Clinical trial NCT01527045
Conditions: Aggressive Non-Hodgkin Lymphoma Blasts Under 5 Percent of Bone Marrow Nucleated Cells Chronic Lymphocytic Leukemia Loss of Chromosome 17p Myelodysplastic/Myeloproliferative Neoplasm Non-Hodgkin Lymphoma Prolymphocytic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Aggressive Adult Non-Hodgkin Lymphoma Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Recurrent Chronic Lymphocytic Leukemia Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive Recurrent Diffuse Large B-Cell Lymphoma Recurrent Hodgkin Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Non-Hodgkin Lymphoma Recurrent Plasma Cell Myeloma Recurrent Small Lymphocytic Lymphoma Waldenstrom Macroglobulinemia
Sponsor: Fred Hutchinson Cancer Center
Start date: 2012-09-25; Completion date: 2019-04-01
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well donor atorvastatin treatment works in preventing severe graft-versus-host disease (GVHD) after nonmyeloablative peripheral blood stem cell (PBSC) transplant in patients with hematological malignancies. Giving low doses of chemotherapy, such as fludarabine phosphate, before a donor PBSC transplantation slows the growth of cancer cells and may also prevent the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also cause an immune response against the body's normal cells (GVHD). Giving atorvastatin to the donor before transplant may prevent severe GVHD.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess whether 2 weeks of donor statin treatment reduces the risk of severe acute GVHD.

SECONDARY OBJECTIVES:

I. To assess whether 2 weeks of statin treatment of normal PBSC donors is feasible, tolerable and safe.

OUTLINE:

DONOR: Donors receive atorvastatin orally (PO) once daily (QD) beginning on day -14 and continuing until the last day of stem cell collection.

NONMYELOABLATIVE PREPARATIVE REGIMEN: If the patient is enrolled on an investigational nonmyeloablative hematopoietic cell transplant (HCT) protocol or a treatment plan that uses a nonmyeloablative preparative regimen with postgrafting cyclosporine (CSP) that does not use acute GVHD as its primary endpoint, the preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan (Protocol 2546 serves as adjunct protocol).

If the patient is not enrolled on an investigational nonmyeloablative HCT protocol or a treatment plan that uses a nonmyeloablative preparative regimen, Protocol 2546 serves as an independent primary treatment protocol. The preparative regimen and immunosuppression after transplant is as follows:

Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0.

TRANSPLANT: Patients undergo donor PBSC transplant on day 0.

POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to 56 with taper to day 180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27.

After completion of study treatment, patients are followed up at 1 year and then annually thereafter.

Arms: arm 1: See Detailed Description
Interventions: intervention 1: Atorvastatin Calcium intervention 2: Cyclosporine intervention 3: Fludarabine Phosphate intervention 4: Laboratory Biomarker Analysis intervention 5: Mycophenolate Mofetil intervention 6: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation intervention 7: Peripheral Blood Stem Cell Transplantation intervention 8: Total-Body Irradiation
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given PO or IV intervention 6: Undergo nonmyeloablative allogeneic PBSC transplant intervention 7: Undergo nonmyeloablative allogeneic PBSC transplant intervention 8: Undergo TBI

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
2546.00: Donor Statin Treatment for Prevention of 
Severe Acute GVHD after Nonmyeloablative 
Hematopoietic Cell Transplantation 
 
NCT01527045 
 
Version 02/06/2018 
 
 


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        FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
SEATTLE CHILDREN’S 
 
Previous version: 02/06/2018 
Current version:  08/04/2017 
 
Title of Protocol:  
Donor Statin Treatment for Prevention of Severe Acute GVHD after  
Nonmyeloablative Hematopoietic Cell Transplantation 
 
 
 
Investigators List: 
Investigators 
Professional Title 
Phone Number 
Marco Mielcarek, MD 
Member, FHCRC, Professor of Medicine, UW 
(206) 667-2827  
Paul Martin MD  
Member, FHCRC, Professor of Medicine, UW 
(206) 667-4798 
Brenda Sandmaier, MD 
Member, FHCRC, Professor of Medicine, UW 
(206) 667-4961 
David Maloney, MD, PhD 
Member, FHCRC, Professor of Medicine, UW 
(206) 667-5616 
Rainer Storb, MD 
Member, FHCRC, Professor of Medicine, UW 
(206) 667-4407 
 
 
 
Biostatistician: 
Barry Storer, PhD 
Member, FHCRC, Professor of Biostatistics, UW (206) 667-6151 
Research Staff: 
Michelle Bouvier, RN 
Research Nurse 
(206) 667-6993 
 
 
 
 
Emergency (24 hour) phone number:  (206) 598-8902 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
INTRODUCTION ........................................................................................................................................................ 6 
BACKGROUND ......................................................................................................................................................... 6 
2.1 
Immunomodulatory effects of statins. ....................................................................................................... 6 
2.2 
Statins for GVHD-prevention: Preclinical and clinical studies .................................................................. 6 
2.3 
Rationale for the Current Study ................................................................................................................ 8 
STUDY OBJECTIVES ................................................................................................................................................ 9 
3.1 
Primary Objective ..................................................................................................................................... 9 
3.2 
Secondary Objective ................................................................................................................................. 9 
STUDY DESIGN ........................................................................................................................................................ 9 
4.1 
Description of Study .................................................................................................................................. 9 
4.2 
Endpoints .................................................................................................................................................. 9 
PATIENT SELECTION ............................................................................................................................................... 9 
5.1 
Inclusion Criteria (If Protocol 2546 serves as an adjunct protocol, the patient only needs to 
meet inclusion criteria 1 through 5A.) ..................................................................................................................... 9 
5.2 
Exclusion Criteria (If Protocol 2546 serves as an adjunct protocol, the patient only needs to 
meet exclusion criteria 1 through 3.) .................................................................................................................... 11 
DONOR SELECTION .............................................................................................................................................. 12 
6.1  
Inclusions ................................................................................................................................................ 12 
6.2 
Exclusions ............................................................................................................................................... 12 
INFORMED CONSENT OF SUBJECT AND DONOR ............................................................................................. 12 
PATIENT AND DONOR REGISTRATION ............................................................................................................... 12 
PLAN OF TREATMENT ........................................................................................................................................... 12 
9.1 
Donor Treatment with Atorvastatin ......................................................................................................... 12 
9.2 
Recipient Treatment (References below to standard practice refer to standard practice at site 
where HCT is being performed.) .......................................................................................................................... 13 
EVALUATION OF PATIENTS .................................................................................................................................. 20 
10.1 
Patient Pre-transplant Evaluation for All Diseases ................................................................................. 20 
10.2 
Patient Post-transplant Evaluation ......................................................................................................... 25 
EVALUATION OF DONORS.................................................................................................................................... 40 
11.1 Safety Evaluations ........................................................................................................................................ 40 
11.2 Donor Statin Compliance.............................................................................................................................. 40 
TOXICITIES AND COMPLICATIONS ...................................................................................................................... 41 
12.1 
Atorvastatin ............................................................................................................................................. 41 
12.2 
GVHD ...................................................................................................................................................... 43 
ADVERSE EVENT MONITORING .......................................................................................................................... 44 
13.1 
Institutional Policy and Definitions .......................................................................................................... 44 


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13.2 
Adverse Events to be Monitored in This Study....................................................................................... 45 
13.3  
Duration of Adverse Event and Unanticipated Problem Monitoring and Recording ............................... 47 
OUTCOMES TO BE ASSESSED ............................................................................................................................ 48 
14.1 
Proportion of Donors who Discontinue Atorvastatin Because of Toxicity .............................................. 48 
14.2 
Acute GVHD ........................................................................................................................................... 48 
14.3 
Chronic GVHD ........................................................................................................................................ 48 
14.4 
Recurrent Malignancy ............................................................................................................................. 48 
14.5 
Non-relapse Mortality (NRM) .................................................................................................................. 48 
14.6 
Overall Survival (OS) .............................................................................................................................. 48 
14.7 
Proportion of Patients Requiring Secondary Systemic Immunosuppressive Treatment ........................ 49 
DATA AND SAFETY MONITORING PLAN ............................................................................................................. 49 
15.1 
Principal Investigator .............................................................................................................................. 49 
15.2 
Data Safety Monitoring Board (DSMB) ................................................................................................... 49 
15.3  
Trial Monitoring ....................................................................................................................................... 50 
DATA MANAGEMENT AND PROTECTION OF CONFIDENTIALITY .................................................................... 50 
STATISTICAL CONSIDERATIONS ......................................................................................................................... 51 
17.1  
Primary Endpoint and Sample Size ........................................................................................................ 51 
17.2 
Secondary Endpoints .............................................................................................................................. 52 
17.3 
Mandatory Ad Hoc DSMB Review .......................................................................................................... 52 
17.4 
Projected Ethnic and Gender Distribution .............................................................................................. 53 
Ethnic Category ........................................................................................................................................................ 53 
Racial Categories ..................................................................................................................................................... 53 
TERMINATION OF STUDY ..................................................................................................................................... 53 
REFERENCES ......................................................................................................................................................... 54 
TABLE OF APPENDICES ........................................................................................................................................ 55 
Serious Adverse Event Report ............................................................................................................................. 70 
Protocol 2546 ....................................................................................................................................................... 70 
Notice of Death ..................................................................................................................................................... 71 
Comorbidities ........................................................................................................................................................... 90 


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ABBREVIATIONS 
 
AABB 
American Association of Blood Banks 
ABW 
actual body weight 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
AML 
acute myeloid leukemia 
ALT 
alanine amino transferase 
AST 
aspartate amino transferase 
β-HCG 
beta human chorion gonadotropin 
BMT 
bone marrow transplantation 
BSA 
body surface area 
BU 
busulfan 
CAT 
computed axial tomography 
CCO 
Clinical Coordinator Office 
CI 
confidence interval 
CML 
chronic myeloid leukemia 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CR 
complete remission 
CSP 
cyclosporine 
Css 
concentration at steady state 
CTCAE 
common toxicity criteria for adverse events 
CTN 
Clinical Trials Network 
CXR 
chest x-ray 
CY 
cyclophosphamide 
DFS 
disease-free survival 
DLCO 
Diffusion capacity of lung—carbon monoxide 
DSMB 
data and safety monitoring board 
DSMP 
data and safety monitoring plan 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
EMG 
electromyogram 
FACT 
Foundation for the Accreditation of Cellular Therapy 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FHCRC 
Fred Hutchinson Cancer Research Center 
FLU 
fludarabine 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
G-CSF 
granulocyte colony-stimulating factor 
GVHD 
graft-versus-host disease 
GVL 
graft-versus-leukemia 
HCT 
hematopoietic cell transplantation 
HIV 
Human immunodeficiency virus 
HLA 
human leukocyte antigen 
HR 
hazard ratio 


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HRPP 
human research protection plan 
HTLV 
human T cell lymphotropic virus 
IBW 
ideal body weight 
IRB 
institutional review board 
IRO  
Institutional Review Office 
IST 
immunosuppressive treatment 
MDS 
myelodysplastic syndrome 
MESNA 
sodium-2-mercapto ethane sulfonate 
MMF 
mycophenolate mofetil 
MTX 
methotrexate 
MUGA 
Multiple gated acquisition 
NIH 
National Institutes of Health 
NCI 
National Cancer Institute 
NRM 
non-relapse mortality 
OS 
overall survival 
OWL 
optical web library 
PBSC 
peripheral blood stem cell 
PCR 
polymerase chain reaction 
PFT 
pulmonary function tests 
PI 
principal investigator 
RV 
residual volume 
SAE 
serious adverse event 
SCCA 
Seattle Cancer Care Alliance 
TAC 
Tacrolimus 
TBI 
total body irradiation 
UPN 
unique patient number 
URD 
unrelated donor 
UW 
University of Washington 
 
 


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INTRODUCTION 
 
This document is a clinical research protocol that will be conducted in compliance with Federal 
regulations and all applicable Institutional Review Board (IRB) requirements. This protocol 
builds on seminal observations from 2 previous studies. 
In two retrospective analyses of outcomes among 1206 recipients of HLA-matched HCT [1,2], 
we found: 
▪ 
Statin use by HLA-identical sibling donors was associated with profound protection 
against severe acute GVHD. GVHD-protection was not offset by increased relapse 
rates. 
▪ 
Recipient statin use beyond day 100 after transplant was associated with a reduced risk 
of chronic GVHD at the expense of an increased risk of relapse. 
▪ 
GVHD-protective effects were restricted to patients given CSP-based postgrafting 
immunosuppression and not observed among those given TAC. 
▪ 
GVHD-protective effects were most pronounced in the gastrointestinal tract. 
 
Based on the favorable outcomes associated with donor statin use in the retrospective 
analyses, the present study seeks to confirm these finding prospectively. Specifically, we 
propose to treat HLA-identical related donors with atorvastatin for 2 weeks prior to collection of 
PBSC aimed at reducing the risk of severe acute GVHD in recipients after nonmyeloablative 
HCT. 
 
BACKGROUND 
 
2.1 
Immunomodulatory effects of statins. 
In recent years, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or 
"statins", have been shown to alter immune function in ways that may contribute to their anti-
atherosclerotic effects. Statins also appear to reduce immune responses to autoantigens and 
alloantigens [3-6]. The best characterized activity of statins involves inhibition of mevalonate 
and cholesterol biosynthesis, which is mediated by binding to HMG-CoA reductase. Blocking 
mevalonate production, however, also inhibits the synthesis of intermediates required for 
isoprenylation of GTP-binding cell signaling proteins such as Ras, Rac and Rho, thereby 
disrupting intracellular signaling pathways [6-9]. Immune functions shown to be promoted by 
statins are Th2-polarization1 and expansion of regulatory T cells (Treg) [10]. At the same time 
statins inhibit lymphocyte trafficking to sites of inflammation [11-13], antigen-presenting cell 
(APC) function [14,15], and the development of Th17 cells [16]. While statin-mediated changes in 
immune function have been studied extensively, the potential immunosuppressive synergism 
between statins and calcineurin inhibitors has not been examined. 
 
2.2 
Statins for GVHD-prevention: Preclinical and clinical studies 
Zeiser et al. observed a significantly reduced mortality related to acute GVHD when either donor 
or recipient mice were given atorvastatin for 10 days before major histocompatibility complex 
(MHC)-mismatched allogeneic HCT [3]. This study also showed that statin-mediated protection 
against GVHD was due to parallel effects on T cells and APC, and that therapy did not simply 


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Table 1: Multivariate analyses for association of recipient and donor statin use with various outcomes.* 
 
All patients 
(n=567) 
Patients with CSP-based GVHD-prophylaxis 
(n=417) 
(R+/D-, n=16) 
(R-/D+, n=75) 
(R+/D+, n=12) 
(R+/D-, n=13) 
(R-/D+, n=54) 
(R+/D+, n=10) 
Endpoint 
HR* 
(95% CI) 
p* 
HR 
(95% CI) 
p 
HR* 
(95% CI) 
p* 
HR* 
(95% CI) 
p* 
HR* 
(95% CI) 
p* 
HR* 
(95% CI) 
p* 
Grade 2-4 
GVHD 
1.01 
(0.5-2.0) 
0.98 
0.89 
(0.6-1.2) 
0.47 
0.33 
(0.1-1.0) 
0.06 
1.10 
(0.5-2.3) 
0.79 
0.79  
(0.5-1.2) 
0.23 
0.22 
(0.1-0.9) 
0.03 
Grade 3-4 
GVHD 
1.78 
(0.6-5.0) 
0.28 
0.28 
(0.1-0.9) 
0.03 
0.00 
(undef.) 
0.06 
1.76 
(0.6-5.0) 
0.29 
0.00 
 (undef) <0.0001 
0.00 
(undef.) 
0.06 
Chronic 
GVHD 
0.93 
(0.5-1.8) 
0.83 
0.82 
(0.6-1.2) 
0.26 
0.58 
(0.3-1.3) 
0.19 
0.79 
(0.4-1.6) 
0.53 
0.94 
 (0.6-1.4) 
0.76 
0.59 
(0.2-1.5) 
0.25 
Relapse/ 
disease 
prog. 
0.97 
(0.4-2.7) 
0.96 
0.63 
(0.4-1.1) 
0.11 
0.74 
(0.2-3.0) 
0.67 
1.27 
(0.4-3.6) 
0.66 
0.72 
 (0.4-1.3) 
0.30 
1.04 
(0.3-4.3) 
0.95 
NRM 
0.45 
(0.2-1.2) 
0.12 
0.72 
(0.4-1.2) 
0.17 
0.66 
(0.2-2.0) 
0.49 
0.36 
(0.1-1.1) 
0.08 
0.67 
 (0.4-1.2) 
0.15 
0.86 
(0.3-2.7) 
0.80 
Overall 
mortality 
0.58 
(0.3-1.2) 
0.16 
0.73 
(0.5-1.1) 
0.10 
0.77 
(0.3-1.9) 
0.56 
0.53 
(0.2-1.2) 
0.14 
0.75 
 (0.5-1.1) 
0.18 
1.00 
(0.4-2.5) 
0.99 
Outcomes are shown for all patients (n=567; left table) and for patients with CSP-based GVHD-prophylaxis (n=417; right 
table). Outcome estimates are in comparison to controls where both donor and recipient did not receive statin treatment at 
the time of HCT (n=464 for “all patients” and n=340 for patients with CSP-based GVHD-prophylaxis). *Adjusted for: Sex-
mismatch, conditioning intensity, donor age >50 years, patient age >50 years, and disease risk. Abbreviations pertaining 
to statin treatment at the time of transplant: R-/D-: neither recipient nor donor; R+/D-, recipient only; R-/D+, donor only;  
R+/D+, both recipient and donor.   
suppress T cell responses in general, as the ability of the transplanted T cells to kill tumor cells 
(GVT effect) was preserved. 
In a recent retrospective analysis of 67 patients who received HLA-matched or mismatched 
related or unrelated allografts for treatment of hematologic malignancies, Hamadani et al. found 
a trend towards a decreased risk of grade 2-4 acute GVHD (10% versus 40%; p=0.08) among 
the 10 recipients who were under treatment with a statin at the time of HCT, compared to those 
who were not [17]. In this analysis, however, the authors did not account for donor statin 
exposure, and definitive conclusions were limited by small sample size and heterogeneity of the 
patient population.  
Most pertinent to the design of the present study was the observation that donor statin use 
was associated with protection against severe acute GVHD after HCT from HLA-identical 
related donors [1]. In retrospective analysis (n=567), we found that compared to allografts 
where neither the donor nor recipient used a statin at the time of transplant (n=464), statin use 
by the donor and not the recipient (n=75) was associated with a profoundly decreased risk of 
grade 3-4 acute GVHD (multivariate hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.1-
0.9; p=0.03) (Table 1). Statin use by both donor and recipient (n=12) was suggestively 
associated with a decreased risk of grade 3-4 acute GVHD (HR, 0.00; 95% CI, undefined; 
p=0.06), while statin use by the recipient and not the donor (n=16) did not confer protection 
against acute GVHD. Donor statin-treatment was associated with significant protection against 
acute GVHD in the gastrointestinal tract (p=0.02) but not in the skin. Surprisingly, statin-
associated GVHD-protection was restricted to recipients with CSP-based postgrafting immuno-
suppression (n=417; 74%; HR, 0.0; 95% CI, undefined; p<0.0001) and was not observed 
among those given TAC (significance of effect modification: CSP vs. TAC, p=0.009). The 
unexpected effect association between statins and CSP raises the question whether the two 
drugs share a cellular target that accounts for the observed immunosuppressive synergism.  
GVHD-protection associated with donor statin use was not offset by increased rates of recurrent 
malignancy. An increased risk of recurrent malignancy and a reduced risk of chronic GVHD 
were only observed among recipients of HLA-matched related and unrelated grafts (n=1206) 


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who were given statins beyond day 100 after transplant [2]. Overall, these results suggest that 
donor statin treatment (without recipient statin treatment) may be a promising strategy for 
preventing severe acute GVHD without compromising immunologic control of the underlying 
malignancy. 
The retrospective analysis also showed that favorable outcomes associated with donor statin 
use were not confined to a specific type of conditioning intensity but seen after both 
nonmyeloablative and myeloablative HCT. Figure 1 shows the cumulative incidence of grade 3-
4 acute GVHD among recipients of nonmyeloablative HCT from HLA-matched donors who has 
CSP-based immunosuppression according to donor statin use. This subgroup analysis shows 
that donor statin treatment has promise to substantially reduce the risk of severe acute GVHD 
and thereby NRM without compromising control of the underlying malignancy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
Rationale for the Current Study 
 
Based on the favorable outcomes associated with donor statin use in the retrospective 
analyses, the present study seeks to confirm these finding prospectively. Specifically, we 
propose to treat HLA-identical related donors with atorvastatin during 2 weeks prior to collection 
of peripheral blood stem cells (PBSC) aimed at reducing the risk of severe acute GVHD in 
recipients. Since the statin-mediated GVHD-protective effect was only seen among patients who 
had CSP-based immunosuppression and not among those given TAC, recipients enrolled in the 
present study will receive an immunosuppressive regimen that includes CSP. The study may be 
offered either as an independent protocol that includes donor statin-treatment and the 
nonmyeloablative preparative regimen (low-dose TBI and fludarabine) or in conjunction with a 
designated separate transplant investigational protocol that uses a nonmyeloablative 
preparative regimen, provided the respective transplant protocol does not use acute GVHD as 
the primary endpoint. 
 
Figure 
1: 
Cumulative 
incidence 
of 
grade 
3-4 
acute 
GVHD 
after 
nonmyeloablative hematopoietic cell transplantation at the Fred Hutchinson 
Cancer Research Center (2001-2007) according to donor statin use. The 
analysis was restricted to patients who had CSP-based immunosuppression after 
transplant (n=162). 


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STUDY OBJECTIVES 
 
3.1 
Primary Objective 
To assess whether 2 weeks of donor statin treatment reduces the risk of severe acute GVHD. 
 
3.2 
Secondary Objective 
To assess whether 2 weeks of statin treatment of normal PBSC donors is feasible, tolerable and 
safe. 
 
STUDY DESIGN 
 
4.1 
Description of Study 
This is a multi-center, single-arm, phase II study, with plans to enroll a maximum of 100 
patients. This study may be an adjunct to a nonmyeloablative protocol or treatment plan, or may 
be a primary treatment protocol.  For Outside Centers, it will be used as an adjunct only. 
 
4.2 
Endpoints 
 
Primary Endpoint 
The primary endpoint is grade 3-4 acute GVHD  
 
Secondary Endpoints 
Secondary endpoints include the following 
o Grades II-IV acute GVHD 
o Proportion of patients requiring secondary systemic immunosuppressive 
therapy 
o Chronic extensive GVHD 
o Recurrent or progressive malignancy  
o Non-relapse mortality at 1 year 
o Overall survival 
o Proportion of donors who have to discontinue atorvastatin because of 
toxicity 
 
 
PATIENT SELECTION 
 
5.1 
Inclusion Criteria (If Protocol 2546 serves as an adjunct protocol, the 
patient only needs to meet inclusion criteria 1 through 5A.) 
 
1) Availability of HLA-identical sibling donor 
2) Transplantation with PBSC 
3) CSP-based postgrafting immunosuppression 


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4) Willingness to give informed consent 
5) 
A. Patient is enrolled on an investigational nonmyeloablative HCT protocol or a 
nonmyeloablative treatment plan with postgrafting CSP that does not use acute 
GVHD as its primary endpoint (protocol 2546 serves as adjunct protocol). 
or 
B. Patient is not enrolled on an investigational nonmyeloablative HCT protocol, in 
which case protocol 2546 serves as an independent primary treatment protocol and 
the patient must meet the following inclusion and exclusion criteria: 
  
a. Patients must have a hematologic malignancy treatable by nonmyeloablative 
HCT.  The following diseases will be permitted although other diagnoses can be 
considered if approved by PCC and the principal investigator: 
• Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as 
diffuse large B-cell NHL – not eligible for autologous HCT, not eligible for 
high-dose allogeneic HCT, or after failed autologous HCT. 
• Mantle-cell NHL - may be treated in first CR. (Diagnostic LP required pre-
transplant) 
• Low grade NHL – with <6 month duration of CR between courses of 
conventional therapy 
• CLL – must have either: 
i. failed to meet NCI Working Group criteria for complete or partial 
response after therapy with a regimen containing FLU (or another 
nucleoside analog) or experience disease relapse within 12 months 
after completing therapy with a regimen containing FLU (or another 
nucleoside analog);  
ii. failed FLU-CY-Rituximab (FCR) combination chemotherapy at any 
time point; or  
iii. have “17p deletion” cytogenetic abnormality. Patients should have 
received induction chemotherapy but could be transplanted in 1st CR;  
iv. Patients with a diagnosis of CLL (or small lymphocytic lymphoma) that 
progresses to prolymphocytic leukemia (PLL); or  
v. patients with T-cell CLL or PLL. 
• Hodgkin lymphoma – must have received and failed frontline therapy. 
• Multiple myeloma – must have received prior chemotherapy. Consolidation 
of chemotherapy by autografting prior to nonmyeloablative HCT is permitted. 
• Acute myeloid leukemia (AML) – must have < 5% marrow blasts at the time 
of transplant. 
• Acute lymphocytic leukemia (ALL) – must have <5% marrow blasts at the 
time of transplant. 
• Chronic myeloid leukemia (CML) – Patients will be accepted if they have 
shown intolerance to tyrosine kinase inhibitors or are beyond CP1 and if 
they have received previous myelosuppressive chemotherapy or HCT, and 
have <5% marrow blasts at time of transplant. 
• Myelodysplasia (MDS)/ myeloproliferative syndrome (MPS) – Patients must 
have <5% marrow blasts at time of transplant.  
• Waldenstrom’s macroglobulinemia – must have failed 2 courses of therapy. 
 


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b. Patients <12 years of age must be approved by the principal investigator and by 
a relevant patient review committee, such as the FHCRC Patient Care 
Conference (PCC). 
c. Patients must have either relapsed after previous high-dose chemotherapy and 
autologous or allogeneic HCT, or else be ineligible for such an approach due to 
age, failure to mobilize sufficient hematopoietic stem cells, medical comorbidities, 
or patient refusal (see d. below). 
d. Patients who refuse to be treated on a conventional autologous or allogeneic 
HCT protocol. 
 
5.2 
Exclusion Criteria (If Protocol 2546 serves as an adjunct protocol, the 
patient only needs to meet exclusion criteria 1 through 3.) 
 
1) Myeloablative preparative regimen. 
2) Participation in an investigational study that has acute GVHD as the primary endpoint. 
3) The allogeneic PBSC donor has a contraindication to statin treatment. 
4) Patients eligible for and willing to receive potentially curative high-dose chemotherapy 
and autologous HCT. 
5) Patients with the following levels of organ dysfunction are ineligible: 
i. 
Cardiac: Cardiac ejection fraction <30% on MUGA scan or cardiac echo or active 
symptomatic coronary artery disease. Patients with cardiac disease should be 
evaluated with appropriate cardiac studies and/or cardiology consultation as 
clinically indicated. 
ii. 
Pulmonary: DLCOcorrected <40% of predicted, TLC < 30% of predicted, FEV1 <30% 
of predicted, or receiving continuous supplementary oxygen. 
iii. 
Hepatic: Patients with clinical or laboratory evidence of liver disease should be 
evaluated in conjunction with the GI consult service for the cause of the liver 
disease, its clinical severity, and the degree of portal hypertension. Patients will 
be excluded if they are found to have fulminant liver failure, cirrhosis of the liver 
with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, 
esophageal varices, a history of bleeding esophageal varices, hepatic 
encephalopathy, refractory ascites related to portal hypertension, bacterial or 
fungal liver abscess, chronic viral hepatitis with total serum bilirubin >3mg/dl, or 
actively symptomatic biliary disease. 
iv. 
Renal: Patients with renal failure are eligible. However, patients with pre-existing 
renal insufficiency will likely have further compromise in renal function and may 
require dialysis. 
6) Patients who are seropositive for human immunodeficiency virus (HIV). 
7) Women who are pregnant or breast-feeding. 
8) Fertile men or women unwilling to use contraception during HCT and for 12 months 
afterward. 
9) Patients with active non-hematological malignancies (except non-melanoma skin 
cancers) or those with non-hematological malignancies (except non-melanoma skin 
cancers) who have been rendered with no evidence of disease, but have a greater than 
20% chance of having disease recurrence within 5 years. This exclusion does not apply 
to patients with non-hematologic malignancies that do not require therapy.  
10) Karnofsky score <60 for adult patients. 
11) Lansky-Play Performance Score <50 for pediatric patients. 
12) Patients with fungal pneumonia with radiological progression after receipt of 
amphotericin formulation or mold-active azoles for greater than 1 month. 


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DONOR SELECTION  
 
6.1  
Inclusions 
 
1) Age ≥ 18 years 
2) HLA genotypically identical sibling 
3) Willingness to give informed consent 
 
6.2 
Exclusions 
 
1) Age < 18 years 
2) History of liver disease. A donor with a history of liver disease would be eligible if the 
serum ALT or AST are <2 times ULN. 
3) History of myopathy 
4) Hypersensitivity to atorvastatin 
5) Pregnancy 
6) Nursing mother 
7) Current serious systemic illness 
8) Concurrent treatment with strong inhibitors of hepatic CYP 3A4 (i.e. clarithromycin, 
erythromycin, protease inhibitors, azole antifungals) 
9) Failure to meet local criteria for stem cell donation 
10) Total creatinine kinase > 2 times the ULN 
 
 
INFORMED CONSENT OF SUBJECT AND DONOR 
 
Patients will be referred to the SCCA or appropriate outside center institution for consideration 
of a growth factor-mobilized blood cell transplant. Both patient and the related donor will be 
completely evaluated. The protocol will be discussed thoroughly with patient, donor and family, 
and all known risks to patient and donor will be described. The procedure and alternative forms 
of therapy will be presented as objectively as possible and the risks and hazards of the 
procedure explained to the patient and donor or, in the case of minors, to responsible family 
members. Consent will be obtained using forms approved by the local IRB. A summary of the 
conference will be dictated for the medical record detailing what was covered. 
 
PATIENT AND DONOR REGISTRATION 
 
Eligible FHCRC donor/recipient pairs will be identified by the Clinical Coordinators Office (CCO) 
(Intake Office) and assigned UPNs (Unique Patient Numbers). The Data Management Office 
will register donors and recipients on to the protocol through the Data Management Office.  For 
patients enrolled at external sites, they will be registered to this study by FHCRC study staff. 
 
PLAN OF TREATMENT 
 
9.1 
Donor Treatment with Atorvastatin  
 
• 
Eligible donors will be given atorvastatin (generic drug preferred, if available; otherwise 
Lipitor™) 40 mg/day orally starting on day -14. The last dose of atorvastatin will be 


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administered in the morning of the last day of stem cell collection (total of 15 doses). 
• 
The following guidelines are to be followed if the day of transplant must be re-scheduled 
while the donor has already started atorvastatin treatment: 
o Transplant moved up: If the transplant date needs to be moved up by ≤ 3 days, a 
shortened atorvastatin treatment course is permissible provided at least 12 days 
of treatments (40 mg/day) can be given to the donor. If the transplant needs to be 
moved up for > 3 days, atorvastatin treatment of the donor will be discontinued 
and patients will not be followed with respect to the primary endpoint of this 
study. 
o Transplant delayed: If the transplant date needs to be delayed, an extended 
atorvastatin treatment course is permissible provided the new transplant date is 
already agreed upon and lies within 14 days from the date the decision to re-
schedule was made. If the re-scheduled transplant date lies beyond 14 days from 
the date the decision to re-schedule is made, the donor will discontinue 
atorvastatin treatment and resume statin treatment on day -14 before the new 
transplant date. 
 
9.2 
Recipient Treatment (References below to standard practice refer to 
standard practice at site where HCT is being performed.) 
 
• 
If the patient is enrolled on an investigational nonmyeloablative HCT protocol or a 
treatment plan that uses a nonmyeloablative preparative regimen with 
postgrafting CSP that does not use acute GVHD as its primary endpoint, the 
preparative regimen and immunosuppression after transplant will be according to 
respective protocol or treatment plan (protocol 2546 serves as adjunct protocol). 
 
• 
If the patient is not enrolled on an investigational nonmyeloablative HCT 
protocol or a treatment plan that uses a nonmyeloablative preparative 
regimen, protocol 2546 serves as an independent primary treatment 
protocol. The preparative regimen and immunosuppression after transplant 
will be as follows, see figure 2: 
Treatment may be initiated in the outpatient department, and patients will be admitted to 
the hospital if medically necessary to address transplant-related complications or other 
medical issues. 
 
TBI Criteria for 2546 as a Primary Protocol: 
 
*Criteria for 3 Gy TBI (only for patients in Regimen A, Flu/TBI):  
Patients need to fulfill one or more of the following criteria for 3 Gy TBI: 
a) Patients with MDS, MPD, CML, or other hematologic malignancies not 
previously treated with myelosuppressive chemotherapy. 
b) Patients who had a previous allogeneic transplant. 
c) Patients who had a prior syngeneic transplant without subsequent 
myelosuppressive chemotherapy. 
d) Patients who have not had myelosuppressive chemotherapy within 3-6 months 
of HCT may be at higher risk of rejection depending on treatment history and 
underlying diagnosis. Confirm TBI dose (2 vs 3 Gy) with PI. 


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TBI Criteria for 2546 as an adjunct Protocol: 
 
*Criteria for 4 Gy TBI: 
Patients on Protocol 2546 as an adjunct protocol, TBI doses can exceed > 3 Gy 
when the protocol serves as adjunct to a reduced intensity treatment plan that 
includes 4 Gy TBI. 
 
A. 
For 2546 as a Primary Protocol: Preparative Regimen and 
Postgrafting Immunosuppression 
 
a) Fludarabine 30 mg/m2/day IV on days -4, -3, and -2 (except for patients who 
had prior autologous HCT or equivalent high-dose therapy without HCT) within 
6 months. 
 
b) Total body irradiation, 2-3 Gy* (6-7 cGy/min; linear accelerator), on day 0 
 
c) Infusion of hematopoietic allograft on day 0 
 
d) Post-grafting immunosuppression: 
i. CSP, 5 mg/kg PO q12 hrs from day -3 to day +56, then tapered to day 
+180  
 
Age < 6 years:  2 mg/kg IV every 8 hours 
Age > 6 years:  2 mg/kg IV every 12 hours 
 
ii. MMF, 15mg/kg PO/IV q12 hrs from day 0 to day +27 
 
Figure 2. Diagram of Treatment Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
            FLU: 
30 mg/m2   on days -4, -3, -2 
 
TBI: 
Single fraction (2-3 cGy*) at 6-7 cGy/min  
 
           MMF:      15 mg/kg p.o. q12 hrs days 0 to +27 
 
* See criteria for TBI dosing 
 
If T-Cell (CD3) chimerism is >50% on day +28, then repeat only on days +84 and +365.**If T-Cell (CD3)  
chimerism is 50% on day +28, then repeat on days +56, +84, +180, & +365.   
 Granulocyte (CD33) chimerism on day +84 only.  
 Natural killer (NK) cell (CD56+) chimerism will be obtained on day 28.  
 Bone Marrow chimerism will be obtained on days +84 & +365 
Immunosuppression 
TBI 
HCT 
Days
              -4  -3 -2         0           14            28               56*                    84                   100 
180* 
Fludarabine
Chimerism
Chimerism 
Chimerism
Evaluation 
MMF 
CSP 
 
Regimen A: Flu/TBI 
  CSP:     5.0 mg/kg p.o. bid days -3 until day +56, taper to day +180 


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 (See Patient Post-Transplant Evaluation for more instructions and exceptions).  
 Treatment starts on Day -4 
  
 
 
 
 
 
 
 
 
 
 
 
 
             TBI: 
Single fraction (2 cGy) at 6-7 cGy/min 
 
           MMF:      15 mg/kg p.o. q12 hrs days 0 to +27 
 
If T-Cell (CD3) chimerism is >50% on day +28, then repeat only on days +84 and +365.*If T-Cell (CD3) chimerism is 
50% on day +28, then repeat on days +56, +84, +180, & +365.   
 Granulocyte (CD33) chimerism on day +84 only.  
 Natural killer (NK) cell (CD56+) chimerism will be obtained on day 28. 
 Bone Marrow chimerism will be obtained on days +84 & +365 
 (See Patient Post-Transplant Evaluation for more instructions and exceptions).  
Treatment starts on Day -3 
 
B. 
Peripheral Blood Stem Cell Infusion 
 
G-CSF-mobilized PBSC from an HLA-identical related donor will be the source of 
hematopoietic stem cells. Two 12-liter leukaphereses on consecutive days, day -1 and 
day 0, will be obtained, and cells will be infused together on day 0 after TBI. Refer to 
institutional practice guidelines for methods of infusion. If the CD34+ cell dose is <5.0 x 
106/kg recipient weight after the second collection, a third day collection should be 
added, with an extra dose of G-CSF given to the donor before the final collection. 
 
C. 
Adjustment of Post-grafting Immunosuppression 
 
Immunosuppression after transplant will be with MMF and CSP, as described above. 
CSP and MMF doses should be based on adjusted body weight. If actual weight is less 
than ideal weight, then actual body weight will be used. MMF will be initiated on day 0, 
with the first dose given 4–6 hours after allograft infusion is complete. In the absence of 
GVHD, CSP and MMF will be tapered and/or discontinued as described above. In the 
presence of GVHD, standard institutional recommendations for acute GVHD therapy 
should be followed. In the event of progression or recurrence of malignancy, and in the 
absence of GVHD, CSP and MMF may be tapered more rapidly to stimulate a graft-vs.-
malignancy effect, at the discretion of the attending physician. Investigational 
medications aimed at treating relapse or GVHD after transplant are permissible. 
 
• 
Guidelines for CSP Administration and Monitoring 
If there is nausea and vomiting at anytime during CSP treatment, consideration should 
be given to administering CSP intravenously at the appropriate dose that was used to 
Immunosuppression 
                         MMF 
                         CSP 
TBI 
HCT 
Days
                    -3            0           14            28               56*                    84                   100 
180* 
Chimerism
Chimerism 
Chimerism
Evaluation 
Regimen B: TBI Alone 
  CSP:     5.0 mg/kg p.o. bid days -3 until day +56, taper to day +180 


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obtain a therapeutic level. For pediatric patients, it is recommended that CSP dosing be 
initiated using the IV formulation and then converted to PO when tolerated.  The 
appropriate dose conversion from PO to IV and IV to PO should be discussed with the 
transplant pharmacist. Blood pressure, renal function and electrolytes (including 
magnesium) should be followed at least 3 times per week during the first month, twice 
weekly until day +100, then once per week until CSP is stopped. 
 
CSP Dose Adjustments: Initial high Cyclosporine (CSP) doses are required based on the 
preclinical nonmyeloablative canine studies, which used an equivalent dose to establish 
an allograft.  After day +28, CSP levels typical for unrelated HCT will be targeted.  Dose 
reduction should only be made if CSP toxicity is present, and/or levels exceed values 
provided in Table 2. There are two methods for calculating CSP levels.  Table 2 provides 
desired levels for specific methods.  To avoid inadequate immune suppression, dose 
reductions should be conservative.  Therapeutic levels of CSP should be maintained. 
 
 
 
Table 2:  CSP Dose Adjustment 
 
 
CSP Level to Target 
Using LC-MS/MS 
Method 
CSP Level to Target 
Using Immunoassay 
Method 
Day “0” – Day +28 
Whole blood “trough” (11-12 hrs 
from prior dose) 
 
400 ng/ml 
 
500 ng/ml 
(upper end therapeutic 
range for this method) 
 
After Day +28 
 
 
120 - 360 ng/ml 
 
 
150 - 450 ng/ml 
 
Levels >480 ng/ml by LC-MS/MS 
Method 
• 
with or without CSP toxicity 
• 
decrease GFR >50% 
• 
increase creatinine 2x 
baseline due to CSP 
 
 
 
 
25% dose reduction 
 
 
 
N/A 
Levels >600 ng/ml by Immunoassay 
Method 
• 
with or without CSP toxicity 
• 
Decrease GFR >50% 
• 
increase creatinine 2x 
baseline due to CSP 
 
 
N/A 
 
 
25% dose reduction 
Patients on Hemodialysis 
320 ng/ml 
400 ng/ml 
 
• 
Guidelines for MMF Administration and Monitoring 
If there is nausea or vomiting at any time preventing the oral administration of MMF, the 
drug should be administered intravenously. It will be left to the discretion of the pediatric 


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attending whether to initiate MMF dosing IV or PO.  The PO to IV or IV to PO dose 
conversion should be discussed with the transplant pharmacist. If clinical judgment 
suggests observed toxicities are related to MMF, the dose may be adjusted. The 
adjustment or discontinuation of MMF at any point should be discussed with the PI and 
documented in the permanent medical record and all Case Report Forms (CRF). 
 
D. 
 Collection of Donor PBSC 
 
• 
G-CSF Administration to Donors: 
G-CSF will be administered by subcutaneous daily injections from day -4 to day 0 at a 
dose of 16 µg/kg/day for 5 consecutive days. The schedule of G-CSF administration and 
PBSC collections should be confirmed with the personnel in the apheresis room. Day 0 
should be scheduled on a Tuesday-Thursday, if possible (FHCRC patients only).  
 
 
 
• 
PBSC Collection: 
Donors will preferably undergo vein-to-vein collections, or may receive an appropriate 
catheter inserted on or before the day of apheresis. PBSCs will be collected on the 
afternoon of day -1 and stored in the refrigerator at 4ºC overnight. A second collection 
will be performed the following afternoon and both collections will be infused on day 0. If 
<5x106 CD34+ cells/kg recipient weight are collected, an additional (third) day of 
collection should be performed. If PBSC cannot be collected by a vein-to-vein technique, 
a percutaneous Mahurkar catheter will be inserted. General procedures will include the 
use of a standard apheresis machine (COBE Spectra, Lakewood Colo.), and processing 
up to 16 liters of whole blood during the collection.  
 
Table 3:  Treatment Schema for HLA-Identical Related Donors 
 
Days 
 -4 
 -3 
 -2 
-1 
 0 
G-CSF 16 
g/kg/SQ 
  X 
  X 
  X 
X 
 X 
G-PBMC 
collection 
 
 
 
X 
 X 
 
Immunophenotyping of the G-PBMC product will be performed by the cryobiology 
laboratory and will include T-cells and their subsets, monocytes, and NK cells.  
 
 
E. 
ABO-Incompatibility 
All patients with ABO incompatibility should be evaluated and treated according to 
institutional standard practice. 
 
 


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F. 
Post-transplant Growth Factors 
In general, patients should not receive post-transplant growth factors during the first 3 
weeks after transplant. Growth factors should not be given unless neutropenia (ANC 
<500/μL) persists past day +21 after transplant. 
 
 
G. 
Infection Prophylaxis 
Patients will receive monitoring for and prophylaxis against viral, bacterial, and fungal 
infections per institutional standard practice. 
 
 
H. 
Evaluation of Chimerism 
 
Definitions:  For the purposes of this protocol, the following definitions will apply:  
For the purposes of this protocol, mixed chimerism will be defined as the detection of 
donor T cells (CD3+) and granulocytes (CD 33+), as a proportion of the total T cell and 
granulocyte population, respectively, of greater than 5% and less than 95% in the 
peripheral blood. Full donor chimerism is defined as > 95% donor CD3+ T cells. Mixed 
or full donor chimerism will be evidence of donor engraftment. Increasing donor 
chimerism is defined as an absolute increase of 20% of CD3+ T cells over the previous 
chimerism evaluation. Decreasing donor chimerism is defined as an absolute decrease 
of 20% of CD3+ T cell chimerism over the previous month. Low donor chimerism is 
defined as < 40% CD3+ T cells after HCT. Low donor chimerism should always be 
confirmed with repeat peripheral blood T cell and granulocyte chimerism analysis.  A 
DNA-based assay that compares the profile of amplified fragment length polymorphisms 
(ampFLP) (or FISH studies or VNTR) of the patient and donor will be used to quantitate 
chimerism of sorted peripheral blood T-cells (CD3+) and granulocytes (CD 33+). The 
same assay should be used in a given patient for repeated studies of chimerism.  This 
DNA-based analysis will also be performed on the whole nucleated cell fraction from 
marrow aspirates. Therapeutic decisions (i.e. DLI) will be made based on the results of 
sorted T-cell studies of peripheral blood. For the purposes of this protocol, rejection is 
defined as the inability to detect or loss of detection of greater than 5% donor T cells 
(CD3+) as a proportion of the total T cell population, respectively, after nonmyeloablative 
HCT. Also for the purposes of this protocol, graft failure is defined as grade IV 
thrombocytopenia and neutropenia after day 21 that lasts > 2 weeks and is refractory to 
growth factor support.  
Bone marrow chimerism (unfractionated cells) will be evaluated at day +84 and one year 
after transplant. In peripheral blood, CD3 chimerism will be evaluated on days +28, +84 
and one year after transplant; CD33 chimerism will be evaluated on day +84; CD56 
chimerism will be evaluated on day +28. Unless clinically indicated (i.e. poor previous 
chimerism, immunotherapy, hematopoietic insufficiency etc.), further chimerism studies 
will not be performed. 
 
I. 
Continuation of immunosuppression.  
In the setting of low donor chimerism, immunosuppression may be continued or 
reinitiated at full dose so that DLI can be administered on a separate protocol. If there is 
disease progression in the setting of low donor chimerism, the algorithm for disease 
progression (below) should be followed. Patients who reject their graft may be eligible for 
a second allogeneic transplant on other protocols. 


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J. 
Discontinuation of immunosuppression.  
Immunosuppression should be discontinued as per protocol unless the patient develops 
GVHD, has falling donor chimerism or has progressive or substantial persistent disease 
(see below). In the setting of GVHD, CSP and MMF may be continued. GVHD at any 
time should be treated as per standard practice. 
 
K. 
Disease progression or persistence and mixed chimerism.  
Evidence of substantial persistent disease at day 80 or beyond may be an indication for 
therapeutic intervention while disease progression, at any time point will always be an 
indication for therapeutic intervention. Intervention for persistent disease at day 80 or 
beyond should be discussed with the Principal Investigator and the guideline below for 
progressive disease should be followed. If the attending physician believes that the 
patient requires very aggressive therapy for rapidly progressive disease, the case will be 
presented at the Patient Care Conference (FHCRC patients only). Otherwise, priority 
should be given to rapid reduction of immunosuppression, option (a) below. Therapeutic 
options include: 
 
a. Discontinuation of immunosuppression. This should be considered the first 
therapeutic maneuver. If there is no GVHD, MMF should be stopped and CSP 
should be tapered over 2 weeks. Bone marrow aspirate and blood chimerism 
studies will be performed 2 weeks after discontinuation of immunosuppression. If 
there is no response to withdrawal of immunosuppression, < 20% increase in 
donor chimerism and there is no GVHD, patients will be considered as treatment 
failures. DLI will not be offered for disease progression or relapse on this 
protocol. In this situation, patients may receive further therapy as per institutional 
protocols for disease relapse or progression after allogeneic HCT. If no GVHD 
occurs, patients with progressive disease may be offered enrollment in other 
institutional protocols for DLI treatment. If there is >20% absolute increase in 
donor chimerism, patients should be observed for additional 2 weeks and 
chimerism studies then repeated. If there is progressive disease that requires 
therapy before 4 weeks or progressive disease occurs despite onset of GVHD, 
patients can be treated off protocol with DLI or be considered for options (b) or 
(c) below. 
b. Intercurrent treatment with chemotherapy or radiation. Conventional 
chemotherapy or radiation therapy should be considered in the setting of life-
threatening progression of malignancy. Patients in this situation would be 
considered treatment failures. After cytoreductive therapy is completed, 
chimerism should be evaluated and the administration of DLI off protocol 
considered. 
c. High-dose allogeneic HCT This option should be discussed with the principal 
investigator. Patients who undergo high-dose allogeneic HCT will be removed 
from the protocol at that time. 
d. CML or Ph (+) ALL patients with Persistent or Increased Minimal 
Residual Disease: At day +84 or beyond, if the patient has persistent or 
increased MRD disease, dose-escalation of BCR/ABL tyrosine kinase inhibitor 
therapy or DLI should be considered 
e. CML and PH (+) ALL patients with Relapse and Disease Progression: 


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See above sections for withdrawal of immunosuppression. If there is no response 
to withdrawal of immunosuppression and no GVHD has developed, dose 
escalation of BCR/ABL tyrosine-kinase inhibitor therapy and or DLI should be 
considered. 
 
L.  
Assessment of Disease Responses 
The initial anti-tumor effect of allogeneic HCT will be evaluated with the intermittent 
analysis of appropriate tumor markers, if available: Responses will be classified as 
complete, partial response or no response. Response criteria for MM, NHL, CLL, CML, 
ALL, AML and MDS to be used in this study are described in Appendix E. Standard 
response criteria specific to other diseases will be used in assessing disease response 
for other patients on study. 
 
 
 
EVALUATION OF PATIENTS 
 
10.1 Patient Pre-transplant Evaluation for All Diseases 
 
1. History: A complete history with full details of the patient’s prior treatment and response. 
2. Careful physical exam with documentation of Karnofsky or Lansky score, HCT-CI score and 
findings related to underlying malignancy. 
3. Standard CBC with differential & platelets, comprehensive metabolic panel, magnesium, uric 
acid, ABO/Rh typing, hepatitis screen, CMV and toxoplasmosis serology, anti-HIV serology, and 
serum LDH. 
4. Pulmonary function tests with corrected DLCO. 
5. CXR (PA and LAT). 
6. ECHO or MUGA for patients > 50 years of age, or history of cardiac disease or anthracycline 
exposure. 
7. Evaluation and prophylaxis of CNS disease as per local practice guidelines. 
 
Immunophenotyping of the PBSC graft. 
Immunophenotyping of the PBSC product will be performed by the Cellular Therapy Laboratory 
and will include CD34, CD3/4 and CD3/8 cells. The residual specimen will be sent to the 
Heimfeld lab for phenotypic characterization of cellular subsets.  For patients enrolled at 
external sites, immunophenotyping will be performed at the local site. 
 
 
Additionally, see the following tables (Tables 4, 5, 6 and 7) for disease specific pre-
transplant evaluation 
 
 


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Table 4: Disease-Specific Pre-Transplant Evaluations for ALL and CML 
 
Note: All bone marrow aspirates and biopsies are unilateral and must be collected within 21 
days of treatment.  See Tables 8 and 10 for post-transplant evaluations and additional lab 
instructions 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
*If previously abnormal 
PCR for bcr/abl, p.210 breakpoint - *see comment 
Clinical 
*CML only  
PCR for bcr/abl, p.190 and p.210 breakpoints - *see 
comment  
Clinical 
*Ph (+) ALL only 
 
Bone marrow biopsy 
 
Pathology- *see comment 
Clinical 
*CML only 


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Table 5: Disease-Specific Pre-Transplant Evaluations for AML and MDS/MPD 
 
 
Note: All bone marrow aspirates and biopsies are unilateral and must be collected within 21 
days of treatment.  See Tables 8 and 10 for post-transplant evaluations and additional lab 
instructions 
  
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
*If previously abnormal 
Bone marrow biopsy 
 
Pathology- *see comment 
Clinical 
*MDS/MPD only 
 


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Table 6: Disease-Specific Pre-Transplant Evaluations for CLL, HL, NHL 
 
Note: All bone marrow aspirates and biopsies are bilateral and must be collected within 30 
days of treatment.  See Tables 8 and 10 for post-transplant evaluations and additional lab 
instructions. If disease status can be determined pre-allo without all specific tests, the tests may 
be omitted.  
 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry- *see comment 
Clinical 
*No HL 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
*If previously abnormal 
PCR for t(11:14) - *see comment 
Clinical 
*Mantle Cell NHL only 
PCR for t(14:18) - *see comment 
Clinical 
*Follicular NHL only 
Bone marrow biopsy 
 
Pathology- *see comment 
Clinical 
*HL – only if history of BM 
involvement 
Peripheral Blood 
 
Quantitative Ig levels 
Clinical 
 
β-2 microglobulin 
Clinical 
 
LDH 
Clinical 
 
ZAP – 70 by flow cytometry- *see comment 
Clinical 
*CLL only – for patients not in CR 
Imaging 
 
CT of chest, abdomen, pelvis (neck if indicated) 
Clinical 
 
 


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Table 7: Disease-Specific Pre-Transplant Evaluations for MM and Waldenstrom’s 
Macroglobulinemia 
 
Note: All bone marrow aspirates and biopsies are bilateral and must be collected within 30 
days of treatment.  See Tables 8 and 10 for post-transplant evaluations and additional lab 
instructions. If disease status can be determined pre-allo without all specific tests, the tests may 
be omitted.   
 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
*If previously abnormal 
Bone marrow biopsy 
 
Pathology 
Clinical 
 
Peripheral Blood 
 
SPEP/IFIX 
Clinical 
 
Quantitative Ig levels 
Clinical 
 
β-2 microglobulin 
Clinical 
 
Cryoglobulins, c-reactive protein, serum 
viscosity - *see comment 
Clinical 
*Serum viscosity only for patients with 
>3gm/dL IgM monoclonal protein or 
>4gm/dL IgA or IgG protein 
Urine 
 
UPEP/IFIX 
Clinical 
 
Protein / creatinine clearance 
Clinical 
 
Imaging 
 
MRI –  *see comment 
Clinical 
*MM only 
Skeletal survey –  *see comment 
Clinical 
*MM only 
CT of chest, abdomen, pelvis (neck if 
indicated) –  *see comment 
Clinical 
*Waldenstrom’s Macroglobulinemia 
only 
 
 


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10.2 Patient Post-transplant Evaluation 
 
See Standard Practice Manual for standard treatment guidelines (Allo) during conditioning, post-
transplant inpatient admission and during first 100 days after initial hospital discharge. See 
Table 8 for disease specific post-transplant evaluation on Day +28, 56, 84, etc; this is a 
recommended evaluation schedule. 
 
See Standard Practice Manual for Evaluation Guidelines After Departure from FHCRC System. 
 
For patients enrolled at external sites, post-transplant evaluations will be performed per local 
standard practice.  The testing listed in Table 8 are recommended evaluations.  All testing will 
be performed at the local institution. 
 
Guidelines for bone marrow evaluations beyond one year after transplant: 
1) Marrow evaluations represent the standard of care for all patients at the one-year LTFU 
visit after HCT. 
 
2) Subsequent marrow evaluations also represent the standard of care if… 
a. The CBC or platelet count shows any abnormalities  
b. If there is any clinical indication for the procedure, OR 
c. If the most recent marrow evaluation or other testing showed any evidence of 
persistent malignancy, OR 
d. If the patient has a disease for which a low-dose maintenance treatment would 
be indicated if disease were discovered after a previous evaluation with no 
evidence of malignant cells.   
 
 
 


2546.00 - Nonablative 
26 
FHCRC Current Version:  02/06/2018 
 
 
Table 8: Post-Transplant Evaluation 
This is a recommended evaluation schedule.  
See Tables 4 - 7 for pre-transplant evaluations.  Additional lab instructions in Table 9. 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Ph (-) ALL 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
27 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Ph (+) ALL 
 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
FISH for  bcr/abl and other 
clonal abnormalities 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
PCR for bcr-abl, p.190 and 
p.210 breakpoints 
Clinical 
* p.190 and p.210 only if 
present in pre-transplant 
marrow 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
28 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
AML 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
29 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
MDS/ MPD 
 
 
BM aspirate *see biopsy 
                    ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal  pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal  pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
*For pts. with evidence or 
history of myelofibrosis 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
30 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
CML 
BM aspirate *see biopsy 
                       ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
FISH for bcr-abl and 
other clonal 
abnormalities 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
BM biopsy 
 
Pathology 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK 
CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
PCR for bcr-abl, and 
p.210 breakpoint 
Clinical 
*p.190 and p.210 only if 
present in pre-transplant 
marrow 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
31 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
CLL 
 
BM aspirate *see biopsy 
                       ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
Flow cytometry 
Clinical 
* If peripheral blood 
involvement pre-transplant 
AND bone marrow not done 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Quantitative Ig levels 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
LDH 
Clinical 
 
 
x 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
32 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
HL - 
No history of 
BM 
involvement 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
 
 
x 
 
x 
 
 
Cytogenetics 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment 
 
*See 
comment 
 
 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
 
*See 
comment 
 
 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
LDH 
Clinical 
 
 
x 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment  x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
33 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
HL - 
History of BM 
involvement 
BM aspirate *see biopsy 
                       ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
LDH 
Clinical 
 
 
x 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment  x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
34 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
NHL – 
No History of 
BM 
involvement  
 
*see separate 
section for 
additional PCR 
on Mantle Cell 
and Follicular 
NHLs in 
suspected CR 
 
 
 
 
 
 
 
 
 
 
BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
 
Pathology 
Clinical 
 
 
 
x 
 
x 
 
 
 
Flow cytometry 
Clinical 
 
 
 
x 
 
x 
 
 
 
Cytogenetics 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment  
*See 
comment  
 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
 
Flow cytometry 
Clinical 
* If peripheral blood 
involvement pre-transplant, if 
bone marrow not obtained 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
β-2 microglobulin 
Clinical 
 
 
 
x 
 
 
 
 
 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment  x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
35 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
NHL– 
History of BM 
involvement 
 
*see separate 
section for 
additional PCR 
on Mantle Cell 
and Follicular 
NHLs in 
suspected CR 
 
BM aspirate *see biopsy 
** ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
Flow cytometry 
Clinical 
* If peripheral blood 
involvement pre-transplant, if 
bone marrow not obtained 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
β-2 microglobulin 
Clinical 
 
 
 
x 
 
x 
 
 
LDH 
Clinical 
 
 
x 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment  x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
36 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Mantle Cell 
NHL in 
suspected CR 
BM aspirate *in addition to complete NHL restaging 
** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
PCR for t(11:14) 
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood  *in addition to complete NHL restaging 
 
PCR for t(11:14) 
Clinical 
*If abnormal pre-transplant, if 
bone marrow not obtained  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Follicular Cell 
NHL in 
suspected CR 
BM aspirate *in addition to complete NHL restaging 
** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
PCR for t(14:18) 
Clinical  
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood  *in addition to complete NHL restaging 
 
PCR for t(14:18) 
Clinical  
*If abnormal pre-transplant, if 
bone marrow not obtained  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
37 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
MM 
 
 
Omit 
SPEP/IFIX and 
UPEP/IFIX for 
non-secretory 
MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate*If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical  
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical   
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical  
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for chrom. 13 (and 
other clonal) abnormalities  
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
SPEP and IFIX 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Quantitative Ig levels 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
β-2 microglobulin 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Cryoglobulins, C-reactive 
protein, viscosity 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
*See 
comment 
 
*See comment 
Urine 
 
Protein/creatinine 
clearance 
Clinical 
 
 
 
x 
x 
x 
x 
x 
UPEP and IFIX 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Imaging 
 
Complete skeletal survey 
Clinical 
 
 
 
 
 
x 
 
x 
Skeletal MRI 
Clinical 
 
 
 
 
 
x 
 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 


2546.00 - Nonablative 
38 
FHCRC Current Version:  02/06/2018 
 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Waldenstrom’s 
Macro-
globulinemia 
 
Omit 
SPEP/IFIX and 
UPEP/IFIX for 
non-secretory 
Waldenstrom’s 
Macro-
globulinemia 
 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical  
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical  
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical  
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for chrom. 13 (and 
other clonal) abnormalities  
Clinical 
*If abnormal pre-transplant  
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
 
 
 
 
 
 
 
 
 
Peripheral blood 
 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
SPEP and IFIX 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Quantitative Ig levels 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
β-2 microglobulin 
Clinical 
 
 
 
 
x 
x 
x 
x 
Cryoglobulins, C-reactive 
protein, viscosity 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
*See 
comment 
 
*See comment 
Urine 
 
 
Protein/ creatinine 
clearance 
Clinical 
 
 
 
x 
x 
x 
x 
x 
UPEP and IFIX 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Imaging 
 
 
 
 
 
 
 
 
 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
GVHD  evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 


2546.00 - Nonablative 
39 
FHCRC Current Version:  02/06/2018 
 
 
Table 9: Additional Lab Instructions (for patients enrolled at FHCRC) 
Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. All 
instructions apply to both pre- and post-transplant evaluations unless specifically identified 
otherwise. Volumes represent desired amounts. 
 
Specimen / 
Test 
Type 
Instructions 
Lab Name 
Contact Information 
Bone marrow 
 
Chimerism  
Clinical 
1-3mL bone marrow in 
green-top tube 
Clinical Immunogenetics 
Lab 
Seattle Cancer Care Alliance 
 (206) 606-7700 
Pathology 
(aspirate) 
Clinical 
2mL bone marrow in EDTA 
formalin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
(206) 606-1355 
Pathology (biopsy) 
Clinical 
1cm bone marrow in 
formalin OR mounted in 
paraffin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
 (206) 606-1355 
Flow Cytometry 
Clinical 
2mL bone marrow in green-
top tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 606-7060 
Cytogenetics 
Clinical 
3mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 606-1390 
FISH 
Clinical 
2mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 606-1390 
PCR  for bcr-abl 
and p190 and/or 
p210 
Clinical 
3mL bone marrow in 
lavender-top tube 
Label “protocol 2546” 
UW Molecular 
Hematopathology Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
PCR t(11:14) or 
t(14:18) 
Clinical 
2mL bone marrow in 
lavender-top tube 
UW Molecular 
Hematopathology Lab  
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
Peripheral blood 
 
Chimerism  
(CD3+), (CD33+) 
NK(CD56+) 
Clinical 
10mL blood in green-top 
tube for Flow sorting, then 
to CIL 
UW Hematopathology Lab, 
routed to Clinical 
Immunogenetics Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
Flow Cytometry 
Clinical 
10mL blood in green-top 
tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 606-7060 
SPEP/IFIX 
Clinical 
3mL blood in red-top tube 
UW Department of 
Laboratory Medicine 
University of Washington 
(800) 713-5198 
Quantitative Ig 
Levels 
Clinical 
3mL blood in red-top tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 606-2057 
β-2 Microglobulin 
Clinical 
3mL blood in red-top tube 
UW Department of 
Laboratory Medicine 
University of Washington 
(800) 713-5198 
LDH 
Clinical 
3mL blood in red-top tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 606-2057 
PCR for bcr-abl 
and p190 and/or 
p210 
Clinical 
7mL blood in lavender-top 
tube 
Label “protocol 2546” 
UW Molecular 
Hematopathology Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
PCR for t(11:14) or 
t(14:18) 
Clinical 
5mL blood in lavender-top 
tube 
UW Molecular 
Hematopathology Lab  
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
ZAP – 70 by Flow 
cytometry 
(pre-transplant 
only) 
Clinical 
5mL blood in green-top 
tube 
UW Hematopathology Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 606-7060 
 
 


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EVALUATION OF DONORS 
 
See Standard Practice Manual for standard Evaluation Guidelines of allogeneic PBSC donors.  
Evaluation of donors at external sites will be per the local standard practice. 
 
11.1 Safety Evaluations 
 
Laboratory parameter monitoring: Rhabdomyolysis (defined as a creatine phosphokinase [CPK] 
value > 10fold the upper limit of normal) and hepatocellular injury are infrequent yet potentially 
serious complications of statin treatment. Therefore, serum levels of CPK and transaminases 
will be assessed before initiation of atorvastatin treatment (baseline) and at its completion (first 
day of leukapheresis). 
 
Muscular symptom monitoring: Because rare cases of rhabdomyolysis have been reported with 
atorvastatin (approximately 1 in 1,000 patients), donors will be instructed to report any new 
muscle symptoms (i.e. myalgias, tenderness, weakness) while taking atorvastatin. Taking into 
account that G-CSF (Neupogen™) frequently causes musculoskeletal symptoms, any 
symptoms temporally related to atorvastatin treatment considered significant according to the 
medical team’s assessment will be evaluated at the attending physician’s discretion. 
 
Liver dysfunction monitoring: Persistent elevations in serum transaminases occurred in 0.7% of 
patients who received atorvastatin in clinical trials and, in most cases, were not associated with 
clinical symptoms. Transaminase elevations related to atorvastatin treatment are usually 
reversible after discontinuation of the drug and measurements of serum transaminase levels are 
generally not recommended until completion of 12 weeks of atorvastatin treatment. As outlined 
under ”Laboratory parameter monitoring”, serum levels of transaminases will be assessed 
before initiation of atorvastatin treatment (baseline) and at its completion (first day of 
leukapheresis). If clinically indicated, additional measurements of serum transaminase levels 
may be performed at the attending physician’s discretion. 
 
Monitoring for other symptoms: Any new and unexplained significant signs or symptoms 
occurring in statin-treated donors should be evaluated according to the judgment of the 
attending physician. Approximately one week after initiation of statin therapy, at the time of 
PBSC collection and one week after donation and discharge from the center, the donor will be 
contacted by study staff (at the local transplant center or by telephone) to follow up on potential 
adverse effects that may require further evaluation. At the same time, the donor will also be 
asked about his/her compliance with the prescribed atorvastatin medication. 
 
If the donor develops clinical signs or symptoms deemed serious and at least possibly related to 
statin treatment, the attending physician, in consultation with the Principal Investigator, will 
decide whether atorvastatin treatment should be discontinued. In this case, the donor will be 
provided with an appropriate follow-up plan, which will be formulated by the attending physician 
and the PI. 
 
 
 
11.2 Donor Statin Compliance 
 
Donor compliance with taking atorvastatin will be monitored at the time of each donor contact 
specified above in Section 11.1. 


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TOXICITIES AND COMPLICATIONS  
 
For the purposes of this protocol, toxicity will be graded using the modified NCI common toxicity 
scale version 4.0. 
 
12.1 Atorvastatin 
• 
Skeletal Muscle 
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been 
reported with atorvastatin (<1 in 1,000 patients). A history of renal impairment may be a risk 
factor for the development of rhabdomyolysis. Patients with renal impairment therefore merit 
closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes 
myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CPK 
values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs 
such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV 
protease inhibitors) increases the risk of myopathy/rhabdomyolysis. Myopathy should be 
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked 
elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, 
tenderness, or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy 
should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or 
suspected.  
 
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, 
serious condition suggestive of a myopathy or having a risk factor predisposing to the 
development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, 
hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and 
uncontrolled seizures). 
 
• Liver Dysfunction 
Atorvastatin has been associated with biochemical abnormalities of liver function. Persistent 
elevations (>3 times the ULN occurring on 2 or more occasions) in serum transaminases 
occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these 
abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One 
patient in clinical trials developed jaundice. Increases in LFTs in other patients were not 
associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug 
interruption, or discontinuation, transaminase levels returned to or near pretreatment levels 
without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment 
with a reduced dose of atorvastatin. 
 
It is generally recommended that liver function tests be performed prior to and at 12 weeks 
following both the initiation of therapy and any elevation of dose, and periodically (e.g., 
semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of 
treatment with atorvastatin. Patients who develop increased transaminase levels should be 
monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN 
persist, reduction of dose or withdrawal of atorvastatin is recommended. Atorvastatin should be 
used with caution in patients who consume substantial quantities of alcohol and/or have a 
history of liver disease. Active liver disease or unexplained persistent transaminase elevations 
are contraindications to the use of atorvastatin. 
 
• 
Endocrine Function 


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Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal 
steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma 
cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not 
been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis 
in premenopausal women are unknown. Caution should be exercised if a statin is administered 
concomitantly with drugs that may decrease the levels or activity of endogenous steroid 
hormones, such as ketoconazole, spironolactone, and cimetidine. 
 
• CNS Toxicity 
Brain hemorrhage, optic nerve vacuolation and degeneration, and CNS vascular lesions were 
seen after long-term treatment of normal dogs with atorvastatin or similar drugs in this class at 
doses that produced plasma drug levels 6-30 times higher than those attainable in humans 
taking the highest recommended statin dose. 
 
 
 
• Additional Adverse Reactions 
Clinical Trial Adverse Experiences: In the Lipitor™-placebo-controlled clinical trial database of 
16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10–93 years, 39% women, 91% 
Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 
9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued therapy due 
to adverse reactions regardless of causality. The five most common adverse reactions in 
patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate 
greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine 
aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly 
reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, 
in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis 
(8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection 
(5.7%). Table 13 summarizes the frequency of clinical adverse reactions from 17 placebo-
controlled trials, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in 
patients treated with atorvastatin (n=8755). 


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Table 13. Clinical adverse reactions occurring in > 2% in patients treated with any dose of 
atorvastatin (Lipitor™) and at an incidence greater than placebo regardless of causality (% of 
patients). 
 
 
Other adverse reactions reported in placebo-controlled studies include: 
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, flatulence, 
hepatitis, cholestasis; Musculo-skeletal system: musculoskeletal pain, muscle fatigue, neck 
pain, joint swelling; Metabolic and nutritional system: transaminases increase, LFT abnormality, 
blood alkaline phosphatase increase, serum CPK increase, hyperglycemia; Nervous system: 
nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: 
vision blurred, tinnitus; Urogenital system: white blood cells urine positive. 
 
12.2 GVHD 
Acute and chronic GVHD are well-recognized complications of allogeneic hematopoietic cell 
transplantation. GVHD will be assessed according to criteria summarized in Appendices B, C 
and D. Recommended primary systemic treatment for acute GVHD will be corticosteroids. Other 
systemic immunosuppressive medications may be used at the discretion of the attending 
physician. 
 
12.3 Total Body Irradiation (TBI) 
TBI will be given in one 200 cGy or up to 400 cGy fraction (per institutional guidelines) from 
linear accelerator at a rate of 6 - 7 cGy/min. Dosimetry calculations are performed by the 
radiation therapist. At the dose used, side effects are not expected. Nevertheless, there may be 
fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects 
including cataract formation, growth retardation, pulmonary damage, carcinogenesis, and 
sterilization. 
 


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12.4 Cyclosporine (CSP) 
See section 9.2. for information about administration and dose adjustment. Side effects are 
generally reversible, and may include renal insufficiency, hypomagnesemia, paresthesias, 
tremor, seizures, visual disturbances, paresis, disorientation, depression, confusion, 
somnolence, coma, nausea, hypertension, hemolytic-uremic syndrome, hyperglycemia, 
gynecomastia, and hypertrichosis 
 
12.5 Mycophenolate Mofetil (MMF) 
See section 9.2. for information about administration and dosage adjustments.  
 
Precautions:  MMF has been studied extensively among patients after nonmyeloablative HCT. 
Previous clinical studies in patients after allografting suggest that the principal adverse reactions 
associated with the administration of MMF include nausea, vomiting, neutropenia, diarrhea. In 
the setting of marrow transplantation, several etiologic factors may contribute to alterations in 
gastrointestinal and hematologic parameters. MMF has an increased incidence of digestive 
system adverse events, including GI tract ulceration, and hemorrhage (3% of patients receiving 
MMF). GI tract perforations have rarely been observed. Most patients in these studies were also 
on other drugs known to be associated with these complications. Up to 2% of patients receiving 
MMF for prevention of rejection developed severe neutropenia (ANC <500). The development 
of neutropenia may be related to MMF itself, concomitant medications, viral infections or some 
combination of these causes. MMF dose adjustments will be made if clinically indicated if in the 
opinion of the attending physician, no other cause is thought to be responsible for the 
abnormality.  These adjustments should be discussed with the principal investigator and 
documented in the medical records and the clinical reporting form (CRF). 
 
12.6 Fludarabine 
The dose of fludarabine used in this protocol is nonmyeloablative, but does cause significant 
immunosuppression. Fludarabine can lower the white blood cell count, in particular the CD4+ T-
cells. The immunosuppression observed with the use of fludarabine increases the risk of 
infection, which can be life threatening. 
 
12.7 Myelosuppression 
Grade IV myelosuppression will be defined as a decrease in ANC to <500/µL and/or platelet 
count to  20,000/µL. If myelosuppression occurs, a bone marrow aspirate and biopsy should 
be considered to exclude disease progression. Samples should be sent for chimerism analysis. 
Myelosuppression may occur in this patient population for a number of reasons such as direct 
toxic effect of drugs (MMF, ganciclovir etc.), rejection, relapse or after DLI.  
 
 
 
ADVERSE EVENT MONITORING 
 
13.1 Institutional Policy and Definitions 
 
• 
Policy 


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The following guidelines are the minimum Cancer Consortium IRB adverse event (AE) reporting 
guidelines. 
In accordance with institutional policy, all serious adverse events (SAEs) which in the opinion of 
the principal investigator are unexpected and related or possibly related to the research and 
serious or suggest that the research places research participants or others at greater risk of 
physical or psychological harm than was previously known or recognized must be reported to 
the IRB within 10 calendar days of learning of the problem. Since only stem cell donors and 
not recipients will be treated with atorvastatin according to this study, monitoring of non-
serious AEs will focus on the donors. Non-serious AEs occurring in the patient will not 
be collected. The Cancer Consortium Expedited Reporting Form for Unanticipated Problems or 
Noncompliance should be completed for all adverse events that meet the expedited reporting 
requirements. The form should be sent to the Institutional Review Office (IRO) within 10 
calendar days of learning of the problem. 
SAE Policy and Reporting at External Sites:  For SAEs that occur in patients enrolled at 
external sites, reporting to the local IRB will be per the local institutional policy.  This will apply to 
expedited and annual reporting.  It will be the responsibility of the external site to submit to 
FHCRC an SAE report for all SAEs that occur in patients and donors.  These reports must be 
sent to FHCRC within 10 days of learning of the event.   
Please see Appendix F for definitions of adverse events, serious adverse events (SAE) and 
serious and unexpected events as well as mechanisms for reporting these events 
 
13.2 Adverse Events to be Monitored in This Study 
 
• 
Serious Adverse Events  
- SAEs: All events occurring in donors and recipients that meet the definition of an SAE will be 
recorded and reported to the IRB, regardless of whether they are related or unrelated to the 
protocol intervention or are expected or unexpected. SAEs observed in donors or recipients that 
are deemed related or possibly related and unexpected to the research will be reported to the 
IRB in an expedited fashion (within 10 calendar days of learning of the problem). All other SAEs 
will be reported to the IRB at the time of annual protocol renewal. 
 
• 
Adverse Events Related to Administration of Atorvastatin 
o Select toxicities will be collected using the National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.0 (Appendix I) 
o Since the primary research intervention in this study is the administration of atorvastatin 
to PBSC donors before stem cell collection (for prevention of severe acute GVHD in 
recipients), reporting of AEs that are not serious will focus on atorvastatin-related events 
in donors. Although highly unlikely, the potential negative impact of donor statin 
treatment on recipient outcomes will be captured through no-harm endpoints that trigger 
mandatory DSMB review as further outlined in 17.3.  
o Donors will be assessed for the following events: 
▪ 
Musculoskeletal and connective tissue disorders: grade 2-5 
▪ 
Hepatobiliary disorders: grade 2-5 
▪ 
Other unexpected events thought related to the use of atorvastatin; grade 2-5 
In cases where the NCI criteria do not apply, intensity will be defined as: 


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FHCRC Current Version:  02/06/2018 
 
 
▪ 
Mild: awareness of symptom or sign, but easily tolerated 
▪ 
Moderate: discomfort is enough to cause interference with normal activities 
▪ 
Severe: inability to perform normal daily activities 
▪ 
Life threatening: immediate risk of death from the reaction as it occurred 
 
 
 
 
 


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13.3  Duration of Adverse Event and Unanticipated Problem Monitoring and 
Recording 
Donor: SAEs and select AEs (see section 13.2) will be monitored and recorded from the time 
the donor starts atorvastatin therapy through 7 days after the discontinuation of the medication. 
 
Figure 3: SAE reporting for patients on Protocol 2546 as an independent 
primary treatment Protocol or as an adjunct: 
 
Protocol 2546 serves 
as adjunct protocol 
 
Protocol 2546 
serves as an 
independent primary 
treatment protocol 
Utilize adapted CTC 
version of primary 
protocol for toxicities 
 
Utilize adapted CTC 
v.4.0 (Appendix J) 
 
SAEs and AEs are 
reported to the IRB 
on the primary 
protocol AND on 
Protocol 2546 
 
SAEs and AEs are 
reported to the IRB 
as Protocol 2546 
events 
 
Donor events are 
ONLY reported on 
Protocol 2546 


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Recipient: SAEs (life-threatening or fatal)  
• 
For 2546 as an adjunct to treatment plan or primary protocol, SAEs will be 
monitored and recorded from the time the recipient starts conditioning therapy through 
day 100 or discharge from the center, whichever occurs earlier. 
 
• 
For 2546 as an adjunct to a nonmyeloblative investigational protocol, follow 
reporting guidelines of nonmyeloblative investigational protocol.  
 
 
OUTCOMES TO BE ASSESSED 
 
14.1 Proportion of Donors who Discontinue Atorvastatin Because of Toxicity 
During treatment with atorvastatin, donors will be evaluated for adverse effects that would 
mandate discontinuation of the drug. Data pertaining to atorvastatin toxicity including those 
mandating discontinuation of the drug will be collected per Section 13. 
 
14.2 Acute GVHD 
All patients will be evaluated for GVHD. It is strongly recommended, when possible, that 
biopsies be taken for histological confirmation of GVHD. The final peak grade of GVHD will be 
determined retrospectively by Dr. Paul Martin. Data pertaining to the diagnosis and treatment of 
acute GVHD will be collected though day +100 post-transplant.  
 
14.3 Chronic GVHD 
Patients will be evaluated for chronic GVHD as described in the NIH consensus project 
guidelines. Graft failure, recurrent malignancy and death without GVHD are considered to be 
competing risks for GVHD.  
 
14.4 Recurrent Malignancy 
Recurrent malignancy will be defined by hematologic criteria. Recurrent malignancy will also be 
defined as any unplanned medical intervention designed to prevent progression of malignant 
disease in patients who have molecular, cytogenetic or flow-cytometric evidence of malignant 
cells after transplantation.  
 
14.5 Non-relapse Mortality (NRM)  
NRM is defined as death in the absence of recurrent or progressive malignancy after HCT.  
 
14.6 Overall Survival (OS) 
Survival without death (OS) will be determined and presented as Kaplan-Meier estimates at 1 
year post-transplant.  
 


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14.7 Proportion of Patients Requiring Secondary Systemic Immunosuppressive 
Treatment  
The need for additional systemic immunosuppressive treatment with agents other than those 
used for prophylaxis and initial therapy, the reason for their administration (acute GVHD, chronic 
GVHD, or other reasons) will be determined. 
 
DATA AND SAFETY MONITORING PLAN 
 
15.1 Principal Investigator 
 
 
• 
Responsibilities 
o Coordinating development of the protocol as well as its subsequent 
amendments. 
o Securing initial IRB and NHLBI approval of the protocol 
o Securing IRB approval of protocol amendments. 
o Reviewing and adjudicating whether SAEs are unexpected and related to 
administration of atorvastatin to donors before stem cell collection.   
o Securing renewal of IRB approval at annual intervals.  
 
• 
Oversight Mechanisms 
To identify trends pertinent to patient or donor safety, the Principal Investigator will meet with 
the research nurse and other key investigators to review enrollment, SAEs and AEs in the 
donors that might be related to administration of atorvastatin. Patient data (day 100 NRM and 
recurrent malignancy) will also be reviewed.   
 
15.2 Data Safety Monitoring Board (DSMB) 
 
• 
Role of the DSMB 
This study will be monitored by a DSMB. The primary role of the DSMB will be to monitor 
protocol specific AEs and SAEs in the donors , even though occurrence of SAEs in donors 
probably or likely related to short-term atorvastatin treatment is considered highly unlikely.  The 
DSMB will monitor acute GVHD, relapse, non-relapse mortality and overall survival in the 
patients.   
 
• 
DSMB Membership 
Membership will consist of one statistician and two senior physicians who are familiar with HCT. 
To avoid any conflict of interest, DSMB members are required to have no study involvement. 
Potential conflicts of interest will be reviewed by the IRB at the time of initial DSMB 
appointment. 
 
• 
Operations and Responsibilities of the DSMB 
The DSMB will meet after the first cohort of 13 donors have completed the stem cell donation 
process. Subsequent meetings will be held at 12-month intervals.  At each meeting the DSMB 
will review data related to donor and patient safety. It is anticipated that the donor safety 
monitoring will include a review of all protocol-specific adverse events and AEs and SAEs. Even 
though there has been no indication based on large retrospective analyses that donor statin 


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treatment may negatively affect recipients’ outcomes [2], rates of recurrent malignancy and day-
100 mortality in recipients will be carefully monitored and considered during DSMB review. 
Based on the information available at each of these meetings, the DSMB is charged with 
deciding whether a) no action is required, b) the protocol should be modified, c) further 
enrollment should be suspended pending additional review, or d) the protocol should be closed.   
The DSMB will keep minutes of its meetings and provide its findings to the Principal Investigator 
within 10 working days. An exception to this time requirement will occur if the DSMB 
recommends study termination, suspension of enrollment or a protocol modification that 
significantly affects donor or patient safety. In these cases, the DSMB will be expected to 
provide their recommendations to the Principal Investigator within 24 hours. Ad hoc meeting or 
discussion with the DSMB will be arranged as deemed necessary by the protocol PI.   
 
• 
Reporting Data to the DSMB 
The Principal Investigator will be responsible for providing the DSMB with summary data 
sufficient to meet its responsibilities.   
 
15.3  Trial Monitoring 
Trial monitoring is provided in accordance with the FHCRC/University of Washington (UW) 
Cancer Consortium Data and Safety Monitoring Plan (DSMP). Under the provisions of the 
DSMP, the Cancer Consortium Clinical Trial Support Office provides monitoring for quality 
process and compliance by qualified monitors unaffiliated with the conduct of the study. 
Monitoring visits occur at specified intervals determined by the assessed risk level of the study 
and the findings of the previous visit. The scope of monitoring is specified in the DSMP 
http://www.cancerconsortium.org/rto/prr/  
Per FHCRC IRB Policy 1.9, all confirmed serious or continuing noncompliance with federal laws 
relating to research involving human subjects, the FHCRC human subject protection program 
(HRPP) or the requirements of the IRB will be reported promptly to either the IRO Director or 
other entities cited in the policy. 
 
 
DATA MANAGEMENT AND PROTECTION OF CONFIDENTIALITY 
Clinical Statistics maintains a subject database at FHCRC to allow storage and retrieval of local 
subject data collected from a wide variety of sources. The investigator will ensure that data 
collected conform to all established guidelines for coding, collection, key entry and verification. 
Each subject is assigned a unique patient number to assure subject confidentiality. Subjects will 
not be referred to by this number, by name, or by any other individual identifier in any 
publication or external presentation. The licensed medical records department, affiliated with the 
Consortium institution where the subject receives medical care, maintains all original inpatient 
and outpatient chart documents. Subject research files are scanned and stored securely in an 
optical web library (OWL). OWL records are maintained by the FHCRC data abstraction staff. 
Access is restricted to personnel authorized by the Division of Clinical Research. 
 
 
 


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Table 14. Confidence of that a true rate of grade 3-4 acute 
GVHD of <9% exists as a function of increasing numbers of 
patients in whom grade 3-4 acute GVHD is observed. 
N cases 
GVHD 
Confidence 
< 9% 
Power1 if 
True = 4% 
Power1 if 
True = 2% 
0 
>99 
2 
13 
1 
>99 
9 
40 
2 
>99 
23 
68 
3 
98  
43 
86 
4 
 95   
63 
95 
5 
 90  
79 
98 
6 
81  
89 
>99 
1Probability of observing indicated number of cases or fewer 
among a total number of 100 patients 
STATISTICAL CONSIDERATIONS 
 
17.1  Primary Endpoint and Sample Size 
The primary endpoint of this study is the proportion of patients who develop grade 3-4 acute 
GVHD after transplantation. The cumulative incidence of this endpoint in patients prepared with 
nonmyeloablative conditioning regimens after HCT from HLA-matched related donors, and with 
CSP-based immunosuppression is approximately 9%. A reduction in the cumulative incidence 
of acute GVHD from 9% to <2% would represent a reasonable goal after nonmyeloablative HCT 
and constitute study success. Patients with GVHD symptoms that are equivocal with respect to 
assigning severity and grade will be reviewed by at least two GVHD attendings to arrive at 
consensus grading. Based on a hypothetical total of 100 patients evaluated, Table 14 illustrates 
the decreasing confidence that a true rate of grade 3-4 acute GVHD of <9% exists 
corresponding to increasing numbers of patients in whom grade 3-4 acute GVHD is observed. 
Having 90% confidence that a true grade 3-4 GVHD rate of <9% exists appears sufficient to 
define success of this study; therefore, donor/patient pairs would be enrolled until the 6th patient 
develops grade 3-4 acute GVHD. If a 6th patient develops grade 3-4 acute GVHD, the study 
would be closed for lack of demonstrable efficacy. Patients with GVHD symptoms that are 
equivocal with respect to assigning severity and grade will be reviewed by at least two GVHD 
attendings to arrive at consensus grading.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stopping rules will be imposed for: 
 
• 
Grade 3-4 acute GVHD in 6/100 patients 
 
Patients who have to discontinue CSP because of toxicity before onset of GVHD and who 
subsequently develop grade 3-4 acute GVHD will not be considered for assessment of efficacy. 
As long as <6 patients have developed grade 3-4 acute GVHD, the study would continue to 
enroll up to a maximum of 100 donor/recipient pairs. 
 


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17.2 Secondary Endpoints 
 
• 
Acute and chronic GVHD 
Grades II-IV and II-IV acute GVHD and chronic GVHD will be assessed with the use of 
cumulative incidence plots. 
 
• 
Non-relapse Mortality 
Non-relapse mortality will be assessed with the use of cumulative incidence plots. This 
secondary endpoint will be characterized and presented as a cumulative incidence at day 100 
and at 1 year after HCT. 
 
• 
Recurrent or progressive Malignancy 
Recurrent or progressive malignancy will be assessed with the use of cumulative incidence 
plots. 
  
• 
Overall survival 
Disease-free survival and overall survival will be evaluated as Kaplan-Meier estimates at 1 year 
after HCT. 
  
• 
Duration of Systemic Immunosuppressive Treatment 
Primary and secondary treatment of acute GVHD and withdrawal of systemic 
immunosuppressive treatment will be assessed with the use of cumulative incidence plots. 
 
• 
 Discontinuation of Atorvastatin Therapy 
The number of donors who prematurely discontinue atorvastatin therapy and the reasons for 
discontinuation will be described.  
 
 
17.3 Mandatory Ad Hoc DSMB Review  
 
This protocol is designed to evaluate GVHD-protective effects associated with donor statin 
treatment as a novel approach to immunosuppression after nonmyeloablative HCT from HLA-
matched related donors. Although deemed extremely unlikely, an ad hoc DSMB review will 
be convened if interim results raise concerns about donor safety, particularly with respect to 
muscle and hepatic toxicity. In large studies using atorvastatin for long-term treatment of 
patients with hyperlipidemia, SAEs were rare (<1%), did not increase across the 10 mg/day to 
80 mg/day dose-range and seldom led to study withdrawal. Based on this review, the DSMB will 
make a determination as to whether the protocol should be closed to accrual.  
Even though there has been no indication based on large retrospective analyses that donor 
statin treatment may negatively affect recipients’ outcomes [2], rates of recurrent malignancy 
and day-100 mortality in recipients will be carefully monitored and considered during DSMB 
review. In the unlikely event that there was evidence suggesting donor statin treatment causes 
harm in recipients, the DSMB may recommend modification or closure of the study. 
 


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17.4 Projected Ethnic and Gender Distribution 
 
Table 15: ETHNIC AND GENDER DISTRIBUTION CHART 
 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
41 
56 
97 
Ethnic Category Total of All Subjects* 
42 
58 
100 
Racial Categories 
 
American Indian / Alaska Native 
1 
1 
2 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
1 
2 
3 
White 
39 
54 
93 
Racial Categories:  Total of All Subjects* 
42 
58 
100 
 
 
 
 
 
TERMINATION OF STUDY 
Participants may withdraw from this study at any time at their discretion. Participants may also 
be removed from this protocol if they develop any untoward side effects from the study 
medications. In addition, stopping rules are in place for lack of efficacy and a DSMB will 
evaluate issues related to excessive toxicity observed in patients or donors thought to be related 
to atorvastatin. 
 
The PI may terminate the study at any time. The IRB and the United States Food and Drug 
Administration also have the authority to terminate the study should it be deemed necessary. 
 
 


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REFERENCES 
 
 1.   Rotta M, Storer BE, Storb RF, Martin PJ, Heimfeld S, Peffer A, Maloney DG, Deeg HJ, Sandmaier 
BM, Appelbaum FR, Mielcarek M. Donor statin treatment protects against severe acute graft-
versus-host disease after related allogeneic hematopoietic cell transplantation. Blood. 
2010;115:1288-1295. 
2.  Rotta M, Storer BE, Storb R, Martin PJ, Flowers MED, Vernon MS, Peffer A, Maloney DG, Deeg 
HJ, Sandmaier BM, Appelbaum FR, Mielcarek M. Impact of recipient statin treatment on graft-
versus-host disease after allogeneic hematopoietic cell transplantation. Biol of Blood Marrow 
Transplant 16:1463-1466 (2010) 
3. Zeiser R, Youssef S, Baker J, Kambham N, Steinman L, Negrin RS. Preemptive HMG-CoA 
reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing 
graft-versus-leukemia activity. Blood. 2007;110:4588-4598. 
 4.  Liao JK, Laufs U. Pleiotropic effects of statins (Review). Annual Review of Pharmacology and 
Toxicology. 2005;45:89-118. 
 5.  Zeiser R, Maas K, Youssef S, Durr C, Steinman L, Negrin RS. Regulation of different inflammatory 
diseases by impacting the mevalonate pathway (Review). Immunology. 2009;127:18-25. 
 6.  Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein 
prenylation to immunomodulation (Review). Nat Rev Immunol. 2006;6:358-370. 
 7.  Blank N, Schiller M, Krienke S, Busse F, Schatz B, Ho AD, Kalden JR, Lorenz HM. Atorvastatin 
inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme A reductase without 
decreasing cholesterol synthesis. J Immunol. 2007;179:3613-3621 . 
 8.  Hillyard DZ, Cameron AJ, McDonald KJ, Thomson J, MacIntyre A, Shiels PG, Panarelli M, Jardine 
AG. Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular 
disease. Atherosclerosis. 2004;175:305-313. 
 9.  Brinkkoetter PT, Gottmann U, Schulte J, van der Woude FJ, Braun C, Yard BA. Atorvastatin 
interferes with activation of human CD4(+) T cells via inhibition of small guanosine triphosphatase 
(GTPase) activity and caspase-independent apoptosis. Clin Exp Immunol. 2006;146:524-532. 
 10.  Mausner-Fainberg K, Luboshits G, Mor A, Maysel-Auslender S, Rubinstein A, Keren G, George J. 
The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. 
Atherosclerosis. 2008;197:829-839. 
 11.  Mira E, Leon B, Barber DF, Jimenez-Baranda S, Goya I, Almonacid L, Marquez G, Zaballos A, 
Martinez A, Stein JV, Ardavin C, Manes S. Statins induce regulatory T cell recruitment via a CCL1 
dependent pathway. J Immunol. 2008;181:3524-3534. 
 12.  Schramm R, Menger MD, Harder Y, Schmits R, Adam O, Weitz-Schmidt G, Schafers HJ. Statins 
inhibit lymphocyte homing to peripheral lymph nodes. Immunology. 2007;120:315-324. 
 13.  Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, 
Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory 
integrin site. Nat Med. 2001;7:687-692. 
 14.  Shimabukuro-Vornhagen A, Liebig T, Bergwelt-Baildon M. Statins inhibit human APC function: 
implications for the treatment of GVHD. Blood. 2008;112:1544-1545. 
 15.  Fehr T, Kahlert C, Fierz W, Joller-Jemelka HI, Riesen WF, Rickli H, Wuthrich RP, Ammann P. 
Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis. 2004;175:83-
90. 
 16.  Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin inhibits IL-17 secretion by 
targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription 
factor RORC in CD4+ lymphocytes. J Immunol. 2008;180:6988-6996. 
 17.  Hamadani M, Awan FT, Devine SM. The impact of HMG-CoA reductase inhibition on the incidence 
and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic 
transplantation. Blood. 2008;111:3901-3902. 
 
 


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TABLE OF APPENDICES 
 
 
Appendix A: 
Lipitor (atorvastatin) Product label 
Appendix B: 
Chronic Graft-Versus-Host Disease Grading 
 
Appendix C: 
Acute GVHD Assessment (by Organ System) 
 
Appendix D:  GVHD Assessment Form 
Appendix E: 
Evaluation of Disease Response 
 
Appendix F: 
The Study Coordinator’s Manual 
 
Appendix G: Serious Adverse Event Report Form 
 
Appendix H: 
Notice of Death Form 
 
Appendix I: 
Coordinating Center Functions 
 
Appendix J: 
Adapted Common Toxicity Criteria, version 4.0 
 
Appendix K: 
Patient Demographics and Registration Form 
 
Appendix L: 
Case Report Form 
 
Appendix M: Donor Safety and Compliance Evaluation 
 
Appendix N: 
The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 
 


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Appendix A: Lipitor (atorvastatin) Product label 
 
 
 
 
 
 
http://labeling.pfizer.com/ShowLabeling.aspx?id=587 
 
 


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APPENDIX B: 
 
CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) 
 
Chronic GVHD in allogeneic transplant recipients resembles autoimmune disorders such as 
scleroderma, Sjogren syndrome, primary biliary cirrhosis, lichen planus, wasting syndrome, 
bronchiolitis obliterans among others manifestations (see below). Approximately 50% of 
patients will develop this complication within 6 months after the transplant despite continued 
treatment with immunosuppressive medications. Close monitoring is recommended during 
the first 2 years after allogeneic stem cell transplantation so that appropriate treatment can be 
instituted promptly in patients who develop chronic GVHD. Debilitation, joint contractures 
and profound immunosuppression resulting in recurrent bacterial infections are prominent 
characteristics of untreated chronic GVHD. 
 
A. Classification of Chronic GVHD 
The purpose of this classification is to identify patients with cGVHD who need long-term 
systemic immunosuppression according to clinical and laboratory findings and risk factors at 
the time of initial diagnosis.  
 
1.  Chronic GVHD not requiring systemic treatment: mild abnormalities involving a 
single site, with platelet count >100,000 and no steroid treatment at the onset of 
chronic GVHD 
a)  Oral abnormalities consistent with cGVHD, a positive skin or lip biopsy, and no other 
manifestations of cGVHD 
b)  Mild liver test abnormalities (alkaline phosphatase ≤2 x upper limit of normal, AST or ALT 
≤3 x upper limit of normal and total bilirubin ≤1.6) with positive skin or lip biopsy, and no 
other manifestations of cGVHD 
c)  Less than 6 papulosquamous plaques, macular-papular or lichenoid rash involving <20% 
of body surface area (BSA), dyspigmentation involving <20% BSA, or erythema involving 
<50% BSA, positive skin biopsy, and no other manifestations of cGVHD 
d)  Ocular sicca (Schirmer’s test ≤5mm with no more than minimal ocular symptoms), 
positive skin or lip biopsy, and no other manifestations of cGVHD 
e)  Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of 
cGVHD 
 
2.   Chronic GVHD requiring systemic treatment: more severe abnormalities or 
involvement of multiple sites, or platelet count <100,000, or steroid treatment 
at the onset of chronic GVHD 
a)  Involvement of two or more organs with symptoms or signs of cGVHD, with biopsy 
documentation of cGVHD in any organ 
b)  ≥15% base line body weight loss not due to other causes, with biopsy documentation of 
cGVHD in any organ 
c)  Skin involvement more extensive than defined for clinical limited cGVHD, confirmed by 
biopsy 
d)  Scleroderma or morphea 
e)  Onycholysis or onychodystrophy thought to represent cGVHD, with documentation of 
cGVHD in any organ 
f)  Decreased range of motion in wrist or ankle extension due to fasciitis caused by cGVHD 
g)  Contractures thought to represent cGVHD 
h) Oral involvement with functional impairment, refractory to topical treatment 
i)  Vaginal involvement with functional impairment, refractory to topical treatment 
j)  Bronchiolitis obliterans not due to other causes 
k)  Positive liver biopsy; or abnormal liver function tests not due to other causes with 
alkaline phosphatase >2 x upper limit of normal, AST or ALT >3 x upper limit of 
normal, or total bilirubin >1.6, and documentation of cGVHD in any organ 
l)  Positive upper or lower GI biopsy 


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m)  Fasciitis or serositis thought to represent cGVHD and not due to other causes 
 
B. Physical manifestations of Chronic GVHD 
Manifestations that are distinctive for chronic GVHD can begin before day 100 after the 
transplant, and manifestations that are typical of acute GVHD can persist long after day 100. 
For this reason, the differential diagnosis between acute and chronic GVHD cannot be made 
solely according to the time interval from transplant. The diagnosis of chronic GVHD 
requires at least one manifestation that is distinctive for chronic GVHD (identified by italic 
print below) as opposed to acute GVHD. In all cases, infection and others causes must be 
ruled out in the differential diagnosis of chronic GVHD. 
 
Karnofsky or Lansky Clinical Performance scores <60%, ≥15% weight loss, and recurrent 
infections are usually signs of clinical extensive chronic GVHD. Abnormalities that could 
indicate chronic GVHD are categorized by organ system are listed below (italic print 
identifies manifestation more distinct of chronic GVHD): 
 
Skin 
Erythema, dryness, pruritis, macular-papular or urticarial rash, pigmentary changes (i.e., hyperpigmentation, 
vitiligo), mottling, papulosquamous or lichenoid plaques, hyperkeratosis, exfoliation (ichthyosis), nodules, 
scleroderma, morphea (one or several circumscribed, indurated and shiny lesions). The extent of skin 
involvement and the skin thickness score for patients with scleroderma needs to be recorded at the time of 
diagnosis, when changes in treatment are made and when assessing treatment response. Medical photos 
are also useful for assessing the extent of skin involvement and response to treatment. 
Nails 
B.     Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying (scalp hair, eyelashes, eyebrows), thinning scalp hair, alopecia, decreased body hair 
Mouth 
Dryness, burning, gingivitis, mucositis, striae, dryness, atrophy, erythema, lichenoid changes, ulcers, labial 
atrophy or pigmentary changes, tightness around the mouth, sensitivity to acidic, strong flavors, heat or cold, 
tooth decay 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vul
va 
Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid changes not induced by ovarian 
failure or other causes 
Liver 
Jaundice and elevated liver function tests not due to other causes (see laboratory tests) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on exertion, history of 
recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, diarrhea, malabsorption, dysphagia, odynophagia 
Myofascial 
Stiffness and tightness with restriction of movement, occasionally with swelling, pain, cramping, erythema 
and induration, most commonly affecting the forearms, wrists and hands, ankles, legs and feet, inability to 
extend the wrists without flexing the fingers or the elbows, contractures 
Muscle 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 
Serosal 
 
 
Unexplained effusions involving the pleural, pericardial, or peritoneal cavities not due to venocclusive disease 
of the liver, cardiac insufficiency, malignancy, infection, GM-CSF toxicity or other causes 
 
 
 
 
 
 
 
 
 
 
 
 
 


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C. Laboratory Testing and Diagnostic Indicators of Chronic GVHD 
 
 
 
D. Guidelines for Treatment of Chronic GVHD after allogeneic HCT 
 
We strongly recommend that you consult the LTFU office before beginning treatment for chronic GVHD 
and before making changes in immunosuppressive treatment. Clinical trials should always be considered 
because current standard therapies are associated with high morbidity and decreased survival for 
patients with high risk chronic GVHD. 
 
Standard treatment of chronic GVHD usually begins with administration of glucocorticoids (1mg/kg/day) 
followed by taper to eventually reach an alternate-day regimen, with or without daily cyclosporine or 
tacrolimus (FK506). Other medications used for treatment of corticosteroid-resistant chronic GVHD are 
summarized on the next page. Telephone consultation with the LTFU medical team is available to you, 
seven days a week, to discuss appropriate treatment and provide other follow up recommendations. In 
addition to immunosuppressive treatment, antibiotic prophylaxis for encapsulated bacterial infections and 
PCP must be given to all patients being treated for chronic GVHD 
 
The duration of systemic immunosuppressive treatment of chronic GVHD varies but requires at least one 
year of therapy. Approximately 80% of patients require systemic immunosuppressive for 2 years and 40% 
of them requires therapy for at least 4 years. 
 
 
Adapted From: Long-Term Followup After Hematopoietic Stem Cell Transplant General Guidelines For 
Referring Physicians, Fred Hutchinson Cancer Research Center Standard Practice Manual, Section X, 
Chronic Graft Versus Host Disease (GVHD), Nov/2003 Version 
 
 
 
Eye 
Schirmer’s test with a mean value ≤ 5 mm at 5 minutes, or values of 6-10 mm in patients who have sicca 
symptoms, or keratitis detected by slit lamp examination 
Liver 
Elevated liver function tests not due to other causes (alkaline phosphatase ≥2 x upper limit, of normal, AST 
or ALT >3 x upper limit of normal or total serum bilirubin ≥1.6) 
Lung 
New obstructive lung defect defined as an FEV1 <80% of predicted with either an FEF 25-75 <65% of 
predicted or RV >120% of predicted, or a decrease of FEV1/FVC by >12% within a period of less than 1 
year, thought not to be caused by an infectious process, asthma or recurrent aspiration from the sinuses or 
from gastroesophageal reflux. In the absence of GVHD in any other organ, the diagnosis of bronchiolitis 
obliterans requires negative microbiological tests from bronchoalveolar lavage, evidence of air trapping by 
high resolution end-expiratory and end-inspiratory CAT scan of the lungs, or confirmation by thoracoscopic 
biopsy. 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by barium swallow, endoscopy or 
manometry 
Intestine 
Endoscopic findings of mucosal edema and erythema or focal erosions with histological changes of apoptotic 
epithelial cells and crypt cell drop out. Patients with unresolved acute GVHD may have more severe 
intestinal mucosal lesions including ulcers and mucosal sloughing. 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis with biopsy revealing no other etiological 
process 
Blood 
Thrombocytopenia (usually 20,000-100,000/l), eosinophilia (> 0.4 x 103/uL), hypogammaglobulinemia. 
Hypergammaglobulinemia and autoantibodies occur in some cases. 


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


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APPENDIX C continued 
 
ACUTE GVHD ASSESSMENT 
 
Overall Grade 
 
The determination of an overall GVHD grade should be based on the organ stage, response to treatment 
and whether GVHD was a major cause of death. 
 
Overall 
Grade 
 Organ Stage 
Qualifying Conditions 
Additional Qualifying Conditions 
I 
Stage 1 -2 skin  
No liver or gut 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD. 
II 
Stage 3 skin  
 
or  
Stage 1 liver  
 
or  
Stage 1 gut 
N/A 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD, but glucocorticoid treatment after 
the onset of GVHD was generally sufficient 
to control the disease. 
III 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
without GVHD as a major 
contributing cause of death 
 
 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD and that additional treatment after 
the onset of GVHD did not readily control 
the disease. 
IV 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
with GVHD as a major 
contributing cause of death 
 
 
GVHD was resistant to both the prophylactic 
immunosuppressive regimen and any 
additional treatment after the onset of the 
disease. 
 
References:  
 
1. Leisenring, WM, Martin, PJ, Petersdorf, EW, et al. An acute graft-versus-host-disease activity 
index to predict survival after hematopoietic cell transplantation with myeloablative conditioning 
regimens, Blood, 2006:108: 749-755. 
2. Przepiorka D, Weisdorf D, Martin PJ, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant. 1995:15: 825-828. 
 
 
 
 
 
 
 
 


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APPENDIX D 
GVHD Assessment Form 
 
GVHD assessment 
form.pdf
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E 
 
Evaluation of Disease Response 
 
Chronic myeloid Leukemia (CML) 
Complete response:  
Normalization of the WBC with complete disappearance of the Ph 
chromosome in 20/20 metaphases whenever possible. Molecular response is 
defined by negative RT-PCR for the BCR/ABL transcripts in bone marrow or 
blood. 
Partial response:  
Normalization of the white count with >0% but ≤35% Ph-metaphases. 
No response:  
Persistence of ≥80% Ph-positive metaphases. 
Progressive disease:  
Acquisition of a new cytogenetic abnormality and/or development of 
accelerated phase or blast crisis. The criteria for accelerated phase will be 
defined as unexplained fever greater than 38.3° C, new clonal cytogenetic 
abnormalities in addition to a single Ph-positive chromosome, marrow blasts 
and promyelocytes >20%. 
 
Acute leukemia (AML, ALL) 
Complete response:  
<5% marrow blasts by pathology and no circulating leukemic blasts. 
Partial response:  
5-30% marrow blasts, or <5% marrow blasts with circulating blasts. 
Stable disease:  
>30% marrow blasts without definite deterioration of performance status or 
worsening of anemia, neutropenia, or thrombocytopenia. 
Progressive disease:  
 
 
Evidence of relapse (>5% blasts) by morphologic or flow cytometric evaluation 
of the bone marrow aspirate or appearance of extramedullary disease. 
 
Chronic lymphocytic leukemia (CLL) 
Complete remission:  
Normal imaging studies (X-ray, CT, MRI) (nodes, liver, and spleen), peripheral 
blood by flow cytometry has no clonal lymphocytes, bone marrow by flow 
cytometry has no clonal lymphocytes, bone marrow by morphology has no 
nodules (or if present, nodules are free from CLL cells by 
immunohistochemistry), and the duration is ≥2 months. 
CR with minimal  
Peripheral blood or bone marrow by flow cytometry >0 - <1 CLL  
residual disease:  
cells/1000 leukocytes (0.1%) 
 
Partial remission:  
Absolute lymphocyte count in peripheral blood ≥50% decrease3 and physical 
exam/Imaging studies (nodes, liver, and/or spleen) ≥50% decrease3, 4. 
Duration is ≥2 months. 
Progressive disease:  
≥1 of: Physical exam/imaging studies (nodes, liver, and/or spleen) ≥50% 
increase or new, circulating lymphocytes by morphology and/or flow cytometry 
≥50% increase, and lymph node biopsy with Richter’s transformation 
Stable disease:  
Did not meet any of the above criteria for complete or partial remission or 
progression. 
Relapsed disease:  
Criteria of progression occurring 6 months after achievement of complete or 
partial remission. 
 
 
Lymphoma [Hodgkin's Disease, Non-Hodgkin's Lymphoma (NHL)] 
Complete response:  
Disappearance of all clinically detectable disease. 
Partial response:  
≥50% reduction of the sum of the products of the perpendicular diameters of 
marker lesions, no progression of any existing lesions, and no new lesions. 
Stable disease:  
Stabilization of all existing lesions with no new lesions (i.e. a <25% increase 
or <50% decrease in disease parameters defined above throughout the 
treatment period). 


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Progressive disease:  
>25% increase in the sum of the products of the perpendicular diameters of 
marker lesions, or the appearance of new lesions. 
 
Multiple Myeloma (MM) 
Complete response:  
Disappearance of plasmacytomas; decrease in marrow plasmacytosis to 
<10%; ≥75% reduction of the monoclonal serum protein. Reduction of the 24 
hour urine M-component to ≤10% of the initial prestudy value and to less than 
0.2 g/day; no increase in the size or number of lytic skeletal lesions; and 
normal serum calcium. 
Partial response:  
≥50%, <75% reduction of the monoclonal serum protein and reduction of the 
24 hour urine M-component to <0.2 gm/day; no increase in serum calcium, or 
in the size or number of plasmacytomas or lytic skeletal lesions. 
Stable disease:  
<50% reduction or <100% increase of the serum myeloma protein. 
Progressive Disease:  
≥100% increase of the serum myeloma protein from its lowest level, or 
reappearance of myeloma peaks that had disappeared with treatment; or 
definite increase in the size or number of plasmacytomas or lytic bone lesions. 
Myelodysplasia (MDS) 
Progressive Disease: 
Any evidence by morphologic or flow cytometric evaluation of the bone 
marrow aspirate of new blasts (>5%). 
 
 
 
 
 
 
1 Without granulocyte colony stimulating factor support. 
2 Without red blood cell transfusions or erythropoietin support. 
3 Compared to before starting therapy. 
4 Defined by the sum of the products of up to 6 lymph nodes with no increase in the size of any single lymph node (ie, an increase of <25 percent 
in a lymph node <2cm is not considered significant) and no new enlarged lymph nodes. 
 
1.  Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR.  National Cancer Institute-
sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for 
diagnosis and treatment.  Blood 87: 4990-4997, 1996. 
  2.   Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, 
Montserrat E, Rai KR, Kipps TJ, International Workshop on Chronic Lymphocytic Leukemia.  
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-
Working Group 1996 guidelines [Erratum appears in Blood. 2008 Dec 15;112(13):5259].  Blood 
111: 5446-5456, 2008. 
  3.   Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International 
Workshop on Chronic Lymphocytic Leukemia.  Ann Intern Med 110: 236-238, 1989. 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F 
 
Study Coordinator’s Manual 
 
I. Introduction 
The mixed chimerism protocols have been opened to multiple sites to increase the referral base and 
accrual. Because of this expansion of collaborators, the data collection procedures are being revised. The 
procedure manual was created to assure consistency of data reporting across the centers and to assure 
compliance with regulations. General expectations of collaborators are that they will comply with 
appropriate regulatory requirements, specified protocol requirements, and provide outcome data. 
 
The manual translates working procedures for study coordination. Its goal is to describe the procedures 
with sufficient clarity to ensure that all study centers will use the same procedures and follow-up 
schedules for participant data management and reporting. Changes to the manual and relevant forms will 
be made as soon as practical and will become effective on receipt of the revised procedures at the study 
centers, unless otherwise noticed. 
 
II. Institutional Review Board Review of Protocols and Modifications 
All research protocols proposed for use that involves human subjects must be reviewed and approved by 
the Institutional Review Board (IRB) prior to implementation. New protocols will undergo review at the 
FHCRC IRB and then will be distributed to sites that wish to participate for their IRB’s review. For Centers 
that have a Federal Wide Assurance (FWA), formal collaboration includes submission of a form 310 and a 
copy of the IRB approved protocol and consent forms to the FHCRC.  For sites without a FWA, an FWA 
form needs to be filed. Once the paperwork is submitted to the Office for Human Research Protection, the 
approval process can take up to a couple of months, and must be completed before collaboration on a 
protocol can begin. 
 
In addition, all amendments and/or revisions to on-going, approved activities must be submitted for review 
and approved prior to implementation at an institution.  No revisions may be implemented at outside 
institutions without the prior approval of the FHCRC Principal Investigator.   The FHCRC and the local 
site’s IRB must review all protocol activities at least once annually. This must be done within 365 days of 
the last review. A copy of annual renewal approvals must be received for collaboration to continue for the 
next year. 
 
III. Registrations 
Collaborating Institutions: The principal investigator of the collaborating institution who will register the 
patient with the FHCRC will identify eligible patients. Registration will include completion of the eligibility 
checklist/demographic form. This form will be faxed (206-667-5378) prior to treatment initiation. Patients 
should be registered prior to treatment initiation for valid registration 
 
IV. Reporting Adverse Events 
The following guidelines are the minimum serious adverse event (SAE) reporting guidelines for Category 
1 and 2 studies conducted at the Fred Hutchinson Cancer Research Center.   
 
Expedited Reporting Requirements  
All adverse events (whether occurring on-site or off-site), which in the opinion of the 
principal investigator are (1) unexpected, and (2) related or possibly related to the 
research and (3) serious or suggests that the research places research participants or 
others at a greater risk of physical or psychological harm than was previously known or 
recognized must be submitted to the IRB within ten (10) calendar days of becoming 
aware of the event. 
 
 
 


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Definitions 
 
An Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, medical treatment or procedure and which does not necessarily 
have to have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, medical treatment or procedure 
whether or not considered related to the medicinal product.  
 
Related or Possibly Related Adverse Event:  An adverse event is “related or possibly related to 
the research procedure” if in the opinion of the principal investigator, it was more likely than not caused by 
the research procedures. Adverse events that are solely caused by an underlying disease, disorder or 
condition of the subject or by other circumstances unrelated to either the research or any underlying 
disease, disorder or condition of the subject are not “related or possibly related.” If there is any question 
whether or not an adverse event is related or possibly related, the adverse event should be reported.  
 
Serious Adverse Event: An adverse event that results in any of the following outcomes:  
▪ 
death  
▪ 
a life-threatening adverse event (real risk of dying) 
▪ 
unplanned inpatient hospitalization or prolongation of existing hospitalization 
▪ 
a persistent or significant disability/incapacity/or change in psychosocial status 
▪ 
a congenital anomaly 
▪ 
requires intervention to prevent permanent impairment of damage 
 
o 
Life-threatening AE is defined as any adverse event that places the patient or subject, in view 
of the investigator, at immediate risk of death from the reaction.  
 
Unexpected Adverse Event: An adverse event is “unexpected” when its nature (specificity), severity, 
or frequency are not consistent with (a) the known or foreseeable risk of adverse events associated with 
the research procedures described in the protocol-related documents, such as the IRB-approved 
research protocol, informed consent document and other relevant sources of information such as product 
labeling and package inserts; and are also not consistent with (b) the characteristics of the subject 
population being studied including the expected natural progression of any underlying disease, disorder 
or condition or any predisposing risk factor profile for the adverse event.  
 
To ensure no confusion or misunderstanding exist of the differences between the terms “serious” and 
“severe,” which are not synonymous the following note of clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) or a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious,” which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life 
or functioning.  Seriousness (not severity) serves as a guide for defining regulatory obligations. 
 
For example, hospitalization, in general, will not be considered a serious adverse event as approximately 
half of evaluable MRD patients AND the majority of evaluable URD patients receiving non-myeloablative 
transplants were hospitalized.  Hospitalization will be considered a serious adverse event if it fulfills the 
criteria for a serious and unexpected adverse event as described above. 
 
Serious events, including deaths, due to GVHD and/or infections will not be reported on an expedited 
basis.  These are well documented, expected, post transplant complications and will be reported 
biannually to the DSMB. 
 


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FHCRC is acting as the Coordinating Center for this multi-institutional study, and it is the responsibility of 
the FHCRC Principal Investigator (or designee) to complete the FHCRC Serious Adverse Event Report 
for all serious adverse events that meet the expedited reporting requirements that are received from the 
participating sites. It is the responsibility of the FHCRC Principal Investigator to notify the sponsor, NIH, 
FDA or other agencies of serious adverse events as required in the protocol. 
 
Procedure for Reporting Serious and Unexpected Adverse Events (SAE) from 
Participating Sites: Regulations defining the responsibilities for reporting serious and unexpected 
adverse reactions are defined above.  
 
Donor: SAEs or any death regardless of cause (serious, unexpected, and related/possibly related) will 
be monitored and recorded from the time the donor starts atorvastatin therapy through 7 days after the 
discontinuation of the medication. These must be reported to the FHCRC Investigator within 10 days of 
learning of the event. 
 
Recipient: SAEs (life-threatening or fatal)  
• 
For 2546 as an adjunct to treatment plan or primary protocol, SAEs or any death 
regardless of cause (serious, unexpected, and related/possibly related) will be monitored and 
recorded from the time the recipient starts conditioning therapy through day 100 or discharge 
from the center, whichever occurs earlier. These must be reported to the FHCRC Investigator 
within 10 days of learning of the event. 
• 
For 2546 as an adjunct to a nonmyeloablative investigational protocol, follow 
reporting guidelines of nonmyeloablative investigational protocol.  
 
The immediate telephone report must be followed by faxed comments to the FHCRC Trial Coordinator at 
(206) 667-5378. This will be followed by detailed written report (See Appendix G) within 10 working days.  
The report must include the date and time of onset, severity and duration of the event, the relationship to 
the study, the treatment given and eventual outcome.  Follow-up information to a SAE report must be 
submitted as soon as the relevant information is available.  
 
 
Reporting of Adverse Events on Case Report Forms (CRF)  
All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur between start of 
conditioning and day 100 during the study will be recorded on the CRF.  These adverse events which are 
observed by the Investigator or reported by the patient, whether or not attributed to the study, will be 
reported on the Case Report Form using the selected (for this protocol) NCI Common Toxicity Criteria 
(NCI-CTC) version 4 (Appendix J). Attributes will include a description, date of onset, maximum severity, 
and assessment of relationship to the study agent or other suspect agent(s). These grade 3 or 4 adverse 
events will be reported to the DSMB as part of the biannual review of the protocol. The DSMB report is 
submitted with the annual IRB renewal. 
 
For 2546 adjunct to a treatment plan (FHCRC or Outside Center) 
Only SAEs (life-threatening or fatal) will be captured on SAE form (Appendix G). No other grade 3 or 4 
Adverse Events will be captured. 
 
Reporting of Unanticipated Problems that Involve Risk to Research Participants or 
Others: Any incident, experience, or outcome that meets both of the following criteria:  
• 
Unexpected (in terms of nature [specificity], severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 


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• 
Indicates that the research places research participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
These must be reported to the FHCRC Investigator within 10 days of learning of the event as described 
above for reporting of SAE. 
 
V. Case Report Forms 
 
Donor CRFs – safety evaluations at three timepoints (CRFs to be provided to external sites) 
(Appendix M) 
• 
Prior to start of statins 
• 
First day of collection 
• 
7 days post collection 
 
Recipient CRFs  
 
For 2546 as an adjunct to treatment plan or primary protocol  
• 
Acute GVHD grading form at approximately Day 100 (Appendix D) 
• 
Patient status on an ongoing basis 
 
For 2546 as an adjunct to a nonmyeloblative investigational protocol 
• 
Follow CRF guidelines and instructions of nonmyeloblative investigational protocol. 
 
VI. Protocol Monitoring 
The guidelines below are intended to guide the reviewers in their assessment of items that significantly 
alter the clinical effectiveness of the treatment or the evaluation of its toxicity. 
 
A. 
Registration/Randomization 
1. Patient was registered prior to treatment and approval by FHCRC PI occurs prior to 
randomization.  
2. Information given at registration represents actual data in medical records (stage, diagnosis, cell 
type, etc.) 
 
B. 
Informed Consent/IRB Approval Dates 
1. The consent was signed prior to registration 
2. The consent is in language was approved by the IRB. IRB approval and reapproval are 
documented including appropriate use of full-board review and proper review of appropriate 
amendments or revisions 
3. Consent was dated and has written witness signature. IRB approval was obtained prior to the 
patient signing the consent form and start of treatment. 
 
C. 
Patient Eligibility 
1. Eligibility criteria and exclusion criteria were met 
2. Treatment/Intervention Administration 
3. Doses were modified according to protocol 
4. Accurate documentation of drug administration 
 
D. 
Study Tests/Evaluation 
1. Protocol specified laboratory tests or diagnostic studies are available 
2. Appropriate record of protocol intervention is documented. 
 
E. 
Study Events/Adverse Drug Experience 
1. Serious Adverse Evens reported according to protocol specifications 


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F. 
Follow-Up 
1. 
Disease status assessed according to the required protocol guidelines documenting response to 
treatment. 
2. 
Accurate determination of cancer progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G 
Serious Adverse Event Report 
Protocol 2546 
 
 
1. Patient’s Name:   
 
2. Date of Serious Adverse Event:   
 
 
3. Nature of Serious Adverse Event:   
 
4. Reasons for AE classification as serious: (mark all that apply) 
 
   Death 
 
   Urgent medical intervention to prevent death or  
   New hospitalization 
 
        disability 
 
   Prolongation of current hospitalization 
 
   New persistent or exacerbation of significant  
 
 
 
 
          disability or incapacity 
 
 
 
 
 
5. Specify any agent(s) suspected of causing adverse event: 
 
#1    
 
                                 
6. Describe the Serious Adverse Event (or attach a copy of relevant medical records or FDA MedWatch 
Form). 
 
7. Signature of Reporter ______________________________________________/___/________ 
 
 
 
 
 
 
 
   Date 
8. PI assessment 
 
Adverse event possibly, probably or definitely related to investigational agent(s)?  ○No   ○Yes  
Adverse event    ○expected   ○unexpected (not listed in protocol, consent, product label or drug 
brochure) 
Expedited report to FHCRC IRB is needed if serious adverse event is unexpected and related to 
investigational agent. 
 
9. Signature of P.I. ______________________________________________/___/____________ 
 
 
                                                                               Date 
 
 
 


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APPENDIX H 
Notice of Death 
 
 
Patient ID:  __________________ 
Date of Death:  ______________ 
 
Place of Event:  ___________________________________________    
 
 
Apparent cause of death (Please be specific.  Attach hospital summary or death summary when 
possible): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Form completed by:  ________________________________Date:   ______________ 
 
 
 
 
 
 


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APPENDIX I 
 
COORDINATING CENTER FUNCTIONS 
 
Outside Center – PI Communication in Hematologic Malignancies 
 
I. 
Study Management, data analysis, and Data and Safety Monitoring 
 
a. Study Management: 
i. 
Each local PI is responsible for selection, training and oversight of local study 
coordinators 
ii. 
The Coordinating Center registers subjects on the study and assigns study IDs 
iii. 
One copy of the research data is retained by the site. Another data set (identified 
only by study IDs) is transmitted to the Coordinating Center to create the master data 
file. All data are kept in locked areas and password protected databases accessible 
only to study staff 
iv. 
The quality of data is monitored in an ongoing fashion with the study team and 
corrective action plans instituted as necessary  
b. Data Analysis: 
i. 
Study staff review data for completeness as it is submitted by the sites 
ii. 
The study statistician is responsible for data cleaning and the conduct of analyses as 
outlined in the protocol and grant 
c. Data Safety and Monitoring: 
i. 
The trial coordinators at collaborating centers or the local PIs will fax an official report 
of an SAE (as defined by the protocol) to the Coordinating Center within ten days. 
ii. 
The SAE report is reviewed by the Overall PI. If the SAE meets the FHCRC criteria 
for reporting then an official signed report is submitted to the IRB 
iii. 
An independent DSMB will meet at six-month intervals and all outcome data is 
reviewed including all adverse events and SAEs reported to the Coordinating Center 
along with those officially reported to the IRB 
iv. 
A report from the DSMB is submitted to the IRB as well as the trial coordinators/local 
PIs participating in the protocol 
 
II.  
Protocol and informed consent document management 
a. A master protocol is maintained by the Coordinating Center and distributed to the sites for 
customization and local IRB review 
b. All protocol and consent modifications initiated by the Coordinating Center are sent to the 
Collaborating Sites following approval by the Coordinating Center IRB, for review and 
approval by the local IRB 
c. Changes required by local IRBs are reviewed by the Coordinating Center and approved 
prior to implementation at local sites 
 
III. 
Assurance of local IRB OHRP-approved assurance 
a. Each site provides their OHRP assurance number and evidence of IRB certification 
b. Study staff monitor maintenance of institutional assurance and IRB certification 
 
 
IV. 
Assurance of local IRB approvals 
a. The Coordinating Center maintains copies of the most current collaborating site Consent 
Forms and IRB approval documentation 
b. No site may enroll subjects until the Coordinating Center has received confirmation of local 
IRB approval 
c. Each site is responsible for preparation and submission of their continuing reviews. Any 
changes to the protocol or consent form will be communicated to the Coordinating Center 


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d. Sites are required to have active IRB approvals to participate in any study related activities 
 
V. 
Any substantive modification by the Collaborating Institution related to risks or alternative 
procedures is appropriately justified 
a.   The Coordinating Center reviews any modifications to consent forms to ensure that site 
consents do not delete or change the basic or additional elements or alternatives required 
in the sample consent form 
 
VI. 
Informed consent is obtained from each subject in compliance with HHS regulations 
a. Subjects must provide written informed consent prior to study participation 
b. The Coordinating Center verifies eligibility and signed consent prior to assigning a study ID 
number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX J 
Adapted from 
COMMON TOXICITY CRITERIA (CTC)  
Version 4.0 
 
 
Grade 
Adverse Event 
3 
4 
5 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Disseminated intravascular 
coagulation 
Laboratory findings and 
bleeding 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Febrile neutropenia 
ANC <1000/mm3 with a 
single temperature of 
>38.3 degrees C (101 
degrees F) or a sustained 
temperature of >=38 
degrees C (100.4 degrees 
F) for more than one hour 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hemolysis 
Transfusion or medical 
intervention indicated 
(e.g., steroids) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hemolytic uremic syndrome 
Laboratory findings with 
clinical consequences (e.g., 
renal insufficiency, 
petechiae) 
Life-threatening 
consequences, (e.g., CNS 
hemorrhage or 
thrombosis/embolism or 
renal failure) 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
CARDIAC DISORDERS 
 
Atrial fibrillation 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker), or ablation 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Atrial flutter 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker), or ablation 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Atrioventricular block 
complete 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Constrictive pericarditis 
Symptomatic heart failure 
or other cardiac symptoms, 
responsive to intervention 
Refractory heart failure or 
other poorly controlled 
cardiac symptoms 
Death 


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Heart failure 
Severe with symptoms at 
rest or with minimal 
activity or exertion; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
Death 
Left ventricular systolic 
dysfunction 
Symptomatic due to drop 
in ejection fraction 
responsive to intervention 
Refractory or poorly 
controlled heart failure due 
to drop in ejection fraction; 
intervention such as 
ventricular assist device, 
intravenous vasopressor 
support, or heart transplant 
indicated 
Death 
Myocardial infarction 
Severe symptoms; cardiac 
enzymes abnormal; 
hemodynamically stable; 
ECG changes consistent 
with infarction 
Life-threatening 
consequences; 
hemodynamically unstable 
Death 
Myocarditis 
Severe with symptoms at 
rest or with minimal 
activity or exertion; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
Death 
Pericardial effusion 
Effusion with physiologic 
consequences 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Pericardial tamponade 
 - 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Ventricular arrhythmia 
Medical intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic compromise; 
urgent intervention 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
GASTROINTESTICAL DISORDERS 
 
Ascites 
Severe symptoms; invasive 
intervention indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Diarrhea 
Increase of >=7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 


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Duodenal ulcer 
Severely altered GI 
function; TPN indicated; 
elective operative or 
endoscopic intervention 
indicated; limiting self care 
ADL; disabling 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Gastric ulcer 
Severely altered GI 
function; TPN indicated; 
elective operative or 
endoscopic intervention 
indicated; limiting self care 
ADL; disabling 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Gastritis 
Severely altered eating or 
gastric function; TPN or 
hospitalization indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Lower gastrointestinal 
hemorrhage 
Transfusion, radiologic, 
endoscopic, or elective 
operative intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Mucositis oral 
Severe pain; interfering 
with oral intake 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Oral hemorrhage 
Transfusion, radiologic, 
endoscopic, or elective 
operative intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Pancreatitis 
Severe pain; vomiting; 
medical intervention 
indicated (e.g., analgesia, 
nutritional support) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Typhlitis 
Symptomatic (e.g., 
abdominal pain, fever, 
change in bowel habits 
with ileus); peritoneal 
signs 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
GENERAL DISORDERS AND ADMINISTARTION SITE CONDITIONS 
 
Multi-organ failure 
Shock with azotemia and 
acid-base disturbances; 
significant coagulation 
abnormalities 
Life-threatening 
consequences (e.g., 
vasopressor dependent and 
oliguric or anuric or 
ischemic colitis or lactic 
acidosis) 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
HEPATOBILIARY DISORDERS 
 


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Cholecystitis 
Severe symptoms; 
radiologic, endoscopic or 
elective operative 
intervention indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Immune system disorders - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
INFECTIONS AND INFESTATIONS 
 
Enterocolitis infectious 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; radiologic, 
endoscopic, or operative 
intervention indicated; 
profuse watery diarrhea 
with signs of hypovolemia;  
bloody diarrhea; fever; 
severe abdominal pain; 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Infections and infestations - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling; limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 


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INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 
Aspartate aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 
Blood bilirubin increased 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
 - 
Carbon monoxide diffusing 
capacity decreased 
Asymptomatic decrease  of 
>8 units drop;  >5 units 
drop along with the 
presence of pulmonary 
symptoms (e.g. , >Grade 2  
hypoxia or >Grade 2 or 
higher dyspnea) 
 - 
 - 
Cardiac troponin I increased 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
 - 
 - 
Cardiac troponin T 
increased 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
 - 
 - 
Creatinine increased 
>3.0 baseline; >3.0 - 6.0 x 
ULN 
>6.0 x ULN 
 - 
Weight gain 
>=20% from baseline 
 - 
 - 
Grade 
Adverse Event 
3 
4 
5 
 
METABOLISM AND NUTRITIONAL DISORDERS 
 
Hypercalcemia 
Corrected serum calcium 
of >12.5 - 13.5 mg/dL;>3.1 
- 3.4 mmol/L;  Ionized 
calcium  >1.6 - 1.8 
mmol/L; hospitalization 
indicated 
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L;  
Ionized calcium  >1.8 
mmol/L; life-threatening 
consequences 
Death 
Hypertriglyceridemia 
>500 mg/dL - 1000 mg/dL;  
>5.7 mmol/L - 11.4 
mmol/L 
>1000 mg/dL; >11.4 
mmol/L;  life-threatening 
consequences 
Death 
Hyperuricemia 
>ULN - 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
>10 mg/dL; >0.59 mmol/L; 
life-threatening 
consequences 
Death 
Tumor lysis syndrome 
Present 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INC CYSTS AND POLYPS) 
 
Treatment related secondary 
malignancy 
Non life-threatening 
secondary malignancy 
Acute life-threatening 
secondary malignancy; blast 
crisis in leukemia 
Death 
Grade 


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Adverse Event 
3 
4 
5 
 
NERVOUS SYSTEM DISORDERS 
 
Dysarthria 
Severe impairment of 
articulation or slurred 
speech 
 - 
 - 
Intracranial hemorrhage 
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Ischemia cerebrovascular 
 - 
 - 
 - 
Leukoencephalopathy 
Severe symptoms; 
extensive T2/FLAIR 
hyperintensities, involving 
periventricular white 
matter involving 2/3 or 
more of susceptible areas 
of cerebrum +/- moderate 
to severe increase in SAS 
and/or moderate to severe 
ventriculomegaly 
Life-threatening 
consequences; extensive 
T2/FLAIR hyperintensities, 
involving periventricular 
white matter involving most 
of susceptible areas of 
cerebrum +/- moderate to 
severe increase in SAS 
and/or moderate to severe 
ventriculomegaly 
Death 
Seizure 
Multiple seizures despite 
medical intervention 
Life-threatening; prolonged 
repetitive seizures 
Death 
Syncope 
Fainting; orthostatic 
collapse 
 - 
 - 
Nervous system disorders - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
RENAL AND URINARY DISORDERS 
 
Chronic kidney disease 
eGFR or CrCl 29 - 15 
ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2; dialysis or 
renal transplant indicated 
Death 
Renal and urinary disorders 
- Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 


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REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
Grade 
Adverse Event 
3 
4 
5 
 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
 
Adult respiratory distress 
syndrome 
Present with radiologic 
findings; intubation not 
indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Apnea 
Present; medical 
intervention indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Bronchopulmonary 
hemorrhage 
Transfusion, radiologic, 
endoscopic, or operative 
intervention indicated 
(e.g., hemostasis of 
bleeding site) 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Hypoxia 
Decreased oxygen 
saturation at rest (e.g., 
pulse oximeter <88% or 
PaO2 <=55 mm Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Death 
Pleural effusion 
Symptomatic with 
respiratory distress and 
hypoxia; surgical 
intervention including 
chest tube or pleurodesis 
indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Pneumonitis 
Severe symptoms; limiting 
self care ADL; oxygen 
indicated 
Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Death 
Pulmonary edema 
Severe dyspnea or dyspnea 
at rest; oxygen indicated; 
limiting self care ADL 
Life-threatening respiratory 
compromise; urgent 
intervention or intubation 
with ventilatory support 
indicated 
Death 
Respiratory failure 
 - 
Life-threatening 
consequences; urgent 
intervention, intubation, or 
ventilatory support 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 


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Erythema multiforme 
Target lesions covering 
>30% BSA and associated 
with oral or genital 
erosions 
Target lesions covering 
>30% BSA; associated with 
fluid or electrolyte 
abnormalities; ICU care or 
burn unit indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
VASCULAR DISORDERS 
 
Capillary leak syndrome 
Severe symptoms; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hypotension 
Medical intervention or 
hospitalization indicated 
Life-threatening and urgent 
intervention indicated 
Death 
Thromboembolic event 
Thrombosis (e.g., 
uncomplicated pulmonary 
embolism [venous], non-
embolic cardiac mural 
[arterial] thrombus), 
medical intervention 
indicated 
Life-threatening (e.g., 
pulmonary embolism, 
cerebrovascular event, 
arterial insufficiency); 
hemodynamic or neurologic 
instability; urgent 
intervention indicated 
Death 
Vasculitis 
Severe symptoms, medical 
intervention indicated 
(e.g., steroids) 
Life-threatening; evidence 
of peripheral or visceral 
ischemia; urgent 
intervention indicated 
Death 
 
 
 
 
 


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APPENDIX K 
Protocol 2546 Patient Demographics and Eligibility Form 
 
 
UPN#:____________________ 
Patient Name: 
_______________________________ 
(Last) 
________________________ 
(First) 
_____  
(MI) 
Date of 
Birth: 
_____ / _____ / __________  Age:________ 
 (Mo)    (Day)         (Year) 
Gender (choose one): 
 Male    
 Female   
 Unknown 
Patient Diagnosis: 
______________________________________   
Planned Day 0: _____/______/_____ 
 
(Mo) 
(Day)  (Year) 
Ethnicity (choose one):  Instruct the patient to select one of the following. 
 Hispanic (A person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race.  Term “Spanish Origin” can also be used in 
addition to “Hispanic” or “Latino”.) 
 Not Hispanic or Latino 
 
 Declined to Report 
Race (check all that apply):  Instruct the patient to select one or more of the following. 
 American Indian/Alaska Native (A person having origins in any of the original peoples of 
North, Central, or South America, and who maintains tribal affiliations or community 
attachment). 
 Asian (A person having origins in any of the original peoples of the Far East, Southeast, 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam). 
       
   Black/African American (A person having origins in any of the black racial groups of 
               Africa).      
 Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of 
Hawaii, Guam, Samoa or other Pacific Islands). 
 White (A person having origins in any of the original peoples of Europe, the Middle East or 
North Africa). 
 Research subject does not know race 
 Declined to report 
 
 
 
The PI confirmed that patient should receive Fludarabine and TBI (If no autologous 
transplant within 6 months or equivalent high-dose therapy without HCT). 
 
Yes        No       Date:    ____________  PI Initials: _____ 
 


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CRITERIA FOR 3 GY TBI (only for patients in Regimen A, Flu/TBI): Patients need to fulfill 
one or more of the following criteria for 3 Gy TBI: 
 
 Patients with MDS, MPD, CML, or other hematologic malignancies not previously 
treated with myelosuppressive chemotherapy 
Patients who have had a previous allogeneic transplant. 
Patients who had a prior syngeneic transplant without subsequent myelosuppressive 
chemotherapy. 
 Patients who have not had myelosuppressive chemotherapy within 3-6 months of 
HCT may be at higher risk of rejection depending on treatment history and underlying 
diagnosis. Confirm TBI dose (2 vs 3 Gy) with PI. 
 
CRITERIA FOR 4 Gy TBI: 
 For outside centers only, 4 Gy TBI may be used when the protocol serves as adjunct 
to a reduced intensity treatment plan that includes 4 Gy TBI. 
 
 
TBI Dose: 
 TBI 2 Gy          
 
OR 
 TBI 3 Gy: 
  
      OR    
 TBI 4 Gy: 
 
 
Signature of Local Principal Investigator:                                                                Date:           
  
   
Transplant Center:  ___________________________________________________________ 
 
Signature of FHCRC Principal Investigator:                                                              Date:  
 
   
      
Study UPN#: _____________________________ 
 
 
 


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APPENDIX K cont’d 
 
Protocol 2546 Eligibility  
 
  2546 is being used as an adjunct Protocol. Patient is enrolled on an investigational 
nonmyeloablative HCT protocol or a nonmyeloablative treatment plan with postgrafting 
CSP that does not use acute GVHD as its primary endpoint. 
• Must meet following inclusion criteria 1 ONLY 
• Must meet following exclusion criteria 16-18 ONLY 
 
OR 
 
  Protocol 2546 serves as an independent primary treatment protocol 
• Must meet all following inclusion and exclusion criteria 
 
Inclusion Criteria:  
 
 
1) Yes 
 No 
 
HLA-identical sibling donor:       
 
Patient 
 
 
 
 
 
A: ________ 
A:_________ 
C: _________ 
C: _________ 
B: _________ 
B: _________ 
DRB1:  _______ DRB1:_______ DQB1:_______ DQB1:_______  
 
Donor 
 
 
 
 
 
A: _________ 
A:_________ 
C: _________ 
C: _________ 
B: _________ 
B: _________ 
DRB1:  _______ DRB1:_______ DQB1:_______ DQB1:_______  
 
 
 
2) Yes 
 No 
  N/A 
  
All children < 12 years must be discussed with the FHCRC PI 
(Marco Mielcarek, MD 206-667-2827) and by a relevant patient 
review committee, such as the FHCRC Patient Care Conference 
(PCC) prior to registration.  
 
3) Yes 
 No 
  
 
Patients must have either relapsed after previous high-dose 
chemotherapy and autologous or allogeneic HCT, or else be 
ineligible for such an approach due to age, failure to mobilize 
sufficient hematopoietic stem cells, medical comorbidities, or 
patient refusal  
 
4) Yes 
 No 
 
Patients who refuse to be treated on a conventional autologous or 
allogeneic HCT protocol. 
 
 
 
 
I) One of the following criteria questions (5-15) must be marked “Yes” for the patient to enter 
on 2546. (The following diseases will be permitted although other diagnoses can be 


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considered if approved by PCC or the participating institution’s patient review committees 
and the principal investigator.) 
 
5) Yes 
 No 
 
Aggressive non-Hodgkin lymphomas (NHL) and other histologies 
such as diffuse large B-cell NHL – not eligible for autologous HCT, not 
eligible for high-dose allogeneic HCT, or after failed autologous HCT. 
 
6) Yes 
 No 
  
Mantle Cell NHL - Diagnostic LP required pre-transplant 
 
7) Yes 
 No 
  
Low grade NHL– with < 6 month duration of CR between courses of 
conventional therapy. 
 
8 Yes 
 No 
 
 
CLL – must have either 1) failed to meet NCI Working Group criteria or 
partial response after therapy with a regimen containing FLU (or another 
nucleoside analog,) or experience disease relapse within 12 months after 
completing therapy with a regimen containing FLU (or another nucleoside 
analog); 2) failed FLU-CY-Rituximab (FCR) combination chemotherapy at 
any time point; or 3) have “17p deletion” cytogenetic abnormality. Patients 
should have received induction chemotherapy but could be transplanted 
in 1st CR; or 4) Patients with a diagnosis of CLL (or small lymphocytic 
lymphoma) that progresses to prolymphocytic leukemia (PLL), or patients 
with T-cell CLL or PLL 
 
 
 
 
 
 
Describe which inclusion is specific for this 
patient:__________________________________________________________                 
                    
9) Yes 
 No 
  
Hodgkin lymphoma – must have received and failed frontline therapy. 
 
 
10) Yes 
 No 
  
Multiple Myeloma – must have received prior chemotherapy.  
Consolidation of chemotherapy by autografting prior to nonmyeloablative 
HCT is permitted. 
 
11) Yes 
 No 
 
Acute Myeloid Leukemia (AML) – must have < 5% marrow blasts at the 
time of transplant. 
 
12) Yes 
 No 
 
Acute Lymphocytic Leukemia (ALL) – must have <5% marrow blasts at 
the time of transplant. 
 
13) Yes 
 No 
  
Chronic Myeloid Leukemia (CML) – Patients will be accepted if they 
have shown intolerance to tyrosine kinase inhibitors or are beyond CP1 
and if they have received previous myelosuppressive chemotherapy or 
HCT, and have <5% marrow blasts at time of transplant.   
 
14) Yes 
 No 
 
Myelodysplasia (MDS)/Myeloproliferative Syndrome (MPS) –must  
 
 
 
have <5% marrow blasts at time of transplant.  
 
15) Yes 
 No 
      Waldenstrom’s Macroglobulinemia – must have failed 2 courses of 
therapy. 
 
 


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II) 
Exclusion criteria:  
Each of the following questions must be marked “No” Or “NA” for the patient to enroll on 2546. 
 
16) Yes 
 No 
  
Patient will undergo a myeloablative preparative regimen. 
 
17) Yes 
 No 
   Patient is participating in an investigational study that has acute GVHD as 
the primary endpoint  
 
18) Yes 
 No 
   The allogeneic PBSC donor has a contraindication to statin treatment. 
 
19) Yes 
 No 
    Patients eligible for and willing to receive potentially curative high  
 
 
 
 
 
dose chemotherapy and autologous HCT 
 
20) Yes 
 No 
     Organ dysfunction. Please check yes if patient meets any of the 
following. 
  
 
 
 
  
 
Yes 
 No 
 
Cardiac: ejection fraction < 30% on MUGA 
scan or cardio echo or active symptomatic 
coronary artery disease.  Patients with cardiac 
disease should be evaluated with appropriate 
cardiac studies and/or cardiology consultation 
as clinically indicated.   
 
  
 
 
 
  
 
Yes 
 No 
 
Pulmonary: DLCO < 40%, TLC <30%, FEV1 
<30% and/or receiving supplementary 
continuous oxygen.  
 
 
 
 
Yes 
 No 
 
Liver function abnormalities:  Patients with 
clinical or laboratory evidence of liver disease 
should be evaluated in conjunction with the GI 
consult service for the cause of liver disease, its 
clinical severity, and the degree of portal 
hypertension.  Patients will be excluded if they 
are found to have fulminant liver failure, 
cirrhosis of the liver with evidence of portal 
hypertension, bridging fibrosis, alcoholic 
hepatitis, esophageal varices, a history of 
bleeding esophageal varices, hepatic 
encephalopathy, refractory ascites related to 
portal hypertension, bacterial or fungal liver 
abscess, chronic viral hepatitis with total serum 
bilirubin >3 mg/dL, or actively symptomatic 
biliary disease.  
 
 
 
 
Yes 
 No 
     Renal: Patients with renal failure are eligible. 
However, patients with pre-existing renal 
insufficiency will likely have further compromise 
in renal function and may require dialysis. 
 
21) Yes 
 No 
              Patients who are seropositive for human immunodeficiency  
 
 
 
       virus (HIV). 
 


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22) Yes 
 No 
 N/A  
 
Women who are pregnant or breast-feeding. 
 
 
23) Yes 
 No 
 N/A  
 
Fertile men or women unwilling to use contraception during HCT 
 
and for 12 months afterward 
. 
24) Yes 
 No 
        Patients with active non-hematological malignancies (except non-
melanoma skin cancers) or those with non-hematological malignancies 
(except non-melanoma skin cancers) who have been rendered with no 
evidence of disease, but have a greater than 20% chance of having 
disease recurrence within 5 years. This exclusion does not apply to 
patients with non-hematologic malignancies that do not require therapy.  
 
25) Yes 
 No 
 
Karnofsky score <60 for adult patients or Lansky-Play Performance Score 
<50 for pediatric patients. 
 
26) Yes 
 No 
 
Patients with fungal pneumonia with radiological progression after receipt 
of amphotericin formulation or mold-active azoles for greater than 1 
month 
 
Note – the HCT-Comorbidity score is:  _______________ 
 
 
 
 FHCRC Patients:  
Signature of person completing form:   
 
 
                                       Date: 
  
 
Signature of Principal Investigator (signing of consent):  
 
 
                Date:            
 
Patient signed IRB approved consent form.  Date:    
 
 
 
 
 
 
IRB file number:   
 
 
 
      
               Date of IRB approval:  
 
 
 
OR 
 
Outside Center Patients:  
 
Signature of person completing form:  
 
 
 
 
 
   Date:  
 
 
Patient signed IRB approved consent form.    Date:  
 
 
 
 
 
IRB file number:                    
 
 
 
     Date of IRB approval:  
 
 
 
Signature of Local Principal Investigator   
 
 
 
 
 
Date:  
 
 
Signature of FHCRC Principal Investigator    
 
 
 
            Date:  
 
 
 
 
 


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APPENDIX L 
2546 Case Report Form 
 
 
2546 CRF v.1.0.pdf
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX M 
 
Protocol 2546 Donor Safety and Compliance Evaluation 
 
Date:  _______________     
 
 
Donor:  __________________________ 
Contact:  phone    in-person 
 
Patient: ________________________ 
 
Time point:  
___ 1 week post start of atorvastatin 
 
 
___ PBSC collection  
 
___ 1 week post collection/discharge 
 
Start date of atorvastatin: __________ 
 
Last dose (date):  ___________ 
 
 
 
 
 
 
Total number of doses taken: ________ 
Safety 
 
Since the start of atrovastatin therapy have you experienced any of the following symptoms: 
      Y    N 
  muscle pain or tenderness     Location:  _____________________________ 
  muscle weakness     Location:  ____________________________________ 
  joint pain     Location:  __________________________________________ 
  diarrhea 
  gas or heartburn 
  nausea 
  other     Describe:  ______________________________________________ 
 
Action/comments: 
 
 
 
Labs 
 
 
 
 
Comments: 
Labs 
Pre 
Post 
Date 
 
 
CK 
 
 
T Bili 
 
 
D Bili 
 
 
ALT 
 
 
AST 
 
 
Alk 
Phos 
 
 
Albumin 
 
 
 
Compliance 
Since the last contact, have you missed any doses of atorvastatin? 
Yes 
No 
If yes, how many doses have been missed?  __________________ 
 
Comments: 
 
 
   
Signature 
 
 
 
 
 
Date 
 
 


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APPENDIX N 
(Not required when 2546 is being used as an adjunct Protocol) 
The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 9/7/10 
Assign scores appropriately if the patient has any of these comorbidities 
  
Patient ____________________________(name),   UPN______________ Date_____________ 
 
 
Comorbidities 
Definitions 
HCT-CI 
scores 
Actual Lab 
Values/Comments 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, and 
ventricular arrhythmias requiring treatment in the patient’s 
past history 
1 
 
Cardiac 
Coronary artery disease†, congestive heart failure, 
myocardial infarction in patient’s past history or EF of 
50% at time of HCT 
1 
 
Inflammatory bowel 
disease 
Crohn’s disease or ulcerative colitis requiring treatment in 
the patient’s past history 
1 
 
Diabetes 
Requiring treatment with insulin or oral hypoglycemic, but 
not diet alone, at time of HCT 
1 
 
Cerebro-vascular 
disease 
Transient ischemic attack or cerebro-vascular accident in 
patient’s past history 
1 
 
Psychiatric 
disturbance 
Depression/anxiety requiring psychiatric consult or 
treatment at time of HCT 
1 
 
Hepatic – mild 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN at time of HCT 
1 
 
Obesity 
Patients with a BMI of 
>35 for adults or with BMI-for-age percentile of ≥ 95th 
percentile for children at time of HCT 
1 
 
Infection 
Documented infection or fever of unknown etiology 
requiring anti-microbial treatment before, during and after 
the start of conditioning regimen 
1 
 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica in patient’s past history  
2 
 
Peptic ulcer 
Requiring treatment in patient’s past history 
2 
 
Renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation at time of HCT 
2 
 
Moderate pulmonary 
DLco and/or FEV1 >65%-80% or 
Dyspnea on slight activity at time of HCT 
2 
 
Prior solid tumor 
• 
Treated at any time point in the patient’s past 
history, excluding non-melanoma skin cancer 
3 
 
Heart valve disease 
At time of HCT excluding mitral valve prolapse 
3 
 
Severe pulmonary 
DLco and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen at time of HCT 
3 
 
Moderate/severe 
hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN at time of HCT 
3 
 
Please provide (KPS): 
 
Karnofsky Performance Score = _______% 
Total 
Score 
=________ 
Signature of 
Provider: 
________________ 
 


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†One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft. 
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid 
arthritis; CTD, connective tissue disease; DLco, diffusion capacity of carbon monoxide; FEV1, forced expiratory 
volume in one second; AST, aspartate aminotransferase; ALT, alanine aminotransferase.