherapy (BEAM) with encouraging results in patients with relapsed lymphoma. 
An analysis of these studies suggest that the burden of tumor, the dose of antibody administered, the 
presence of circulating antigen, and the rate of antigen modulation may influence the biodistribution of 
radiolabeled antibodies and the efficacy of RIT.  Similar to problems with immunotoxin therapy, larger 
tumor masses present formidable penetration barriers to antibodies because of the inefficiency of 
diffusion that exists in bulkier disease.  This latter problem may be addressed by using alternative 
radionuclides whose particle energy (MeV) and path length may be more favorable for treating bulky 
disease.  It is for this and the results we have obtained in this program and other reasons 
summarized below that we have focused on the use of 90Y labeled antibodies in the treatment of 
patients with B–Cell lymphoma who are candidates for aHSCT. 
Patients with B–Cell lymphoma (LGL, MCL, DLCL) expressing the CD20 antigen on the cell surface 
are the target for this approach with particular emphasis on developing regimens that can be used to 
cure lymphoma in older patients where the disease is more common and transplant based 
therapeutics are limited.  Our studies indicate that the disease is sensitive to radiolabeled therapy and 
in the high–dose setting some patients can achieve long–term control of the disease.  For patients 
with advanced lymphoma, we utilized a dosimetry–based high–dose 90Y anti–CD20 immunoconjugate 
combined with high–dose VP–16 60 mg/kg and Cy (100 mg/kg), the 2 year DFS was 81% with a 
relapse rate 15% without an increase in transplant toxicity or compromise of engraftment.  For those 
older patients with lymphoma, a 90Y anti–CD20 antibody was added at a high–dose regimen of 
BEAM.  With a median age of 61 (40–81) 17 patients have received treatment.  Currently, 70% of the 
patients are alive and PFS is with a median follow–up of 12 months.  We had hypothesized that a 
major contributing cause of relapse following autologous Bone Marrow Transplant (aBMT) is the 
residual sites of disease, and that 90Y labeled CD20 specific MAb may be utilized to increase the 
targeted efficacy of the preparatory regimen used for patients undergoing transplantation for B–Cell 
lymphoma.  The short half life of this heavy metal also leads to an increased dose rate at tumor sites, 
which can enhance the therapeutic killing effect.  Of additional importance, the high emission (2.3 
MeV max) allows for more effective crossfire from targeted cells to cells that have not been bound by 
antibody, either for antigenic reasons or for tumor bulk.  The average path length is 6 mm in contrast 
to iodine which is 0.8 mm (59).  Localization of any released 90Y to bone will also increase the BM 
dose, which is an important residual site in patients with lymphoma, particularly those with follicular 
histology. 
The results described above for incorporation of radiolabeled anti–CD20 antibody therapy for younger 
and older patients with lymphoma undergoing aHSCT, and the data obtained for the patient trial of 
RIC AHSCT, provide the rationale for a clinical trial to incorporate an effective targeted anti–tumor 
agent as a component of the RIC AHSCT regimen for patients with lymphoma who are not 
candidates for aHSCT. 
3.6.4 
RADIATION DOSIMETRY 
Estimations of Radiation Absorbed Doses (RADs) for 111In–Zevalin® and 90Y–Zevalin® were 
performed using sequential Whole (Total) Body Images (WBIs) and MIRDOSE 3 software.20, 41  
Estimated RADs to organs and BM from a course of the Zevalin® therapeutic regimen are 
summarized in TABLE 2.  Absorbed dose estimates for lower large intestine, upper large intestine, and 
small intestine have been modified from the standard MIRDOSE 3 output to account for the 
assumption that activity is within the intestine wall rather that the intestine contents. 


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TABLE 2 
ESTIMATED RADIATION ABSORBED DOSES (RADS) TO ORGANS AND MARROW FROM A 
COURSE OF THE ZEVALIN® THERAPEUTIC REGIMEN 
ORGAN 
90Y–ZEVALIN® MGY/MBQ 
111IN–ZEVALIN® MGY/MBQ 
MEDIAN 
RANGE 
MEDIAN 
RANGE 
Spleen1 
9.4 
1.8 – 14.4 
0.9 
0.2 – 1.2 
Testes1 
9.1 
5.4 – 11.4 
0.6 
0.4 – 0.8 
Liver1 
4.8 
2.3 – 8.1 
0.7 
0.3 – 1.1 
Lower Large Intestinal Wall1 
4.8 
3.1 – 8.2 
0.4 
0.2 – 0.6 
Upper Large Intestinal Wall1 
3.6 
2.0 – 6.7 
0.3 
0.2 – 0.6 
Heart Wall1 
2.8 
1.5 – 3.2 
0.4 
0.2 – 0.5 
Lungs1 
2.0 
1.2 – 3.4 
0.2 
0.1 – 0.4 
Small Intestine1 
1.4 
0.8 – 2.1 
0.2 
0.1 – 0.3 
Red Marrow2 
1.3 
0.7 – 1.8 
0.2 
0.1 – 0.2 
Urinary Bladder Wall3 
0.9 
0.7 – 2.1 
0.2 
0.1 – 0.2 
Bone Surfaces2 
0.9 
0.5 – 1.2 
0.2 
0.1 – 0.2 
Ovaries3 
0.4 
0.3 – 0.5 
0.2 
0.2 – 0.2 
Uterus3 
0.4 
0.3 – 0.5 
0.2 
0.1 – 0.2 
Adrenals3 
0.3 
0.0 – 0.5 
0.2 
0.1 – 0.3 
Brain3 
0.3 
0.0 – 0.5 
0.1 
0.0 – 0.1 
Breasts3 
0.3 
0.0 – 0.5 
0.1 
0.1 – 0.3 
Gallbladder Wall3 
0.3 
0.0 – 0.5 
0.3 
0.1 – 0.4 
Muscle3 
0.3 
0.0 – 0.5 
0.1 
0.0 – 0.1 
Pancreas3 
0.3 
0.0 – 0.5 
0.2 
0.1 – 0.2 
Skin3 
0.3 
0.0 – 0.5 
0.1 
0.0 – 0.1 
Stomach3 
0.3 
0.0 – 0.5 
0.1 
0.1 – 0.2 
Thymus3 
0.3 
0.0 – 0.5 
0.1 
0.1 – 0.2 
Throid3 
0.3 
0.0 – 0.5 
0.1 
0.0 – 0.1 
Kidneys1 
0.1 
0.0 – 0.2 
0.2 
0.1 – 0.2 
Total Body3 
0.5 
0.2 – 0.7 
0.1 
0.1 – 0.2 
1 Organ Region of Interest (ROI) 
2 Sacrum Region of Interest (ROI)[42] 
3 Whole Body Regions of Interest (ROI) 
 
 
3.7 
PERIPHERAL BLOOD B CELL DEPLETION WITH RITUXIMAB 
To maximize the therapeutic effects and minimize the side effects of Zevalin, we aim to deplete circulating 
B-lymphocytes by rituximab prior to the administration of In-111 Zevalin and Y-90 Zevalin. The goal would 
be to deplete circulating B-lymphocytes but not to saturate the binding sites within the lymphoma cells 
(lymph nodes).  To achieve this goal, a careful and individualized dosing of rituximab would be necessary.  
From the phase I study of rituximab (65), there was a dose-dependent, rapid, and specific B cell depletion 
in all patients. It is generally agreed that when there is a detectable level of rituximab in serum, circulating 
B cell numbers are minimal.  
 
Pharmacokinetic (PK) data obtained from the patients treated in the pivotal rituximab trial have been 
analyzed by Bernstein et al. (66). At 3 months post-treatment, they found the median serum level in 62 
responders was 25.4 μg/ml compared with 5.9 μg/ml in 42 non-responders (p=0.001). In addition, serum 
levels correlated inversely with bulk of disease.  While it is unknown whether the non-responders had less 
than saturating levels of rituximab within the tumor, it would be reasonable to assume that the serum 
rituximab level of 25 μg/ml may be too high for the current study.  
 
In this study, we consider a rituximab level at 10 μg/ml would be a reasonable target in achieving 
sufficient B cell depletion without saturating the CD20 binding sites in the malignant lymph nodes.  Since 
we expect some of the study patients may have a preexisting rituximab from prior therapy, we will test the 


15 
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rituximab levels in all study patients. Pre-treatment with rituximab may be given on days -21 and -14 
according to its serum level.  
 
The level of Rituxan in the serum is measured in a competitive binding assay using a TRF (time resolved 
fluorometry) format.  An anti-mouse IgG Fab antibody is coated on the plate and then standards, control 
samples are added in addition to dilutions of the patient‟s serum.  A Europium labeled Rituxan is then 
added.  The Rituxan in the serum competes with the Eu-Rituxan-DTPA and the amount of competition is 
compared to the standard curve.  The assay has been validated and is performed under SOPs.  This 
assay is performed by a California licensed Med Tech who has demonstrated his proficiency in 
performing the assay.  The laboratory is run under the continuing supervision of the Department of 
Pathology.  The laboratory is operating under CLIA rules and has been inspected by CAP. 
 
 
4.0 
DRUG FORMULATION Ω §§ A.012, B.002, B.003, E.002–E.003, E.006, G.001–G.002 
4.1 
RITUXAN® (IDEC–C2B8 OR RITUXIMAB) Ω §§ A.012 
4.1.1 
MODE OF ACTION:  genetically engineered chimeric murine/human MAb directed against 
CD20 antigen on surface of normal and malignant B lymphocytes; an IgG1 
containing murine VL and VH chain region sequences and human constant region 
sequences; composed of 2 VH chains of 451 aa and 2 VL chains of 213 aa (based on 
cDNA analysis) with molecular weight of ~145 kD; has binding affinity for CD20 antigen 
of ~8.0 nM. 
The Fab domain of Rituxan® binds to the CD20 antigen on B lymphocytes, and the Fc 
domain recruits immune effector functions to mediate B–Cell lysis in vitro.  Possible 
mechanisms of cell lysis include Complement–Dependent Cytotoxicity (CDC) and 
Antibody–Dependent Cell Mediated Cytotoxicity (ADCC).  The antibody has been 
shown to induce apoptosis in the DHL–4 Human B–Cell Lymphoma Line. 
Normal Tissue Cross–Reactivity:  Rituxan® binding was observed on lymphoid cells in 
the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral 
blood and lymph nodes.  Little or no binding was observed in the non–lymphoid tissues 
examined. 
4.1.2 
TOXICOLOGY:  infusional toxicity of chills and rigors are common with first administration 
of Rituxan® but rarely with subsequent doses; decreased rate of infusion and 
administration of antihistamines can control these toxicities. 
4.1.3 
PACKAGING AND FORMULATION:  10 ml (100 mg) and/or 50 ml (500 mg) pharmaceutical 
grade glass vials at concentration of 10 mg protein/ml. 
4.1.4 
STORAGE AND STABILITY:  vials stable at 2–8°C (36–46°F); NOT to be used beyond 
expiration date on carton; vials should be protected from direct sunlight; solutions for 
infusion shown to be stable for additional 24 hours at room temperature; due to 
absence of preservatives, solutions should be stored refrigerated (2–8°C); no 
incompatibilities between Rituxan® and polyvinylchloride or polyethylene bags 
observed. 
4.1.5 
ADMINISTRATION:  administered by slow IV infusion having been diluted to 1–4 mg/ml in 
an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in 
Water, USP.  This initial Rituxan® infusion will be through a dedicated line.  If patient 
has had Rituxan before, begin infusion at 100 mg/hr.  If no adverse reactions occur, 
escalate rate gradually at 100 mg/hr every 30 minutes to a maximum of 400 mg/hr.  If 
patient has not had Rituxan before, begin infusion at 50 mg/hr.  If no adverse reactions 
occur, escalate rate at 50 mg/hr every 30 minutes to a maximum of 400 mg/hr.  If 
hypersensitivity or infusion related events develop, the infusion will be temporarily 


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slowed or interrupted.  The infusion can be continued at half the previous rate when 
symptoms abate. 
4.1.6 
SUPPLIER:  commercially available (Rituxan® will not be provided by Biogen Idec). 
4.1.7 
Refer to RITUXAN® (IDEC–C2B8 OR RITUXIMAB) package insert for more information. 
4.2 
ZEVALIN® (IDEC–2B8–MX–DTPA OR IBRITUMOMAB TIUXETAN) Ω §§ A.012 
4.2.1 
MODE OF ACTION:  immunoconjugate resulting from thiourea covalent bond between 
MAb Ibritumomab and linker–chelator Tiuxetan [N–{2–bis(carboxymethyl)amino}–3–(p–
isothiocyanatophenyl)propyl]–[N–{2–bis(carboxymethyl)amino}–2–(methyl)–ethyl] 
glycine; linker–chelator provides high affinity, conformationally restricted chelation site 
for 111In or 90Y; molecular weight is ~148 kD; antibody moiety is Ibritumomab, murine 
IgG1 
surface of normal and malignant 
1 VH 
L chains of 213 aa each. 
4.2.2 
TOXICOLOGY:  myelosuppression is dose limiting toxicity in standard dosing regimens; 
with marrow support, liver, kidney, and lung are likely to be dose limiting organs; 
infusional toxicity of chills and rigors are common with first administration but rarely with 
subsequent doses; decreasing rate of infusion and administration of antihistamines 
should control these toxicities.  May cause nausea and rarely may cause vomiting. 
4.2.3 
PACKAGING AND FORMULATION:  2 ml glass septum vial containing 2 ml (3.2 mg) in low 
metal normal saline at 1.6 mg/ml. 
4.2.3.1 
111IN–CHLORIDE:  fixed dose 5 mCi of 111In–chloride supplied in .05 M HCl. 
4.2.3.2 
90Y–CHLORIDE:  maximum dose 32 mCi 90Y–chloride supplied in .05 M HCl. 
4.2.4 
STORAGE AND STABILITY:  antibodies stored in investigational pharmacy at 4°C until day 
of use; once diluted, unlabeled antibody is to be used in ≤ 24 hours if held at 4°C and 
an additional 12 hours if held at room temperature; radiolabeled solutions should be 
used in ≤ 6 hours and should be held at 2–8°C until administered. 
4.2.5 
ADMINISTRATION: 
4.2.5.1 
IMAGING DOSE:  administered over approximately 10 minutes by slow IV 
injection following infusion of Rituxan®; 0.22 micron filter must be on line 
between patient and infusion port; flush line with at least 10 mls of normal 
saline following 111In–Zevalin® infusion. 
4.2.5.2 
THERAPY DOSE:  0.4 mCi/kg 90Y administered over approximately 10 minutes by 
slow IV injection following infusion of Rituxan®; 0.22 micron filter must be on 
line between patient and infusion port; flush line with at least 10 mls of normal 
saline following 90Y–Zevalin® infusion. 
4.2.6 
SUPPLIER:  commercially available (Zevalin® will not be provided by Biogen Idec). 
4.2.7 
Refer to ZEVALIN® (IDEC–2B8–MX–DTPA OR IBRITUMOMAB TIUXETAN) package insert for 
more information. 
4.3 
FLUDARA  (2–FLUORO–ARA–AMP, FLUDARABINE PHOSPHATE OR FLUDARABINE) Ω §§ E.002–E.003, 
E.006 
4.3.1 
MODE OF ACTION:  Fludarabine Phosphate analogous to that of ara–C and ara–A; active 
metabolite appears to be triphosphate, F–ara–ATP; like ara–CTP and ara–ATP 2–F–


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IRB # 05149, Version 22 
 
11/25/13 
ara–ATP is substrate for DNA polymerase and is incorporated into DNA causing strand 
breaks and inhibition of DNA synthesis. 
4.3.2 
TOXICOLOGY:  major toxicity has been myelosuppression; at higher dose levels or in 
patients with renal impairment CNS toxicity seen characterized by numbness, 
paraparesis and cortical blindness. 
4.3.3 
PACKAGING AND FORMULATION:  supplied as white lyophilized solid cake; each vial 
contains 50 mg Fludarabine Phosphate, 50 mg mannitol and sodium hydroxide to 
adjust pH to 7.7; when reconstituted with 2 ml sterile water each ml will contain 25 mg 
of Fludarabine Phosphate. 
4.3.4 
STORAGE AND STABILITY:  intact vials are refrigerated (2–8°C); reconstituted solutions 
should be used in ≤ 8 hours due to lack of preservatives. 
4.3.5 
ADMINISTRATION:  dilute dose in D5W or NS and infuse in ≥ 30 minutes iv. 
4.3.6 
SUPPLIER:  commercially available. 
4.3.7 
Refer to FLUDARA  (2–FLUORO–ARA–AMP, FLUDARABINE PHOSPHATE OR FLUDARABINE) 
package insert for more information. 
4.4 
ALKERAN  (L–PHENYLALANINE MUSTARD, L–PAM or MELPHALAN) Ω §§ E.002–E.003, E.006 
4.4.1 
MODE OF ACTION:  alkylating agent. 
4.4.2 
TOXICOLOGY:  most commonly reported toxicity is myelosuppression; other commonly 
reported adverse reactions reported are nausea, vomiting and hypersensitivity 
reactions. 
4.4.3 
PACKAGING AND FORMULATION:  supplied as freeze dried powder; each single–use vial 
contains Melphalan Hydrochloride equivalent to 50 mg Melphalan and 20 mg 
Providone; each vial of diluent provided contains sodium citrate 0.2 g, propylene glycol 
6 ml, ethanol (96%) 0.52 ml and water for injection for total 10 ml; reconstitute each 50 
mg vial by rapidly injecting 10 ml diluent provided; immediately shake vial vigorously 
until clear solution is obtained; provides 5 mg/ml solution. 
4.4.4 
STORAGE AND STABILITY:  intact vials stored at room temperature (15–30°C) and 
protected from light; once reconstituted with diluent provided, solution is chemically 
stable at room temperature for ≤ 90 minutes. 
4.4.5 
ADMINISTRATION:  reconstituted, undiluted Melphalan has been administered via CVC 
line using dose of 100–200 mg/m2 over 2–20 minutes. 
4.4.6 
SUPPLIER:  commercially available. 
4.4.7 
Refer to ALKERAN  (L–PHENYLALANINE MUSTARD, L–PAM or MELPHALAN) package insert 
for more information. 
4.5 
PROGRAF® (FK–506 OR TACROLIMUS) Ω §§ G.001–G.002 
4.5.1 
MODE OF ACTION:  calcineurin inhibitor; immunosuppressive agent that interferes with 
IL–2–mediated T–cell activation. 
4.5.2 
TOXICOLOGY:  most commonly reported toxicities are renal insufficiency, tremors, 
hypomagnesaemia, hypertension, hyperglycemia and seizures. 


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4.5.3 
PACKAGING AND FORMULATION:  supplied as sterile solution in 1 ml ampoules containing 
equivalent of 5 mg anhydrous Tacrolimus per ml, in boxes of 10 ampoules; also 
available as 1 mg and 0.5 mg capsules for oral administration. 
4.5.4 
STORAGE AND STABILITY:  store at 5–25°C (41–77°F); Prograf® capsules are stored at 
controlled room temperature, 15–30°C (59–86°F). 
4.5.5 
ADMINISTRATION:  injection must be diluted with 0.9% Sodium Chloride Injection or 5% 
Dextrose Injection to concentration of 0.004–0.02 mg/ml; solution should be stored in 
glass or polyethylene containers and should be discarded if > 24 hours; solution should 
not be stored in PVC container due to decreased stability and potential for extraction of 
phthalates; when more dilute solutions are used (eg, pediatric dosing, etc), PVC–free 
tubing should be used to minimize potential for significant drug adsorption onto tubing; 
parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit; due to 
chemical instability of Tacrolimus in alkaline media, Prograf® injection should not be 
mixed or co–infused with solutions of ≥ pH 9 (eg, ganciclovir or acyclovir). 
4.5.6 
SUPPLIER:  commercially available. 
4.5.7 
Refer to PROGRAF® (FK–506 OR TACROLIMUS) package insert for more information. 
4.6 
RAPAMUNE® (SIROLIMUS) Ω §§ G.001–G.002 
4.6.1 
MODE OF ACTION:  induces T–cell apoptosis and unresponsiveness through inhibition of 
mTOR, a kinase that regulates cell cycle entry in response to IL–2 signaling and other 
cellular functions. 
4.6.2 
TOXICOLOGY:  most commonly reported toxicities are hyperlipidemia, arthralgia, 
cytopenias, epistaxis, edema and rash. 
4.6.3 
PACKAGING, FORMULATION, PREPARATION AND STORAGE: 
4.6.3.1 
SIROLIMUS ORAL SOLUTION:  Rapamune® oral solution (bottles and foil pouches) 
should be refrigerated at 2–8 C (36–46 F) and protected from light; 
Rapamune® oral solution is stable for ≤ 24 months under this storage condition; 
when bottle is opened, it should be kept in refrigerator and contents used in ≤ 1 
month; however, both opened bottles and pouches may be stored at room 
temperature (15–30 C; 59–86 F) for ≤ 1 month; amber syringe and cap 
provided for dosing from bottle and product may be kept in syringe for ≤ 24 
hours at room temperatures ≤ 25 C (77 F) or refrigerated at 2–8 C (36–46 F); 
syringe should be discarded after single use; after dilution, preparation should 
be used immediately; Rapamune® oral solution provided in bottles may 
develop slight haze when refrigerated; if haze occurs, allow product to stand at 
room temperature and shake gently until haze disappears; presence of haze 
does not affect quality of product. 
4.6.3.2 
SIROLIMUS TABLETS:  Rapamune® tablets are available as white triangular 
shaped tablets marked RAPAMUNE 1 mg in bottles of 100 tablets or as 
cartons containing 10 blister cards of 10 tablets each; Rapamune® tablets 
should be stored at 20–25°C (68–77°F); cartons should be used to protect 
blister cards and strips from light; Rapamune® tablets should be dispensed in a 
tight, light–resistant container. 
4.6.4 
ADMINISTRATION:  for adults, Sirolimus will be administered at 12 mg orally loading dose 
on DAY –3, followed by 4 mg orally single morning daily dose (target serum level 3–12 
ng/ml by HPLC).  For Pediatric patients < 40 kg, Sirolimus will be administered at 3 
mg/m2 orally on DAY –3, followed by 1 mg/m2 orally single morning daily dose.  Dosing 


19 
IRB # 05149, Version 22 
 
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of Sirolimus will be based on adjusted ideal body weight.  If actual body weight is < 
ideal body weight, actual body weight will be used. 
4.6.5 
SUPPLIER:  commercially available. 
4.6.6 
Refer to RAPAMUNE® (SIROLIMUS) package insert for more information. 
4.7 
METHOTREXATE 
4.7.1 
MODE OF ACTION: See package insert. 
4.7.2 
TOXICOLOGY: See package insert. 
4.7.3 
PACKAGING, FORMULATION, PREPARATION AND STORAGE: See package insert. 
4.7.4 
ADMINISTRATION:  See package insert and COH SOP G.001.04: Acute Graft versus 
Host 
Disease 
Prophylaxis 
 
http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Prophylaxis.pdf 
 
and 
http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Addendum_A.pdf 
    
 (accessibility verified 04/01/10) 
4.7.5 
SUPPLIER:  commercially available. 
4.7.6 
Refer to METHOTREXATE package insert for more information. 
 
4.8 
NEUPOGEN® (G–CSF, GRANULOCYTE–COLONY STIMULATING FACTOR OR FILGRASTIM) Ω §§ B.002, 
B.003 
4.8.1 
MODE OF ACTION:  Filgrastim, recombinant human G–CSF, r–metHuG–CSF, protein 
produced by Escheria coli into which has been inserted human G–CSF, differs from 
natural protein in that N–terminal amino acid is a methionine and is not glycosylated. 
4.8.2 
TOXICOLOGY:  bone pain is major toxicity in Phase II and III trials (20–25% patients); 
bone pain, often preceded by rise in circulating neutrophil count; occurred more 
frequently in patients treated with 20–100 µg/kg/day iv and less often in lower and/or 
subcutaneous doses; pain is generally mild to moderate in severity, usually controlled 
with non–narcotic analgesics such as acetaminophen; other toxicities include transient 
but reversible increases of alkaline phosphatase, lactate dehydrogenase and uric acid 
levels presumed secondary rapid expansion of myeloid compartment; less frequently 
reported toxicities include subclinical splenomegaly, exacerbation of pre–existing skin 
rashes, effusions, thrombocytopenia and cutaneous vasculitis. 
Rarely, allergic–type reactions occur; since commercial introduction, reports suggest 
allergic–type reaction (< 1 in 4,000 patients), but immune component has not been 
demonstrated; these have generally been characterized by systemic symptoms 
involving at least 2 body systems, most often skin, respiratory and cardiovascular; 
some reactions occurred in initial exposure; reactions tended to occur in ≤ first 30 
minutes after administration and appeared to occur more frequently in patients who 
received recombinant G–CSF intravenously; rapid resolution of symptoms occurred in 
most cases after standard supportive care; symptoms recurred in > half patients when 
rechallenged; recombinant G–CSF should be used with caution in patients with pre–
existing cardiac conditions such as hypertension, angina pectoris and cardiac 
dysrhythmias. 


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4.8.3 
PACKAGING AND FORMULATION:  supplied as clear, colorless preservative free liquid for 
parenteral administration; single use vials contain recombinant G–CSF, 300 µg/ml in 
preservative free solution with 0.59 mg/ml acetate, 50 mg/ml sorbitol, 0.004% Tween 7 
80, 0.035 mg/ml sodium, and water for injection, USP, pH 4.0 to make 1 ml; may be 
diluted in 5% dextrose. 
4.8.4 
STORAGE AND STABILITY:  refrigerate at 2–8°C (36–46°F); avoid shaking; may be 
allowed to reach room temperature for ≤ 24 hours; vials left at room temperature for > 
24 hours should be discarded; parenteral drug products should be inspected visually 
for particulate matter and discoloration prior to administration, whenever solution and 
container permit; if particulates or discoloration observed, container should not be 
used. 
Diluted to concentrations of 5–15 Fg/ml should be protected from absorption to plastic 
materials by adding albumin (human) to final concentration of 2 mg/ml when diluted in 
5% dextrose or 5% dextrose plus albumin (human); compatible with glass bottles, PVC 
and polyolefin iv bags, and polypropylene syringes; dilution to final concentration of < 5 
µg/ml is not recommended at any time; do not dilute with saline at any time; product 
may precipitate. 
4.8.5 
ADMINISTRATION:  donors will receive G–CSF as per City of Hope standard operating 
procedures; schedule of G–CSF administration and PBSC collections can only be 
ascertained when DAY 0 is identified; when treatment regimen schedule has been fixed 
and schedule of G–CSF administration and PBSC collections made, schedule has to 
be confirmed with personnel in apheresis room; DAY 0 should be fixed on a Tuesday–
Friday; marrow collection allowed in cases of pediatric donors unable to receive G–
CSF due to age, or for donors unable to collect minimum target CD34+ cell dose. 
4.8.6 
SUPPLIER:  commercially available; 2 vial sizes, 300 µg/1 ml and 480 µg/1.6 ml; 
recombinant G–CSF, Filgrastim or Neupogen® (Amgen Inc trademark). 
4.8.7 
Refer to NEUPOGEN® (G–CSF, GRANULOCYTE–COLONY STIMULATING FACTOR OR 
FILGRASTIM) package insert for more information. 
5.0 
PATIENT SELECTION Ω §§ B.001, C.001, H.003 
Patients with LG, IG and MCL NHL with inability to collect adequate numbers of SCs, failed previous 
therapies or autologous transplant, or who have multiple relapses and are unlikely to benefit from an 
autologous transplant will be screened for this study.  Patients with MCL in first PR or CR, or in any 
disease state will also be evaluated for this study.  
5.1 
INCLUSION CRITERIA Ω §§ C.001, H.003 
5.1.1 
Age ≥ 18 and < 70 years 
5.1.2 
6/6 HLA matched sibling donor or related donor, or acceptable matched unrelated 
donor  
5.1.3 
Biopsy (Bx) proven diagnosis of LG (including SLL/CLL, lymphoplasmacytic 
lymphoma, marginal zone, MALT lymphoma and FL grade 1 and 2), IG (FL grade 3 
and DLCL) or MCL NHL 
5.1.4 
Prior demonstrated monoclonal CD20+ malignant B–Cell population in lymph nodes 
and/or BM Bx specimen 
5.1.5 
LG NHL; must have relapsed after achieving a CR or PR to prior therapy or have never 
responded to prior therapy, including chemotherapy and/or MAb therapy. 


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5.1.6 
MCL NHL in any disease state.  
5.1.7 
Other aggressive B-cell lymphomas (excluding Burkitt lymphoma or Burkitt-like 
lymphoma) having had at least one relapse or having been refractory to chemotherapy. 
5.1.8 
BM aspiration and Bx (≤ 42 days prior to imaging dose) which show < 25% 
lymphomatous involvement of total cellularity; in CLL, peripheral lymphocyte count < 
5000/mm3 
5.1.9 
Salvage chemotherapy/MAbs to reduce BM lymphomatous involvement and reduce 
disease bulk allowed. 
5.1.10 
Normal renal function test with serum creatinine of 
 1.5 mg/dl, or a creatinine 
clearance of ≥ 60 ml/min 
5.1.11 
Adequate pulmonary function as measured by FEV1 > 65% of predicted measured, or 
a DLCO ≥ 50% of predicted measured 
5.1.12 
Cardiac Ejection fraction of > 50% by Echocardiogram (ECHO) or MUGA 
5.1.13 
Adequate liver function tests with a bilirubin of  1.5x normal and SGOT or SGPT  2x 
normal 
5.1.14 
Negative Human Immunodeficiency Virus (HIV) antibody 
5.1.15 
KPS > 80 
5.1.16 
No active Central Nervous System (CNS) disease or prior history of CNS disease 
5.1.17 
Involved field External Beam Therapy (EBT) to area excluding lung, heart, liver and 
kidney allowed, but evaluated on a case–by–case basis. 
5.1.18 
Recovery from last therapy and therapy dose (Y-90 Zevalin) must be ≥ 4 weeks from 
prior systemic chemotherapy 
5.2 
EXCLUSION CRITERIA Ω §§ C.001, H.003 
5.2.1 
Presence of Human Anti–Zevalin® Antibody (HAZA) 
5.2.2 
Prior RIT 
5.2.3 
Prior AHSCT; but prior aHSCT is allowed; Prior FTBI in the conditioning regimen will be 
evaluated on an individual basis. 
5.2.4 
Prior malignancy, except for: adequately treated basal cell or squamous cell skin 
cancer; adequately treated noninvasive carcinomas; or other cancer from which the 
patient has been disease–free for at least 5 years.  MDS is excluded from this criterion. 
5.2.5 
Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive. 
5.2.6 
Total peripheral lymphocyte count > 5,000/mm3 if SLL/CLL 
5.2.7 
Burkitt lymphoma or Burkitt-like lymphoma 
 
 


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5.3 
DONOR SELECTION Ω §§ B.001, H.003 
5.3.1 
INCLUSION CRITERIA 
5.3.1.1 
Age < 75 years 
5.3.1.2 
HLA genotypically identical related donor or acceptable matched unrelated 
donor  
5.3.1.3 
Must consent to G–CSF administration and leukapheresis for matched sibling 
donor, but for unrelated donor, the donor will sign a standard consent for 
donation at their designated donor or collection center. 
5.3.1.4 
Must have adequate veins for leukapheresis or agree to placement of Central 
Venous Catheter [CVC (femoral, subclavian)] 
5.3.2 
EXCLUSION CRITERIA 
5.3.2.1 
Age < 12 years 
5.3.2.2 
Identical twin 
5.3.2.3 
Pregnancy 
5.3.2.4 
HIV Infection 
5.3.2.5 
Inability to achieve adequate venous access 
5.3.2.6 
Known allergy to G–CSF 
5.3.2.7 
Current serious systemic illness or any disease that may preclude the use of 
G–CSF (eg, recent thromboembotic event); for unrelated donors, considered 
ineligible by NMDP donor evaluation center 
 
5.4 
GENDER AND MINORITY INCLUSIONS AT CITY OF HOPE NATIONAL MEDICAL CENTER (COHNMC) Ω 
§§ A.003, A.011, B.001, C.001 
5.4.1 
PLANNED GENDER AND MINORITY INCLUSION FOR TRANSPLANT PATIENTS WITH LYMPHOMA 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, not of 
Hispanic 
Origin 
Hispanic 
White, not of 
Hispanic 
Origin  
White, Hispanic or 
not–Hispanic 
Unknown 
Other or 
Unknown 
Total 
Female 
0% 
9% 
4% 
16% 
54% 
17% 
0% 
100% 
Male 
0% 
5% 
2% 
20% 
60% 
12% 
1% 
100% 
Unknown 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
6.0 
STUDY DESIGN
 Ω §§ A.011, A.012, J.001– J.003 
This is a single center Phase II trial.  Registration will be done at COHNMC according to § 14.2 
REGISTRATION GUIDELINES.  Prior to 90Y–Zevalin® treatment, patients are required to undergo an imaging 
scan to verify that they have a favorable biodistribution.  Study design considerations and targeted 
response rates are found in § 15.0 STATISTICAL CONSIDERATIONS. Patients will receive 90Y–Zevalin® to 
deliver 0.4 mCi/kg, Fludarabine 125 mg/m2, Melphalan 140 mg/m2 
6.1 
Toxicity Grading and Reporting Ω §§ J.001– J.003 


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Toxicities will be graded using the National Cancer Institute (NCI)/Cancer Therapy Evaluation Program 
(CTEP) Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) which can be found 
at: http://ctep.cancer.gov/reporting/ctc.html and the Modified Bearman Toxicity Scale (Appendix I).  The 
Modified Bearman Toxicity Scale will be used up to day 100 post transplant.  Adverse events will be 
reported according to Adverse Event Reporting Requirements for Clinical Trials: Policies and Procedures 
of the City of Hope (City of Hope National Medical Center and Beckman Research Institute) November 
2003 found at http://www.coh.org/irb/Documents/irb3810.doc.  To be evaluable for toxicity a patient must 
receive a complete course of treatment and be observed for at least 90 days after the administration of 
the 90Y.  Patients without a durable graft at 90 days, but otherwise not qualifying as graft failure, have up 
to 100 days to document a durable graft before being considered a graft failure. All patients who are not 
evaluable for toxicity will be replaced. Toxicities observed will be summarized in terms of type (organ 
affected or laboratory determination), severity (by NCI CTC and nadir or maximum values for the 
laboratory measure) and time of onset.  For grade 4 neutropenia, duration will be recorded.   
6.1.1 
Definition of Graft Durability – maintenance of normal blood counts at 100 days, 6 
months, and 12 months post–transplantation according to the following criteria: 
6.1.1.1 
PLT count > 50,000 (50 x 109/l) without transfusion for at least 2 weeks prior to 
the follow–up visit. 
6.1.1.2 
Hemoglobin level ≥ 10 g/dl with no erythropoietin or transfusions for at least 2 
weeks prior to the follow–up visit. 
6.1.1.3 
ANC > 1,000 (1 x 109/l) with no G–CSF for at least 1 week prior to the follow–
up visit. 
6.1.2 
Definition of Graft Failure – confirmation of one or both of the following: 
6.1.2.1 
No durable graft in 2 cell lines of red blood cells, leukocytes, and PLTs (using 
definitions of durability above) at 100 days post–transplantation with no 
evidence of other causes, such as recurrent progressive leukemia, renal 
failure, chronic bleeding, severe infection, drug–induced cytopenias or 
development of new hematologic problems (nutritional or otherwise). 
6.1.2.2 
ANC < 500 (0.5 x 109/1) by 28 days post–transplantation. 
7.0 
TREATMENT PLAN
 Ω §§ A.011–A.012, B.002–B.006, C.002, D.001–D.013, E.002–E.003, E.006, F.001–F.011, G.001–G.005, H.001–H.002 
7.1 
TREATMENT SCHEMA
 Ω §§ A.011–A.012, B.002–B.006, C.002, D.001–D.013, E.002–E.003, E.006, F.001–F.011, G.001–G.002, 
H.001–H.002 
OUTLINE OF PREPARATIVE REGIMEN (REDUCED INTENSITY CONDITIONING (RIC))  
Day -23 or -22:  
Blood draw for Rituxan level (see note below figure 7.1.1) 
Day –21: 
RII with 111In–Zevalin® (per §§ 7.2.1.1, 7.2.1.2, 7.2.1.5)  following 250 
mg/m2 Rituxan or no Rituxan (depending on Rituxan level drawn on day 
-23 or -22; refer to table guide below fig. 7.1.1) 
Day -16 or -15:  
Blood draw for Rituxan level (see note below figure 7.1.1) 
Day –14: 
RIT with 90Y–Zevalin® per §§ 7.2.1.3, 7.2.1.4, 7.2.1.5 following 250 
mg/m2 Rituxan or no Rituxan (depending on Rituxan level drawn on day 
-16 or -15; refer to table guide below fig. 7.1.1) 
Days –9 to –5:  
Fludarabine Administration per § 7.2.2.1 (given outpatient if possible) 
Day –4:  
 
Melphalan Administration per § 7.2.2.2 (given inpatient) 
Days–3 to +30:  
Tacrolimus and Sirolimus per §§ 7.3.1, 7.3.2, 7.8 (GVHD prophylaxis) 
Days +1, +3, +6:  
Mini-MTX GVHD prophylaxis (for certain pts as per COH SOP 
G.001.04)  http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Prophylaxis.pdf   
and http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Addendum_A.p
df (accessibility verified 04/01/10) 


24 
IRB # 05149, Version 22 
 
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Days –4 to 0: 
Granulocyte–Colony Stimulating Factor (G–CSF) Administration to 
Donor per § 7.4.1 
Days –1 to 0: 
Hematopoietic Stem Cell (PBSC) Collection from Donor per § 7.4.2 
Day 0: 
Allogeneic Hematopoietic Stem Cell Transplant (AHSCT) per § 7.5 
Day +1: 
 
Possible Rituxan 250 mg/m2 (refer to guide table below fig. 7.1.2). 
Day +8 
Rituxan 250 mg/m2 (this will be administered regardless of previous 
Rituxan doses) 
 
 
Figure 7.1.1 
Day -23 or -22 
Rituxan level 
Give Day -21 Rituxan? 
Day -16 or -15 
Rituxan level 
Give Day -14 Rituxan? 
≥ 10 g/ml 
No 
≥ 10 g/ml 
No 
< 10 g/ml 
Yes 
< 10 g/ml 
Yes 
NOTE: On Monday holidays, the Rituxan level will be drawn the Friday before.  If the level is ≥15 
g/ml, another sample on Monday does not need to be drawn (because the level will not 
have decreased to < 10 g/ml by Monday).  Additionally, if the value is <10 g/ml, another 
sample on Monday again does not need to be drawn (because the patient will be receiving 
Rituxan according to the table above).  However, if the value is ≥10 g/ml but < 15 g/ml, 
then a Rituxan level draw will be repeated on Monday. 
 
 
Figure 7.1.2 
Received Rituxan Day -21? 
Received Rituxan Day -14? 
Give Rituxan Day +1? 
Give Rituxan Day +8? 
No 
No 
Yes 
Yes 
Yes 
Yes 
No 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
No 
Yes 
 
7.2 
REDUCED INTENSITY CONDITIONING (RIC) REGIMEN Ω §§ C.002, E.002–E.003, E.006, F.001–F.011, G.001–G.002 
7.2.1 
RADIOIMMUNOTHERAPY (OUTPATIENT) 
On DAY –21, patients will receive the fixed dose of approximately 5.0 mCi 111In–Zevalin® 
possibly preceded by an initial infusion of 250 mg/m2 Rituxan®; on DAY –14, patients will 
receive 0.4 mCi/kg 90Y–Zevalin®, possibly preceded by an initial infusion of 250 mg/m2 
Rituxan®.  The day -21 and day -14 Rituxan dosing is based on the Rituxan levels in the 
blood which will be drawn on day -23 or -22 (for the imaging dose), and on day -16 or -15 (for 
the therapy dose) [See figure 7.1.1 above]. 
7.2.1.1 
RITUXAN® (DAY OF IMAGING):  on DAY –21, if Rituxan® is given, it will be 
administered by slow iv infusion having been diluted to 1–4 mg/ml in an 
infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in 
Water, USP.  This initial Rituxan® infusion will be through a dedicated line.  If 
patient has had Rituxan before, begin infusion at 100 mg/hr.  If no adverse 
reactions occur, escalate rate gradually at 100 mg/hr every 30 minutes to a 
maximum of 400 mg/hr.  If patient has not had Rituxan before, begin infusion 
at 50 mg/hr.  If no adverse reactions occur, escalate rate at 50 mg/hr every 30 
minutes to a maximum of 400 mg/hr.  If hypersensitivity or infusion related 
events develop, the infusion will be temporarily slowed or interrupted.  The 
infusion can be continued at half the previous rate when symptoms abate.  


25 
IRB # 05149, Version 22 
 
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Note: prior to the start of Rituxan infusion, blood samples (1 EDTA purple top 
tube and 1 red top tube) will be obtained for analysis of antibody clearance 
(see 7.2.1.2). 
7.2.1.2 
111IN–ZEVALIN® IMAGING: following the Rituxan® infusion, if given, 111In–Zevalin® 
will be administered over approximately 10 minutes by slow IV injection.  A 
0.22 micron filter will be on the line between the patient and the infusion port.  
The line will be flushed with at least 10 mls of normal saline following the 111In–
Zevalin® infusion. 
Whole body gamma camera images will be obtained at approximately 1–24 
hours, approximately 48–72 hours and an optional third scan at approximately 
90–120 hours post–infusion to confirm results.  Exceptions to this time frame 
will be made if the optional scan falls on a weekend or a holiday.  Spot planar 
views and SPECT scans may be obtained at the discretion of the PI or Co-PI.  
Blood samples (1 EDTA purple top tube and 1 red top tube) will be obtained at 
approximately time 0 (pre-Rituxan, if given, and pre-In-111-Zevalin), 2 hours, 
4–6 hours, 1 day, 2 days, 3-4 days, 5 days and 6 days post–infusion of the 
antibody, if available.  These samples will be used for analysis of antibody 
clearance and bone marrow dose estimation.  Urine samples will be collected 
daily for 6 days for analysis of radioisotope clearance, if available.  Results will 
provide investigators a means to evaluate toxicities. 
Patients with unfavorable biodistribution (eg, localization to the spleen and/or 
failure of isotope to clear kidneys) indicating increased toxicities and 
unacceptable risks will be taken off study, not to proceed with 90Y–Zevalin® 
RIT.  If patients do not show unfavorable biodistribution, 90Y–Zevalin® will be 
administered on DAY –14. 
7.2.1.3 
RITUXAN® (DAY OF THERAPY):  on DAY –14, if Rituxan® is given, it will be 
administered by slow iv infusion having been diluted to 1–4 mg/ml in an 
infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in 
Water, USP.  This second Rituxan® infusion will be through a dedicated line at 
a rate of 100 mg/hr.  If hypersensitivity or infusion–related events do not occur, 
the infusion will be escalated at a rate of 100 mg/hr every 30 minutes to a 
maximum rate of 400 mg/hr.  If hypersensitivity or infusion related events 
develop, the infusion will be temporarily slowed or interrupted.  The infusion 
can be continued at half the previous rate when symptoms abate. 
7.2.1.4 
90Y–ZEVALIN® THERAPY:  following the Rituxan® infusion, if given, 0.4 mCi/kg of 
90Y–Zevalin® will be administered over approximately 10 minutes by slow IV 
injection.  A 0.22 micron filter will be on the line between the patient and the 
infusion port.  The line will be flushed with at least 10 mls of normal saline 
following the 90Y–Zevalin® infusion. 
7.2.1.5 
PRODUCT DOSE AND SCHEDULE 
7.2.1.5.1 
RITUXAN® 
7.2.1.5.1.1 
DAY –21:  250 mg/m2 (if given, see figure 7.1.1) 
7.2.1.5.1.2 
DAY –14:  250 mg/m2 (if given, see figure 7.1.1) 
7.2.1.5.1.3 
Day +1: 
250 mg/m2 (if given, see figure 7.1.2) 
7.2.1.5.1.4  
Day +8: 
250 mg/m2 


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7.2.1.5.2 
111IN–ZEVALIN® and 90Y–ZEVALIN®:  An 111In and 90Y isotope order 
form will be completed and faxed to the designated isotope vendor 
prior to RII/RIT.  Dosing of ZEVALIN®: 
7.2.1.5.2.1 
111IN–ZEVALIN®:  5.0 mCi fixed dose. 
7.2.1.5.2.2 
90Y–ZEVALIN®:  0.4 mCi 90Y/kg.  Dose will be calculated 
using patient‟s actual body weight at time of baseline 
evaluation [NOT TO EXCEED 32 MCI (MAXIMUM DOSE) +/- 
20% 
PER 
NUCLEAR 
REGULATORY 
COMMISSION 
GUIDELINES]. 
7.2.2 
CHEMOTHERAPY (Fludarabine to be given OUTPATIENT if possible.  Melphalan given 
INPATIENT) 
7.2.2.1 
DAYS –9 TO –5 FLUDARABINE:  25 mg/m2/day iv; based on actual body weight, 
given outpatient if possible. 
7.2.2.2 
DAY –4 MELPHALAN:  140 mg/m2 iv; based on actual body weight. 
7.3 
IMMUNOSUPPRESSION [Graft–VERSUS–HOST–DISEASE (GVHD) PROPHYLAXIS] Ω §§ E.002–E.003, 
G.001– G.002, G004 
7.3.1 
DAY –3 TACROLIMUS TREATMENT:  commence Tacrolimus at 0.02 mg/kg iv daily until oral 
intake resumes; then switch to oral at 2–3x the iv dose and taper based on disease 
status as described in § 7.8 GUIDELINES FOR TAPERING IMMUNOSUPPRESSION.  Dosing of 
Tacrolimus will be based on adjusted ideal body weight; if actual body weight is < ideal 
body weight, then actual body weight will be used. 
7.3.1.1 
GUIDELINES 
FOR TACROLIMUS DOSE ADJUSTMENT 
AND MANAGEMENT 
OF 
TOXICITIES:  if vomiting occurs in ≤ 20 minutes after an oral dose of Tacrolimus, 
the dose should be repeated.  Anti–nausea medications may be given as 
needed.  Intractable nausea and vomiting may require intravenous 
administration of Tacrolimus at one third the oral dose.  Tacrolimus may cause 
impaired renal function, hyperbilirubinemia, increased serum transaminase 
levels, hypertension, tremor, and seizures.  Impaired renal function may 
require Tacrolimus dose reductions.  Tacrolimus treatment may be 
DISCONTINUED, INTERRUPTED or SUSPENDED at any time for patient refusal to 
continue treatment, severe drug related toxicity or Serious Adverse Event 
(SAE). 
Tacrolimus dose adjustments should not be based exclusively on serum 
levels.  Tacrolimus levels should be used as a guide in conjunction with clinical 
observations of the biologic effects of the drug, (ie, toxicity and 
immunosuppression).  Blood pressure, renal function tests (creatinine, BUN), 
electrolytes and magnesium need to be followed at least 3x/week while 
receiving Tacrolimus at full dose and then twice weekly or per attending until 
Tacrolimus is discontinued. 


27 
IRB # 05149, Version 22 
 
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SUGGESTED TACROLIMUS DOSE ADJUSTMENT GUIDELINES 
PLASMA LEVELS 
TOXICITY GRADE 
TACROLIMUS DOSE 
< 5 ng/ml 
0 
↑ 25% 
5–10 ng/ml 
0, I 
No change 
5–10 ng/ml 
II 
↓ 25% 
5–10 ng/ml 
III 
↓ 50% 
5–10 ng/ml 
IV 
Stop 100% 
10-15 ng/ml 
0 
↓ 25% every 3–4 days 
>15 ng/ml 
0 
Hold x 24 hrs, then 
restart at ↓ 25% 
7.3.1.2 
TACROLIMUS BLOOD LEVELS:  Tacrolimus trough levels should be measured at 
least weekly during the first 50 days post–transplant.  Target levels of 5–10 
ng/ml are acceptable in patients who manifest no evidence of toxicity or 
GVHD.  Trough plasma levels should be drawn 10–12 hours after the last dose 
if possible. 
7.3.1.3 
TACROLIMUS DRUG INTERACTIONS 
7.3.1.3.1 
Drugs that may INCREASE Tacrolimus levels:  Fluconazole, 
Itraconazole, Ketoconazole, erythromycin, H2 Blockers, Verapamil, 
Diltiazem, Nicardipine, Danazol, Bromocriptine, Metoclopramide, 
Methylprednisolone, Somatostatin (Octreotide). 
7.3.1.3.2 
Drugs that may DECREASE Tacrolimus levels:  Rifampin, 
Phenobarbital, Phenytoin, Carbamazepine, Octreotide (may lower 
Serum Levels by DECREASING Intestinal Absorption of the Oral 
Drug). 
7.3.1.3.3 
Drugs that may result in ADDITIVE Nephrotoxicity:  
Aminoglycosides, Amphotericin B, Acyclovir, Furosemide, 
Trimethoprim–Sulfamethoxazole (TMP–SMX). 
7.3.2 
DAY –3 SIROLIMUS TREATMENT:  Sirolimus will be administered at 12 mg orally loading 
dose on DAY –3, followed by 4 mg orally single morning daily dose (target serum level 
3–12 ng/ml by HPLC).  Dosing of Sirolimus will be based on adjusted ideal body 
weight.  If actual body weight is < ideal body weight, actual body weight will be used.  
Taper or continue based on disease status as described in § 7.8 GUIDELINES FOR 
TAPERING IMMUNOSUPPRESSION. 
7.3.2.1 
GUIDELINES FOR SIROLIMUS DOSE ADJUSTMENT AND MANAGEMENT OF TOXICITIES:  
dose adjustments are based on clinical toxicity, blood levels, GVHD and 
clinical judgment involving the rate of rise or decline of the serum level.  For 
levels < 3 ng/ml, it is suggested that the dose be increased by approximately 
25% increments no more frequently than every 2 days, rounded to the nearest 
full milligram until the target range is achieved.  Conversely, for levels > 12 
ng/ml, it is suggested that the dose be decreased by ~25% no more frequently 
than every 2 days until the target level is achieved.  If vomiting occurs ≤ 20 
minutes of administration the dose should be repeated.  Anti–nausea 
medication may be given as needed. 


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IRB # 05149, Version 22 
 
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Sirolimus treatment may be DISCONTINUED, INTERRUPTED or SUSPENDED at any 
time for patient refusal to continue treatment or drug related SAE (§§ 11.0 
EXTERNAL REGULATORY REQUIREMENTS and 12.0 INTERNAL REGULATORY 
REQUIREMENTS).  The most serious reported SAEs from Sirolimus in previous 
clinical studies after HSCT included hyperlipidemia, hypertension, rash, 
thrombocytopenia, leukopenia, arthralgias, diarrhea and HUS. 
For management of cytopenias, it is recommended that patients receive 
growth factors or transfusions if necessary.  For patients with HUS (defined as 
presence of microangiopathy and rise in serum creatinine > 2x upper limit of 
normal, not attributed to other causes), Sirolimus should be adjusted to 
maintain therapeutic levels; discontinuation of Tacrolimus is recommended in 
this setting, particularly for cases requiring hemodialysis, seizures or severe 
hemolysis.  Plasmapheresis may be used at the discretion of the treating 
physician.  No dose modification is recommended for hyperlipidemia; lipid–
lowering agents should be instituted, with careful attention to the occurrence of 
rhabdomyolysis when HMGCoA reductase inhibitors are used. 
Sirolimus treatment may also be interrupted for inability to swallow due to 
stomatitis; for patients with severe stomatitis who may not be able to resume 
oral intake in several days, MMF may be started as GVHD prophylaxis, at a 
dose of 15 mg/kg intravenously twice a day, until oral intake resumes, when 
Sirolimus may substitute MMF. 
Sirolimus should be adjusted for hepatic impairment, as follows: for bilirubin > 
2.0, reduce maintenance dose by 30%.  Sirolimus may be re–instituted if, in 
the judgment of the investigator, the primary clinical cause(s) for dose 
adjustment have been resolved. 
7.3.2.2 
SIROLIMUS SERUM LEVELS:  Sirolimus trough levels should be measured at least 
weekly during the first 50 days post–transplant.  Levels of 3–12 ng/ml are 
considered therapeutic.  Trough levels should be measured 20–24 hours after 
the last dose. 
7.3.2.3 
SIROLIMUS DRUG INTERACTIONS:  Sirolimus is a substrate for both cytochrome 
CYP3A4 and P–glycoprotein. 
7.3.2.4 
DRUGS THAT MAY INCREASE SIROLIMUS BLOOD CONCENTRATIONS INCLUDE: 
7.3.2.4.1 
Calcium Channel Blockers:  Diltiazem, Nicardipine, Verapamil 
7.3.2.4.2 
Calcineurin Inhibitors:  Cyclosporine 
7.3.2.4.3 
Antifungal Agents:  Ketoconazole, Clotrimazole, Fluconazole, 
Itraconazole 
7.3.2.4.4 
Macrolide Antibiotics:  Clarithromycin, Erythromycin, 
Troleandomycin 
7.3.2.4.5 
Gastrointestinal Prokinetic Agents:  Cisapride, Metoclopramide 
7.3.2.4.6 
Other Drugs:  Rifampin, Bromocriptine, Cimetidine, Danazol, HIV–
Protease Inhibitors (eg, Ritonavir, Indinavir) 
7.3.2.4.7 
DUE TO EXTREME INTERACTIONS WITH VORICONAZOLE, THE DOSE OF 
SIROLIMUS SHOULD BE REDUCED TO 25% WHEN GIVEN WITH 
VORICONAZOLE.   


29 
IRB # 05149, Version 22 
 
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7.3.2.5 
DRUGS THAT MAY DECREASE SIROLIMUS CONCENTRATIONS INCLUDE: 
7.3.2.5.1 
Anticonvulsants:  Carbamazepine, Phenobarbital, Phenytoin 
7.3.2.5.2 
Antibiotics:  Rifabutin, Rifapentine 
7.3.2.5.3 
Herbal Preparations:  St. John's Wort (Hypericum Perforatum) 
could result in REDUCED Sirolimus Concentrations. 
7.3.2.5.4 
Care should be exercised when drugs or other substances that are 
metabolized by CYP3A4 are administered concomitantly with 
Rapamune®.  Grapefruit Juice REDUCES CYP3A4–mediated 
metabolism of Rapamune® and MUST NOT BE USED FOR DILUTION. 
7.3.3 
DAY +1, +3, +6  MINI METHOTREXATE TREATMENT:  Certain patients will receive mini-MTX 
in addition to Tacrolimus and Sirolimus as part of the acute GVHD prophylaxis regimen 
as per COH SOP G.001.04, Acute Graft versus Host Disease Prophylaxis  
http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Prophylaxis.pdf  and 
http://www.coh.org/hct-
sop/Section%20G/G.001.04_Acute_Graft_versus_Host_Addendum_A.pdf   
(accessibility verified 04/01/10) 
   
7.4 
COLLECTION OF DONOR HEMATOPOIETIC STEM CELLS (PBSCS) Ω §§ B.001–B.005 
7.4.1 
G–CSF ADMINISTRATION TO DONORS 
All donors will receive G–CSF per City of Hope standard operating procedures.  G–CSF will be 
administered by a subcutaneous daily injection.  The schedule of G–CSF administration and 
PBSC collections can only be ascertained when DAY 0 is identified.  When a treatment regimen 
schedule has been fixed and the schedule of G–CSF administration and PBSC collections made 
this has to be confirmed with the personnel in the apheresis room.  DAY 0 will be fixed on a 
Tuesday–Friday.   
7.4.2 
PERIPHERAL BLOOD STEM CELLS (PBSC) COLLECTION 
The Donor will preferably undergo collections vein–to–vein; or through appropriate CVC inserted 
on or before day of treatment regimen.      
 
TREATMENT SCHEMA FOR DONOR 
Days 
-5 
–4 
–3 
–2 
–1 
0 
G–CSF as per COH 
SOP 
X 
X 
X 
X 
X 
 
PBSC collection 
 
 
 
X 
X 
 
PBSC infusion 
(t
l
t)
 
 
 
 
 
X 
PBSCs will be collected in the afternoon of DAY –1, stored in the refrigerator at 4ºC overnight.  A 
second collection may be performed the following afternoon to try to achieve the target cell dose, 
and both collections will be transfused on DAY 0. 
The target dose of PBSCs to be collected will be specified at 5–10 x 106 CD34+ cells/kg, with a 
minimum of 2 x 106 CD34+ cells/kg.  For donors not achieving a minimum CD34+ cell count of 2 x 
106/kg after 3 daily collections, BM harvesting may be recommended at the discretion of the 
treating physician. 


30 
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If PBSCs cannot be collected by a vein–to–vein technique, a percutaneous Quinton Catheter or 
its equivalent will be inserted.  General procedures will include the use of a standard apheresis 
machine, and processing ≤ 16 L of whole blood during the collection.   
Marrow collection is allowed in the case of pediatric donors unable to receive G-SCF due to age, 
or for donors unable to collect a minimum target CD34+ cell dose or for donors who are unable to 
receive G-CSF or refuse to donate PBSC. 
In circumstances in which the donor is unable to donate cells on the date requested, 
cryopreservation of the stem cell product is allowed as per COH SOP. 
7.5 
HEMATOPOIETIC STEM CELL (PBSC) INFUSION Ω §§ B.006 
All patients will receive unmodified G–CSF mobilized PBSCs from an HLA identical related or 
unrelated donor on DAY 0 of the treatment regimen. For unrelated donor, the stem cell product will 
either be unmodified G–CSF mobilized PBSCs or bone marrow.   
7.6 
DONOR LYMPHOCYTE INFUSION (DLI) Ω §§ B.004–B.005, H.001–H.002 
DLI will be an option off protocol for subjects who relapse or have persistent disease post transplant.  
If the patient requires DLI, he/she will be taken off protocol.  For aggressive PD after transplant, such 
that the treating physician believes that the patient cannot wait to undergo DLI, the patient may 
receive alternative treatments such as chemotherapy or radiation off protocol. 
7.7 
SUPPORTIVE CARE Ω §§ D.001–D.013, F.001–F.011, G01–G.007 
Supportive care will be given as per City of Hope standard operating procedures. 
7.7.1 
ACCESS TO VESSELS 
Prior to admission, during pre–transplant evaluation, all patients will have a permanent CVC 
placed. 
7.7.2 
HYPERALIMENTATION 
All patients will receive appropriate Hyperalimentation as soon as necessary after admission.  
The goal will be to prevent even a short duration of negative nitrogen balance. 
7.7.3 
PLATELET TRANSFUSION 
7.7.3.1 
INDICATION.  Platelets are transfused to prevent bleeding and an attempt is made 
to keep the circulating level > 15–20,000/mm3 at all times.  This goal may be 
changed by the attending physician as clinically indicated. 
7.7.3.2 
IRRADIATION.  All blood products are irradiated with 1,500 cGy prior to infusion. 
7.7.4 
MANAGEMENT OF FEVER/INFECTIONS 
Treatment of patients on this protocol is not intended to restrict the freedom of the managing 
physician to treat suspected or documented infections.  In neutropenic patients, however, the 
following guidelines will be followed: 
7.7.4.1 
All febrile, neutropenic patients will be treated with IV antibiotic(s), the choice of 
which will be guided by the patient‟s clinical history, institutional practices and 
subsequent culture results. 


31 
IRB # 05149, Version 22 
 
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7.7.4.2 
Patients with documented, invasive fungal infection or with persistent, 
unexplained fevers while neutropenic and on broad–spectrum antibiotic therapy 
will receive appropriate antifungal therapy. 
7.7.5 
POST–TRANSPLANT GROWTH FACTORS 
Growth factors will not be given unless severe persistent neutropenia develops or persists past 
DAY 21 post–transplant (ANC < 100/m3 for > 5 days). 
7.7.6 
INFECTION PROPHYLAXIS 
Levofloxacin (or non–absorbable oral antibiotics for levofloxacin allergy) for gastrointestinal 
decontamination will be given in certain cases per treating physician discretion. Otherwise, 
prophylactic antibiotics will be given per institutional guidelines.  TMP–SMX (pentamidine or 
atovaquone for sulfa allergy) will be administered from DAY –9 to DAY –3 and prophylaxis will be 
reinstituted when white blood cells are > 3000 and continued until 6 months post–transplant.  The 
choice of TMP–SMX as a prophylactic agent may be altered based on a history or sensitivity to 
this agent or associated cytopenias.  Empiric broad-spectrum antibiotics will be used as clinically 
indicated, per institutional guidelines.  Anti–fungal prophylaxis will be administered beginning on 
DAY 1 and continued daily until granulocytopenia resolves; continuation of anti–fungal therapy 
beyond this point will be at the discretion of the treating physician.  Herpes prophylaxis with 
acyclovir for patients with HSV+ serology will begin on DAY –1.  CMV monitoring will commence 
21 days post–transplant and continue until 80–100 days post–transplant; treatment for 
reactivation will be given according to institutional guidelines.  Patients may participate in clinical 
protocol for prevention of infections. 
7.8 
GUIDELINES FOR TAPERING IMMUNOSUPPRESSION Ω §§ G.001–G.005 
Individual tapering of immunosuppression will be at the discretion of the treating physician.  In 
general, no evidence of GVHD should be present and the following guidelines will be observed: 
7.8.1 
For patients with persistent or progressive disease at 30 days post–transplant, begin 
simultaneous taper of Tacrolimus and Sirolimus over 2–4 months. 
7.8.2 
For patients with CR/PR at 30 days post–transplant, begin tapering Tacrolimus and 
Sirolimus 3–6 months post–AHSCT over 3–6 months as tolerated. 
8.0 
PATIENT EVALUATIONSΩ §§ A.011–A.012, B.002–B.006, C.002, D.001–D.013, E.002–E.003, E.006, F.001–F.011, G.001–G.005, H.001–
H.002 
8.1 
EVALUATION/TESTS DURING THE 111IN–ZEVALIN® IMAGING PERIOD Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–
J.003 
8.1.1 
Vital signs will be obtained approximately every 15 minutes for the first hour during the 
Rituxan® infusion, approximately hourly during the remainder of the infusion, and 
approximately every 15 minutes x 4 following the start of 111In–Zevalin® infusion.  If vital 
signs are unstable, they will be monitored approximately at 5 minute intervals until 
stable. 
8.1.2 
The purpose of 111In–Zevalin® imaging is twofold: 
8.1.2.1 
To evaluate biodistribution of whole body γ–camera images. 
8.1.2.2 
To assess whether biodistribution is acceptable to proceed with 90Y–Zevalin® 
RIT. 
8.1.3 
The biodistribution of 111In–Zevalin® is to be determined from a visual evaluation of 
whole body γ–camera images during the first day (1–24 hours) and the second or third 


32 
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day (48–72 hours) after injection.  A third scan may be taken on the fourth or fifth day 
(90–120 hours) if needed to confirm results. 
8.1.3.1 
EXPECTED BIODISTRIBUTION: 
8.1.3.1.1 
Easily detectable uptake in the blood pool areas (including but not 
limited to the heart, major abdominal blood vessels, vascular areas 
of the head, lungs and pelvis) on the first day image, with less 
activity in the blood pool areas on the second or third day image. 
8.1.3.1.2 
Moderately high to high uptake in normal liver and spleen during the 
first day and the second or third day images. 
8.1.3.1.3 
Moderately low or very low uptake in normal kidneys, urinary 
bladder, and normal bowel on the first day image and the second or 
third day image. 
8.1.3.1.4 
Tumor uptake may be visualized in soft tissue as areas of increased 
intensity, and tumor bearing areas in normal organs may be seen as 
areas of increased or decreased intensity. 
8.1.3.2 
ALTERED BIODISTRIBUTION 
8.1.3.2.1 
Diffuse uptake in normal lung more intense than the cardiac blood 
pool on the first day image, or more intense than the liver on the 
second or third day image. 
8.1.3.2.2 
Kidneys with greater intensity than the liver on the posterior view of 
the second or third day image. 
8.1.3.2.3 
Intense areas of uptake throughout the normal bowel comparable to 
the liver on the second or third day images. 
8.1.4 
Biodistribution of 111In–Zevalin® will be assessed on the first day image and second or 
third day image.  If desired, a third image may be obtained at 90–120 hours to support 
the decision.  If the patient has an altered biodistribution, the patient will be taken off 
study before proceeding to 90Y–Zevalin® RIT. 
8.2 
EVALUATIONS/TESTS DURING THE 90Y–ZEVALIN® TREATMENT PERIOD UP TO MONTH 3 Ω §§ B.001, 
C.001, D.003, I.001–I.003, J.001–J.003 
8.2.1 
Vital signs will be obtained approximately every 15 minutes for the first hour during the 
Rituxan® infusion, approximately hourly during the remainder of the infusion, and 
approximately every 15 minutes x 4 following the start of 90Y–Zevalin® infusion.  If vital 
signs are unstable, they will be monitored approximately at 5-minute intervals until 
stable. 


33 
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9.0 
STUDY CALENDAR Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
9.1 
STUDY CALENDAR ― PRE–STUDY THROUGH DAY 0 (TRANSPLANT DAY) Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
REQUIRED STUDIES 
PRE–
STUDY1 
DAY -23 
OR -22 
DAY 
–21 
DAY -16 
OR -15 
DAY 
–14 
DAY –9 DAY –8 
 
DAY -7 
DAY –6 DAY –5 DAY –4 DAY –3 DAY –2 DAY –1 DAY 0 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H and PE with KPS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC & PLT 
X3 
 
 
 
 
X5 
 
 
 
 
X 
X 
X 
X 
X 
WBC Differential 
X3 
 
 
 
 
X5 
 
 
 
 
 
 
 
 
 
Reticulocyte Count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAZA@ 
X# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive Metabolic 
Panel, LDH 
X 
 
 
 
 
X5 
 
 
 
 
 
 
 
 
 
Basic Metabolic Panel 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABO/Rh Typing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B2 Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative Igs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Panel (incl Hep B 
surf Ag) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eval & Rx of CNS Dz if 
indicated (pts w/BM inv 
w/large cell NHL, testicular 
inv or neurologic sx) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unilateral Bone Marrow 
Aspiration/Biopsy* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine Clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 cc Sodium Heparin 
Blood to HLA Laboratory 
for DNA Storage 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for RTX level  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Costim Assays2 
 
X 
 
 
 
 
X4 
 
 
 
 
 
 
 
 
DIAGNOSTIC 
TESTS/RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO/FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans NCAP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG–PET Scan as 
indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituxan® 
 
 
X% 
 
X% 
 
 
 
 
 
 
 
 
 
 
111In–Zevalin®+ 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
90Y–Zevalin® 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Bactrim or Equivalent 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Fludarabine 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Melphalan 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Acyclovir 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Allo–HSC Infusion** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Commence Tacrolimus$ 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Commence Sirolimus^ 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
# Serum must be drawn 4 wks prior to imaging dose.  Results are required prior to enrollment for those pts who have been prev rx w/murine proteins including Rituxan®. 
* Send for morphology, flow cytometry, and cytogenetics.  Whenever possible, for patients with MCL, and patients with a history of peripheral blood involvement by 
follicular lymphoma, PCR gene rearrangement studies for bcl-1 or bcl-2 will be done.  (PCR may be done on PB or BM). 
+ Including dosimetry studies.   
3    for pts with CLL or PB involvement, CBC, Diff & PLT to be done  1 wk prior to imaging dose. 
@  Draw at least 5 ml blood into a red top tube. Deliver specimen to the RIT lab. 
1 All pre-study tests must be done 42 days prior to start of treatment (imaging dose). 
 
 
$ Tacrolimus tapered as described in § 7.3 of protocol 
 
 
 
 
^ Sirolimus tapered as described in § 7.3 of protocol 
%  If required per protocol, see table, figure 7.1.1. 
** For sibling/related donor HSC only: send approx. 1 ml of the HSC product to the Virology Lab, Familian Science Bldg., Room C209D (x68419).  The sample will be 
obtained at the end of HSC collection (a segment of the collection tubing will be heat sealed and removed for transport).  Donor consent will be obtained.  Note: this 
sample will not be collected for MUDs.  DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS PROCEDURE PERFORMED. 
2   Draw two 6 ml sodium heparin green top tubes, AND two 4 ml sodium heparin green top tubes for an amount of whole blood of about 20 ml and send to Virology Lab, 
Familian Science Bldg., Room C209D (x68419).  DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS PROCEDURE PERFORMED. 
4   Day -8 costim draw may be done +/- 2 days. DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS PROCEDURE PERFORMED. 
5   +/- 3 days. 


34 
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9.2 
STUDY CALENDAR ― DAY 1 THROUGH DAY 84 POST–TRANSPLANT Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
REQUIRED STUDIES 
DAY 1 DAY 75 
DAY 8 
DAY 145 
DAY 215 DAY 283 
WK 63 
WK 83 
WK 103 
WK 123 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
H and PE with KPS11 
 
 
 
X 
 
X 
 
X 
 
X 
Acute GVHD 
Monitoring 
 
 
 
X 
X 
X 
X 
X 
 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
CBC/PLT1,9 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
WBC Differential7,9 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HAZA10 
 
 
 
 
 
 
 
X 
 
 
Comprehensive 
Metabolic Panel, LDH, 
Mg8,9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quantitative Igs 
 
 
 
 
 
X 
 
X 
 
X 
CMV Culture or PCR# 
 
 
 
 
X 
X 
X 
X 
 
X 
Unilateral Bone 
Marrow 
Aspiration/Biopsy* (see 
note bottom of section 
9.3) 
 
 
 
 
 
X+ 
 
 
 
 
Chimerism on PB or 
bone marrow with 
STR, Q-PCR or sex 
chromosomes 
 
 
 
 
 
X 
 
 
 
 
Costim Assays2 
 
 
 
 
X 
X 
 
X 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
CT Scans (N)CAP 
 
 
 
 
 
 
X6,&,4 
 
 
 
FDG–PET/CT Scan 
 
 
 
 
 
 
X6,4 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
Rituxan 
X** 
 
X 
 
 
 
 
 
 
 
Commence Anti–
Fungal Prophylaxis% 
X 
X 
 
X 
 
 
 
 
 
 
Trimethroprim–
Sulfamethoxazole@ 
 
 
 
 
 
 
 
 
 
 
Continue Tacrolimus$ 
X 
X 
 
X 
X 
X 
Continue Sirolimus^ 
X 
X 
 
X 
X 
X 
@ Trimethoprim–Sulfamethoxazole Prophy will be reinstituted when WBC > 3000 & continued through month 6 unless pt has sensitivity to this agent. 
% Anti–Fungal Prophylaxis will be administered on DAY 1 and continued daily until granulocytopenia resolves. 
$ Tacrolimus will continue daily and taper as described in § 7.3 of protocol 
^ Sirolimus will continue daily and taper as described in § 7.3 of protocol 
* Send for morphology, flow cytometry, cytogenetics and engraftment studies.  Whenever possible, for patients with MCL, and patients with a history of 
peripheral blood involvement by follicular lymphoma, PCR gene rearrangement studies for bcl-1/bcl-2 will be done. 
1 Daily from DAY 0 until discharge.   
3 +/– 1 week 
5 +/– 4 days 
6 For pts whose PET scan prior to conditioning showed no lymphomatous involvement, the week 6 CT & FDG-PET are not required.  For patients with 
CLL/SLL, restaging scans at week 6 are not required. 
&  At wk 6, separate diagnostic CT only if indicated. 
7 Differential will be done daily from day 14 to day 21, as long as the patient is inpatient on those days. 
8 To be done weekly until discharge. 
9 CBC, DIFF, PLT, CMP, LDH and mg to be done twice a week after discharge until day 90-100. 
10  Draw at least 5 ml blood into a red top tube. Deliver specimen to the lab in RIT. 
#    At least weekly up to day 80-100, or per COH SOP F.007.003: http://www.coh.org/hct-
sop/Section%20F/F.007.03_Cytomegalovirus_Surveillance,_Prophylaxis_and_Therapy_Guidelines_rev._11.11.09.pdf 
(accessibility verified 04/01/10) 
+  Only required for pts who have BM involvement by lymphoma at study enrollment. (see note bottom of section 9.3) 
**  If required per protocol, see table, figure 7.1.2. 
2   Draw two 6 ml sodium heparin green top tubes, AND two 4 ml sodium heparin green top tubes for an amount of whole blood of about 20 ml and send to 
Virology Lab Familian Science Bldg, Room C209D (x68419).  DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS 
PROCEDURE PERFORMED. 
4 +/- 2 weeks. 
11 KPS will not be required when subjects are inpatient. 


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IRB # 05149, Version 22 
 
11/25/13 
9.3 
STUDY CALENDAR ― DAY 90 THROUGH YEAR 5 POST–TRANSPLANT FOLLOW–UP Ω §§ B.001, C.001, D.003, I.001–I.003, 
J.001–J.003 
REQUIRED STUDIES 
DAY 90–
1003 
 
DAY 
1203 
MO    
6% 
MO   
9% 
MO 12  
(1 YR)
 4 MO 184 MO 24 
(YR 2)
 4 MO 304 MO 36 
(YR 3)
 4 
MO  
424 
MO 48 (YR 
4)
 4 
MO 544 MO 60 
(YR 5)
 4 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
H and PE with KPS11 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chronic GVHD 
Monitoring 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAZA@ 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
CBC, Diff, Platelets 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
Comprehensive 
Metabolic Panel, LDH, 
Mg 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
B2 Microglobulin 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
PCR Gene 
Rearrangement 
Studies on PB ( 
BCL-1/BCL-2)5 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
Unilateral Bone 
Marrow 
Aspiration/Biopsy* 
(see note below) 
X& 
 
X+ 
 
X 
 
X 
 
 
 
 
 
X 
Chimerism on PB or 
bone marrow with 
STR, Q-PCR or sex 
chromosomes 
X 
 
X 
 
X$ 
 
 
 
 
 
 
 
 
Costim Assays2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CD137 (4-1BB) 
expression** 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
DIAGNOSTIC TESTS/ 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
ECHO 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DLCO/FEV1 
 
 
 
 
X 
 
 
 
 
 
 
 
 
CXR (PA & Lateral) or 
CT chest 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scans (N)CAP# 
X^ 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
FDG–PET Scan if 
indicated# 
X^ 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
* send for morphology, flow cytometry, cytogenetics, and engraftment studies. Whenever possible, for patients with MCL, and patients with a history of 
peripheral blood involvement by follicular lymphoma, PCR gene rearrangement studies for bcl-1/bcl-2 will be done.  (Engraftment studies are not required 
after year 1.  Note that engraftment studies can be done on either bone marrow or peripheral blood.) 
3 +/– 2 weeks          11 KPS will not be required when subjects are inpatient. 
%   +/- 1 month 
4 +/-2 months 
@  draw at least 5 ml blood into a red top tube. Deliver specimen to the lab in RIT. 
+  BM exam only required at month 6 if the BM exam at day 100 was positive. 
$   as clinically indicated thereafter. 
#   preferably, both a CT and FDG-PET will be done, however, either is acceptable at all of these time points.  Note: for patients with CLL/SLL, CT should be 
done at 6 months and 1 year, PET not required at these time points unless transformation to large cell. 
&  Bone marrow examination is only required at day 90-100 if the bone marrow exam at day 28 was positive. 
^  Not necessary if the week 6 exam showed no lymphomatous involvement.  For patients with CLL/SLL, restaging scans at day 100 are not required. 
2   Draw two 6 ml sodium heparin green top tubes, AND two 4 ml sodium heparin green top tubes for an amount of whole blood of about 20 ml and send to 
Virology Lab Familian Science Bldg, Room C209D (x68419).  DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 WILL NOT HAVE THIS 
PROCEDURE PERFORMED. 
**  Draw about 25-30 ml (4 green top tubes) and send to Weimin Tsai, FOX South (x63199).  DUE TO FUNDING, PATIENTS ENROLLED AFTER 6/20/12 
WILL NOT HAVE THIS PROCEDURE PERFORMED. 
5 Whenever possible, for patients with MCL, and patients with a history of peripheral blood involvement by follicular lymphoma. 
NOTE:  Bone marrow examinations post transplant will be done following these parameters: 
 
For pts who have had previous bone marrow involvement by lymphoma:  do at YR1, YR2, and YR5. 
 
For pts who have bone marrow involvement by lymphoma at study enrollment: do at d28, d100 (if pos at d28), M6 (if pos at d100), YR1, YR2, and 
YR5. 
 
For pts who have never had bone marrow involvement by lymphoma: recommend to do at YR1, YR2, and YR5, as clinically indicated. 


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11/25/13 
10.0 
MEASUREMENT OF EFFECT Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
10.1 
STAGING CRITERIA Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
Staging of disease must be evaluated ≥ 28 days after the end of the last chemotherapy and ≤ 42 days 
prior to transplant.  Ann Arbor Staging Criteria will be used.  Stage is determined based on extent of 
disease at the time of diagnosis. 
ANN ARBOR CLASSIFICATION 
STAGE I 
Involvement of a single lymph node region (1) or a single extralymphatic organ or site (1); 
or localized involvement of a single extralymphatic organ or site in the absence of any 
lymph node involvement (IE) (rare in Hodgkin lymphoma). 
STAGE II 
Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or 
localized involvement of an extralymphatic organ or site in association with regional lymph 
node involvement with or without involvement of other lymph node regions on the same 
side of the diaphragm(IIE). 
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (III) which may be 
accompanied by localized involvement of an associated extralymphatic organ or site (IIIE) 
or spleen (IIIS) or both (IIISE). 
STAGE IV 
Diffuse or disseminated involvement of 1 or more extralymphatic organs with or without 
associated lymph node involvement, or isolated extralymphatic organ involvement in the 
absence of adjacent regional lymph node involvement, but in conjunction with disease in 
distant site(s). Any involvement of the liver or bone marrow, or nodular involvement of the 
lung(s). 
A = Asymptomatic 
B = Fever, sweats, weight loss > 10% of body weight 
10.2 
Criteria for Evaluations & Endpoint Definitions 
Revised Response Criteria for Malignant Lymphoma 
  Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
10.2.1 
SENSITIVITY OF DISEASE:  patients are grouped into 1 of 3 groups based on sensitivity of 
disease: 
10.2.1.1 
INDUCTION FAILURE:  patients who did not achieve a CR or PR from induction 
chemotherapy. 
10.2.1.2 
RESISTANT RELAPSE:  patients who did not achieve a CR or PR from the most 
recent standard salvage chemotherapy. 
10.2.1.3 
SENSITIVE RELAPSE:  patients who did achieve a CR or PR from the most recent 
standard salvage chemotherapy. 
10.2.2 
MEASURABLE DISEASE:  tumor that can be accurately measured in size. This information 
can be used to judge response to treatment. 
                                                          
 REFERENCE: BRUCE D. CHESON, BEATE PFSTNER, MALIK E. JUWEID, RANDY D. GASCOYNE, LENA SPECHT, 
SANDRA J. HORNING, BETRAND COIFFIER, RICHARD I. FISHER, ANTON HAGENBEEK, EMANUELE ZUCCA, STEVEN T. 
ROSEN, SIGRID STROOBANTS, T.ANDREW LISTER, RICHARD T. HOPPE, MARTIN DREYLING, KENSEI TOBINAI, JULIE 
M.VOSE, JOSEPH M. CONNORS, MASSIMO FEDERICO, AND VOLKER DIEHL .  Revised Response Criteria for Malignant 
Lymphoma.  Journal of Clinical Oncology, 25(5):579–586, February 2007. 


37 
IRB # 05149, Version 22 
 
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Bidimensionally measurable lesions with clearly defined margins by:  1) medical 
photograph (skin or oral lesion), or plain x–ray with at least 1 diameter .5 cm or greater 
(bone lesions are not included) or, 2) CT, MRI or other imaging scan with both 
diameters > the distance between cuts of the imaging study, or 3) palpation with both 
diameters ≥ 2 cm. 
10.2.3 
EVALUABLE DISEASE:  unidemensionally measurable lesions, masses with margins not 
clearly defined, lesions with both diameters < 0.5 cm, lesions on scan with either 
diameter smaller than the distance between cuts, palpable lesions with either diameter 
< 2 cm, bone disease. 
10.2.4 
NON–EVALUABLE DISEASES:  pleural effusions, ascites, disease documented by indirect 
evidence only (eg, lab values). 
10.2.5 
OBJECTIVE STATUS, TO BE RECORDED AT EACH EVALUATION:  if an organ has too many 
measurable lesions to measure at each evaluation, choose 3 to be followed before 
patient is entered on study.  Remaining measurable lesions in that organ will be 
considered evaluable for the purpose of objective status determination.  Unless PD is 
observed, objective status can only be determined when ALL is measurable and 
evaluable sites and lesions are assessed. 


38 
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10.2.6 
RESPONSE CRITERIA (RC) 
 
 
Revised Response Criteria for Malignant Lymphoma 
Response Definitions for Clinical Trials (Cheson et al) 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
a) FDG-avid or PET 
positive prior to therapy; 
mass of any size 
permitted if PET 
negative 
b) Variably FDG-avid or 
PET negative; 
regression to normal 
size on CT. 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and 
no new sites 
50% decrease in SPD 
of up to 6 largest 
dominant masses; no 
increase in size of other 
nodes 
a)FDG-avid or PET 
positive prior to therapy; 
one or more PET 
positive at previously 
involved site 
b) variably FDG-avid or 
PET negative; 
regression on CT 
50% 
decrease in 
SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in 
size of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to 
attain CR/PR 
or PD 
a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior 
sites of disease and no 
new sites on CT and 
PET 
b) Variably FDG-avid or 
PET negative; no 
change in size of 
previous lesions on CT 
 
 
Relapsed 
Disease 
or PD 
Any new lesion 
or increase by 
50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) >1.5 cm in 
any axis, 50% 
increase in SPD of 
more than one node, 
or 50% increase in 
longest diameter of a 
previously identified 
node >1cm in short 
axis. 
Lesions PET positive if 
FDG-avid lymphoma 
or PET positive prior 
to therapy. 
 
>50% increase 
from nadir in 
the SPD of 
any previous 
lesions 
New or recurrent 
involvement 
From  “Revised Response Criteria for Malignant Lymphoma”, B.D. Cheson, et. al. J Clin Oncol 
25:579-586, 2007 
 
 


39 
IRB # 05149, Version 22 
 
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10.2.7 
END POINT DEFINITIONS 
10.2.7.1 
MAJOR END POINTS OF INTEREST 
10.2.7.1.1 
RELAPSE:  return of signs and symptoms of cancer after a period of 
improvement. 
Reappearance of any clinical evidence of lymphoma in a patient who 
has had a CR; relapse for PR is defined as PD relative to disease 
status during the PR; Relapsed Disease requires the following: 
 
appearance of any new lesion or increase by ≥ 50% in the size of 
previously involved sites. 
 
≥ 50% increase in greatest diameter of any previously identified node 
> 1 cm in its short axis or in the SPD of > 1 node. 
10.2.7.1.2 
RELAPSE–FREE SURVIVAL (RFS):  Defined as the time from transplant 
to the first observation of relapsed disease or death due to any 
cause, whichever occurs first.  If the patient has not relapsed or died, 
relapse-free survival is censored at the time of last follow-up. 
10.2.7.1.3 
PROGRESSION–FREE SURVIVAL (PFS):  Time from transplant to 
disease progression or death from NHL. 
10.2.7.1.4 
TRANSPLANT–RELATED 
DEATH 
(TRD)/TRANSPLANT–RELATED 
MORTALITY (TRM):  death that occurs during transplant admission; 
death due to causes unrelated to the underlying disease; death or 
mortality due to toxicities, adverse events or side effects occurring 
during or due to treatment; may be due to treatment procedures, 
drug toxicities, allergic reactions, and/or infections; patients relapsing 
are censored as surviving at the time of relapse. 
10.2.7.1.5 
MEAN SURVIVAL TIME:  average time that patients in clinical study 
remain alive; time is measured beginning either at diagnosis or start 
of treatment. 
10.2.7.1.6 
OVERALL SURVIVAL (OS)/SURVIVAL RATE (SR):  Defined as the time 
from transplant to death due to any cause.  If a patient is alive, 
survival time is censored at the time of last follow-up. 
10.2.7.1.7 
RESPONSE RATE (RR):  percentage of patients whose cancer shrinks 
or disappears after treatment. 
10.2.7.2 
SECONDARY END POINTS OF INTEREST 
10.2.7.2.1 
DURATION OF RESPONSE/RESPONSE DURATION (DR):  interval from 
onset of response to PD; initial documentation of response until date 
of relapse or PD. 
For patients with PR, measured from initial documentation of PR to 
time when cancer begins to enlarge or spread again. 
10.2.7.2.2 
TIME–TO–[DISEASE]–PROGRESSION (TTP):  interval from first infusion 
to PD; entry onto trial until date of initial observation of PD or death 
due to any cause; measure of time after a disease is diagnosed (or 
treated) until the disease starts to get worse. 


40 
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10.2.7.3 
PROGRESSION OF DISEASE/PROGRESSIVE DISEASE (PD):  cancer that continues to 
grow or spread, increasing in scope or severity; increase in the size of a tumor 
or spread of cancer in the body. 
50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of 
products of all measurable lesions over smallest sum observed (over baseline 
if no decrease) using the same techniques as baseline, OR clear worsening of 
any evaluable disease, OR reappearance of any lesion which had disappeared, 
OR appearance of any new lesion/site, OR failure to return for evaluation due to 
death or deteriorating condition (unless clearly unrelated to this cancer); for 
scan only bone disease, increased uptake does not constitute clear worsening; 
worsening of existing non–evaluable disease not constitute PD. 
10.2.7.3.1 
Lymphoma:  new sites of lymphadenopathy or increase of > 25% in 
lymph node size (as assessed by CT scans, blood or BM 
involvement with clonal B cells. 
10.2.7.3.2 
CLL:  new sites of lymphadenopathy or increase of > 25% BM 
involvement or increase in > 25% blood involvement (if lymphocyte 
count > 50,000). 
10.2.8 
RESPONSE ASSESSMENT:  response is currently assessed on the basis of clinical, 
radiologic, and pathologic (ie, BM) criteria. 
10.2.8.1 
CT scans remain the standard for evaluation of nodal disease; thoracic, 
abdominal, and pelvic CT scans are recommended even if those areas were 
not initially involved because of the unpredictable pattern of recurrence in NHL; 
studies will be performed no later than two months after treatment has been 
completed to assess response; interval may vary with type of treatment, eg, a 
longer period may be more appropriate for biologic agents where the 
anticipated time–to–response may be greater. 
10.2.8.2 
A BM aspirate and Bx will only be performed to confirm a CR if they were 
initially positive or if it is clinically indicated by new abnormalities in the PB 
counts or blood smear. 


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10.3 
PERFORMANCE STATUS Ω §§ B.001, C.001, D.003, I.001–I.003, J.001–J.003 
ECOG (ZUBROD)/KARNOFSKY PERFORMANCE STATUS SCALES/SCORES 
PERFORMANCE STATUS CRITERIA 
Karnofsky performance scores are intended to be multiples of 10. 
ECOG (ZUBROD) 
KARNOFSKY 
Scor
e 
Description 
Score 
Description 
0 
Fully active, able to carry on all pre–
disease performance without 
restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carryout work of a light or sedentary 
nature (eg, light housework, office 
work). 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
2 
Ambulatory and capable of all self 
care but unable to carry out any 
work activities. Up and about > 50% 
of waking hours.  
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
Capable of only limited Self care, 
confined to bed or chair > 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
Completely disabled. Cannot carry 
on any self care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
 
 
 
11.0 
INTERNAL REGULATORY REQUIREMENTS Ω §§ A.002, A.011, A.012, J.001–J.003 
11.1 
INSTITUTIONAL REVIEW BOARD (IRB) Ω §§ A.002, A.011, A.012, J.001–J.003 
This protocol has been submitted to and approved by the IRB according to COHNMC ethical and 
regulatory guidelines. 
11.2 
CANCER PROTOCOL REVIEW AND MONITORING COMMITTEE (CPRMC) Ω §§ A.002, A.011, A.012, J.001–J.003 
This protocol has been submitted to and approved by the CPRMC according to COHNMC ethical and 
regulatory guidelines. 
11.3 
DATA AND SAFETY MONITORING  
A) Definition of Risk Level  
 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring 
Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx involving the use of RIT 
and chemotherapy as preparative conditioning for patients undergoing allogeneic 
hematopoietic stem cell transplantation for treatment of high-risk non-Hodgkin Lymphoma. 
Given that 1) the preparative regimen is considered novel and 2) if successful, the impact of 
this treatment on high-risk lymphoma may be great, this protocol has been classified as a Risk 
Level 4 study. 


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B) Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, 
CRA/protocol nurse, and statistician is responsible for monitoring the data and safety of this 
study, including implementation of the stopping rules for safety and efficacy.  
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
Data and safety will be reported to the COH DSMC using the PMT report and submitted 
quarterly from the anniversary date of activation.  Protocol specific data collection will include 
the following items: (on Teleform and MIDAS case report forms) patient-, donor-, disease-, 
treatment-characteristics, toxicity/complication data, and outcome data (e.g., disease status 
post transplant and vital status).  From these data the PMT will monitor: 1) the patients‟ ability 
to tolerate the conditioning regimen, 2) complication/toxicity data watching for an excessive 
events including infections, delayed engraftment, and acute- chronic- GVHD, and 3) treatment 
related mortality events.  
 
C) Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not 
listed in the investigator‟s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected 
adverse event that results in any of the following outcomes: 
 
Death 
 
Is life-threatening event (places the subject at immediate risk of death from the event 
as it occurred); 
 
Unplanned hospitalization equal or greater than 24 hours   or prolongation of existing 
hospitalization 


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A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary Malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject‟s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all three of 
the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved 
research protocol, informed consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcomes may have been caused 
by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
 
D. Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH DSMC 
and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs 
during the study conduct will be reported to the DSMC and IRB by submitting electronically in 
iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and 
guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 2 below.  Those 
SAEs 
that 
require 
expedited 
reporting 
will 
be 
submitted 
electronically 
in 
iRIS 
(http://iris.coh.org/).  After day 100 post transplant, expedited reporting of SAEs are only 
required for SAEs that are considered Unanticipated Problems, or second malignancies. 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems will be reported only in the 
continuation reports and PMT reports (see Table 2 below). 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for the 
DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 


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Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. 
The DSMC will review the case and make a determination as to whether the study will be 
suspended, terminated, amended, or allowed to continue without amendment. 
 


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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
 
 
12.0 
ETHICAL CONSIDERATIONS Ω §§ A.003–A.007 
12.1 
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPPA) Ω §§ A.003–A.007 
Protected Health Information (PHI) of those taking part in this protocol will not be made available to 
persons or entities not granted authority by a public health agency pursuant to the HIPPA of 1996 and 
the HIPPA Privacy Rule (Standards for Privacy of Individually Identifiable Health Information).  
COHNMC will not share PHI with others not authorized.  PHI may be made available to the National 
Institutes of Health (NIH), Center for Disease Control (CDC), Health Resources and Services 
Administration (HRSA), Occupational Safety and Health Administration (OSHA), Substance Abuse 
and Mental Health Services Administration (SAMHSA), tribal health agencies, state public health 
agencies, local public health agencies, and/or entities granted authority by a public health agency.  
The Privacy Rule does permit disclosure of PHI for specified public health purposes. 
12.2 
MEASURES TO ASSURE PROTECTED HEALTH INFORMATION (PHI) CONFIDENTIALITY Ω §§ A.003–A.007 
PHI in Patient Medical Records and Clinical Research Protocol Data is maintained in strictest 
confidence. 
12.2.1 
HEALTH INFORMATION MANAGEMENT SERVICES (HIMS) 
HIMS controls and maintains all inpatient and outpatient medical records and the original 
documents within.  All patients are assigned a Medical Record Number (MRN).  Patient medical 
records are filed and requested by that MRN, not the patient‟s name. 
12.2.2 
DIVISION OF INFORMATION SCIENCES/DEPARTMENT OF CLINICAL RESEARCH INFORMATION 
MANAGEMENT 
A CRA will be assigned to this protocol by the Department of Clinical Research Information 
Management.  The CRA will be responsible for all protocol data collection and maintenance.  The 
data collected on each patient will be captured on case report forms that are kept within a 
research file folder.  Each patient‟s research file folder will be stored in a locked file room.  Access 
is restricted to personnel authorized by the Division of Information Sciences.  Each patient‟s 
research file can be requested and accessed by protocol number and Research Participant 
Number (RPN), not the patient‟s name or MRN. 


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Should results from this protocol be reported in a medical journal or at a scientific meeting, PHI 
will be withheld.  Any publications or presentations will refer to the patient by protocol number and 
RPN, not by name or medical record number. 
13.0 
FORMS AND DATA MANAGEMENT Ω §§ A.003–A.007, A.011, A.012, B.001, B.004, C.001 
13.1 
INFORMED CONSENT Ω §§ A.003–A.007, A.011, A.012, B.001, B.004, C.001 
A conference will be held with each patient and family to discuss this protocol and alternative 
treatments.  The PI will conduct the conference.  The patient will each be provided the COHNMC IRB 
approved Informed Consent for Participation in Research Activities (ICF) and Experimental Subject 
Bill of Rights. 
The consent as well as all potential risks associated with RIT, Chemotherapy, Immunosuppressive 
Drugs, AHSCT and DLI will be discussed and explained as objectively as possible.  The procedure 
for collecting Peripheral Blood Mononuclear Cells (PBMCs) and the toxicities of G–CSF will be 
explained to the donor.  The donor will be counseled as to the risks of treatment with G–CSF and will 
be informed that leukapheresis at several time points will be necessary.  The Principal Investigator(s) 
will allow ample time for questions and answers if or as requested by the patient and/or sibling donor. 
Upon agreeing to participate, each patient will sign and date the ICFs/Bill of Rights.  Copies of these 
documents will be provided to each patient and sibling donor.  The originals and copies of ICFs/Bill of 
Rights and any other appropriate assurances or agreements required will remain on site at COHNMC 
(originals in patient‟s/donor‟s medical records and copies in the Department of Clinical Research 
Information Management). 
13.2 
REGISTRATION GUIDELINES Ω §§ A.007, A.011, A.012, B.001, B.004, C.001 
Registration will occur centrally at COHNMC.  Each patient will be registered upon signing and dating 
the ICF/Bill of Rights and a medical evaluation to determine eligibility.  To register a patient, the 
protocol nurse or CRA at COHNMC must complete the eligibility form and registration form to verify 
eligibility.  The CRA will then assign a study number, a dose and register the patient onto the study. 
13.3 
PROCEDURES FOR WAIVERS OF ELIGIBILITY AND TREATMENT DEVIATIONS Ω §§ A.011, A.012 
The PI must approve all Waivers of Eligibility prior to patient registration and all Treatment Deviations 
prior to treatment.  The treating physician must contact the PI.  Upon approval, the PI must submit a 
protocol amendment to the IRB. 
13.4 
DATA MANAGEMENT Ω §§ A.003–A.007, B.001 
The Department of Clinical Research Information Management maintains a database to store and 
retrieve patient data collected from a wide variety of sources.  The investigator will assure that data 
collected conform to all established guidelines for coding, collection, key–entry, and verification. 
13.5 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE Ω §§ A.003–A.007, B.001 
14.5.1 
CONFIDENTIALITY OF RECORDS:  Original data collection forms will be filed in secure 
cabinets in Biostatistics.  All RIT associated data will be filed in RIT. 
14.5.2 
PATIENT AND DONOR CONSENT FORMS:  At the time of registration, the signed and dated 
ICFs/Bill of Rights must be available for patient, donor, chart, and Department of 
Clinical Research Information Management. 
14.0 
Statistical Considerations 
 
This phase II study is designed to demonstrate broad non-inferiority of RIT with conventional RIC 
treatment. This study is expected to accrue 46 patients. The primary endpoint will be relapse/progression 


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IRB # 05149, Version 22 
 
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rate at two years. Based on a similar COH, FHCRC, and Stanford University cohort, the relapse rate at 2 
years was estimated to be approximately 36%27-31.  Assuming a non-inferiority null hypothesis with a 20% 
delta bound, a test with a one-sided type 1 error rate of 0.10 would have 80% power for rejecting the 
inferiority hypothesis if the long-run relapse rate was in fact 0.36.  In addition, approximately 15 patients 
(of the required 46) will have samples collected pre- post-AHCT as part of costimulatory studies.  
Products from sibling donors will also be studied among this subset of patients.  The expected number is 
8, which is approximately 50-60%, which aligns with the expected rate of allo transplants that will utilize a 
sibling donor.  The projected total study accrual, including primary study objective and secondary 
costimulatory studies, is 54 patients (46 patients + 8 donors). 
  
Phase II Monitoring           
 
Early stopping rules are incorporated into this trial for excessive toxicity however, there will be no interim 
analysis for efficacy. Toxicities will be recorded using two distinct grading systems; the modified Bearman 
Scale (Bearman, S., et al, JCO, Vol 6, No 10 (Oct), 1988, pp1562-1568. See appendix I for details.) and 
the NCI CTCAE 3.0 Scale. Generally, the modified Bearman Scale will be used to define (grade) „early 
stopping‟ events (toxicities), and the NCI CTCAE 3.0 Scale will be used for reporting adverse events. The 
only exception relates to how hematologic toxicities are graded and incorporated into the early stopping 
criteria. For hematologic toxicities the CTCAE 3.0 Scale will be used. The table below will be consulted as 
relevant toxicities are encountered, so there will be no accrual-based interim analysis point. 
 
Early Stopping Criteria: For each adverse outcome, stop if the cumulative number of patients reaches or 
exceeds the following limits: 
 
 
Table of Early Stopping Criteria 
 
# of patients 
treated  
 
# of patients with 
grade 3 toxicities 
that would require 
an evaluation for 
safety per 
Bearman Scale*  
 
# of patients with 
treatment related 
grade 4 or 5 
toxicity that would 
stop the study** 
 
Cumulative probability of 
early stopping given a 
DLT rate of: 
1/6 
22% 
1/3 
12 
4 
3 
0.04 
0.09 
0.27 
18 
6 
5 
0.05 
0.12 
0.39 
24 
8 
6 
0.05 
0.14 
0.47 
30 
10 
8 
0.06 
0.15 
0.52 
36 
12 
9 
0.06 
0.16 
0.56 
42 
14 
11 
0.06 
0.16 
0.60 
* Note: 
For hematologic toxicities: Any grade 4 neutropenia associated with fever or infection and 
lasting beyond three weeks, or grade 4 neutropenia lasting for more than 28 days per CTCAE 
3.0 toxicity criteria should be counted toward the early stopping rule. 
 ** Note:  The stopping rules are not statistically based; expected treatment related mortality not to 
exceed 25%. Grade 4 for Bearman, Grade 5 for CTCAE 3.0. 
 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will be 
assessed periodically according to the treatment schedule for the development of any toxicity. The toxicity 
rule for safety will be assessed as each patient reaches day +30 post transplantation. If more than the 
specified number of patients (noted in the table above) have significant treatment related toxicities, then 
the safety of the study will be evaluated.  
 
Analysis of Clinical Endpoints 
 
Toxicities observed will be summarized in terms of type (organ affected or laboratory determination), 
severity (by NCI CTC and nadir or maximum values for the laboratory measure) and time of onset. For 
grade 4 neutropenia, duration will be recorded.  In accordance with the primary study objectives, we will 
perform descriptive statistical analyses on these data after the study is complete. Response rates and 
duration of response will be estimated. Confidence intervals for the response rate will be established by 
calculating the exact 95% confidence limits for a binomial parameter. Additional analyses will be 


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conducted to evaluate the post transplant toxicity/complication profile including acute and chronic GvHD 
and infectious complications. 
 
Descriptive statistics will be used to characterize the expression of six costimulatory molecules (PD-1, 
CTLA-4, CD28, ICOS, OX40 and 4-1BB) pre- post- RIT based ASCT. Exploratory analyses will also be 
performed to assess the impact of these molecules on the NK and T cells of lymphoma patients pre- post- 
RIT based ASCT. 
 
The product-limit method of Kaplan and Meier will be utilized to estimate time-to-event endpoints such as 
relapse/progression-free survival, overall survival, and non-relapse/progression mortality rate. We will 
consider univariate Cox models for the analysis of potential prognostic factors of time-to-event endpoints, 
including such factors as histologic grade, age at transplant, and disease stage as independent variables, 
first performing diagnostics to confirm the validity of the proportional hazards assumption. Descriptive 
comparisons with recent historical data from similar patient populations will be made to evaluate 
differences in relapse/progression-free survival, overall survival, relapse/progression rate, and toxicities. 


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15.0 
REFERENCES 
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3. Armitage JO, Weisenburger DD: New Approach to Classifying Non–Hodgkin Lymphomas: 
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Appendix I 
Modified Bearman Toxicity Scale 
 
 
Grade I 
Grade II 
Grade III 
 
Cardiac  
Toxicity 
 
Mild EKG abnormality, not 
requiring medical  
intervention; or noted heart 
enlargement on chest x-ray with 
no clinical symptoms 
 
Moderate EKG abnormalities 
requiring and responding to medical 
intervention; or requiring continuous 
monitoring without treatment; or 
congestiveheart failure responsive 
to digitalis or diuretics  
 
 
Severe EKG abnormalities with 
no or only partial response to 
medical intervention; or heart 
failure with no or only minor 
response to medical intervention; 
or decrease in voltage by more 
than 50%  
 
Bladder 
Toxicity 
 
Macroscopic hematuria after 2 
days from last chemotherapy 
dose with no subjective 
symptoms of cystitis and not 
caused by infection  
 
 
Macroscopic hematuria after 7 days 
from last chemotherapy dose not 
caused by infection; or hematuria 
after 2 days with subjective 
symptoms of cystitis not caused by 
infection  
 
Hemorrhagic cystitis with frank 
blood, necessitating invasive 
local intervention with installation 
of sclerosing agents, 
nephrostomy or other surgical 
procedure  
 
Renal Toxicity  
 
 
Increase in creatinine up to 
twice the baseline value (usually 
the last recorded before start of 
conditioning)  
 
Increase in creatinine above twice 
baseline but not requiring dialysis  
 
 
Requirement of dialysis  
 
 
Pulmonary 
Toxicity  
 
 
Dyspnea without chest x-ray 
changes not caused by infection 
or congestive heart failure; or 
chest x-ray showing isolated 
infiltrate or mild interstitial 
changes without symptoms not 
caused by infection or 
congestive heart failure  
 
 
Chest x-ray with extensive localized 
infiltrate or moderate interstitial 
changes combined with dyspnea 
and not caused by infection or CHF; 
or decrease of PO2 (> 10% from 
baseline) but  
not requiring mechanical ventilation 
or > 50% O2 on mask and not 
caused by infection or CHF 
 
Interstitial changes requiring 
mechanical ventilatory support or 
> 50% oxygen on mask and not 
caused by infection or CHF  
 
 
Hepatic 
Toxicity 
 
Mild hepatic dysfunction with 
bilirubin ≥ 2.0 mg/dL and ≤ 6.0 
mg/dL or weight gain > 2.5% 
and < 5% from baseline, of non-
cardiac origin; or SGOT 
increase more than 2-fold but 
less than 5-fold from lowest 
preconditioning  
 
Moderate hepatic dysfunction with 
bilirubin > 6.0 mg/dL and < 20 
mg/dL; or SGOT increase > 5-fold 
from preconditioning; or clinical 
ascites or image documented 
ascites > 100 mL; or weight gain > 
5% from baseline of non-cardiac 
origin  
 
Severe hepatic dysfunction with 
bilirubin > 20 mg/dL; or hepatic 
encephalopathy; or ascitis 
compromising  
respiratory function  
 
 
CNS Toxicity 
 
Somnolence but the patient is 
easily arousable and oriented 
after arousal  
 
 
Somnolence with confusion after 
arousal; or other new objective CNS 
symptoms with no loss of 
consciousness not more easily 
explained by other medication, 
bleeding or CNS infection  
 
Seizures or coma not explained 
(documented) by other 
medication, CNS  
infection, or bleeding  
 
 
Stomatitis 
 
 
Pain and/or ulceration not  
requiring a continuous IV  
narcotic drug  
 
 
Pain and/or ulceration requiring a 
continuous IV narcotic drug 
(morphine drip)  
 
 
Severe ulceration and/or  
mucositis requiring  
preventive intubation; or  
resulting in documented  
aspiration pneumonia with or  
without intubation  
 
GI Toxicity 
 
Watery stools > 500 mL but  
< 2,000 mL every day not  
related to infection  
 
 
Watery stools > 2,000 mL every day 
not related to infection; or 
macroscopic hemorrhagic stools 
with no effect on cardiovascular 
status not caused by infection; or 
subileus not related to infection 
 
Ileus requiring nasogastric  
suction and/or surgery and not 
related to infection; or 
hemorrhagic enterocolitis 
affecting cardiovascular status 
and requiring transfusion  
NOTE: Grade IV regimen-related toxicity is defined as fatal toxicity.