Clinical trial NCT00104858
Conditions: Chronic Lymphocytic Leukemia Prolymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Stage III Chronic Lymphocytic Leukemia Stage III Small Lymphocytic Lymphoma Stage IV Chronic Lymphocytic Leukemia Stage IV Small Lymphocytic Lymphoma T-Cell Large Granular Lymphocyte Leukemia
Sponsor: Fred Hutchinson Cancer Center
Start date: 2004-12-01; Completion date: 2018-03-30
Enrollment: 66 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine whether nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation (HCT) improves survival at 18 months for patients with fludarabine (fludarabine phosphate)-refractory, fludarabine/cyclophosphamide/rituximab (FCR)-failed, or del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H (alemtuzumab).

SECONDARY OBJECTIVES:

I. Estimate the overall response rate (complete remission \[CR\] + partial remission \[PR\]) by standard morphologic, flow cytometric, and molecular techniques.

II. Assess the rate of relapse/progression.

III. Define incidences of regimen-related toxicities (RRT) and infections within the first 100 days and the incidence of transplant-related mortality (TRM) within the first year.

IV. Estimate incidences of grade II-III and III-IV acute graft-versus-host disease (GVHD) and chronic GVHD.

V. Determine whether the addition of rituximab to the nonmyeloablative conditioning and allogeneic HCT improves survival at 18 months over our historical data (57% at 18 months).

VI. Determine the incidence of serious adverse events with the addition of rituximab in comparison to historical data of unrelated nonmyeloablative HCT.

VII. Evaluate the pharmacokinetics of rituximab.

VIII. Evaluate B-cell and T-cell immune reconstitution in comparison to historical data of unrelated nonmyeloablative HCT.

IX. Describe donor and host polymorphisms of the FCgammaRIIIa receptor and cluster of differentiation (CD)32 and evaluate their impact on disease response and relapse.

X. Investigate the mechanism of disease resistance in relapsed/nonresponding patients.

XI. Isolate donor cytotoxic T lymphocytes specific for host minor histocompatibility antigens.

OUTLINE:

Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38.

Patients undergo single fraction low-dose total-body irradiation (TBI) on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. Patients then receive rituximab IV on days 10, 24, and 38.

Patients receive an immunosuppressive regimen comprising cyclosporine orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or three times daily (TID) on days 0-40 followed by a taper to day 96 (unrelated recipients).

After completion of study treatment, patients are followed up at 6 months, 1 year, 18 months, 2 years, and then annually thereafter.

Arms: arm 1: Patients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38.

Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38.

Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients).
Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Cyclosporine intervention 3: Fludarabine Phosphate intervention 4: Laboratory Biomarker Analysis intervention 5: Mycophenolate Mofetil intervention 6: Peripheral Blood Stem Cell Transplantation intervention 7: Pharmacological Study intervention 8: Rituximab intervention 9: Total-Body Irradiation
Intervention descriptions: intervention 1: Undergo HSCT intervention 2: Given PO intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given PO intervention 6: Undergo HSCT intervention 7: Correlative studies intervention 8: Given IV intervention 9: Undergo TBI

Protocol documents:
Prot_SAP_000.pdf: 
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FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
SEATTLE CHILDREN’S 
 
Current Version: 1/13/2016 
Previous Version: 12/25/2014 
 
Nonmyeloablative Conditioning with Pre- and Post-Transplant Rituximab followed by 
Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients with 
Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial 
 
Principal Investigators:  Fred Hutchinson Cancer Research Center 
Mohamed L. Sorror, MD 
Associate Member, FHCRC, Associate Professor of 
Medicine, UW 
667-2765 
David G. Maloney, MD 
Member, FHCRC, Professor of Medicine, UW,  
667-5616 
Brenda M. Sandmaier, MD 
Member, FHCRC, Professor of Medicine, UW,  
667-4961 
Stanley Riddell, MD 
Member, FHCRC, Professor of Medicine, UW 
667-5249 
Mary E.D. Flowers, MD 
Member, FHCRC, Professor of Medicine, UW 
667-5115 
Rainer Storb, MD 
Member, FHCRC, Professor of Medicine UW 
667-4407 
 
Statistician: 
 
Barry Storer, Ph.D., Affiliated Associate Professor of Biostatistics, UW, 
Member, FHCRC (667-6533). 
 
Research Nurse: 
Michelle Bouvier, RN (206) 667-6993, pager (206) 995-7658 
 
 
 
Emergency (24 hour) Phone: (206) 598-8902 Fax: (206) 598-4034 
 
Additional Performance Sites 
Investigators 
Emergency Phone Numbers 
Rigshospitalet                                  Niels Andersen, MD                    +45 35 45 1134 
City Hlth & Sci - Torino 
Benedetto Bruno, MD 
011-39-0339-1129064 
Veterans Affairs Puget Sound 
Health Care System 
Thomas Chauncey M.D., PhD 
 
(206) 762-1010 for the oncologist on-
call 
Mayo Clinic 
William Hogan, MD 
(507) 284-2511 
 
 
 
 
 
 
 
 


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1.   Introduction 
 
Chronic lymphocytic leukemia (CLL) is a proliferative disorder of functionally abnormal 
lymphocytes. CLL is grouped with a spectrum of diseases known as low-grade 
lymphoproliferative disorders. CLL is the most common form of leukemia (25% of all cases) in 
western countries, and 95% of all cases are of B-cell phenotype. [1,2] Median age at diagnosis is 
70 years, and only 10-15% of patients are younger than 50 years. [3] Despite some therapeutic 
progress, standard treatment is not curative for CLL. This, together with the advanced age of 
most patients and the relatively indolent course of the disease for some patients, makes symptom 
palliation a reasonable treatment goal. Therefore, chlorambucil or fludarabine are usually given 
for CLL patients who have anemia, thrombocytopenia, hepatosplenomegaly, and/or 
lymphadenopathy. Even though fludarabine was shown to result in higher response rates and 
longer progression free survival (PFS) compared to single-agent or combination chemotherapy, 
overall survival (OS) was not improved. [4-6] The use of fludarabine-rituximab or fludarabine-
cyclophosphamide-rituximab combinations may improve PFS and appears to improve OS based 
on historical controls[7,8]. Despite these advances, most patients who live long enough 
eventually fail fludarabine therapy, and about 20% of CLL patients have primary refractoriness 
(defined by failing to meet NCI Working Group Criteria for complete or partial responses: see 
Appendix H). Fludarabine-refractory CLL patients have a poor prognosis with median survival 
of 12 months. [9,10] Re-treatment with fludarabine or other nucleoside analogues such as 
cladribine or pentostatin, combination chemotherapy with or without fludarabine, and new 
biological agents such as Rituximab and Campath-1H has not demonstrably improved PFS. 
[9,11-17] 
HCT using myeloablative conditioning has been increasingly used to treat young patients with 
CLL who have early stage disease and limited prior treatment. [18] Autologous high-dose HCT 
for CLL has shown long-term remissions and transplant-related mortality (TRM) of less than 
10%. However, this treatment option was associated with high relapse rates reaching 56%[19]. 
Allogeneic HCT with high-dose conditioning has the theoretic advantage of graft-versus-
leukemia (GVL) effects, and has resulted in tumor eradication and lower relapse rates compared 
to autologous HCT. However, TRM is higher than after autologous HCT by 20-40%. Unrelated-
donor HCT has not been widely used for treatment of CLL because of the higher TRM as 
compared to related-donor HCT[20-22]. Hence, there has been no standard curative therapy for 
patients with fludarabine-refractory CLL. The Cancer Therapy Evaluation Program (CTEP) at 
the National Institute of Health (NIH) has recommended clinical trials for patients who have 
failed fludarabine treatment. 
Allogeneic HCT after nonmyeloablative conditioning with fludarabine and low dose total body 
irradiation (TBI) and postgrafting immunosuppression with cyclosporine (CSP) and 
mycophenolate mofetil (MMF) was developed in an attempt to eradicate hematologic 
malignancies by GVL effects while avoiding morbidities and mortalities associated with 
myeloablative HCT. This approach using unrelated donor grafts has resulted in an encouraging 
OS and PFS rates of 67% at 2 years in 16 patients with fludarabine-refractory CLL. [23] Our 
updated results with longer follow-up show OS and PFS of 50% and 39%, respectively, at 5-
years, which exceed any conventional salvage therapy for patients with fludarabine-refractory 
CLL. [24] However, disease relapse remain a cause of treatment failure with 5-years rate of 38%. 
NRM was the other cause of treatment failure (23% at 5-years), which resulted mainly from 
GVHD and infections. Outcomes were comparable between related and unrelated recipients.  


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The current protocol will attempt to better define safety and efficacy of allogeneic HCT after 
nonmyeloablative conditioning as salvage therapy for high-risk CLL patients. We propose to add 
the chimeric monoclonal anti-CD20 antibody Rituximab once immediately prior and three times 
in the weeks following the current non-myeloablative conditioning regimen. Our main goal is to 
reduce disease relapse. We will collect pharmacokinetic data to better define the optimal dosing 
of Rituximab and its impact on response. In addition, we will attempt to identify the 
recipient/donor pairs that benefit the most from Rituximab. This will be done by assessing 
recipient and donor polymorphisms of the FCγRIIIa receptor, which have been shown in some 
series to affect responsiveness to Rituximab.  
  
2.    Background 
 
A. Diagnosis, epidemiology, staging and prognosis of CLL 
 
CLL is characterized by a progressive accumulation of atypical monoclonal lymphocytes in the 
bone marrow, peripheral blood and other organs. CLL is part of a spectrum of diseases grouped 
as low-grade lymphoproliferative disorders. It is the most common form of leukemia in western 
countries and constitute 25% of all cases. [1] The current annual incidence estimates vary from 
approximately 8100 to 12,500 new cases in the United States, [25,26] with annual CLL-related 
deaths of 4500. [27] The National Cancer Institute-sponsored Working Group (NCI-WG) on 
CLL had revised their guidelines for diagnosis of CLL. [28] All patients must meet all the 
following criteria to be diagnosed as CLL: 
 
 An absolute peripheral lymphocytosis greater than 5,000 mature-appearing 
lymphocytes/l. 
 One or more B-cell markers (CD19, CD20, CD23) plus CD5 by flow cytometry. 
 
Mature lymphocytes with less than 55% cells being atypical lymphocytes, 
prolymphocytes or lymphoblasts. 
 A normal to hypercellular bone marrow aspirate with  30% of the nucleated cells being 
of lymphoid origin.  
 
Patients with CLL are staged utilizing either the Rai or Binet systems. Both systems discriminate 
CLL based on the sites of disease and/or degree of cytopenias induced by leukemic marrow 
replacement after exclusion of autoimmune etiologies. While, the Binet classification divides 
CLL patients into three stages as noted in, the Rai classification originally defined five stages of 
CLL (See Appendix R). However, in 1987, a modified Rai system was developed creating three 
prognostic risk categories (low, intermediate, and high risk) equivalent to the three stages of the 
Binet system. Factors predictive of poor prognosis in CLL patients include older age, male 
gender, a diffuse bone marrow pattern, a lymphocyte doubling time of less than one year, serum 
levels of B2-microglobulin greater than 4.0 mg/L, serum thymidine kinase levels greater than 7.0 
U/L, and higher serum soluble CD23 levels. [29-32] Chromosomal analysis can also be used to 
assign risk. Patients with a normal karyotype, or isolated 13q14 deletions have a benign course. 
[33] However, 17p13 or 11q23 deletions (10-15% of patients) are associated with very poor 
prognosis. [34,35] 
 


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CLL has been categorized into two prognostic subsets based on the immunoglobulin variable-
heavy chain (IgVH) mutational status. It was found that Binet stage A CLL patients with 
somatically unmutated IgVH genes have a median survival of 8 years compared to 25 years in 
patients with mutated genes. [36,37] Further, the two IgVH subsets are distinct and do not 
metamorphose from one into the other. Although surface CD38 expression was originally 
suggested as a surrogate assay for V gene mutations, [36] it appears that there is a 30% 
discordance between the assays. [38] Furthermore, CD38 expression was found to change in 
25% of cases during the course of the disease, and therefore was not a useful prognostic 
indicator. [38] More recently, zeta-chain-associated protein 70 (ZAP-70), a kinase linked to T-
cell receptor activation, was shown to be as excellent surrogate marker for the V gene mutational 
status with a sensitivity and specificity of 91% and 100%, respectively. [39] Unlike CD38, ZAP-
70 surface expression does not change over time. [39] Given the difficulty in performing IgVH 
sequencing in a routine diagnostic laboratory, ZAP-70 detection with flow cytometry can be 
utilized efficiently in determining the prognosis of CLL patients or ensuring molecular complete 
remission (CR) after clinical trials. 
  
B. Fludarabine-refractory CLL 
Fludarabine has been considered frontline therapy for symptomatic CLL. Three large phase III 
trials of fludarabine in symptomatic untreated CLL patients have shown a higher response rate 
with prolongation of PFS compared to chlorambucil or combination chemotherapy. [5,6,40] 
There was no survival advantage in any of these studies likely due to crossover to fludarabine in 
the other arms. All surviving eventually failed fludarabine therapy, while approximately 20% of 
patients were refractory to primary therapy. Patients with fludarabine-refractory CLL have a very 
poor prognosis with a median survival of one year and less than 5% have responded to re-
treatment with single-agent fludarabine. [9,41,42] These patients have had limited treatment 
options, and most investigators encourage their participation in clinical trials. [43-45] Several 
clinical trials have been performed on patients with 
fludarabine-refractory CLL using other nucleoside analogs 
like cladribine or pentostatin, combination chemotherapy, 
and monoclonal antibodies such as Rituximab or Campath-
1H with limited improvement in disease-free survival and 
OS. In the current protocol, fludarabine-refractory CLL 
will be defined by failure to meet NCI-WG Criteria 
(Appendix H) for complete or partial response after a 
regimen containing fludarabine (or other nucleoside 
analogue) or relapse /progression within 12 months after 
completion of a regimen containing fludarabine (or other 
nucleoside analogue such as pentostatin or cladribine).   
 
The best clinical outcomes for patients with fludarabine-
refractory CLL were associated with the use of Campath-
1H. [14,17,46] Campath-1H is a humanized anti-CD52 monoclonal antibody that has been 
approved by the United States Food and Drug administration for treatment of fludarabine-
refractory CLL (reviewed in [47]). Ninety-three CLL patients who were refractory to fludarabine 
were given Campath-1H in a prospective phase II trial involving 21 centers worldwide. The 
overall response rate was 33% however, only 2% achieved CR. Median time to progression was 
 
Figure 1. OS curve for patients with fludarabine-
refractory CLL treated with Campath-1H. 


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4.7 months and median survival was 16 months. OS was approximately 45% at 18 months 
(Figure 1). [14] Since this was the best reported outcome for salvage therapy for fludarabine-
refractory CLL patients, we will use this outcome as the gold standard for comparison in the 
current protocol. Campath-1H caused substantial toxicities that included infusion-related fevers 
and chills, infections in 55% of patients (25 of 93 patients had grade III-IV infections), and 
hematological toxicity (21% had grade IV neutropenia). Updated results in 152 fludarabine-
refractory CLL patients who received CAMPATH-H1 showed 42.5% overall response rate and 
CR rate of 5%.[17] This update included 29 patients with T-cell prolymphocytic leukemia (T-
PLL) who showed lower overall response rate of 24%, but 14% were in CR. CMV disease 
occurred in 4 patients and 5 patients died from infections. Duration of response and OS rate were 
not available in this update. 
Rituximab which is a chimeric human-mouse monoclonal antibody directed against the CD20 
antigen present on B cells, has been investigated in the treatment of fludarabine-refractory CLL. 
A trial of thrice-weekly dosing of rituximab in 33 patients with CLL/small lymphocytic 
lymphoma (SLL), 52% of whom were fludarabine-refractory, the overall response rate among 
the fludarabine-refractory subset was 41% with a median response duration of 6 months. [11] A 
dose-escalation study of 40 patients with CLL showed that only 20% of fludarabine-refractory 
patients achieved PR and none CR. In a multiple parameter analysis, sensitivity to fludarabine 
was the only factor that correlated significantly with response to rituximab[12], a finding that 
reflects the limited activity of rituximab as a single agent for treating fludarabine-refractory CLL 
patients. 
 
Combination chemotherapy with nucleoside analogs has not resulted in better outcomes than that 
of Campath-1H. Twenty-eight patients with fludarabine-refractory CLL were treated with a 
combination of cyclophosphamide and fludarabine[9]. Overall response rate was 39% with 3% 
of patients achieving CR.  Median survival was 12 months with OS rate of 30% at 18 months. 
Thirteen patients with fludarabine-refractory CLL or SLL were treated with pentostatin plus 
cyclophosphamide resulting in an overall response rate of 77% with only one patient achieving 
CR, but responses were transient and median survival was only 16 months[15]. Cladribine has 
shown modest clinical activity and considerable toxicity. In one study, cladribine was given 
alone to treat 28 fludarabine-refractory CLL patients who had modest fludarabine or 
chemotherapy exposure and lacked pre-treatment neutropenia and thrombocytopenia. Despite 
this selection, Overall response rate was 32% without achieving CR with median PFS of 9 
months. Grades III-IV toxicities were frequent and included infections (43%), neutropenia 
(75%), and thrombocytopenia (68%)[13]. Another trial explored a combination of cladribine and 
cyclophosphamide in 16 purine analog-refractory patients. The overall response rate was 25% 
and only one patient achieved CR. Toxicities were significant with myelosuppression being the 
dose limiting toxicity[16]. A combination of fludarabine, cyclophosphamide, and rituximab was 
used to treat 102 CLL patients of whom 27 were refractory to fludarabine[48]. Overall response 
rate among the fludarabine-refractory patients was 59% with CR rate of 7%. Survival data were 
not reported in this study 
 


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C. Autologous HCT for CLL 
 
Autologous HCT has been offered only to selected groups of patients with CLL. The main 
criteria of eligibility for autologous HCT were documented chemosensitivity, minimal tumor 
burden (typically requiring several cycles of cytoreductive chemotherapy), and successful 
collection of enough hematopoietic progenitor cells. Best results have been achieved in patients 
undergoing autologous HCT earlier in their disease course and in those with fewer previous 
treatments or relapses. [49] Concerns about studies investigating autologous HCT for CLL 
include 1) the limited applicability due to the judicious selection of patients likely to benefit from 
the approach, 2) the high probability of disease relapse, and 3) the long-term risk of treatment-
related secondary malignancies (reviewed in[50]). Failure to respond to pretransplant debulking 
chemotherapy has been one of the difficulties with autologous HCT. [51] In a series of 20 CLL 
patients, 10 patients did not meet the eligibility criteria either because of chemotherapy 
resistance (n=5, 4 died from progression), mortality from chemotherapy complications (n=2), or 
failure to mobilize adequate numbers of C34+cells (n=3). [52] Others have described poor 
hematopoietic cell collection due to advanced disease stage[49,53], or from prior marrow toxic 
chemotherapy including fludarabine and chlorambucil[54,55]. Available purging methods were 
found to either have no impact on survival[56] or increase the risk of life threatening 
infections[57], thereby causing morbidity and mortality[58].  
Two large studies using autologous HCT for CLL, one from the European Group for Blood and 
Marrow Transplantation (EBMT) and one from the International Project for CLL are 
summarized in Table.1.  
 


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Table1. Autologous HCT for CLL  
 
 
EBMT[59] 
(n=482) 
International project for 
CLL[19] (n=124) 
Age, median (range), years 
50 (22-66) 
49 (22-64) 
Median interval from 
diagnosis to HCT (range), 
months 
26 (4-215) 
36 (5-218) 
Prior regimens 
50% received <3 regimens 
* 
Prior fludarabine exposure 
26% 
* 
Chemo-sensitive disease at 
time of HCT 
85% (CR=31%) 
73% 
Overall disease response  
(n=239) 87% (CR=78%) 
* 
TRM 
11% at 3-years 
6% at 3 months 
Relapse 
41% at 3-years 
58% at 5 years 
DFS 
* 
32% at 5 years 
OS 
79% at 3-years, no plateau 
63% at 5 years 
Factors predicting better 
outcome 
Early HCT (<36 months 
from diagnosis), low number 
of prior regimens, and being 
in CR at HCT 
Early stage (Rai 0), short 
interval between diagnosis 
and HCT (<36 months0, low 
marrow involvement, and <1 
prior regimens  
 
* Not reported 
 
The German CLL Study group treated 65 patients, median age of 49 years, with 
TBI/cyclophosphamide followed by transplantation of immunomagnetically purged autologous 
stem cells[60]. Median interval from diagnosis to HCT was 14 months, and 94% of patients were 
chemotherapy naïve. Protocol failures before HCT occurred in 25% of patients either because 
they were not in remission (n=7), had poor mobilization (n=3), and/or protocol violations (n=4). 
One-year DFS was 95% by clinical and 69% by molecular criteria. The same authors have 
shown that persistence of the leukemic clone was found among 24 of 30 studied patients (80%) 
by sensitive Taqman CDR3 amplification for clone-specific primers {Dreger P, von Neuhoff, et 
al. 2000 23081 /id}. The German CLL Study concluded that autologous HCT does not appear to 
cure CLL even if performed early.  


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The Fred Hutchinson Cancer Research Center (FHCRC) has enrolled 7 patients under protocol 
962 for autologous HCT. All had advanced stage CLL and had failed primary therapy. Their 
median age was 57 years. Only 5 patients were able to receive their HCT. Two patients died after 
HCT, one from respiratory failure secondary to acute pneumonitis with pseudomonas septicemia 
4 months after HCT and the other after receiving a second HCT for secondary AML 39 months 
after the initial HCT. Three patients are alive, 2 of whom have relapsed 50 and 52 months after 
HCT, and one of whom developed Hodgkin’s disease 69 months after HCT. 
 
In summary, autologous HCT has remained restricted to younger patients without heavy prior 
chemotherapy regimens and with early stage chemo-responsive disease with fewer numbers of 
prior regimens. Although autologous HCT resulted in relatively low TRM, has not been shown 
to eradicate CLL on the molecular level. Therefore, patients had remained at risk of relapse, and 
there has been no plateau in DFS or OS. Autologous HCT has never been studied in patients with 
fludarabine-refractory CLL. 
 
D. Allogeneic HCT for CLL 
Allogeneic HCT for CLL has been characterized by high TRM and low relapse incidence. The 
risk for TRM has been higher for older patients and those who have received unrelated donor 
grafts. Most reported studies using myeloablative allogeneic HCT for CLL focused on younger 
patients with good performance status and limited numbers of preceding chemotherapy 
regimens. 
 
Despite the low relapse rate, survival after allo-HCT has been lower than after autologous HCT 
mainly because of high TRM up to 50% even in experienced centers[61]. The majority of 
allotransplants have used related donors, and the experience with unrelated donors is limited 
(reviewed in[62]). 
 
Table 2 summarizes data reported from 4 large studies investigating the role of allogeneic 
myeloablative HCT from related or unrelated donor for treatment of CLL.  


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Table 2. Allogeneic myeloablative HCT for CLL 
 
International 
project for 
CLL[19] 
(n=48) 
Nebraska and 
Tennessee[63] 
(n=23)  
EBMT[59] 
(n=209) 
CLL working 
group-NMDP[64] 
(n=40) 
Donor 
Related 
Unrelated 
 
100% 
0% 
 
87% 
13% 
 
96% 
4% 
 
0% 
100% 
Age, Median 
(range), years 
43 (28-60) 
46 (29-60) 
47 (22-64) 
44 (26-57) 
Interval between 
diagnosis and 
HCT, median 
(range), months 
26 (5-148) 
19 (4-160) 
45 (5-198) 
45 (8-121) 
Number of 
chemotherapy 
regimens 
* 
Median (range): 
2 (1-6) 
73% received 
<3 regimens 
Median (range): 
3 (0-5) 
Chemotherapy 
sensitivity 
57% refractory 
61% refractory 
56% chemo-
responsive 
50% chemo-
refractory 
Fludarabine 
exposure 
* 
65% received 
prior FLU 
21% received 
prior FLU 
80% received prior 
FLU 
Type of 
conditioning 
* 
70% VP/CY/TBI 
and 26% CY/TBI 
64% TBI-based 
92% TBI-based 
Acute GVHD 
* 
II-IV=52% 
II-IV=40% 
III-IV=28% 
Chronic GVHD 
* 
68% 
40% 
35% extensive 
Disease response 
67% CR 
87% CR 
78% CR 
64% CR 
TRM 
31% at 3 
months 
35% 
40% at 3 years 
* 
Relapse 
* 
* 
25% at 3 years 
13% at 3 years 
DFS 
50% at 3 years 
61% at a median 
follow up of 26 
months 
* 
44% at 3 years 
OS 
56% at 3 years 
* 
55% at 3 years 
41% at 3 years 
Factors predicting 
outcome 
Phase of disease 
predicted 
survival while 
chemo-
sensitivity 
predicted 
relapse 
* 
Prior exposure 
to FLU is 
associated with 
better outcome 
CR at HCT and 
Karnofsky score of 
90% predicted 
better survival 
*Not reported 
 
Twenty-six patients with advanced stage and/or refractory CLL have undergone allogeneic stem 
cell transplantation from HLA-matched related donors at the FHCRC between 1980 and 1999. 
Patients were a median of 49 (range 14-59) years old. Twenty-one had B-cell CLL, one had T-


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CLL and four patients did not undergo phenotyping. One patient had Richter’s transformation 
and one patient evolved to prolymphocytic leukemia prior to transplant. Nineteen patients had 
received fludarabine with a median of 4 different regimens prior to HSCT. All patients had 
persistent disease at the time of transplant; 19 were Rai stage IV, 3 were stage III, 2 were stage 
II, and 2 were Rai stage 0. Patients received conditioning with busulfan (14 mg/kg) and CY (150 
mg/kg) or CY/TBI (10-16 Gy). One patient underwent conditioning with etoposide 60 mg/kg, 
CY 100 mg/kg and 12 Gy TBI.  Patients received HSCT from HLA-matched, sibling donors 
(n=22), syngeneic donors (n=3) or DRB1 mismatched sibling (n=1). Twenty-two patients 
engrafted. VOD occurred in 12 patients and renal failure occurred in 6 patients. Fourteen patients 
had GVHD ≥ grade 2 requiring therapy. Thirteen patients (50%) achieved CR by bone marrow 
morphology, and six of seven evaluable patients achieved CR by flow cytometry. Eighteen 
patients (69%) have died at a median follow-up of 139 days (range 16-1906 days) from multi-
organ failure (n=6), infection (n=5), GVHD + infection (n=2), Relapse (n=2), other/unknown 
(n=3). Eight patients survive at a median of 39 (range 9.5-101) months. The 5-year actuarial 
survival is 31% for all patients, and 56% for patients receiving conditioning with TBI after 1992 
(n=14). 
 
Five patients with advanced stage and/or refractory CLL (n=4) or CLL transformed to PLL (n=1) 
were given unrelated HCT between 1990 and 2000 at FHCRC. Median age was 46 (range 35-49) 
years and median interval between diagnosis and HCT was 22 (range 12-55) months. Patients 
were conditioned with cyclophosphamide/TBI (13.2Gy). After HCT, three patients had grade II 
and one grade III acute GVHD. Chronic extensive GVHD developed in 3 patients. Overall 4 
patients died, one patient achieved CR, but died from multiorgan failure, one died from 
complications of a second HCT given for rejection of the first graft, one died from renal failure 
associated with progressive disease, and one from pneumonia with persistent disease. One 
patient who was in CR at time of HCT, is alive in CR at 1091 days after HCT. 
 
In summary, conventional allogeneic HCT, while potentially curative as evidenced by the low 
relapse rates, was associated with a high TRM ranging from 31% to 50% (reviewed in[62]), even 
in patients less than 50 years of age. Unrelated donor HCT carries even higher risk of TRM with 
low survival advantage.   
     
E. Reduced-dose regimens for allogeneic HCT 
The use of nonmyeloablative regimens are appealing as treatment for patients with CLL for 
several reasons. First there are data that graft-versus-leukemia (GVL) effects appear to be 
effective in treating patients with CLL. The reduced toxicity of the nonablative conditioning was 
anticipated to result in lower TRM as compared to conventional conditioning. Third CLL 
patients are generally older than usual age where ablative HCT is offered. 
 
The experience with reduced intensity transplants for CLL has been limited. Two large studies 
using reduced intensity conditioning and HCT for CLL, one from the Cooperative German 
Transplant Study Group[65] and one from the EBMT representing 29 European centers[66] are 
summarized in Table.3.  


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Table 3. Allogeneic reduced-intensity HCT for CLL 
 
Cooperative German 
Transplant Study Group 
(n=30) [65] 
EBMT (n=77) [66] 
Donor 
Related 
Unrelated 
 
50% 
50% 
 
82% 
18% 
Age, Median (range), years 
50 (12-63) 
54 (30-66) 
Interval between diagnosis and 
HCT, median (range), months 
48 (12-510) 
49 (8-146) 
Number of chemotherapy 
regimens, median (range) 
3 (0-8) 
3 (0-8) 
Disease status at HCT 
Responsive (CR/PR) 
Refractory (SD/PD) 
 
46% 
46% 
 
65% 
35% 
Fludarabine exposure 
33% fludarabine-refractory 
82% previous exposure, no 
report on refractoriness 
Type of conditioning 
Fludarabine/ busulfan/ rabbit 
anti-thymocyte globulin 
65% low dose TBI or 
cyclophosphamide-based 
35% fludarabine/busulphan 
or high dose melphalan 
combinations 
Acute GVHD 
Grade II-IV 
Grade III-IV 
 
56% 
20% 
 
34% 
16% 
Chronic GVHD 
Limited 
Extensive 
 
54% 
21% 
 
58% limited+extensive 
Disease response (CR+PR) 
(40+53%) 
(69%+22%) 
TRM 
All patients 
Unrelated donor 
recipients 
 
15% at 2 years 
28% at 2 years 
 
18% at 1-year 
Relapse 
* 
31% at 2-years 
PFS 
67% 
56% at 2-years 
OS 
72% 
72% at 2-years 
*Not reported 
SD indicates stable disease; and PD, progressive disease 
 
 
F. Our preliminary results of nonmyeloablative conditioning and allogeneic HCT for CLL 
Based on preclinical studies in a canine model, [67] we developed a nonmyeloablative 
conditioning regimen for hematopoietic cell transplantation (HCT) for patients with 
hematological malignancies. The regimen was first used in patients receiving HCT from HLA-


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matched related donors[68] and from January 2000, for patients given HCT from HLA-matched 
unrelated donors. [69,70]  
In 2005, we reported our encouraging early results of allogeneic hematopoietic cell 
transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced 
chronic lymphocytic leukemia (CLL). Patients were given HCT from related (n = 44) or 
unrelated (n = 20) donors. Patients had multiple risk factors: median age was 56 years; median 
interval between diagnosis and HCT was 4.4 years; CCI scores of ≥1 for pretransplantation 
comorbidities were present in 48% of patients; chemotherapy resistance to pretransplantation 
salvage treatment was present in 53% of patients and untreated relapse occurred in 11% of 
patients; there was a median of four prior treatment regimens; and disease refractoriness to at 
least one regimen was present in all but two patients (97%). Thirty patients (47%) were refractory 
to one regimen, 23 patients (36%) were refractory to two regimens, and nine patients (14%) were 
refractory to three regimens. Eighty-eight percent of patients were refractory to fludarabine, 
25% of patients were refractory to rituximab, 30% of patients were refractory to alkylating 
agents, and 22% of patients were refractory to other miscellaneous regimens. In addition, patients 
had multiple adverse disease burden characteristics: bulky lymphadenopathy (lymph node 
diameter ≥5 cm, 28%), splenomegaly (47%), 
CD5/CD9 coexpression of CD38 more than 
30% (58%), beta2-microglobulin more than 
2.5 µg/mL (53%), ≥50% marrow infiltration 
with CLL cells (52%), and unfavorable 
cytogenetics (39%). No significant differences 
in adverse disease burden characteristics were 
present between related and unrelated 
recipients.  After HCT, Sixty-one of 64 
patients had sustained engraftment, whereas 
three patients rejected their grafts. The 
incidences of grades 2, 3, and 4 acute and 
chronic graft-versus-host disease were 39%, 
14%, 2%, and 50%, respectively. Three 
patients who underwent transplantation in 
complete remission (CR) remained in CR. 
The overall response rate among 61 patients 
with measurable disease was 67% (50% CR), 
whereas 5% had stable disease. All patients 
with morphologic CR who were tested by 
polymerase chain reaction (n = 11) achieved 
negative molecular results, and one of these 
patients subsequently experienced disease 
relapse. The 2-year incidence of 
relapse/progression was 26%, whereas the 2-
year relapse and nonrelapse mortalities were 
18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 
52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related 
HCT. Two-year OS and DFS of related compared with unrelated recipients were 56% v 75% (P = 
.33) and 44% v 75% (P = .15), respectively (Figure 2). 
 
Figure 2. Cumulative incidences of nonrelapse mortality 
(NRM), relapse-related mortality, overall survival (OS), and 
disease-free survival (DFS) for (A) related and (B) unrelated 
recipients. 


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Recently, Here, we have extended the follow-up to a median of 5 years and have included data 
on an additional 18 patients. Grafts were from related (n = 52) or unrelated (n = 30) donors. 
Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, 
respectively. Higher CR rates were noted after 
unrelated HCT (67% v 48%). The 5-year incidences of 
nonrelapse mortality (NRM), progression/relapse, 
overall survival, and progression-free survival were 
23%, 38%, 50%, and 39%, respectively. Among 25 
patients initially reported in CR, 8% relapsed and 8% 
died as a result of NRM, whereas 84% have remained 
alive and in CR. Among 14 responding patients who 
were tested and who had molecular eradication of their 
disease, two died as a result of NRM, two relapsed, and 
10 have remained negative. The 5-year prevalence of 
patients alive after discontinuation of all 
immunosuppressive medications was 38% (35% for 
related and 44% for unrelated recipients, Figure 3); the median performance status in each group 
was 100% and 90%, respectively. Lymphadenopathy > or = 5 cm, but not cytogenetic 
abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had 
lymphadenopathy less than 5 cm and no comorbidities 
had a 5-year OS of 71%.  
Outcomes of patients with favorable (normal or 13q 
deletion) versus unfavorable (all others) cytogenetic 
abnormalities were comparable (Figure 4). Seven 
patients had 17p deletion, of whom 4 (57%) are alive 
and in CR, 1 died with NRM while in CR, and 2 died 
from relapse. 
 
In summary, Nonmyeloablative HCT resulted in a 
median survival of 5 years for patients who had 
fludarabine-refractory CLL with sustained remissions 
and in the continued resolution of chronic graft-versus-
host disease in surviving patients. The approach 
appeared feasible with acceptable NRM, high rates of 
disease responses, and a good evidence of GVL effect. 
Outcomes of related and unrelated recipients were 
similar, providing the rationale to combine both grafts 
in this protocol.   However, disease relapse remained as 
a cause of treatment failure with 5-years rate of 26%. 
NRM was the other cause of treatment failure, 24% at 
5-years, and it resulted mainly from GVHD and its 
complications and infections.  We thought to further 
improve our results by adding peri-transplant 
Rituximab with the main goal of more robust disease-
control and a secondary goal of limiting GVHD and its complications. 
 
Figure 3. CLL: OS based on donor type and 
resolution of GVHD following allogeneic HCT. 
 
Figure 4. Comparable 5-year relapse and PFS 
rates among CLL patients with unfavorable 
(17p deletion, 11q deletion, trisomy 12, and 
complex) versus favorable (normal and 13q 
deletion) cytogenetic abnormalities following 
nonmyeloablative allogeneic HCT. 
Unfavorable cytogenetics 
Relapse 
P = 0.65 
Favorable cytogenetics 
Favorable cytogenetics 
PFS 
P = 0.88 
Unfavorable cytogenetics 


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G. Update on results of CLL patients with poor prognosis 
Recently, investigators from MD Anderson Cancer Center have presented at the American 
Society of Clinical Oncology 2007 Meeting results of 77 patients with CLL who have failed 
initial treatment with combination chemo-immunotherapy comprising fludarabine, 
cyclophosphamide, and rituximab (FCR). Ten of those patients have not required therapy while 
67 patients received first salvage therapy with a variety of regimens. Overall response rate was 
39% and CR rate was 17%. Median survival after the first salvage therapy was 30 months (28 
deaths) and was shorter for patients with PR or refractory disease (10 months). Of interest, 13 
patients who failed the first salvage therapy went to receive allogeneic HCT after reduced 
intensity regimens. Of those 13 patients, 3 died early, one relapsed, 2 in PR, and 7 in CR. 
Survival at 3 years is 76%. The authors concluded that patients who failed to obtain CR or 
nodular PR after FCR or first salvage therapy should be considered for allogeneic HCT.52 
 
Alternatively, patients with advanced CLL and 17p deletion genomic feature have a very poor 
prognosis even after intensive chemotherapy. The hierarchical model of Dohner and colleagues 
identified the prevalence of this genomic aberration to be of 7%.53 Patients with 17p deletion had 
only 0.75 year treatment-free interval and 2.7 years median survival from time of diagnosis.53 
Recently, investigators from Germany have shown that patients with 17 p deletion had 
statistically significantly shorter median PFS (11 versus 24 months, p=0.002) and median OS 
(15.9 months versus not reached, p<0.001) compared to patients without 17p deletion following 
fludarabine-based regimens (Figure 5).54  Similar findings were also reported by investigators of 
the US Intergroup Phase III Trial E2997, where patients with 17p deletion had median PFS of 
0.9 years after initial therapy with fludarabine ± cyclophosphamide.55 Further, investigators from 
MD Anderson Cancer Center have shown at the American Society of Hematology 2007 Meeting 
that 17p deletion +/- other genomic aberrations was the strongest independent predictor for 
shorter survivals and poor response to the combination FCR 
as an initial therapy for CLL.56 
 
 
Updated results suggest that patients who fail FCR 
combination chemotherapy at any time point and patients 
with “de novo” or acquired 17p deletion cytogenetic 
abnormality, who received induction chemotherapy should 
be enrolled in nonmyeloablative protocols. 
 
H. Peri-transplant Rituximab to improve early disease 
control and reduce relapse risk 
 
The cell-surface antigen CD20 is a 297-amino acid 
transmembrane phosphoprotein that is expressed on more 
than 90% of mature B-cell leukemias and lymphomas. [71] 
Rituximab is a chimeric anti-CD20 monoclonal antibody, 
which has been shown to be active against CLL either as a 
single agent[72]or in combination with chemotherapy. [73].The proposed mechanisms for the 
cytotoxic action of rituximab include complement-dependent cytotoxicity,[71]antibody-
 
Figure 5. Kaplan-Meier survival for CLL patients 
(n=375) with versus without 17p deletion following 
initial treatment with fludarabine ± 
cyclophosphamide. 


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dependent cellular cytotoxicity, [71] and signaling-induced apoptosis [74,75] in addition to 
synergistic effects with chemotherapeutic agents[71] and radiation therapy. [76] 
 
Theory: 
 
The antitumor effects of NM HCT are substantial, but disease progression occurs in a substantial 
fraction of patients. In our earlier results with nonmyeloablative HCT for patients (n=64) with 
advanced CLL, we found that the median time to early progression was 3.3 months, while 
median time to the first sign of disease eradication, complete resolution of cytogenetic 
abnormalities, by GVL was 3 months. Patients with progressive disease frequently have a larger 
tumor burden prior to transplant and fail to develop T cell responses to CLL, suggesting that 
tumor antigens are not efficiently presented or reactive T cells are tolerized by the high tumor 
burden. Based on these findings, we could hypothesize that improvement of disease control 
could be achieved by 1) additional treatment in the early few weeks after HCT and 2) earlier 
and/or stronger generation of GVL effects. Rituximab given days before and after HCT could 
hypothetically meet these two objectives. Rituximab through antibody-dependent cytotoxicity 
could prevent disease progression in the early interval after HCT[71]. Further, investigators 
found that anti-CD20 antibodies, by induction of apoptosis, could promote uptake and cross 
presentation of cell-derived peptides by antigen-presenting dendritic cells. [77] In these lines, 
Rituximab could allow cross-priming and generation of specific donor-derived cytotoxic T cells 
resulting in earlier “switch-on” of GVL effects. [78,79] 
 
Tolerability: 
 
Rituximab, alone or in combination with various chemotherapy regimens, was generally well 
tolerated in clinical trials in patients with advanced-stage indolent or aggressive B-cell NHL or 
B-cell CLL. The most common types of adverse events in these trials were infusion-related 
reactions, hematological adverse events and infections. Infusion-related reactions that occur in 
the majority of patients, most within 2 hours of the first infusion, are generally mild to moderate 
flu-like symptoms that usually resolve upon slowing or stopping the infusion, and become less 
frequent with subsequent infusions. Severe (grade 3/4) reactions, including severe cytokine 
release syndrome, occur in 10% of patients and may also require supportive care (e.g. analgesic, 
antihistamine, oxygen, intravenous fluids, bronchodilators, vasopressors and/or corticosteroids). 
The true incidence of rituximab-related infections has not been determined, but nonrandomized 
trial data showed a 31% overall (19% bacterial, 10% viral) and 2–4% incidence of severe 
infectious events. (Biogen Idec Inc., Genentech Inc. Rituxan® (Rituximab): prescribing 
information. 2006 Feb 28; and Roche Registration Limited. MabThera 100mg (concentrate for 
solution for infusion): summary of product characteristics[online]. Available from URL: 
www.rocheuk.com [Accessed 2006 Mar 10]). Overall, treatment with rituximab, in combination 
with fludarabine or as part of the FCR regimen, was well tolerated by patients with B-cell CLL 
in phase II trials[80-82], Incidences of severe neutropenia and infections were comparable to 
those seen with fludarabine-based regimens[81]. Myelosuppression was considered 
predominantly chemotherapy, rather than rituximab related. [80-82] 
 


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Fig. 6  Rituximab ELISA. The mean of triplicate 
assays was 41.1 +/- 5.5 g/ml and 11.8 +/- 0.7 
g/ml for 2 spiked samples of 40.0 and 10.0 
g/ml. 
Pharmacokinetics: 
 
Some facts are known from the intravenous administration of Rituximab in patients with B-cell 
malignancies: 
 
1) The drug serum concentration is directly proportional to the 
administered dose and to the clinical response [71]. However, 
they are inversely correlated to the absolute level of circulating 
peripheral B cells and the tumor bulk measurements at baseline. 
[83] 2) Repeated administration results in accumulation of the 
drug due to reduction in the population of both normal and 
malignant CD20-positive B cells and the reduction or saturation 
of CD20-binding sites[71]. 3) There is wide interindividual 
variability reflecting the variable tumor responsiveness and 
burden among patients with B-cell malignancies. 4) Clinically 
relevant drug concentrations were detectable by ELISA in the 
serum of these patients up to 6 months after treatment [71]. 5) 
Rituximab serum concentrations were significantly lower in patients with B-cell CLL. [84] This 
is probably due to the presence of the soluble CD20 antigens, found in patients with CLL, that 
act as a ‘sink' for rituximab, increasing clearance and reducing delivery of the drug to malignant 
B cells. 
 
Very limited information is available though on pharmacokinetics of Rituximab in the settings of 
allogeneic HCT. We aim to study these pharmacokinetics in the current patient population and 
ask questions about serum concentrations and correlations to drug dose and clinical responses at 
different time points after HCT. There is no commercial assay available to determine serum 
concentrations of rituximab. The Maloney lab has developed a murine anti-idiotype (anti-Id) 
monoclonal antibody (18C9) which binds specifically to rituximab, to the murine parent 
antibody used to construct rituximab, and to Fab’ fragments of these antibodies and which does 
not cross-react with other human IgG1 antibodies or human serum (Fig. 6). The 18C9 anti-Id 
was used to develop an ELISA to measure serum rituximab concentrations. This assay can 
quantify rituximab levels in fresh, refrigerated or frozen human serum to <1 μg/ml. We will use 
this assay to measure rituximab levels in patients before and after allogeneic HCT; we will 
correlate serum levels with response and relapse rates, and evaluate the effectiveness of our 
dosing regimen in consistently achieving trough serum rituximab levels of >25 μg/mL based on a 
reported correlation of trough levels >25 μg/mL with disease response [83]. 
 
Genetic determinants of responsiveness to Rituximab 
 
Polymorphisms of the FcRIIIa receptor predominantly expressed on NK cells, have been shown 
to affect the antitumor activity of Rituximab in some but not all studies. [85-87] The FcRIIIa of 
individuals that are homozygous for valine at position 158 (158V/V) has a higher affinity for 
human IgG1 than FcRIIIa that are homozygous for F (158F/F), and confers greater antibody 
dependent cell mediated cytotoxicity in vitro. [85] Patients with 158V/V have better and more 
durable responses to Rituximab than patients with 158F/F, while 158 V/F heterozygotes have a 
variable response. Maloney lab has developed a method to genotype FCRIIIa by PCR and 


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Figure 7: (A) PCR amplification of FCγRIIIa exon 4 from 3 patients, (B) 
SSCP analysis of the 3 samples, V/V, V/F, and F/F. Data from D. Maloney. 
single-strand conformation polymorphism (SSCP). A region of exon 4 of FCRIIIa was 
amplified by PCR and the 125 bp product verified on a 2% agarose gel and by sequencing (Fig 
7A). The PCR products were denatured and then electrophoresed through pre-cast 20% TBE in 
Xcell II Mini-Cell gel 
electrophoresis unit in 1% TBE 
buffer to separate the different 
strands (Fig. 7). This is a sensitive 
method to identify FcRIII 
polymorphisms from small amounts 
of DNA isolated from patient or 
donor cells. A similar method has 
been developed to detect the 
position 131 (histidine/arginine) polymorphism in the Fc receptor CD32, which has also been 
correlated with Rituximab response in some studies. [85]  This method will be used to determine 
the genotype of these polymorphisms in hematopoietic cells pre and post NM HCT.  
 
Patients with FcR polymorphisms that provide high affinity binding for human IgG1 had higher 
response rates or longer duration of remission following Rituximab therapy in some studies. This 
has not been evaluated in the context of allogeneic HCT, where the FcR status may change pre 
and posttransplant. We hypothesize that CD16 158 (VV) and CD32 131(HH) will be associated 
with increased efficacy and better outcome. It is unknown whether donor or recipient FcRIII 
genotype will be more relevant for the efficacy of Rituximab in NM HCT. 
 
GVHD 
Cumulative incidence of extensive chronic GVHD in our 82 CLL patients was 50%. We will 
study in this protocol whether the addition of Rituximab would reduce chronic GVHD rates in 
comparison to our historical CLL patients given nonmyeloablative HCT. This is based on several 
reports indicating efficacy of Rituximab in treating refractory chronic GVHD. [88-92]  
Responses have been limited to cutaneous and musculoskeletal features[88-90] with few 
exceptions. [93] The precise role of B cells in chronic GVHD and the mechanism of benefit from 
rituximab remain controversial. Autoantibodies have been implicated in the pathogenesis of 
chronic GVHD by some groups [94], and rituximab may function by suppressing their 
production [89]. Alternately, rituximab-mediated B-cell depletion may modulate T-cell 
alloreactivity, as in other autoimmune diseases [95]. Given the clinical benefit in established 
chronic GVHD, administration of rituximab in the early post-transplant period may have a 
prophylactic effect, reducing the incidence or severity of chronic GVHD. 
 
 
I. Assessment of Pretransplant Comorbidities 
Charlson Comorbidity Index (CCI) is a well-known simple index to score comorbidities which 
was developed to provide prediction of risks of survival after treatment of chronic medical 
illnesses.[96] The Seattle team used this index in 2004 to score pretransplant comorbidities 
among patients diagnosed with hematological malignancies and offered HCT. The CCI was 
helpful in predicting risks of non-relapse mortality and survival[97,98]. However, the CCI 
showed a limited ability in capturing comorbidities among the transplanted population. 
Therefore, the same authors investigated the possibility of modifying the original CCI to better 


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capture comorbidities among transplanted patients.[99] They tried to a) better define previously 
identified comorbidities utilizing pretransplant laboratory data, b) investigate additional HCT-
related comorbidities, and c) establish comorbidity scores that were suited for HCT. This 
resulted in developing a new HCT-specific comorbidity index (HCT-CI), which captured 
comorbidities among 62% of patients with scores >0 compared to 12% captured by the original 
CCI.[99] Additionally, the new index was superior to the old CCI in prediction of survival 
(likelihood ratio of 23.7 versus 7.1 and c statistics of 0.661 versus 0.561, P=<0.0001, 
respectively).  Recently, the HCT-CI was shown to be an important prognostic and risk-
assessment factor in comparing outcomes of patients diagnosed with CLL and given 
myeloablative versus nonmyeloablative HCT. [100]  
 
 
3.   Proposal 
 
We intend to study whether allogeneic HCT after nonmyeloablative conditioning and peri-HCT 
Rituximab is effective therapy for CLL. We intend to demonstrate this by comparing survival of 
patients transplanted under this protocol to that achieved in the historical controls after treatment 
with CAMPATH. 
 
4.   Objectives 
 
A.  Primary objective 
1. Determine whether nonmyeloablative conditioning and allogeneic HCT 
improves survival at 18 months for patients with fludarabine-refractory, FCR-
failed, or del 17p CLL over that of historical controls (45% at 18 months) 
given CAMPATH-1H.[14]  
 
B.  Secondary objectives 
1. Estimate the overall response rate (CR + PR) by standard morphologic, flow 
cytometric, and molecular techniques. 
 
2. Assess the rate of relapse/progression. 
 
3. Define incidences of RRT and infections within the first 100 days and the 
incidence of TRM within the first year. 
 
4. Estimate incidences of grade II-III and III-IV acute GVHD and chronic 
GVHD. 
 
5. Assess the impacts of Rituximab 
 
a. Determine whether the addition of Rituximab to the nonmyeloablative 
conditioning and allogeneic HCT improves survival at 18 months over 
our historical data (57% at 18 months). 


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b. Determine the incidence of serious adverse events with the addition of 
Rituximab 
in 
comparison 
to 
historical 
data 
of 
unrelated 
nonmyeloablative HCT. 
c. Evaluate the pharmacokinetics of Rituximab. 
d. Evaluate B-cell and T-cell immune reconstitution in comparison to 
historical data of unrelated nonmyeloablative HCT.  
e. Describe donor and host polymorphisms of the FCγRIIIa receptor and 
CD32 and evaluate their impact on disease response and relapse. 
 
6. Graft-versus-leukemia analysis 
 
a. Investigating mechanism of disease resistance in relapsed/non-
responding patients 
b. Isolation of donor cytotoxic T lymphocytes specific for host minor 
histocompatibility antigens 
 
5.   Patient Selection 
A. Inclusions: 
1. Patients with a diagnosis of CLL (or small lymphocytic lymphoma) or Diagnosis of 
CLL that progresses to prolymphocytic leukemia (PLL).  
2.   Patients with B-Cell CLL or PLL who:  
a. Failed to meet NCI Working Group criteria2 (Appendix H) for complete or partial 
response after 2 cycles of therapy with a regimen containing fludarabine (or another 
nucleoside analog, e.g. 2-CDA, pentostatin) or with disease relapse within 12 months 
after completing therapy with a fludarabine (or another nucleoside analog) containing 
regimen. 
b. Failed FCR or PCR combination chemotherapy at any time point. 
c. Patients with novo or acquired “17p deletion” cytogenetic abnormality. Patients 
should have received induction treatment but could be transplanted in 1st CR. 
3. Patients who have suitable HLA-matched related or unrelated donors willing to 
receive G-CSF, undergo leukapheresis to collect PBMC, and to donate stem cells. 
4.  Patients who are older than 18 years old. 
 
 
B. Exclusions: 
      1. Infection with HIV. 
2. Active diagnosis of CNS involvement with CLL.  For LP requirement, see Appendix N. 
3. Patients unwilling to use contraceptive techniques before and for 12 months after HCT 
4. Pregnant women or females who are breastfeeding. 
5. The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase                 
    inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose   
    cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the  
    initiation of conditioning.   


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6. Active bacterial or fungal infections unresponsive to medical therapy. 
7. Performance status: 
      a. Karnofsky score < 60 (see Appendix B) for adult patients              
8. Severe organ dysfunction: 
a.  Cardiovascular: 
      i. Cardiac ejection fraction < 40%. Ejection fraction is required if age > 50 years or 
there is a history of prior transplant, anthracycline exposure or history of cardiac 
disease.  
ii. Poorly controlled hypertension despite multiple antihypertensives. b.
 Pulmonary:i.
 DLCO < 40%, TLC <40%, FEV1 <40%and/or requiring continuous supplementary oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service.ii.
 The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules.c.
 Hepatic: 
Patients with clinical or laboratory evidence of liver disease would be evaluated for 
the cause of liver disease, its clinical severity in terms of liver function, 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, 
hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a 
history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic 
synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites 
related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, 
chronic viral hepatitis with total serum bilirubin >3 mg/dl, or symptomatic biliary 
disease.  
 
9.  Patients with active non-hematologic malignancies (except non-melanoma skin cancers). 
This exclusion does not apply to patients with non-hematologic malignancies that do not 
require therapy. 
10. Patients with a history of non-hematologic malignancies (except non-melanoma skin 
cancers) currently in a complete remission, who are less than 5 years from the time of 
complete remission, and have a >20% risk of disease recurrence. 
This exclusion does not apply to patients with non-hematologic malignancies that do not 
require therapy. 
 
 
 
 


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6.   Donor Selection 
 
A. Inclusions 
 
1. Related donors 
When more than one potential donor exists, priority should be given to donors based 
on HLA identity > CMV seronegativity > ABO compatibility > sex matching. 
Eligibility guidelines for donor PBMC apheresis based on immunization status are 
shown in Appendix A. 
a. Donor who is HLA phenotypically or genotypically identical at the allele 
level at HLA-A, -B, -C, -DRB1, and -DQB1. 
b. Donor must consent to G-CSF administration and leukapheresis. 
c. Donor must have adequate veins for leukapheresis or agree to placement of 
central venous catheter (femoral, subclavian). 
d. Only G-CSF mobilized PBMC only will be permitted as a HSC source on this 
protocol. 
 
2. Unrelated donors 
 
a. FHCRC matching allowed will be Grades 1.0 to 2.1 (Appendix O): 
Unrelated donors who are prospectively: 
i) Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;  
ii) Only a single allele disparity will be allowed for HLA-A, B, or C as 
defined by high resolution typing (see Appendix O for other donor 
selection details). 
b.  Donors are excluded when preexisting immunoreactivity is identified that 
would jeopardize donor hematopoietic cell engraftment. This determination is 
based on the standard practice of the individual institution. The recommended 
procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to 
obtain a panel reactive antibody (PRA) screens to class I and class II antigens 
for all patients before HCT. If the PRA shows >10% activity, then flow 
cytometric or B and T cell cytotoxic cross matches should be obtained. The 
donor should be excluded if any of the cytotoxic cross match assays are 
positive.  For those patients with an HLA Class I allele mismatch, flow 
cytometric or B and T cell cytotoxic cross matches should be obtained 
regardless of the PRA results. A positive anti-donor cytotoxic crossmatch is 
an absolute donor exclusion.  
c. Patient and donor pairs homozygous at a mismatched allele in the graft 
rejection vector are considered a two-allele mismatch, i.e., the patient is 
A*0101 and the donor is A*0102, and this type of mismatch is not allowed.  
d. Only G-CSF mobilized PBMC will be permitted as a HSC source on this 
protocol. 
 
 
 


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B. Exclusions 
1. Age < 12 years 
2. Identical twin 
3. Pregnancy 
4. Infection with HIV 
5. Inability to achieve adequate venous access 
6. Known allergy to filgrastim (G-CSF) 
7. Current serious systemic illness 
 
 
7.   Informed Consent 
 
Patient 
A conference conducted by the outpatient, attending physician will be held with the patient and 
family to discuss this study and alternative treatments available for treatment of advanced CLL. 
The goals of the study, requirement for data collection, and requirement for release of medical 
records will be discussed with the patient.  All potential risks associated with the use of 
fludarabine, low dose TBI, Rituximab, immunosuppressive drugs, HCT, and disease 
progression/recurrence will be discussed as objectively as possible. Discussion of potential 
complications should include graft rejection, GVHD, infections, and death. It should be 
explained that patients offered this protocol have advanced malignancy with life expectancy of 
about 10 months with conventional treatments, and are at high risk of early transplant mortality 
with conventional allogeneic HCT and high relapse rate after an autologous transplant. It should 
also be explained to the patient that our preliminary results showed no difference in outcomes 
after related or unrelated donor nonmyeloablative allogeneic HCT. 
 
Informed consent from the patient will be obtained using a form approved by the Institutional 
Review Board (IRB) of the Fred Hutchinson Cancer Research Center and the local IRB if the 
patient is treated in a collaborating institution. The patient is also required to sign a HIPPA 
consent form. 
 
Donor 
For the family member stem cell donor, the procedure for collecting peripheral blood 
mononuclear cells and toxicities of G-CSF will be explained.  The donor should be counseled as 
to the risks of treatment with G-CSF and be informed that leukapheresis at several time points 
may be necessary. Informed consent from the patient and donor will be obtained using forms 
approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. All 
patients enrolled at collaborating centers will engage in institution-specific informed consent 
conferences after completion of the pre-transplant evaluation. Informed consent from the donor 
and patient will be obtained using a form approved by the Institutional Review Board for each 
treatment center. 
 
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8.   Protocol Registration 
A. FHCRC patients: Eligible patients will be assigned to the protocol by the Clinical 
Coordinator who will register the patient with the Registration Office (206-667-4728) 
between 8:30 am and 4:00 pm, Monday through Friday. After hours, the Registration 
Office can be reached by paging (206) 995-7437.  B. Collaborating institutions:Eligible patients will be identified by the principal investigator of the collaborating institution who will register the patient with the FHCRC Registration Office. Registration will include completion of the eligibility checklist and demographic form (Appendix L). This form and a copy of the signed informed consent will be faxed to the Trial Coordinator (206-667-5378). Questions regarding eligibility or protocol information should be directed to the Principal Investigators, Mohamed Sorror, M.D. (206-667-2765) or David Maloney, M.D. (206-667-5616).
9.   Plan of Treatment 
A.    Outline of treatment plan 
The plan for treatment is shown below in Figure 8 and described in Table 4. 
 
B.    HCT   
Patients will undergo HCT as soon as eligibility requirements are met and donor 
leukapheresis, for related recipients, is scheduled (in practice approximately 7-21 days after 
the arrival conference). For unrelated recipients, HC source will be G-PBMC collected as per 
NMDP or other regulatory protocol. Two (12 liters) leukaphereses will be obtained on 
consecutive days, and collections will be infused together on day “0”. 
 
Patients will only be admitted as medically necessary for control of transplant complications 
or for the infusion of HCT.  
For unrelated recipients, standard cryopreservation of 10% of the G-PBMC will take place 
for DLI. 


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C.   Cytoreduction  
Cytoreduction and /or radiation therapy may be given by the referring physician or the 
attending physician as determined on clinical grounds or to meet eligibility requirements of 
the protocol for patients with advanced malignancy or to reduce tumor bulk. Cytoreduction 
can be performed with any appropriate therapy for CLL.  The choice of therapy will depend 
on prior regimens and the current disease status and may be selected at the discretion of the 
attending physician and/or the referring physician. However, no intensive chemotherapy can 
be given within three weeks (or the interval in which a cycle of standard chemotherapy 
would be administered in a non-transplant setting) prior to initiating the nonmyeloablative 
transplant conditioning (see exclusion criteria page 19). The need for this therapy should be 
discussed with the principal investigator. The referring oncologist may be asked to 
administer this therapy. Alemtuzumab should be given only >60 days before allogeneic HCT 
to avoid its lingering immunosuppressive effect on the donor graft. 
 
Definition of Preceding Chemotherapy and Biologic Modifiers: For the purposes of this 
protocol, preceding chemotherapy is defined as any exposure to systemic chemotherapy. 
Exceptions to this definition include cytokine therapy, low dose cytarabine, chlorambucil, or 
rituxan. 
 
D.   Conditioning regimen 
Conditioning will begin four days prior to stem cell infusion. i.
 On days –4 to –2 patients will receive fludarabine intravenously at a dose of 30mg/m2/day.ii.
 On day -3, patients will receive rituximab intravenously at a dose of 375 mg/m2
.
 Follow SCCA general oncology guidelines for infusion of drug 
 Follow SCCA general oncology guidelines for rituximab pre-meds and 
prn reactions iii.
 On day 0, 200cGy of TBI will be administered at 6-10cGy/min from a linear accelerator. TBI will be administered between 10:00 a.m. and 2:00 p.m. to avoid proximity to the start of immunosuppression.iv.
 G-PBMC from an HLA-matched donor, will be infused on day 0, following TBI.
v. Patients will receive rituximab intravenously at a dose of 375 mg/m2
 at three 
time points after stem cell transplantation. These time points are set up at days 
10+, 24+, and 38+. However, if there are clinical reasons that prohibit giving 
Rituximab at one of these specified time points the dose can be delayed to a 
maximum of 5 days. Following doses should be attempted to be given at the 
scheduled time points. If doses need to be delayed more than 5 days from the 
specified time points, then patient should only get the next scheduled dose 
Day 38+ dose can be delayed up to 100 days after HCT.    
 


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Table 4. Conditioning Schema and Immunosuppression Schedule 
Day number 
-4 
-3 
-2 
-1 
0 
+1 
+10 
+24 
+27 
+38 
+40 
+56 
+96 
+100 
+180 
Fludarabine 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TBI 
 
 
 
 
200 cGy 
 
 
 
 
 
 
 
 
 
 
Rituximab 
 
X 
 
 
 
 
XA 
XA 
 
XA 
 
 
 
 
 
Stem cell 
infusion 
 
 
 
 
Infusion 
 
 
 
 
 
 
 
 
 
 
Related recipients 
CSP  
 
Start 
 
 
 
 




 
TaperB
 
 
Stop 
MMF 
 
 


StartC



Stop


 


 
AThese are recommended time points that can be delayed for a maximum of 5 days for clinical reasons.  
BTaper will be a ~6% dose reduction per week x 17 weeks. 
CThe first dose of MMF is to be given 4-6 hours after the stem cell infusion. 
Unrelated recipients 
CSP  
 
Start 










TaperC 
Stop 
MMF  
 
 
 
 
StartD  
 
 
 
 
 
TaperD 
 
Stop 
 
 
CTaper will be a ~8% dose reduction per week x 11 weeks. 
DThe first dose of MMF is to be given 4-6 hours after the stem cell infusion 
 
E.   Immunosuppression 
 Postgrafting immunosuppression with CSP and MMF will be used to permit engraftment and provide GVHD prophylaxis.
 Day –3. Commence CSP at 5.0 mg/kg PO Q12 hrs, continue to day +56 for related and day +100 for unrelated recipients, then taper to day +180. CSP should be routinely taken at 9:00 a.m. and 9:00 p.m.
 
 
Day 0: After HCT on day 0, MMF will be given based on adjusted body weight, at 15 
mg/kg PO, 4-6 hours after HCT is complete. 
o For related recipients MMF to be given at 15 mg/kg PO Q12 hrs, continue to 
day +27, then stop abruptly.   
o For unrelated recipients MMF to be given at 15 mg/kg PO Q8 hrs, continue to 
day +40, then start to taper to day +96 
 
CSP and MMF treatment and taper schedules are described below and depicted in Table 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 8. Diagram of treatment plan 
 
 
 
 
 
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 PatientPost-Transplant Evaluation for more details)
 
 
1. CSP a.
 CSPAdministration Plani. Starting dose: CSP (Neoral is preferred) is given orally based on adjusted body weight at 5.0 mg/kg Q12 hrs PO from starting day –3. Doses should be adjusted to maintain high therapeutic CSP levels as discussed below.ii. If there is no evidence of GVHD, for related recipients: a CSP taper will be initiated on day +56. CSP will be tapered so that patients will be off of CSP by day +180 (approximately 6% decrease every seven days). For unrelated recipients: a CSP is to be tapered from day +100 at 8% of the pre-taper therapeutic dose per week to be discontinued at the end of 11 


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- 27 - weeks (day +180). The referring physician, who will receive explicit instructions and guidelines for detecting and managing GVHD, will manage this.iii. If there is evidence of chronic GVHD, then the standard recommendations for chronic GVHD with CSP/prednisone will be followed.iv. If there is evidence of CLL disease progression, please see section K.
 
b. Guidelines for CSP Dose Adjustment and Monitoring 
 
i. Blood pressure, renal function (serum creatinine, BUN), electrolytes and 
magnesium need to be followed at least three times per week during the 
first month, twice weekly until day +100, then once per week until CSP is 
stopped, unless clinical circumstances suggest the need for more frequent 
evaluations. 
 
ii. CSP, whole blood "trough" levels (i.e., just prior to the next dose) will 
be evaluated on day 0 and twice weekly post-transplant until the initiation 
of the taper and adjusted if necessary to maintain blood levels that target 
upper end of therapeutic range (see Table A) during the 28 days. 
 
 
 
 


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Table A:  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 mg/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 mg/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 
 
iii. CSP Monitoring: CSP determinations should be performed on a twice 
weekly basis for the first month and then weekly until day +56 for related 
and day +100 for unrelated recipients unless high levels are detected (i.e., 
>600ng/ml), or toxicity is suspected in which case more frequent 
monitoring will be performed as clinically indicated. Routine monitoring 
of CSP will not be required for patients on a CSP taper after day + 140 
unless clinically indicated. 
 
iv. CSP Dose Adjustment: Initial high Cyclosporine (CSP) doses are 
required based on the pre clinical nonmyeloablative canine studies, which 
used an equivalent dose to establish an allograft.  After day +28, CSP 
levels typical for related or unrelated HCT will be targeted.  Dose 
reduction should only be made if CSP toxicity is present, and/or levels 
exceed values provided in Table A.  There are two methods for calculating 
CSP levels.  Table A provides desired levels for specific methods.  To 
avoid inadequate immune suppression, dose reductions should be 
conservative.  Therapeutic levels of CSP should be maintained. 
 
v. After day +28, typical serum CSP transplant levels for related or 
unrelated HCT between 120 and 360 will be targeted. 


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vi. Dose reductions should only be made if CSP toxicity is present or 
levels exceed 480 ng/ml - 600ng/ml depending on method (see Table A), 
in the absence of toxicity.  Dose reductions for high levels without toxicity 
should be conservative e.g. 25%, to avoid inadequate immunosuppression. 
 
vii. If there is nausea and vomiting at anytime during CSP treatment the 
drug should be given intravenously at the dose that was used to obtain a 
therapeutic level.  Oral to IV conversion: 
Oral CSP dose  2.5 = IV dose 
 
Oral Sandimmune may be substituted for oral Neoral. 
 
viii. Patients requiring hemodialysis should be have CSP levels maintained 
in the high therapeutic range (Table A). 
 
ix. Drugs that may affect CSP levels are:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*
*Discontinuation of fluconazole or itraconazole may lower CSP levels, 
and if used for antifungal prophylaxis, then changes in these drugs should 
be avoided during the first 2 months posttransplant. 
 
 
2. MMF 
a. Initiating MMF therapy: For related recipients: Oral administration of MMF 
will be at a daily total dose of 30 mg/kg/day based on adjusted body weight (15 
mg/kg/d every 12)  
 
For unrelated recipients: Oral administration of MMF will be at 15 mg/kg Q8 
hours (45mg/kg/day), based on adjusted body weight.  
 
Decrease CSP levels Increase CSP levels 
Enhance Potential for 
Nephrotoxicity 
Phenytoin 
Phenobarbital 
Carbamazepine 
Primidone 
Rifampicin 
Nafcillin 
Octreotide 
Sulfonamides 
Trimethoprim 
Metoclopramide 
Erythromycin        Diltiazem       
Alcohol                 Doxycycline 
Ketoconazole        Verapamil   
Acetazolamide      Nifedipine 
Fluconazole*        Nicardipine 
Colchicine            Azithromycin 
Itraconazole*        Imipenem      
Fluoroquinolones                   
Voriconazole              
Caspofungin             
Clarithromycin 
Aminoglycosides 
Loop diuretics (furosemide)  
Amphotericin formulations 
 


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b. The first dose will be on the evening of day 0 (i.e. first dose to follow 4-6 hours 
after stem cell infusion).  
 
c. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).  
 
d. If there is nausea and vomiting at any time preventing the oral administration of 
MMF, MMF should be administered intravenously at 15 mg/kg Q8 hours. 
 
e. Stoppage/Tapering of MMF: For related recipients, MMF will be given until 
day +27 post-transplant and then stopped without tapering in the absence of 
GVHD that requires therapy (e.g. steroids). If treatment for GVHD is required 
prior to day +27, MMF will be continued at full dose until a steroid taper begins. 
 
For unrelated recipients, MMF will be given based on adjusted body weight 
daily at 15 mg/kg Q8 hrs until day +40 post transplant and then tapered by 
12%/week to be discontinued after day +96, in the absence of GVHD requiring 
therapy. 
 
 
f. Guidelines for MMF dose adjustment for drug toxicity: If in the clinical 
judgment of the investigator and/or attending physician the observed toxicity is 
related to MMF administration, a dose adjustment will occur.  The 
discontinuation of MMF at any point should be discussed with the Study PI and 
should be documented in the permanent medical record and all Case Report 
Forms (CRF). Based on previous organ transplant studies, dose adjustments are 
likely to occur because of hematopoietic or rarely gastro-intestinal adverse 
effects. 
 
i. 
Neutropenia: A thorough evaluation of neutropenia should occur 
including peripheral blood chimerism studies, marrow aspiration 
and review of marrow suppressive medications (e.g. bactrim). G-
CSF may be started at 5g/kg subcutaneously qd to facilitate 
neutrophil recovery for patients with ANC <750/ul 21 days after 
HCT. Dose adjustments of MMF will only be made for severe 
neutropenia that develops or persists after day 21 post-transplant 
(ANC < 100/l for > 5 days) that is refractory to G-CSF treatment 
independent of any other toxicity. In this case dose reductions 
could be made and should be conservative (20-25%). MMF should 
only be discontinued temporarily. The MMF should be restarted at 
20% reduced dose when the underlying toxicity subsides. Any 
planned dose adjustments for hematologic toxicity must be 
discussed with the principal investigator. 
 
ii. 
Gastrointestinal toxicity: In the event of gastrointestinal toxicity 
that requires medical intervention including medication for control 
of persistent vomiting or diarrhea and is considered to be due to 
MMF, a 20% dose reduction will occur first and if there is no 


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improvement, MMF will be reduced a further 20%.  For severe 
G.I. toxicity related to MMF, then MMF may be stopped.  Patients 
should be evaluated by a Gastroenterology consultant to determine 
the need for dose adjustments for this indication.   
 
 
F.    Collection and infusion of donor G-PBMC 
1. G-CSF Administration to Donors:  
For related recipients: From day -4 to day –0, all PBSC donors will receive G-
CSF, at a dose of 16 μg/kg/day, for 5 consecutive days (Table 5). G-CSF will be 
administered by a subcutaneous daily injection. The schedule of G-CSF 
administration and PBSC collections can only be ascertained once day 0 is 
identified. Once a treatment regimen schedule has been fixed and the schedule of 
G-CSF administration and PBSC collections made this has to be confirmed with 
the personnel in the apheresis room.  Day 0 should be fixed on a Tuesday-
Thursday. 
For unrelated recipients: Timing of G-PBMC collection is prearranged through 
the NMDP. Day 0 should be fixed on a Monday-Thursday when possible. G-CSF 
will be administered by subcutaneous injection to the unrelated donor starting 5 
days prior to the day of HCT (see Table 5) as per NMDP protocol. Donors will 
receive approximately 10g/kg of G-CSF each day of mobilization. A 12 liter 
apheresis will be obtained on day –1 and possibly on day 0 for a total of 12 to 24 
liters of apheresis collection that will be infused on day 0. 
 
Table 5. Treatment Schema for donor 
Day 
-5 
-4 
-3 
-2 
-1 
0 
G-CSF (10-16 ug/kg) 
X  
X 
X 
X 
X 
 
G-PBMC collection 
 
 
 
 
X 
X 
 
2. G-PBMC Collection:  
For related recipients: donors will preferably undergo vein-to-vein collections or 
may receive an appropriate catheter inserted on or before day of apheresis. Two 
12-liter leukaphereses on consecutive days will be obtained, and cells will be 
infused together on day 0. First, PBSCs will be collected in the afternoon of day -
1, stored in the refrigerator at 4ºC overnight. A second collection will be 
performed the following afternoon and both collections will be transfused on day 
0. If < 5 x 106 CD34+ cells/kg are collected an additional day of collection will be 
performed. If PBSCs 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 
For unrelated recipients: G-PBMC scheduling and collection is arranged through 
the NMDP. The schedule of GCSF administration and collection of PBMC is 


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determined as per NMDP protocol. The physician responsible for HC collection 
will obtain informed consent from the donor. 
 
3. HCT infusion: All patients will receive unmodified G-PBMC infusion on day 0 
of the treatment regimen (Refer to institutional practice guidelines for methods of 
infusion). 
 
G. ABO incompatibility 
 
All patients with ABO incompatibility should be evaluated and treated according to the standard 
practice of the individual institution. Recommendations are provided in Appendix C. It should be 
noted that two cases of recipient hemolysis have been documented in patients with minor ABO 
mismatch with their donor. The suspected cause is donor anti-host hemagglutinin production 
from “passenger lymphocytes” in the donor G-PBMC that may expand posttransplant[101]. 
Therefore, these patients should be monitored and treated aggressively when there is any 
evidence of hemolysis. 
 
H.    Post-transplant growth factors 
Patients are not eligible to receive post-transplant growth factors such as G-CSF during the first 
21 days. Growth factors should not be given unless severe persistent neutropenia develops or 
persists past day 21 post-transplant (ANC <500/μl). 
 
I.    Infection prophylaxis 
Patients should receive prophylaxis for PCP, VZV, HSV, CMV and candida according to the 
standard practice of the individual institution for a conventional allogeneic HCT. Recommended 
infectious prophylaxis is provided in Appendix D. Standard CMV monitoring and prophylaxis 
should commence at the time of initial transplant and should continue until 1 year post HSCT. 
Recommendations for monitoring and evaluation of infectious complications are specified in 
Appendix D. In case of low donor chimerism or disease progression that necessitates transfer of 
DLI to the patient, modifications in infection prophylaxis will be made according to that 
protocol. 
 
J.    Chimerism 
 
 
1. Definition 
For the purposes of this protocol, definitions will be: 
 
a. 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. 
b. Full donor chimerism is defined as > 95% donor CD3+ T cells.  Mixed 
or full donor chimerism will be evidence of donor 
engraftment 


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c. Increasing donor chimerism is defined as an absolute increase of 20% 
of donor CD3+ T cells over the previous chimerism evaluation. 
d. 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. 
e. Decreasing donor chimerism is defined as an absolute decrease of ≥ 
20% of CD3+ T cell chimerism over the previous month. 
 
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 nuclear cell fraction from marrow aspirates. 
 
2. Evaluation 
Patients will have peripheral blood and whole bone marrow evaluations for 
chimerism at various time points through one year post transplant. If the patient 
has not obtained > 95% donor chimerism in CD+3 by one year continue to 
evaluate through 5 years post transplant as clinically necessary. Peripheral blood 
will be sorted to evaluate T-cell (CD+3), granulocyte (CD+33), and/or NK cell 
(CD56) compartments. (See Patient Post Transplant Evaluation section for 
instructions and exceptions). 
 
3. Continuation of immunosuppression  
a. In case of low or decreasing donor chimerism. Immunosuppression 
should be continued or reinitiated at full dose until the low donor 
chimerism is corrected or the patient may be eligible for another 
protocol for DLI according to institutional practice. 
b. Patients who reject their graft may be eligible for a second allogeneic 
transplant on other protocols. 
 
4. Definition of mixed donor/host chimerism, engraftment, graft failure and 
rejection. 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 


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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/or 
neutropenia after day 21 that continue, uninterrupted, for >3 
weeks and is refractory to transfusions and growth factor 
support, respectively. 
 
 
K. Management of disease progression 
 
In case of disease progression and >40% T-cell donor chimerism. Evidence of 
substantial disease progression (as defined in Appendix H) will be an indication 
for therapeutic intervention. In part, this will be dependent on where a patient is 
relative to the standard tapering schedule. If the attending physician believes that 
the patient requires very aggressive therapy, the case will be presented to the 
institutions’ patient review committee. Otherwise, priority should be given to 
rapid reduction of immunosuppression, option (i) below. Therapeutic options 
include: 
 
1. Early discontinuation of immunosuppression (prior to day +28 for related and 
day +100 for unrelated recipients). This should be considered the first 
therapeutic maneuver. If there is no GVHD, MMF is to be stopped if still 
being taken, and CSP tapered over 2 weeks. Bone marrow aspirate and blood 
chimerism studies will be performed when off immunosuppression after 2 
weeks. If disease continues to progress 2 weeks after stoppage of all 
immunosuppression, <20% increase in donor chimerism and there is no 
GVHD, patients will be considered as treatment failure. The patient may then 
be eligible for DLI treatment according to institutional practice. 
 
2. Early discontinuation of immunosuppression (between days +28 and +180 for 
related and days +100 and +180 for unrelated recipients). If there is no 


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GVHD, CSP is to be stopped. Bone marrow aspirate and blood chimerism 
studies will be performed when off immunosuppression after 4 weeks. If 
disease 
continues 
to 
progress 
2 
weeks 
after 
stoppage 
of 
all 
immunosuppression, T cell chimerism has not significantly increased (<20% 
increase) and there is no GVHD, patients will be considered as treatment 
failure. The patient may then be eligible for DLI treatment or according to 
institutional practice. 
 
3. Intercurrent treatment with chemotherapy or radiation. Conventional 
chemotherapy or radiation therapy should be considered in the setting of life 
threatening disease progression. Patients in this situation would be considered 
treatment failures. After therapy is completed, the patient may then be eligible 
for DLI treatment or according to institutional practice. 
 
4. Conventional allogeneic HCT. This option should be discussed with the 
institutions’ patient review committee and the principal investigator. Patients 
who undergo conventional allogeneic HCT will be removed from the protocol 
at that time. 
 
 
10.   Patient and Donor Evaluations
 A. Patient Pretransplant Baseline Evaluation
 
1. History: A complete history with full details of the patient’s prior treatment and 
response  
 
2.   Assessment of patient pretransplant comorbidities and scoring them using the HCT-
Comorbidity Index (HCT-CI; see Appendix Q).  
 
3. Careful physical exam with determination of Karnofsky score (Appendix B). 
 
4.  Complete blood count (CBC), serum sodium, potassium, chloride, CO2, creatinine, 
BUN, uric  acid, calcium, magnesium, phosphate, total bilirubin, alkaline 
phosphatase, AST, ALT, ABO/Rh typing, hepatitis screen, CMV, VZV, HSV and 
toxoplasma serology, and anti-HIV serology.  
 
 
5. Chest X-ray (CXR), PA and lateral views. 
 
6. Pulmonary function tests with corrected DLCO.  
 
7. MUGA scan or echocardiogram to evaluate cardiac ejection fraction for patients > 50 
years of age, or history of cardiac disease or prior transplant or anthracycline exposure. 
 
 


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Additionally, see Table 6 for further pre-transplant evaluations. 
 
 
Table 6: Disease-Specific Pre-Transplant Evaluations 
 
Note: Bone marrow aspirates and biopsies are recommended to be bilateral and to be collected within 30 
days of treatment. See Tables 7, 8 and 9 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 
 
Bone marrow biopsy 
 
Pathology 
Clinical 
 
Peripheral Blood 
 
Storage for chimerism analysis 
Clinical 
 
Quantitative Ig levels 
Clinical 
 
β-2 microglobulin 
Clinical 
 
LDH 
Clinical 
 
ZAP – 70 by flow cytometry– *see comment 
Clinical 
*for patients not in CR 
Rituxan trough levels – *see comment 
Research - 
Maloney Lab 
*Should be done immediately prior 
to the Day -3 dose 
Imaging 
 
CT of chest, abdomen, pelvis (neck if indicated) 
Clinical 
 
 
 
 
 


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Pre-conditioning/Pre-transplant Research Studies only for FHCRC patients who have signed 
Consent D; 
 
1. Send  40cc heparinized blood and one 10ml red top tube to the Maloney Lab (206-667-4284; 
FHCRC D1-331) for cryopreservation of tumor cells.  Label the samples "Protocol 1840." 
 
These cells will be used as a possible source of leukemia against which the efficacy of killer 
T cells could be evaluated. The option of leukapheresis for sample acquisition will be 
discussed with the patient and Attending Physician.   
 
2. Leukapheresis may be done in order to collect a large volume of mononuclear cells.  
Leukapheresis will be performed using the apheresis machines at the Seattle Cancer Care 
Alliance and will be done prior to the start of transplant conditioning. 
 


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1. See Table 7 for disease specific post-transplant evaluation on Day +28, 56, 84, etc. This 
is a recommended evaluation schedule. 
Additionally, include the following for all diseases:  
 
2. CBC three times a week, or more often if clinically indicated, from day 0 until day +28, 
and twice weekly until 2 months post-transplant or later if clinically indicated. 
 
3. Electrolyte panel and renal and hepatic function 3 times per week until day +28 and then 
weekly.   
 
4. Evaluate at Day +84 
GVHD evaluation guidelines: 
a. History and physical exam with attention to the evaluation of chronic 
GVHD (Appendix G) 
b. Complete blood count, serum IgG, and serum total bilirubin, alkaline 
phosphatase, ALT, and AST 
c. Skin biopsy 
d. Schirmer's tear test 
e. Pulmonary function test 
f. Oral exam  
g. Dietician assessment 
h. Gynecological assessment (adult female) 
 See Section 11 for diagnosis and treatment guidelines for acute and chronic GVHD.
 
5. Patients should be assessed for the need of IVIG monitoring and replacement therapy per 
Institutional Guidelines 
 
 
 
 
 
 
 
 
 


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Table 7: Post-Transplant Evaluation (See text for pre-transplant evaluations) 
This is a recommended evaluation schedule. Note that research draws are for FHCRC patients only.  See Table 8 for peripheral blood research studies.   
See Table 9 for additional lab instructions. 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days  
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
CLL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate - unilateral * After one year from transplant if patient is in CR, bone marrow is recommended only as clinically indicated.   
    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 
Clinical 
*If abnormal pre-transplant 
*see 
comment 
*see 
comment 
*see 
comment 
*see 
comment 
*see 
comment 
*see 
comment 
*see comment 
BM biopsy – unilateral* After one year from transplant if patient is in CR, bone marrow is recommended only as clinically indicated.  
 
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 abnormal 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 
Β2 microglobulin 
Clinical 
*If abnormal pre-transplant 
 
 
*see 
comment 
 
 
 
 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Additional research 
studies 
Research – 
Maloney Lab 
 
See Table 8 for additional peripheral blood research studies 
 
Imaging 
 
CT of chest, abdomen, 
pelvis (neck if indicated) 
Clinical 
* Needed on Day 56 only if 
abnormal pre-transplant 
 
*see 
comment 
x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
 
 
 
x 
 
 
 
 


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Table 8: Peripheral blood research studies 
 
Disease 
Specimen 
Research 
Comment 
Days 
Years 
10 
24 
35 
38 
49 
60 
63 
80 
84 
110 140 
180 
1 
1.5 
CLL 
T cell response 
studies 
Research – 
Maloney Lab 
Only for pts. who have 
signed Consent D 
 
 
 
 
 
 
 
 
x 
 
 
x 
x 
 
Polymorphism 
studies 
Research – 
Maloney Lab 
For all Patients 
 
 
 
 
 
 
 
 
x** 
 
 
 
 
 
Rituxan trough 
levels* 
Research – 
Maloney Lab 
For all Patients 
x 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
Rituxan 
pharmacokinetics  
Research – 
Maloney Lab 
For all Patients 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
*Rituxan trough level on Day +10, Day +24, and Day +38 should be done immediately prior to rituximab dose 
** Polymorphism studies is included with the T-cell response draw, no extra blood will be drawn 
 


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Additional information for research studies is as follows: 
 
The blood obtained from the T cell response studies will be used as a source of donor T cells that 
recognize recipient minor histocompatibility or leukemia associated antigens. Briefly, mononuclear 
cells (PBMC) will be separated from the blood and aliquots will be cryopreserved.  Aliquots of the 
posttransplant PBMC will be stimulated in vitro with irradiated (3300 rads) recipient PBMC and 
leukemia cells that were cryopreserved pretransplant (Section 10). The pretransplant recipient 
PBMC may be activated with CD40L prior to irradiation and use as stimulator cells. Cultures will 
be restimulated at weekly intervals, supplemented with IL-2 (10-20 U/ml), and assayed for cytolytic 
and proliferative responses against recipient PHA induced T cell blasts, EBV-LCL, CLL and 
fibroblasts and against donor target cells generated from the donor PBMC. Independent aliquots of 
cultures exhibiting responses to recipient CLL but not donor cells will be depleted of CD4+ or CD8+ 
T cells to determine the subset of cells mediating cytolytic activity.  CD8+ and CD4+ T cells from T 
cell lines that are reactive with the patient CLL will be cloned by limiting dilution and the T cell 
clones will be further analyzed for specificity and function. 
CD3+ CD8+ T cell clones will be tested for cytolytic activity against 51Cr labeled donor and 
recipient B-LCL, PHA-induced T cell blasts, skin fibroblasts, and recipient CLL. T cell clones that 
lyse recipient hematopoietic cells but not dermal fibroblasts or donor hematopoietic cells (<5% lysis 
at E/T of 5:1) will be characterized for the class I MHC restricting allele using a panel of B-LCL 
from donors that are partially matched at HLA with the recipient.  T cell clones specific for minor 
histocompatibility antigens expressed by CLL and presented by common class I alleles (e.g. HLA 
A0101, A0201, A0301, A1101, A2402, B0702, B0801, B3501, B4001, and B4402) will be 
preferentially selected for gene discovery using cDNA expression cloning or genetic linkage 
analysis. 
 
The blood obtained for the polymorphism studies will be used to determine polymorphisms of 
FCγRIIIa and CD32 in comparison to pre-transplant polymorphisms. 
 
 
 
 
 


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Table 9: Additional Lab Instructions 
 
Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. 
Off-site providers may use local facilities for the tests. All research studies are for FHCRC patients only. 
 
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) 288-7700 
Pathology 
(aspirate) 
Clinical 
2mL bone marrow in 
EDTA formalin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
(206) 288-1355 
Pathology (biopsy) 
Clinical 
1cm bone marrow in 
formalin OR mounted 
in paraffin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-1355 
 
Flow Cytometry 
Clinical 
2mL bone marrow in 
green-top tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-7060 
Cytogenetics 
Clinical 
3mL bone marrow in 
green-top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
FISH 
Clinical 
2mL bone marrow in 
green-top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
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) 288-7060 
Flow Cytometry 
Clinical 
10mL blood in green-
top tube 
Label “protocol 1840) 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-7060 
Quantitative Ig 
Levels 
Clinical 
3mL blood in red-top 
tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 288-2057 
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) 288-2057 
ZAP – 70 by Flow 
cytometry 
Clinical 
5mL blood in green-
top tube 
UW Hematopathology Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 288-7060 
T cell response 
studies 
Research 
Pretransplant: 10mL 
blood in red-top tube 
and if Consent D is 
signed: 40 mL in 
green-top tube  
Label “protocol 1840” 
Maloney Lab 
FHCRC D1-331 
(206) 667-4260 
T cell response 
studies 
Research 
Posttransplant: 10mL 
blood in red-top tube 
and if Consent D is 
signed: 30 mL in 
Maloney Lab 
FHCRC D1-331 
(206) 667-4260 


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Specimen / 
Test 
Type 
Instructions 
Lab Name 
Contact Information 
green-top tube  
Label “protocol 1840” 
Polymorphism 
studies 
Research 
10mL blood in green-
top tube (only if no T-
cell response drawn) 
Maloney Lab 
FHCRC D1-331 
(206) 667-4260 
Rituxan trough 
levels 
Research 
10mL blood in red-top 
tube 
Maloney Lab 
FHCRC D1-331 
(206) 667-4260 
Rituxan 
pharmacokinetics 
Research 
10mL blood in red-top 
tube 
Maloney Lab 
FHCRC D1-331 
(206) 667-4260 
 
Outside institutions may use VNTR analysis (sex- matched transplants) or sex chromosome FISH-analysis 
(sex-mismatched transplants) for PB chimerism analysis. 
 
C. Donor Evaluation 
1. Unrelated donors will undergo evaluation for allogeneic hematopoietic cell donation 
at the collection center by NMDP standard. The attending physician of the collection 
center will review the results of the donor evaluation.  
2. A blood sample (10cc heparinized blood) from related and unrelated donors should be 
sent to the Maloney lab for determination of patient FCγRIIIa and CD32 
polymorphisms prior to HCT.  
 
 
11.    Drugs and toxicities Detailed treatment-related adverse events will be reported using the adapted NCI Common Toxicity Criteria (Appendix P).
 
A.  TBI 
TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 6 - 10 cGy/min. 
Dosimetry calculations are performed by the radiation therapist. At the dosage of TBI used in this 
protocol, patients have not experienced the adverse effects associated with myeloablative TBI such 
as fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, and mucositis. Late effects are 
unknown but may include cataract formation, growth retardation, pulmonary damage, and 
carcinogenesis.  
B.  CSP 
See section 9.E.1 for information about administration and dosage adjustments. Side effects are 
generally reversible and may include renal insufficiency and failure, hypomagnesemia, paresthesias, 
tremor, seizures, visual disturbances, paresis, disorientation, depression, confusion, somnolence, 
coma, nausea, hypertension, hemolytic-uremic syndrome, hyperglycemia, gynecomastia, and 
hypertrichosis. 
C.  MMF 
Mycophenolate mofetil (MMF): is supplied in 250mg hard gelatin capsules. Capsules 


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may be stored at room temperature. 
 
1. Precautions: MMF has not extensively been studied in patients after HSC transplantation. 
Previous clinical studies in patients after kidney transplantation suggested that the principal 
adverse reactions associated with the administration of MMF include leukopenia, sepsis, 
vomiting and diarrhea. Patients will be monitored for the development of these complications. 
 
2. Adverse Events: Studies in solid organ transplant recipients suggest that MMF may be 
associated with vomiting, diarrhea, anemia, leukocytopenia and infection. In the setting of 
marrow transplantation, however, several etiologic factors may contribute to above mentioned 
symptoms. 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 causative for the abnormality. These 
adjustments should be discussed with the principal investigator. Dose administration and 
adjustments are described in Section 9.E.2. 
D.  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. 
E. Rituximab (rituxan)  
 
Chemistry and Mechanism of Action.  The rituximab antibody is a genetically engineered chimeric 
murine/human monoclonal antibody directed against the CD20 antigen found on the surface of 
normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing 
murine light- and heavy-chain variable region sequences and human constant region sequences. 
Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino 
acids (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab 
has a binding affinity for the CD20 antigen of approximately 8.0 nM. 
 
Stability and Storage: Rituximab solutions for infusion are stable at 2 to 8 C (36 to 46 F) for 24 
hours and at room temperature for an additional 12 hours.  Rituximab vials should be protected 
from direct sunlight.  
 
Adverse Events. The predominate toxicity of Rituximab is infusion related fever, chills, 
rigors, hypotension during the initial infusion.   Premedication with acetaminophen and 
diphenhydramine may decrease the severity of the infusion complex.  In the event of an 


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infusion reaction, the infusion should be slowed or stopped until the symptoms resolve or 
are successfully treated.  The infusion should be restarted at one half the previous rate. 
Rapid depletion of B-lymphocytes may produce tumor lysis syndrome.  Rituximab 
administration must be followed precisely.  Patients on antihypertensive medications, or 
with prior history of cardiac arrhythmias may require additional clinical monitoring.  . Other 
adverse events of lowering of white blood cell or platelet counts, abnormal heart rhythms 
and/or congestive heart failure have also occurred.  Rituximab treatment may involve risks 
to the embryo or fetus that are unknown and both women and men should practice 
contraception.  Since Rituximab has only recently been approved by the FDA for use in the 
treatment of lymphoma, there is no long term information regarding toxicity.  Very rarely, in 
about 1 per 1000 patients treated, severe reactions resulting in death have been associated 
with Rituximab infusion. 
F.  GVHD 
For related recipients: In our phase I/II trials, grade II-IV acute GVHD associated with primary 
engraftment occurred in 49% of 192 evaluable patients, and the addition of fludarabine did not 
influence the incidence of grade II-IV or III-IV acute GVHD.  Clinical extensive chronic GVHD 
occurred in 74 (67%) of 110 evaluable patients. Two of the first 10 evaluable patients receiving an 
HLA matched sibling donor transplant after conditioning with fludarabine and TBI on Protocol 
#1533 died of grade IV acute GVHD following discontinuation of CSP at day +56. Fifteen of 21 
evaluable patients on Protocol #1533 had to restart immunosuppression after tapering off of CSP for 
clinically acute GVHD. The median day post-transplant for patients restarting immunosuppression 
for clinically acute GVHD was day +85 (range 65 to 107). These results prompted revision of the 
protocol (Protocol #1596) with extension of CSP to day +56 followed by a CSP taper that is 
adjusted based on the risk of relapse. 
For unrelated recipients: After nonmyeloablative HCT from 10/10 HLA-antigen matched 
unrelated donors, the incidences of grades II, III and IV acute GVHD in patients who received G-
PBMC grafts were 42%, 9% and 2% in protocol 1463 (with MMF q12hrs), and 39%, 10%, 2% in 
protocol 1641 (with MMF q8hrs) respectively. Acute GVHD has been readily controlled in most 
patients with high dose corticosteroids. Psoralen activated ultraviolet light (PUVA) has been 
required on occasion. Chronic extensive GVHD has occurred in 40 and 45% of patients in protocols 
1463 and 1641, respectively. 
1. Diagnosis:  
a.  On the day of GVHD evaluation, the diagnosis of acute or chronic GVHD 
will be made based on clinical criteria (Appendix F and G). Skin involvement 
will be assessed by biopsy and percentage of involved body surface area will 
be recorded in the medical record and CRF. GI symptoms suspicious for 
GVHD will be evaluated by biopsy as indicated. 
 
b. If manifestations of GVHD satisfy criteria for acute GVHD (Appendix F) 
and are not pathognomonic for chronic GVHD (Appendix G), for purposes of 
documentation and treatment, GVHD will be considered acute. The day post-
transplant will not be used to discriminate acute from chronic GVHD. This 


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recommendation is based on the observation77[102] that the onset of acute 
GVHD can be delayed after nonmyeloablative conditioning. 
 
c. If manifestations of GVHD are pathognomonic of chronic GVHD 
(Appendix G), for purposes of documentation and treatment, GVHD will be 
considered chronic even if concurrent manifestations satisfy criteria for acute 
GVHD (Appendix F). 
 
2.  Recommended Treatment: 
 
a. Patients developing acute GVHD > grade II while on CSP taper or off 
immunosuppression: 
i. 
CSP 5.0 mg/kg PO Q12 hrs. If there is concern of GI 
absorption use IV route (1.5 mg/kg Q12hrs). 
ii. 
Prednisone (2 mg/kg/day) may be added at diagnosis or if the 
GVHD manifestations are mild when there is no response after 
72 hours or if there is progression of GVHD during the 24 
hours after the start of CSP. Patients who respond to steroids 
after 10 to 14 days of treatment, should begin a 6 week steroid 
taper See below section 2.b. for MMF and CSP taper 
recommendations. 
iii. 
Patients may also be eligible for institutional trials of GVHD 
therapy. 
 
b.  Patients who develop acute GVHD  grade II prior to day +56 for related 
and prior to day +100 for unrelated recipients: 
 
Related recipients:  
i. Patients who develop acute GVHD > grade II prior to day +28 
should receive prednisone (2 mg/kg/day) or intravenous equivalent. 
MMF should not be discontinued on day +28. If nausea and/or 
vomiting prevent the oral administration of MMF, MMF should be 
administered intravenously at 15 mg/kg q8hrs.  Patients who respond 
to steroids after 10 to 14 days of treatment, should begin a 6 week 
steroid taper. MMF may be discontinued without taper, once 
prednisone has been tapered to a dose of 0.5 mg/kg/day. 
ii. Patients who develop acute GVHD > grade II after day +27 should 
receive prednisone (2 mg/kg/day) or intravenous equivalent. MMF 
need not be restarted. 
iii. Patients may also be eligible for institutional trials of GVHD 
therapy. 
 
 
 
 
 
 
 
 
Unrelated recipients: 
i. Patients who develop acute GVHD  grade II prior to day +40 
should receive prednisone (2 mg/kg/day) or intravenous equivalent. 


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Patients who respond to steroids after 10 to 14 days of treatment, 
should begin a 6 week steroid taper.  When steroids are tapered to 0.5 
mg/kg p.o. q.d then an MMF taper should be initiated. In the absence 
of a GVHD flare, the MMF and prednisone tapers should continue 
until completion. The suggested sequence for tapering MMF and CSP 
is as follows: taper MMF over 1-2 months, then taper the 
Cyclosporine such that the completion of the taper is NOT prior to 
Day + 180 post transplant.  If nausea and/or vomiting prevent the oral 
administration of MMF, MMF should be administered intravenously 
at 15 mg/kg TID.  
 
ii. Patients who develop acute GVHD  grade II after day +90 should 
receive prednisone (2 mg/kg/day) or intravenous equivalent. MMF 
need not be restarted. 
 
iii. Patients may also be eligible for institutional trials of GVHD 
therapy. 
 
c. Patients with clinical extensive chronic GVHD: CSP 5.0 mg/kg PO Q12hrs  
and prednisone 1 mg/kg qd or eligible protocols at the time. The patient 
should receive antibiotic prophylaxis with daily double strength Bactrim. 
 
d. Patients off immunosuppression who develop concurrent manifestations of  
GVHD that satisfy criteria for > grade II acute GVHD (e.g. erythematous 
rash, diarrhea, hyperbilirubinemia) and are pathognomonic of clinical 
extensive chronic GVHD (e.g. lichenoid oral changes, ocular sicca, 
scleroderma, bronchiolitis obliterans, contractures), should receive 
prolonged immunosuppressive therapy similar to that for chronic 
extensive GVHD. 
G.  Myelosuppression 
Grade IV myelosuppression will be defined as a decrease in ANC to <500/L and/or platelet count 
to  20,000/uL. If myelosuppression occurs, a bone marrow aspirate and biopsy should be 
performed in the proper clinical circumstances to exclude disease progression or graft rejection. 
Samples should be sent for chimerism analysis by a DNA-based assay that compares the profile of 
amplified 
fragment 
length 
polymorphisms 
(ampFLP) 
(or 
FISH 
studies 
or 
VNTR). 
Myelosuppression may occur in this patient population for a number of reasons such as direct toxic 
effect of drugs, rejection, or relapse.  
 
Patients with myelosuppression may be managed as follows:  1. Suspected MMF toxicity: refer to sections 9.E.2.fGuidelines for MMF dose adjustmentfor management recommendations.2. Suspected ganciclovir toxicity: consider changing to foscarnet.


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- 48 - 3. Patients who are > 21 days after HCT with a hypoplastic marrow and an ANC of 
750/uL may receive G-CSF 5
g/kg/day S.C.4. Thrombocytopenic patients will receive platelet transfusion as per standard care.
12.   Toxicity Reporting Guidelines 
 Detailed treatment-related adverse events will be reported using the adapted NCI Common Toxicity Criteria (Appendix P).13.    Records
Clinical records will be maintained as confidentially as possible by all collaborating institutions. 
Collection of Case Report Forms (CRF) at standard intervals is the primary method of collecting 
data from collaborating centers. Clinical Statistics at FHCRC maintains a patient database to allow 
storage and retrieval of patient data collected from a wide variety of sources. The principal 
investigator will ensure that data collected conform to all established guidelines for coding 
collection, key entry and verification. These data are then entered into a secure dedicated database 
operated by a data manager.  Any publication or presentation will refer to patients by a unique 
patient number and not by name to assure patient confidentiality. The licensed medical records 
department, affiliated with the institution where the patient receives medical care, maintains all 
original inpatient and outpatient chart documents. 
 At the FHCRC, patient research files are kept in a locked room. They are maintained by the FHCRC data collection staff that is supervised by an A.R.T. Access is restricted to personnel authorized by the Division of Clinical Research.
Collection of Survival and Disease Response Data Centers enrolling patients will complete case report forms within 120 days of HCT that detail events occurring within the 100 days after HCT (Appendix M).  The case report form provides detailed descriptions of the transplantation procedure, disease response, and complications. Detailed treatment-related adverse events will be reported using the NCI Common Toxicity Criteria (Appendix P). The coordinating center will contact subjects when they return to the HCT center for routine HCT follow-up at 3, 6, 12 and 24 months to ascertain the patient’s disease status and survival. Referring physicians are required to report the date and cause of death within 48 hours of occurrence. Supporting medical records must be available upon request to substantiate data on the case report forms. Death information including date and cause will be reviewed from these medical records, and will be confirmed by death certificate.
 
 
14. Statistical Consideration and Criteria of Termination of Study 
 
The primary objective of this protocol is to estimate survival using allogeneic HCT from related or 
unrelated donors after nonmyeloablative conditioning and peri-transplant Rituximab in patients with 
advanced CLL, and to gain a preliminary indication as to whether survival is improved compared to 
treatment with conventional salvage therapies.   The primary endpoint will be survival at 18 months.  
The 18 months time point is chosen because prior experience with HCT indicates that survival 


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reaches a relative plateau by that time, and thus offers an endpoint that can be evaluated somewhat 
more rapidly than 2 year survival.   The estimated 18 months survival with standard treatment 
(Campath-1H) from historical patients is approximately 0.45.  This treatment approach will be 
deemed promising for further study if we can achieve reasonable confidence that survival exceeds 
0.45.  Reasonable confidence will be taken to mean that the lower limit of a one-sided 90% 
confidence interval for the true survival fraction at 18 months is greater than 0.45. 
 
Protocol 1840 has enrolled 14 patients so far before the current changes. We anticipate enrolling 
eighty new patients in eight years from the data when peri-transplant Rituximab was added to the 
inclusion criteria.  The total targeted accrual for the protocol will be 94 but only the last 80 patients 
will be evaluated for the study objectives. 
 
Eighty new patients will be evaluated; thus the above criterion will be met if 43 or more of 80 
patients are alive at 18 months, then we will be at least 90% confident that the true survival rate 
exceeds 0.45.  We assume based on our prior studies that we will achieve 100% ascertainment of 
this endpoint in these closely followed patients.  The probability of such a favorable outcome is 
89%, if the true survival fraction at 18 months is 60% and 63% if the true fraction is 55%.  Our 
current experience with non-myeloablative HCT from unrelated donor in CLL indicates that this is 
a reasonable expectation. 
 
A secondary objective of this protocol is to test the hypothesis that pre- and post-transplant 
rituximab will reduce the incidence of chronic GVHD. Therefore, the incidence of chronic GVHD 
in the study population will be compared to that seen in our published historical controls receiving 
non-myeloablative allogeneic HCT without rituximab.  Enrollment of a total of 80 new patients will 
yield 90% power to detect an absolute decrease of 15% in the risk of chronic GVHD (45%→30%), 
and 64% power to detect a 10% absolute risk reduction for chronic GVHD (45%→35%), at the 1-
sided 0.1 level of significance. 
Criteria for Termination of Study 
This will be a single stage trial of a single cohort of 80 patients.  However, safety stopping rules will 
be imposed for acute grade IV GHVD at anytime that precludes the diagnosis of chronic GVHD, 
and transplant-related mortality at 200 days. If sufficient evidence exists to suggest that the true rate 
of transplant related mortality at day 200 exceeds 0.30, or the true rate of grade IV acute GVHD 
exceeds 0.10, then the protocol will be terminated.  Sufficient evidence will be taken to be any 
observed rate for which the lower limit of a one-sided 80% confidence interval exceeds the target 
rate.  
 
Therefore, stopping rules will be imposed for: 
 Transplant-related mortality at day 200 > 30% 
 Grade IV acute GVHD >10% at anytime that precludes the diagnosis of chronic GVHD 
 
These rules will be evaluated after every tenth patient is evaluable for the endpoint in question. 
Operationally, this will occur: 


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 Transplant-related mortality (by day 200. 30% threshold): 3/5, 5/10, 7/15, 9/20, 10/25, 
12/30, 14/35, 15/40, 19/50, 22/60, 25/70, 28/80 
 Grade IV acute GVHD (10% threshold) at anytime that precludes the diagnosis of 
chronic GVHD: 2/5, 3/10, 3/15, 4/20, 5/25, 5/30, 6/35, 7/40, 8/50, 9/60, 10/70, 11/80.   
  
These stopping criteria are listed in Table 10. Patients may continue to be enrolled pending the 
evaluation of these stopping rules after every tenth patient, but the outcome in subsequent patients 
cannot be used to override a stopping rule triggered in an earlier number. The operating 
characteristics of these stopping rules are given in Table 11.  
 
Table 10. Criteria for stopping trial based on day 200 evaluation 
Number of patients 
enrolled 
Number of Patients with 
Grade IV GVHD  
Number of Patients 
Experiencing day-200 TRM 
10 
3 
5 
20 
4 
9 
30 
5 
12 
40 
7 
15 
50 
8 
19 
60 
9 
22 
70 
10 
25 
80 
11 
28 
 
 
 


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Table 11. Operating characteristics of stopping rules 
 
Day 200 TRM 
Grade IV acute GVHD at anytime that 
precludes the diagnosis of chronic GVHD 
True rate 
of event 
Probability 
of stopping* 
Average N 
at stopping* 
True rate 
 of event 
Probability of 
stopping* 
Average N at 
stopping* 
0.35 
70% 
46 
0.15 
77% 
44 
0.40 
91% 
32 
0.20 
96% 
28 
0.45 
98% 
23 
0.25 
>99% 
19 
 
 
15. Targeted Planned Enrollment Table 
Table 12 shows the anticipated distribution of subjects based on data from the US Census Bureau and 
the age-adjusted incidence of CLL in populations in the United States from SEER. 
 
Table 12. Targeted Planned Enrollment Table 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
 
 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
     1 
     2 
     3 
Not Hispanic or Latino 
     32 
     45 
     77 
Ethnic Category Total of All Subjects* 
     33 
     47 
     80 
                             Racial Categories 
 
American Indian / Alaska Native 
      
     1 
     1 
Asian 
     1 
     1 
     2 
Native Hawaiian or Other Pacific Islander 
      
      
      
Black or African American 
     1 
     1 
     2 
White 
     31 
     44 
     75 
Racial Categories:  Total of All Subjects* 
     33 
     47 
     80 
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of All Subjects”. 
This is the targeted planned enrollment after adding peri-transplant rituximab and allowing grafts from related or 
unrelated HLA-matched donors). 
 
 
 


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16. Data Safety Monitoring Board and Adverse Events Reporting 
 
A. Monitoring the progress of trials and the safety of participants 
 
This protocol is a multi-institutional clinical trial that is monitored by the principal investigators 
(PI), Drs. Sorror and Dr. Maloney, with oversight by Dr. Sandmaier, and Dr. Storb, a Data Safety 
and Monitoring Board (DSMB), the Protocol and Data Monitoring Committee (PDMC) and the 
Institutional Review Board (IRB). The PI reviews outcome data with the protocol mentors for each 
local individual patient on a weekly basis at a minimum of 3 months after HCT and the updated 
data are presented at Mixed Chimerism Meetings that includes peer review by co-investigators.  
Adverse events are reported to the trial coordinator, one of the study nurses, or directly to the PI. 
The trial coordinators at collaborating centers or the local PIs will fax an official report of a serious 
adverse event to the coordinating center (FHCRC) within ten days. The serious adverse event report 
is reviewed by Dr. Sorror and Dr. Maloney. If the serious adverse event meets the FHCRC and/or 
NCI criteria for reporting then an official signed report is submitted to the FHCRC Institutional 
Review Office (IRO). All deaths, regardless of the cause, are reported to the IRB. This protocol has 
a dedicated independent DSMB responsible for monitoring patient safety on this clinical trial. The 
DSMB meets twice a year and all outcome data is reviewed including all adverse events reported to 
the coordinating center (FHCRC) along with those officially reported to the FHCRC IRO. The 
DSMB confirms whether or not the trial has met any stopping rules and reviews any patient safety 
problems necessitating discontinuation of the trial. A report from the DSMB is submitted to the 
FHCRC IRB as well as the trial coordinators/local PIs of this protocol. Furthermore, the FHCRC 
also has a PDMC that reviews the progress of the protocol with respect to the monitoring plan at the 
time of each annual renewal. An initial IRB review and approval will occur before any patients are 
enrolled in the trial and an annual IRB review and approval also is required. The DSMB will 
discontinue the review of outcomes when this protocol is closed to accrual.  
With respect to safety, all patients are monitored for the development of GVHD, myelosuppression, 
infections, and organ-specific toxicities. All patients, regardless of diagnosis, will be considered in 
the safety analysis. Because of the older age profile of the patients, complications of HCT, GVHD 
and infections, may be less well tolerated than patients on other protocols. These events will be 
closely monitored and severity of GVHD graded. Formal stopping rules for TRM, defined as death 
before day 100 not related to progression of disease, will be closely monitored and stopping rules 
are provided above in section 14 Statistical Consideration and Criteria Termination of Study. This 
endpoint encompasses serious problems associated with the potential complications of severe 
GVHD, infections, and rejection. 
Flow of information concerning clinical trial participants originates with the clinicians and nurses in 
the clinic or referring clinicians at other institutions and is transmitted to the Trial coordinator. At 
the FHCRC, health care providers and rotating attending physicians assess patients and record their 
observations regarding toxicity and response outcomes in the medical record. This documentation is 
extracted by the study nurse within 140 days +/- after HCT via chart review and collection of copies 
of source documents and entered into a hard copy or electronic Case Report Form (CRF). Drs. 
Sorror and Maloney will review the official CRF and primary source documents. When the CRFs 
are verified, they are signed by PI. Thus, multiple health care providers provide independent 


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observations and participate in monitoring this trial. Drs. Sorror or Maloney may be a clinician for 
some patients entered on this trial. However, assessments are the sum total of the primary health 
care provider (fellow or physician assistant), floor or outpatient nurse and the PI or other attending 
clinician involved with the patient averting possible conflict of interest having the PI as the 
attending clinician for protocol patients.  In addition, direct oversight from other PIs including Dr. 
Sandmaier and Dr Storb, will further minimize potential conflict of interest inherent in the PI 
serving as primary study monitor.  If determination of adverse events is controversial, co-
investigators will convene on an ad hoc basis as necessary to review the primary data and render a 
decision.  
This protocol is a multi-institutional protocol and all collaborating centers sign an agreement with 
the FHCRC stating that data generated from patients from the protocol will be reported accurately 
in a timely manner to the FHCRC. All centers have an IRB that review the protocol and that the 
local PIs contact when an adverse event on the protocol occurs. Most of the centers have internal 
auditing mechanisms that assure accurate assessment of clinical outcomes. Clinical outcome data 
are summarized and transmitted from collaborating centers as CRFs. When possible, primary source 
documents regarding patient outcomes are collected with patients’ names removed and replaced by 
Unique Patient Numbers (UPNs). The CRFs are generated from the collaborating centers at defined 
time points (100 days, 6 months, and yearly). The local PI will review the official CRF and primary 
source documents. When the CRFs are verified, they are signed by the local PI and the data are 
entered into a central database managed by the Trial Coordinator. 
 
B.  Plans for assuring compliance with requirements for reporting adverse events 
 
The adverse event reporting in this multi-institution clinical trial will follow the FHCRC Guidelines 
for serious adverse event (SAE) reporting. The FHCRC guidelines have been expanded to give 
further details on what events meet expedited reporting requirements for consistency in SAE 
reporting across the centers.  Definitions of particular events that require reporting are in Appendix 
P. These guidelines (attached in Appendix I.) detail the expedited reporting requirements, 
definitions of particular events. The trial coordinators at collaborating centers or the local PIs will 
fax an official report of an SAE to the coordinating center (FHCRC) within ten days.  The SAE 
report is reviewed by Dr. Maloney and Dr. Sorror.  If the SAE meets the FHCRC criteria for 
expedited reporting then an official signed report is submitted to the FHCRC Institutional Review 
Office (IRO) within 10 days.  All deaths, regardless of the cause, are reported to the IRB.  For 
patients being cared for at the FHCRC, health care providers communicate with the PI, trial 
coordinator or research nurses as events occur triggering subsequent reporting. For patients not 
being cared for at FHCRC the outside facilities communicate with the PI, trial coordinator, or 
research nurse for these reporting purposes. All other deaths and expected serious adverse events 
are reported to the IRB at the time of annual renewal and at the biannual mixed chimerism meeting.  
The PI for a study is responsible for this reporting and the IRO assures adverse event reporting on 
an annual basis.  The PI in the annual application for grant continuation will summarize reports of 
toxicities.  Furthermore, an additional safeguard for adverse event analysis and reporting in this 
protocol is provided by stopping rules. All collaborating PIs have fulfilled all NIH requirements for 
training in human subjects’ protection. 
 


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C. Plans for assuring that any action resulting in a temporary or permanent suspension of 
an NCI-funded clinical trial is reported to the NCI grant program director responsible for 
the grant 
 
This clinical research trial uses commercial agents and there is no associated Investigational New 
Drug (IND) or Investigational Device Exemption (IDE). Any temporary or permanent suspension, 
as determined by the PI, IRB, or PDMC, of this clinical research trial will be reported to the NCI 
grant program director by the PI. 
 
D. Plans for assuring data accuracy and protocol compliance 
 
Collaborating sites send signed consents, eligibility forms, and CRFs with source documents 
demonstrating eligibility, treatment, and serious adverse events (if applicable) to the study staff. 
These are reviewed for eligibility, adherence to the protocol, accuracy, and completeness by the 
study staff. Queries are sent to the collaborating investigators if CRFs are inaccurate or incomplete.  
 
The study is monitored under the FHCRC Monitoring Plan. The FHCRC Data and Safety 
Monitoring Plan details the full scope and extent of monitoring and provides for immediate action 
in the event of the discovery of major deviations.   
 
 
 
 


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 81.  Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, 
Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H.  Early 
results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and 
rituximab as initial therapy for chronic lymphocytic leukemia.  J Clin Oncol 23: 
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MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, 
Shen D, Dallaire BK.  Rituximab chimeric anti-CD20 monoclonal antibody therapy 
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 85.  Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H.  
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 87.  Weng WK, Levy R.  Two immunoglobulin G fragment C receptor polymorphisms 
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Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, 
Ritz J, Alyea E.  Rituximab for steroid-refractory chronic graft-versus-host disease.  
Blood 108: 756-762, 2006. 
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Falda M, Vener C, Laszlo D, Alessandrino PE, Narni F, Sica S, Olivieri A, Sperotto 
A, Bosi A, Bonifazi F, Fanin R.  Treatment of refractory chronic GVHD with 
rituximab: a GITMO study.  Bone Marrow Transplant 40: 273-277, 2007. 
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 91.  Ratanatharathorn V, Horowitz MM, Logan B, Arora M, Wang D, Uberti JP, Gale RP, Antin 
JH, Bornhaeuser M, Hale GA, Ringden O, Cairo MS, Gupta V, Cutler C, Anasetti C, 
Pavletic SZ.  Prior therapy with rituximab correlates with less acute graft-versus-host 
disease and better survival in B-cell lymphoma patients who received allogeneic 
peripheral blood stem cell transplantation (PBSCT).  Blood  110 (Part 1): 322a, 
#1063, 2007.(Abstract) 
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 92.  Ratanatharathorn V, Ayash L, Reynolds C, Silver S, Reddy P, Becker M, Ferrara JL, Uberti 
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 95.  Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, Amadori S.  
Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-
cell subsets in patients with idiopathic thrombocytopenic purpura.  Blood 110: 2924-
2930, 2007. 
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 96.  Charlson ME, Pompei P, Ales KL, MacKenzie CR.  A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation.  J Chronic Dis 40: 
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 97.  Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, 
Storb R.  Comparing morbidity and mortality of HLA-matched unrelated donor 
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 98.  Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, 
Storb R.  Morbidity and mortality with nonmyeloablative compared to myeloablative 
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 99.  Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B.  
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for 
risk assessment before allogeneic HCT.  Blood 106: 2912-2919, 2005. 
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 100.  Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R.  Outcomes after 
allogeneic hematopoietic cell transplantation with nonmyeloablative or 
myeloablative regimens for treatment of lymphoma and chronic lymphocytic 
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 101.  Ferrebee JW, Thomas ED.  Infusions of marrow in the treatment of radiation casualty.  
Cincinnati J Med 41: 515-524, 1960. 
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 102.  Thomas ED, Herman EC, Jr., Greenough WB, III, Hager EB, Cannon JH, Sahler OD, 
Ferrebee JW.  Irradiation and marrow infusion in leukemia.  Arch Intern Med 107: 
829-845, 1961. 
Reference ID: 41 
 
 


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APPENDICES – TABLE OF CONTENTS 
 
 
APPENDIX A  
ELIGIBILITY GUIDELINES FOR DONOR PBSC APHERESIS FOR 
TRANSFUSION 
APPENDIX B 
THE KARNOFSKY PERFORMANCE STATUS SCALE 
APPENDIX C  
ABO INCOMPATIBILITY 
APPENDIX D  
INFECTIOUS DISEASE GUIDELINES 
APPENDIX E 
GRAFT-VERSUS-HOST DISEASE DATA COLLECTION FORM 
APPENDIX F 
ACUTE GRAFT-VERSUS-HOST DISEASE GRADING 
APPENDIX G 
CHRONIC GRAFT-VERSUS-HOST DISEASE GRADING 
APPENDIX H 
EVALUATION OF DISEASE RESPONSE FOR CLL 
APPENDIX I 
STUDY COORDINATOR’S MANUAL INCLUDING PROCEDURE FOR 
REPORTING ADVERSE EVENTS 
APPENDIX J 
ADVERSE EVENT REPORT 
APPENDIX K 
NOTICE OF DEATH FORM 
APPENDIX L 
PATIENT DEMOGRAPHICS AND REGISTRATION FORM 
APPENDIX M 
CORE CASE REPORT FORM 
APPENDIX N 
INTRATHECAL THERAPY ADMINISTRATION 
APPENDIX O  
HLA MATCHING REQUIREMENTS FOR UNRELATED DONORS AT   
THE SCCA/FRED HUTCHINSON ALLIED SYSTEM  
APPENDIX P 
ADAPTED COMMON TOXICITY CRITERIA 
APPENDIX Q 
HCT COMORBIDITY INDEX 
APPENDIX R 
STAGING OF CLL 
 APPENDIX S 
WEIGHT/ ADJUSTED BODY WEIGHT FOR DRUG DOSING 
APPENDIX T 
COORDINATING CENTER FUNCTIONS 


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APPENDIX A 
 
ELIGIBILITY GUIDELINES FOR DONOR PBSC APHERESIS FOR 
TRANSFUSION 
 
  
IMMUNIZATION  
 
DONOR ELIGIBILITY 
  
Cholera 
 
 
 
No wait 
 
  
Diphtheria 
 
 
 
No wait 
 
  
Flu 
 
 
 
 
24 hour wait 
 
  
Gamma globulin 
 
 
No wait unless for hepatitis 
  
(Immune serum globulin) 
 
  
 Hepatitis B vaccine 
 
 
No wait unless given for hepatitis exposure 
 
  
Measles (Rubella) 
 
 
1 month wait 
 
  
Mumps 
 
 
 
2 week wait 
 
  
Polio - Sabin (inj) 
 
 
No wait 
 
  
Plague  
 
 
 
No wait 
 
  
Rabies  
 
 
 
1 year wait if given as treatment for bite.  2 
week wait if given as prophylaxis (DMV's or 
zoo workers) 
 
  
Smallpox 
 
 
 
2 week wait 
 
  
Tetanus toxoid 
 
 
No wait 
 
  
Typhoid 
 
 
 
No wait 
 
  
Typhus 
 
 
 
No wait 
 
  
Yellow Fever  
 
 
2 week wait 


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APPENDIX B 
 
THE KARNOFSKY PERFORMANCE STATUS SCALE 
 
 
General 
 
 
        
Index  
Specific criteria 
 
Able to carry on normal  
 
100 
Normal, no complaints, no  
activity; no special care needed. 
  
evidence of disease. 
 
  
 
 
 
 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease. 
 
  
 
 
 
 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
 
Unable to work, able to live at  
70 
Care for self, unable to carry 
home and care for most personal 
 
on normal activity or to do 
needs, varying amount of 
 
 
work. 
assistance needed. 
  
 
 
 
 
60 
Requires occasional assistance from others but 
able to care for most needs. 
 
  
 
 
 
 
50 
Requires considerable assistance from others 
and frequent medical care. 
 
Unable to care for self, requires 
40 
Disabled, requires special 
institutional or hospital care or  
 
care and assistance. 
equivalent, disease may be 
rapidly progressing. 
  
 
 
 
 
30 
Severely disabled, hospitalization indicated, 
death not imminent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
 
 
 
 
 
 
 
10 
Moribund 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 


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 APPENDIX C 
ABO INCOMPATIBILITY 
 
Red Blood Cell - Incompatibility (Major): 
Occasional patients may have antibodies directed against red blood cell antigens found on the 
donor's cells. These are generally ABO or Rh antigens, although incompatibility with other red cell 
antigens identified by donor-recipient crossmatch may occur. Although the volume of red blood 
cells (RBC) in most PBMC products will only be 2-5% of the product volume before infusion, the 
small quantity may cause a hemolytic transfusion reaction. According to the FHCRC policy it is 
generally acceptable to infuse a volume of about 10ml RBCs per product. If the recipient shows an 
anti-donor titer of  1:32 or the RBC volume is greater than 10ml (or > 20ml in two products 
combined) the PBMC components should be RBC depleted by Starch Sedimentation (flowsheet 
below). Refer to the Clinical Coordinator's Patient Information Sheet for instructions regarding 
management of a specific patient.  
Post transplant blood component support will be according to Standard Practice Guidelines. 
 
Timing: Every attempt should be made to infuse red cell depleted PBMC products within 2 hours 
of depletion. 
Expected Results: Red blood cell depleted PBMC products will contain < 10ml of red blood cells 
and  90% nucleated cell recovery. 
 
Red Blood Cell - Incompatibility (Minor): 
Occasional donors may have antibodies directed against red blood cell antigens (ABO, Rh, or other 
antigen system) found on the recipient's cells. The risk of hemolysis of recipient red cells 
immediately after transplant is not of very much clinical import. Due to the high number of 
lymphocytes in the PBMC inoculum, recipients may be at much greater risk for a delayed type of 
hemolysis that can be severe. PBMC products contain < 200ml of plasma according to FHCRC 
policy and no deleterious effects have been observed so far. However, if donors show an anti-
recipient titer  1:256, the PBMC component should be plasma depleted (see flowsheet below). 
Refer to the Clinical Coordinator's Patient Information Sheet for instructions regarding 
management of a specific patient.  
Post transplant blood component support will be according to Standard Practice Guidelines. 
 
Timing: Every attempt should be made to infuse plasma-depleted PBMC within 2 hours of 
depletion. 
Expected Results: The plasma depletion should not affect the nucleated cell recovery. 
 
Red Blood Cell – Bidirectional Incompatibility: 
Patients undergoing transplants for bidirectional RBC incompatibility should be managed according 
to both algorithms shown below. Most red cell depletion techniques also deplete plasma from the 
PBMC component with no additional cell loss. Refer to the Clinical Coordinator's Patient 
Information Sheet for instructions regarding management of a specific patient.  
Post transplant blood component support will be according to Standard Practice Guidelines. 


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Appendix C (continued) 
 
 
MAJOR ABO INCOMPATIBLE 
Recipient anti-
Donor titer 
 1:32 
<20ml RBC total 
  Infuse without modification 
>20ml RBC total 
  RBC depletion of component 
 1:16 
  
Infuse without modification 
MINOR ABO INCOMPATIBLE 
Donor anti-
Recipient titer 
 1:256 
Plasma depletion of component 
 1:128 
Infuse without modification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
INFECTIOUS DISEASE GUIDELINES 
Please note that the content of these PDFs is from the Fred Hutchinson Clinical Research Division 
Standard Practice Manual and does not contain research related procedures. 
 
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment 
HSV-VZV
 
CMV Prevention: Surveillance and Preemptive Therapy 
CMV Prevention
 
CMV Disease: Diagnosis and Treatment 
 
Antifungal Therapy Guidelines 
Antifungal Therapy
 
Pneumonia / Pneumocystis Jiroveci Prophylaxis 
 
Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GvHD 
Requiring Immunosuppressive Therapy 
AntibioticProphylaxis
-Encapsulated
 
Vaccinations 
 
Foscarnet 
 


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APPENDIX E 
 
GRAFT-VERSUS-HOST DISEASE DATA COLLECTION FORM 
 
GVHD TREATMENT: 
 
Check each agent used to treat GVHD:  
Date Treatment Started
 None 
 
 
 Cyclosporine  
 
 
 
 
 
__ __/__ __/__ __ __ __ 
 
 Systemic Corticosteroids  
 
 
__ __/__ __/__ __ __ __ 
 
 Topical Corticosteroids 
 
 
 
__ __/__ __/__ __ __ __ 
 
 Beclomethasone  
 
 
 
 
__ __/__ __/__ __ __ __ 
 
 Rapamycin 
 
 
 
 
 
 
__ __/__ __/__ __ __ __ 
 
 MMF  
 
 
 
 
 
 
 
__ __/__ __/__ __ __ __ 
 
 ATG 
 
 
 
 
 
 
 
 
__ __/__ __/__ __ __ __ 
 
 In Vivo anti-T lymphocyte McAb  
__ __/__ __/__ __ __ __ 
 
 Blinded Randomized Trial 
 
 
__ __/__ __/__ __ __ __ 
 
 
Specify_____________________ 
 
 Other, specify________________ 
__ __/__ __/__ __ __ __ 
 
 
___________________________ 
 
Date of Death: 
 
 
 
 
__ __/__ __/__ __ __ __ 
 
Was an autopsy done? 
 
 
 
  Yes 
  No 
 
Was GVHD found at autopsy? 
 
  Yes 
  No  
  N/A 
 
 
If yes: 
 
 Skin 
 
 
 
 Liver 
 
 
 Gut 
GVHD SUMMARY 
 
Date of onset:  
 
__ __/__ __/__ __ __ __  Day____________ 
 
Overall Grade________________ 
 
Skin______________ 
Liver______________ 
Gut_____________ 
 
Comments______________________________________________________________________
______________________________________________________________________________ 
_______________________________________________________________________________ 
 
 
 


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BIOPSIES 
 
Was skin biopsy done? 
 
 
 
   Yes 
   No 
Date of skin biopsy: 
 
 
 
 
__ __/__ __/__ __ __ __ 
Results: 
 
 Negative  
 
 
 Positive GVHD 
 
 Positive Other 
 
Was liver biopsy done? 
 
 
 
   Yes 
   No 
Date of liver biopsy:  
 
 
 
__ __/__ __/__ __ __ __ 
Results: 
 
  Negative 
 
 Positive GVHD 
 
 Positive Other 
Did patient have any GI Biopsy?  
 
   Yes 
   No 
 
Date of biopsy: 
 
 
 
__ __/__ __/__ __ __ __ 
Results: 
 
 Negative 
 
 Positive GVHD 
 
 Positive Other 
CLINICAL SKIN 
 
Did patient ever have rash after transplant?  
   Yes 
   No 
 
Was rash thought to be due to GVHD?  
 
   Yes 
   No 
 
Date of onset of rash:  
 
 
 
__ __/__ __/__ __ __ __ 
 
Extent of rash on date of first treatment for GVHD: ___________________ 
Maximum severity of rash: 
  
 0 – No rash 
 1 – Maculopapular rash <25% BSA 
 2 – Maculopapular rash 25-50% BSA 
 3 – Generalized erythroderma 
 4 – Generalized erythroderma with bullous formation and desquamation 
 
 
Date of maximum rash severity:  
__ __/__ __/__ __ __ __ 
 
CLINICAL LIVER 
 
Bilirubin level on date of first treatment for GVHD:  
 
 
 
 
 
 
Maximum Bilirubin 
 
Date 
 
__ __/__ __/__ __ __ __ 
 
 
 0 – Bilirubin < 2.0 mg/dl 
 
 1 – Bilirubin 2.0 – 3.0 mg/dl 
 
 2 – Bilirubin 3.1 – 6.0 mg/dl 


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 3 – Bilirubin 6.1 – 15.0 mg/dl 
 
 4 – Bilirubin >15.0 mg/dl 
 
Did patient have other liver process?  
 
   Yes 
   No 
 
 VOD 
 
 Cyclosporine Toxicity 
 
 Sepsis 
 
 Other liver complication 
CLINICAL GUT 
 
GI consult? 
   Yes 
   No  
Date of Consult:__ __/__ __/__ __ __ __ 
 
Stool volume on date of first treatment for GVHD: 
 
____________ 
 
Maximum Daily Stool Output after day 21 
 
 
 
 
 
 
 
 0 - 0 - 200 ml  
 
 
 
 1 - >200 but 1000 ml 
  
 
 2 - >1000 but 1500 ml 
  
 
 3 - >1500 ml  
 
  
 
 4 - Severe abdominal pain with or without ileus 
 
Date of maximum stool output: 
 
__ __/__ __/__ __ __ __  
 
Was stool mixed with urine on day of Maximum Stool Output? 
   Yes 
   No 
If stool volume not measurable, what was maximum number of stools/day?    _______ 
 
Date of maximum number of stools/day: __ __/__ __/__ __ __ __ 
Did patient have the following process?  
 
 Frank blood in stool attributed to GVHD 
 
 CMV infection of GI tract at time of maximum stool volume 
 
 Narcotic withdrawal at time of maximum stool volume 
 
 C. difficile infection at time of maximum stool volume 
 Other GI process Specify___________________________________ 
 
Date Completed __ __/__ __/__ __ __ __  
Completed by:    
 
 
 
 
 
 
 
 
 


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APPENDIX F 
ACUTE GRAFT-VERSUS-HOST DISEASE GRADINGa 
 
Severity of Individual Organ Involvement 
Skin 
 
 +1 
 
a maculopapular eruption involving less than 25% of the body surface 
  
 
 
+2 
a maculopapular eruption involving 25-50% of the body surface 
  
 
 
+3 
generalized erythroderma 
  
 
+4 
generalized erythroderma with bullous formation and often with desquamation 
 
Liver 
 
+1 
    bilirubin (2.0-3.0 mg/100 ml) 
  
 
 
+2 
bilirubin (3-5.9 mg/100 ml)  
  
 
 
+3 
bilirubin (6-14.9 mg/100 ml)  
  
 
 
+4 
bilirubin > 15 mg/100 ml  
 
Gut 
 
Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or anorexia 
caused by GVHD is assigned as +1 in severity 
  
 
 
The severity of gut involvement is assigned to the most severe involvement noted. 
  
 
 
Patients with visible bloody diarrhea are at least stage +2 gut and grade +3 overall 
 
Diarrhea 
  
 
 
+1 
 1000 ml of liquid stool/day* ( 15ml of stool/kg/day)† 
  
 
 
+2 
>1,000 ml of stool/day* (> 15ml of stool/kg/day)† 
  
 
 
+3 
>1,500 ml of stool/day* (> 20ml of stool/kg/day)† 
  
 
 
+4 
2,000 ml of stool/day* ( 25ml of stool/kg/day)† 
 
*In the absence of infectious/medical cause 
†For pediatric patients 
 
Severity of GVHD 
Grade I  
+1 to +2 skin rash 
  
 
 
No gut or liver involvement 
 
 
Grade II  
+1 to +3 skin rash  
 
 
 
+1 gastrointestinal involvement and/or +1 liver involvement  
 
Grade III 
+2 to +4 gastrointestinal involvement and/or 
  
 
 
+2 to +4 liver involvement 
  
 
 
with or without a rash 
 
Grade IV 
Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms 
or death 
_______________ 
a From “Graft-vs-host disease” Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas, K. Blume, S. 
Forman, Blackwell Sciences; 1999, pages 518-519 


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


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


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GRADING OF CHRONIC GRAFT-VERSUS-HOST DISEASE 
 
A Clinical limited chronic GVHD 
1. Oral abnormalities consistent with chronic GVHD, a positive skin or lip biopsy, and no 
other manifestations of chronic GVHD 
2. Mild liver test abnormalities (alkaline phosphatase  2x upper limit of normal, AST or ALT 
 3x upper limit of normal and total bilirubin  1.6) with positive skin or lip biopsy, and no 
other manifestation of chronic GVHD 
3. Less than six papulosquamous plaques or limited skin rash or dyspigmentation (< 20% of 
the body surface), positive skin biopsy, and no other manifestations of chronic GVHD 
4. Ocular sicca (Schirmer’s test  5mm), positive skin or lip biopsy, and no other 
manifestations of chronic GVHD 
5. Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of 
chronic GVHD 
 
 
B. Clinical extensive chronic GVHD 
1. Involvement of two or more organs with symptoms or signs of chronic GVHD, with biopsy 
documentation of chronic GVHD in any organ 
2. > 15% base line body weight loss not due to other causes, with biopsy documentation of 
chronic GVHD in any organ 
3. Skin involvement more extensive than defined for limited chronic GVHD, confirmed by 
biopsy 
4. Scleroderma or morphea 
5. Onycholysis or onychodystrophy thought to represent chronic GVHD, with documentation 
of chronic GVHD in any organ 
6. Decreased range of motion in wrist of ankle extension due to fasciitis caused by chronic 
GVHD 
7. Contractures thought to represent chronic GVHD 
8. Bronchiolitis obliterans 
9. Positive liver biopsy; abnormal liver function tests not due to other causes with alkaline 
phosphatase > 2x upper limit of normal, AST or ALT > 3x upper limit of normal, or total 
bilirubin > 1.6, and documentation of chronic GVHD in any organ 
10. Pericarditis or pleuritis not due to other causes 
11. Positive upper or lower GI biopsy 
 
 
_________________ 
a From Standard Practice Guidelines for “Chronic Graft-versus-Host Disease Classification at the time of presentation” developed 
by Long Term Follow-Up at the FHCRC 


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APPENDIX H 
 
EVALUATION OF DISEASE RESPONSE FOR CLL  
 
CLL: Modified response criteria based on the NCI-Working Group and the International Workshop Group 
Joint Formal Criteria for evaluating disease response for CLL. [1-3] 
 
Complete Remission (CR) 
 
Imaging studies (Xray, CT, MRI)  (nodes, liver, and spleen) 
Normal 
Peripheral blood by flow cytometry 
No clonal lymphocytes 
Bone marrow by morphology 
No nodules; or if present, nodules are free 
from CLL cells by immunohistochemistry 
Duration  
≥2 months 
CR with minimal residual disease 
 
Peripheral blood or bone marrow by flow cytometry 
>0 - <1 CLL cells/1000 leukocytes (0.1%) 
Partial Remission (PR):  
 
Both  criteria: 
 
Absolute lymphocyte count in peripheral blood 
≥50% decrease3 
Physical exam/Imaging studies (nodes, liver, and/or spleen) 
≥50% decrease3,4 
Duration  
≥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 
Lymph node Biopsy 
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. 
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 


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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 I 
 
STUDY COORDINATOR’S MANUAL 
INCLUDING PROCEDURE FOR REPORTING ADVERSE EVENTS 
 
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 regardless of the policies of the institution. 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 and a copy of the signed 
informed consent will be faxed (206-667-5378) prior to treatment initiation. Patients must be 
registered prior to treatment initiation for valid registration 


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Appendix I (continued) 
 
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 unexpected and serious adverse events which may be due to study treatment or 
intervention must be reported to the FHCRC Institutional Review Office as soon as possible 
but within at least 10 calendar days of the investigator learning of the event. 
 
Definitions 
 
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.  
 
Life-threatening Adverse Event – Any adverse event that places the patient or subject, in view of 
the investigator, at immediate risk of death from the reaction.  Study toxicities are graded using the 
NCI Common Toxicity Criteria (where appropriate use the criteria for transplant patients.)  All 
Grade 4 (life-threatening) toxicities occurring between start of conditioning to day 200 that meet 
expedited reporting requirements must be reported as soon as possible but within at least 10 
calendar days of the investigator learning of the event.  
 
Unexpected Adverse Event – An adverse event, the nature or severity of which is not consistent 
with the applicable product information (e.g., Investigator’s Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product).  If applicable product information is not available, such as for studies that do not involve 
pharmaceutical products or devices, an unexpected adverse event is an adverse event that was not 
described in the study protocol or informed consent. 
 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following 
outcomes:   
 Death – start of conditioning to day 200, regardless of cause,  
 A life-threatening adverse event (see above)  
 A persistent or significant disability/incapacity,  
 A congenital anomaly  
 Requires intervention to prevent permanent impairment or damage.  
 
 


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Appendix I (continued) 
 
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 nonmyeloablative 
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. 
 
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. 
 
Attribution - The FHCRC designation for the determination of whether an adverse event is related 
to a medical product, treatment or procedure will be as follows: 
 Related – includes adverse events that are definitely, probably, or possibly related to the medical 
treatment or procedure. 
 Not Related – includes adverse events are doubtfully related or clearly not related to the medical 
treatment or procedure. 
 
The FHCRC Serious Adverse Event (SAE) Report Form should be completed for all adverse events 
that meet the expedited reporting requirements.   All available information should be submitted but 
it is acceptable to fax an incomplete report form at the initial report.  A completed report should be 
faxed as soon as possible but must be received within 10 calendar days. 
 
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. 
 
Serious adverse events that do not meet the requirement for expedited reporting (not related to study 
treatment or expected) will be reported to the IRB as part of the annual renewal of the protocol. 
 
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.   
 
 
 
 


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Appendix I (continued) 
 
Procedure for Reporting Serious and Unexpected Adverse Events from Participating Sites 
Regulations defining the responsibilities for reporting serious and unexpected adverse reactions are 
defined above.  Serious and unexpected adverse events must be reported to the FHCRC Investigator 
within 10 days of learning of the event. This includes patient deaths (serious, unexpected, and 
related/possibly related), regardless of cause, occurring start of condition to day 200 post-transplant 
procedure.  The immediate telephone report must be followed by faxed comments to the Trial 
Coordinator at (206) 667-5378. This will be followed by detailed written report (See Appendix J) 
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. 
 
Obligation of Investigators 
All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur between 
start of conditioning to day 100 during the study will be recorded on the Case Report Form 
(Appendix M).  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 
modified (for HSCT) NCI Common Toxicity Criteria (Appendix P).  Attributes will include a 
description, date of onset, maximum severity, and assessment of relationship to the study agent or 
other suspect agent(s). 
 
Adverse events will be graded accordingly: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life 
threatening or debilitating, and 5 = fatal.   All Grade 4 (life-threatening) or Grade 5 (fatal) events on 
the NCI scale meet expedited reporting requirements. 
 
Association or relatedness to the study agent will be graded as follows: 1 = unrelated, 2 = unlikely, 
3 = possibly, 4 = probably, and 5 = definitely related. 
 
V. Case Report Forms 
 
Case report forms must be completed for all patients registered onto the protocol and submitted to 
the FHCRC data coordinating center. The first case report form (day 28) is due on day 50.  For 
outside centers a Staging Form must accompany the form with the patient staging at registration, 
day 28, day 56, day 84 and day 100. Staging forms should also be completed with each Follow Up 
Form completed on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter. For Outside 
Centers, case report forms are expected to be submitted no later than 30 days following the 
scheduled follow up date.  
 


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VI. Protocol Monitoring 
 
As the coordinating center, FHCRC will monitor accrual at the outside institutions. 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. 
 
 
Appendix I (continued) 
 
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 institution’s 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 
 
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 J 
Fred Hutchinson Cancer Research Center 
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
 
FHCRC IR File Number: 
 
FHCRC Protocol Number: 
 
FHCRC Unique Patient #  
 FHCRC/SCCA   
  Other 
Gender:  
 Male  
 Female 
Age:   
FHCRC Principal Investigator:  
 
 
Phone Number: 
Mailstop: 
 
Date study staff became aware of event: ______________ 
 
Date of Report:              
 
 
 Initial Report 
 Follow-Up Report #  
 Other 
Date Serious Adverse Event Started: 
Date Ended:      
Or 
 Ongoing (if ongoing – must submit follow up report) 
Adverse Event: 
 
 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
(Or attach a MedWatch Form or other SAE reporting form if one has been completed.)  Use Page 2, if necessary: 
 
Outcomes Attributed to adverse event:  (Check all that apply) 
 Death            /           /     
 Life-Threatening 
 Hospitalization (initial or prolonged) 
 
 Disability 
 Congenital Anomaly 
 Required intervention to prevent permanent                      
impairment/damage 
Specify Agent(s) and/or Procedure(s) involved in this protocol: 
 
#1 
Pharmaceutical product/medical treatment/procedure 
 
#2 
Pharmaceutical product/medical treatment/procedure 
 Not Related (Unrelated, Unlikely) 
 Not Related (Unrelated, Unlikely) 
 Related (Possible, Probable, Definite) 
 Related (Possible, Probable, Definite) 
 
 
 Follow-up Report Required 
 Final Report (PI must sign final report) 
 
Report Completed by: 
 
Date: 
 
The PI has determined that the consent form must be revised: 
 Yes      
 No 
 
Does this study involve the deliberate transfer of recombinant DNA or DNA or RNA derived from recombinant 
DNA, into human subjects (human gene transfer)? 
 yes  
 no  If yes and the activity involves the SCCA 
outpatient clinic, a copy of this Protocol Modification Form and any supporting documents to be reviewed and 
approved, will be forwarded to the FHCRC’s Institutional Biosafety Committee (IBC) by the Protocol Office 
(Mailstop:  LM-230). 
 
Signature of Principal Investigator 
 
Date: 


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Page 2 
Fred Hutchinson Cancer Research Center  
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
 
 
 
FHCRC IR File Number: 
 
FHCRC Protocol Number: 
 
FHCRC Unique Patient #  
Date of Report:              
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX K 
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 L 
Patient Demographics and Eligibility Form 
1840 
Please Fax this completed form to (206)-667-5378 for patient registration. 
Questions regarding eligibility should go to Mohamed Sorror, M.D., 206-667-2765. 
 
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 research subject 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 research subject 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). 
 Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of Hawaii, Guam, 
Samoa or other Pacific Islands). 
 Black/African American (A person having origins in any of the black racial groups of Africa). 
 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 
 
 
Protocol 1840 Eligibility  
 
Inclusion Criteria:  
All of the following questions must be marked “Yes” for the patient to enter the study.  
 
 
1. 
 Yes 
 No Patient signed IRB approved consent form.  
 
     Date: ___________ 
IRB File Number:   
 
 
 
Date of IRB Approval:  
 
 
 
 
 
   


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   2.        
 Yes 
 No Patient has a diagnosis of CLL (or small lymphocytic lymphoma) or 
Diagnosis of CLL that progresses to prolymphocytic leukemia (PLL).  
 
 3.   
 Yes 
 No   Patient has at least one of the following: 
 
 
 
 
 
a. 
 Yes 
 No 
 Has B-Cell CLL or PLL and failed to meet NCI 
Working Group criteria (Appendix H) for complete 
or partial response after 2 cycles of therapy with a 
regimen containing fludarabine (or another 
nucleoside analog, e.g. 2-CDA, pentostatin) or 
disease relapse within 12 months after completing 
therapy with a fludarabine (or another nucleoside 
analog) containing regimen. 
 
 
 
b. 
 Yes 
 No 
Has B-Cell CLL or PLL and failed FCR or PCR    
combination chemotherapy at any time point. 
 
 c. 
 Yes 
 No 
Has B-Cell CLL or PLL and had de novo or 
acquired “17p deletion” cytogenetic abnormality. 
Patients should have received induction treatment 
but could be transplanted in 1st CR. 
 
4.      
 Yes 
 No 
Related donor who is genetically phenotypically HLA-identical 
 
 
 
OR 
 
 
 
Unrelated donors who are prospectively: 
i) Matched for HLA-A,B,C, DRB1 and DQB1 alleles by high 
resolution typing AND 
ii) Only a single allele disparity will be allowed for HLA-A, B, or C 
as defined by high resolution typing (See appendix O for other donor 
selection details). 
 
 
 
 
 
Patient 
A:  ________
A:_________
C: _________
C: _________
B: _________
B: _________
DRB1:  ________
DRB1: ________
DQB1: ________
DQB1: ________
Donor 
 
A: _________
A:_________
C: _________
C: _________
B: _________
B: _________
DRB1:  ________
DRB1:_______
DQB1: ________
DQB1: _______
 
 


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iii) 
 Yes 
 No Have a negative anti-donor cytotoxic crossmatch. 
      
N/A      
Cytotoxic crossmatch not done as patient and donor are  
 
 
 
 
 
phenotypically identical by molecular methods.   
 
iv) 
 Yes 
 No Patient and donor pairs must not be homozygous at a mismatched 
allele. 
        
5.     
 Yes 
 No 
Patient is 18 years of age or older. 
 
 
Exclusion criteria:  
Each of the following questions must be marked “No” Or “NA” for the patient to enroll in the study.  
 
 
6.    
 Yes 
 No  
 Has active CNS involvement with CLL.  For LP requirement, see                                 
                                       Appendix N.   
 
7.    
 Yes 
 No  
 Patients with active non-hematologic malignancies (except non-        
melanoma skin cancers). 
This exclusion does not apply to patients with non-hematologic 
malignancies that do not require therapy 
 
 
8.   
 Yes 
 No            Patients with a history of non-hematologic malignancies (except non-
melanoma skin cancers) currently in a complete remission, who are less 
than 5 years from the time of complete remission, and have a >20% risk 
of disease recurrence. 
This exclusion does not apply to patients with non-hematologic 
malignancies that do not require therapy 
 
9. 
 Yes 
 No 
 NA  Fertile man or woman unwilling to use contraceptive techniques during 
and for 12 months following treatment.  
 
 10. 
 Yes 
 No 
 NA  Female who is pregnant or breastfeeding. 
 
        11. 
 Yes 
 No  
   The addition of cytotoxic agents for “cytoreduction” with the 
exception of tyrosine kinase inhibitors (such as imatinib mesylate), 
cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or 
rituxan within three weeks of the initiation of conditioning. 
 
12. Patient has organ dysfunction as described below. Please check YES if patient has any of     
the following. 
  
 
 
 
  
 
a. Cardiovascular: 
                          
 Yes 
 No  
Cardiac Ejection Fraction <40%. Ejection fraction is 
required if age >50 years or there is a history of prior 
transplant, anthracycline exposure or history of cardiac 
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 Yes 
 No  
Poorly controlled hypertension despite  
 
 
  
 
 
multiple antihypertensives. 
 
b. Pulmonary: 
 
 Yes 
 No  
 DLCO < 40%, TLC <40%, FEV1 <40% and/or is 
requiring supplementary continuous oxygen, or severe 
deficits in pulmonary function testing as defined by 
pulmonary consultant service.  The FHCRC PI of the 
study must approve of enrollment of all patients with 
pulmonary nodules. 
 
                                    PI Signature:  
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
c. Hepatic 
 
 
 
 Yes 
 No  
Patients with clinical or laboratory evidence of liver disease 
would be evaluated for the cause of liver disease, its 
clinical severity in terms of liver function, 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, hepatic damage with 
bridging fibrosis, alcoholic hepatitis, esophageal varices, a 
history of bleeding esophageal varices, hepatic 
encephalopathy, uncorrectable hepatic synthetic 
dysfunction evidenced by prolongation of the prothrombin 
time, ascites related to portal hypertension, bacterial or 
fungal liver abscess, biliary obstruction, chronic viral 
hepatitis with total serum bilirubin >3 mg/dl, or 
symptomatic biliary disease. 
 
. 
13. 
 Yes 
 No     Performance status: 
                               a. Karnofsky score < 60 (see Appendix B) for adult patients 
 
14. 
 Yes 
 No      Infection with HIV 
 
 
   15. 
 Yes 
 No 
Active bacterial or fungal infections unresponsive to medical  
                                    therapy. 
 
Note: The HCT-CI score is:_____________________________ 
(fax HCT-CI worksheet with registration—see Appendix Q) 
 
Signature of person completing form:  
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
Signature of Principal Investigator:   
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 


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APPENDIX M 
 
CORE CASE REPORT FORMS 
CRFs
 


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APPENDIX N 
 
INTRATHECAL THERAPY ADMINISTRATION 
 
IntrathecalTherapy.
pdf


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Appendix O 
 
HLA Matching Requirements For Unrelated Donors At The SCCA/Fred 
Hutchinson Allied System 
 
Human Leukocyte Antigen (HLA) Terminology. The HLA region consists of genes that encode two 
classes of HLA molecules. HLA class I molecules, HLA-A, -B, and –C, are composed of a single 
glycoprotein chain that is expressed in association with 2-microglobulin on most tissue cells. HLA class II 
molecules, HLA-DR, -DQ, and –DP, are heterodimers consisting of and glycoprotein chains. HLA class 
I and HLA class II molecules are highly polymorphic. 
 
 
HLA Typing Methods. At the Seattle Cancer Care Alliance Clinical Immunogenetics Laboratory (CIL) 
DNA-based methods of HLA-A, B, C, DRB1, DQB1 typing are now performed routinely. High resolution 
typing is required to define individual alleles and the level of mismatching between donor and recipient. 
High resolution data are reported with four or more digits (e.g., A*0201, A*0205, B*1504, or DRB1*0401). 
A current listing of recognized HLA alleles and their sequences can be found at the 
Immunogenetics/HLA sequence database website at www.anthonynolan.org.uk/HIG/data.html. 
 
 
Initial typing reports obtained through the international marrow donor registries may consist of intermediate 
resolution typing. Intermediate resolution defines alleles in groups of related families historically defined 
as antigens by alloantisera. Intermediate resolution typing results are reported as two digits (e.g., A*02, 
B*15, or DRB1*04). In cases where the HLA-A, B and C loci are typed at intermediate resolution and high 
resolution data are not available, it should be understood that unidentified allele disparity might be present. 
 
 
Donor Selection. Final selection of an unrelated donor should be based upon results of high resolution 
typing of HLA-A, B, C, DRB1, DQB1 alleles. Cross match assay is not required when high resolution typing 
indicates matching for HLA-A, B, C, DRB1 and DQB1 AND the platelet reactive antibody (PRA) screen is 
not elevated (defined as ≤10%). A negative cross match test result is required for final donor selection in the 
following situations: 1) PRA screen is positive (>10%), or 2) high resolution typing indicates mismatching 
for one or more HLA-A, B, C, DRB1 and DQB1 alleles. A positive anti-donor cytotoxic crossmatch 
absolutely excludes the donor. 
 
 
Donor Selection Criteria. Protocols and treatment plans must specify donor inclusion and exclusion criteria, 
using terminology indicated below. 
 
Donor inclusion criteria must specify 1) the allowable genetic relationship between the patient and donor 
(related and/or unrelated), 2) the allowable limits of mismatch, and if applicable 3) any modification of 
mismatch criteria according to type of disease or patient characteristics. 
 
 
 
 
 


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HLA Matching Requirements For Unrelated Donors At The SCCA/Fred 
Hutchinson Allied System 
 
 
Acceptable levels of recipient-donor mismatch for research related treatment protocols or standard treatment 
plans include the following: 
Allele-match for HLA-A, B, C, DRB1 and DQB1. 
Single allele disparity for HLA-A, B, C, or DRB1 or DQB1 
Two allele disparities for HLA-A, B, or C. 
Single allele disparity for HLA-DRB1 and/or a single DQB1 antigen or allele disparity. 
Single antigen plus single allele disparity for HLA-A, B, or C. 
 
The following levels of patient-donor mismatch should be restricted to research protocols: 
Two antigen disparity, either HLA-A plus C or HLA-B plus C. 
Single antigen disparity for HLA-DRB1 with or without DQB1 allele or antigen disparity 
Combined disparity of class I and class II loci, i.e. disparity for HLA-A, or B, or C, and any 
additional disparity for DRB1 or DQB1 
 
 
Donor Exclusion Criteria to be considered for protocols or standard treatment plans include: 
Double locus disparity. Two disparities are not allowed when they both involve the same locus, i.e., 
the patient is A*0101, A*0201 and the donor is A*0102 and A*0205. 
Recipient and donor homozygous at mismatched locus. Patient and donor pairs homozygous at 
the mismatched locus are considered a two-locus mismatch, i.e., the patient is A*0101 and the donor 
is A*0201, and this type of mismatch is not allowed. 
Recipient homozygous at mismatched locus. If the recipient is homozygous at HLA-A, B, or C 
and the donor is mismatched at that locus, i.e., patient is A*0101 and donor is A*0101 and A*0201, 
the risk of rejection is increased. Such a donor should be avoided if there is already an appreciable 
risk of rejection, i.e., in patients with CML/MDS/Severe Aplastic Anemia (SAA) or those receiving 
reduced conditioning. 
 
 
Relevance of HLA matching for transplantation of unrelated hematopoietic cells: 
Human Leukocyte Antigen (HLA) typing of patients and prospective hematopoietic stem cell (HSC) donors 
is carried out to identify and match for HLA determinants associated with successful HSC transplant 
outcome. While several preliminary studies (1, 2, 3) suggested the importance of allele level matching in 
hematopoietic cell transplantation (HCT), recent comprehensive studies confirmed that allele-level typing 
and matching is necessary to optimize clinical outcome in hematopoietic cell transplantation (4, 5, 6, 7). 
 
 The pervasiveness of occult HLA mismatch was shown by Petersdorf, et al in an analysis of 300 CML/CP 
unrelated donor-recipient pairs matched for HLA-A and B by serologic typing, and matched for the DRB1 
alleles.(4) The percent of patient-donor pairs found to be matched at the allele level for all 5 loci (HLA-A, B, 
C, DRB1, DQB1) was only 47% (n=142). High resolution typing demonstrated previously undetected 
mismatches in 53% (158), indeed 26% (79) pairs were mismatched for multiple alleles. Mismatch of class I 
HLA was found at one locus in 55 pairs (18%) and at two or more loci in 35 pairs (12%). A single mismatch 
of class II HLA was 


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detected in 24 pairs (8%), whereas 7 pairs (2%) had multiple class II mismatches, and 37 pairs (12%) had 
multiple mismatches involving both class I and class II. These data show the  
 
 
HLA Matching Requirements For Unrelated Donors At The SCCA/Fred 
Hutchinson Allied System 
 
 
importance of high resolution typing for defining the degree of mismatching between potential unrelated 
patient-donor pairs. 
 
 
The degree of HLA mismatch, as well as the locus of mismatch, influence the development of alloimmune 
reactions and have significant implications for the outcome of HSC transplants. Studies of patient-donor 
pairs have shown an increased risk for graft failure with multiple mismatches that involve at least one class I 
allele. The incidence of graft failure was 29% in pairs where the mismatch involved more than one class I 
allele mismatch and 12% for mismatches involving both class I and class II alleles, compared with 2% or less 
for pairs with either no mismatch or mismatch confined to a single HLA-A, B, C, DRB1 and DQB1 allele. 
The risk of developing grades III-IV acute GVHD also has been shown to be influenced by the number and 
class of mismatched alleles. In studies involving primarily Caucasian patient-donor pairs, the highest risk for 
severe acute GVHD was observed for multiple mismatches involving both class I and class II alleles (2.0 
hazard ratio and p=0.02). Pairs with a single class I mismatch did not have a significant increase in acute 
GVHD compared with matched recipients, but a single class II mismatch or multiple class I mismatches both 
appeared to confer a higher (though not significant) hazard of severe GVHD. As results of future studies 
further define risks of mismatches, particularly in nonCaucasian populations, we may be able to delineate 
more precisely “low risk” from “high risk” mismatches. Until then, the donor selection process should 
endeavor to identify the best matched donor within the time allowed by the clinical situation. 
 
 
References: 
1. Petersdorf EW, Longton GM, Anasetti C, Martin PJ, Mickelson EM, Smith AG, Hansen JA. The significance of 
HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. 
Blood 1995: 86:1606-1613. 
2. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, Smith AG, Martin PJ, Hansen JA. Definition of HLA-DQ 
as a transplantation antigen. Proc. Natl. Acad. Sci. USA 1996; 93: 15358. 
3. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, McKinney SK, Smith AG, Martin PJ, Hansen JA. 
Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood 1997: 89: 
1818. 
4. Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, Hansen JA. 
Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in 
the donor and recipient. Blood 1998: 92: 3515. 
5. Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H, Yoshida T, Kimura A, Akaza T, 
Kamikawaji N, Kodera Y, Takaku F. Importance of HLA-class I allele matching for clinical outcome after unrelated 
donor hematopoietic stem cell transplantation. New Engl J Med 1998: 339: 1177. 
6. Hansen JA, Yamamoto K, Petersdorf E, Sasazuki T. The role of HLA matching in hematopoietic cell 
transplantation. Reviews in Immunogenetics 1999: 1: 359. 
7. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer B, Mickelson E, Smith A, Anasetti 
C. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. New Engl J Med 
2001: 345: 1794. 


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8. Bodmer JG, Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Hansen JA, Mach B, Mayr 
WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GMTh, Strominger JL, Svejgaard A, Terasaki PI. Nomenclature 
for factors of the HLA system, 1998. Tissue Antigens 1999: 53: 407. 
9. List of known HLA allele sequences: www.anthonynolan.org.uk/HIG/data.html. 
10. Information on HLA complex: http://www.ebi.ac.uk/imgt/hla/intro.html. 
 
 
 
HLA Matching Requirements For Unrelated Donors At The SCCA/Fred 
Hutchinson Allied System 
 
References continued:  
 
11. Little AM and Parham P. Polymorphism and evolution of HLA class I and II genes and molecules. Reviews in 
Immunogenetics 1999: 1: 105. 
12. Schreuder GMTh, Hurley CK, Marsh SGE, Lau M, Maiers M, Kollman C, Noreen H. The HLA Dictionary 2001: A 
summary of HLA-A, B, C, DRB1/3/4/5, DQB1 alleles and their association with serologically defined HLA-A, B, C, 
DR, and DQ antigens. Tissue Antigens 2001: 58: 109-140. 
13. Smith A, McKinney S, Menninger O, Warnock S, Hansen JA. Detection of a novel “nonexpression” HLA-B*15 
allele adds to data on the frequency of class I expression variants in a hematopoietic transplant population. Human 
Immunology 29th Annual ASHI Meeting Abstracts 2003: 64: S159. 
14. Hurley CK, Baxter Lowe LA, Logan B, Karanes C, Anasetti C, Weisdorf D, Confer DL. National marrow donor 
program HLA-matching guidelines for unrelated marrow transplants. Biology of Blood and Marrow Transplantation 
2003: 9. 
15. Petersdorf, E.W., Anasetti, C., Martin, P.J., Gooley, T., Radich, J., Malkki, M., Woolfrey, A., Smith, A., Mickelson, 
E., Hansen, J.A. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood, (in press). 
 
 
Approved by the Standard Practice Committee January 16, 2002 (Donor Selection Matching Requirements.doc) 
HLA_matching_for_URD_selection.doc 
Approved by the Medical Advisory Committee (Medical Exec. Comm.) April 9, 2002 
Approved by the Clinical Sectional Meeting April 16, 2002 
Revised by the Standard Practice Committee June 15, 2005 
Minor wording change approved by SPC chairperson March 13, 2006 
 
 
 
 
 


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APPENDIX P 
Adapted from 
COMMON TOXICITY CRITERIA (CTC) 
 
Grade 
Adverse Event 
3 
4 
 
ALLERGY/IMMUNOLOGY 
Allergic 
reaction/hypersensitivity 
(including drug fever) 
Symptomatic bronchospasm, requiring 
parenteral medication(s), with or 
without urticaria; allergy-related 
edema/angioedema  
Anaphylaxis  
Vasculitis  
Requiring steroids  
Ischemic changes or requiring amputation 
Allergy/Immunology – Other 
(Specify,_______________) 
Severe 
Life-threatening or disabling  
 
BLOOD/BONE MARROW 
Bone marrow cellularity 
 
 
Hemolysis (e.g., immune 
hemolytic anemia, drug-related 
hemolysis, other) 
Requiring transfusion and/or medical 
intervention (e.g., steroids) 
Catastrophic consequences of hemolysis 
(e.g., renal failure, hypotension, 
bronchospasm, emergency splenectomy)  
For BMT studies, if specified in 
the protocol.   
 
 
For pediatric BMT studies, if 
specified in the protocol.   
>4 u pRBC in 24 hours  
 
 
 
>30mL/kg in 24 hours 
Hemorrhage or hemolysis associated with 
life-threatening anemia; medical 
intervention required to improve 
hemoglobin  
 
Hemorrhage or hemolysis associated with 
life-threatening anemia; medical 
intervention required to improve 
hemoglobin  
Grade 
Adverse Event 
3 
4 
 
CARDIOVASCULAR (ARRHYTHMIA) 
 
Cardiovascular/Arrhythmia
-Other (Specify, 
__________) 
Symptomatic, and requiring 
treatment of underlying cause 
Life-threatening (e.g., arrhythmia 
associated with CHF, hypotension, 
syncope, shock) 
CARDIOVASCULAR (GENERAL) 
 
Acute vascular leak 
syndrome 
Respiratory compromise or 
requiring fluids 
Life-threatening;  requiring pressor 
support and/or ventilatory/support 
 
Cardiac-
ischemia/infarction 
Angina without evidence of 
infarction 
Acute myocardial infarction 


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APPENDIX P (continued) 
 
 
Grade 
Adverse Event 
3 
4 
CARDIOVASCULAR (GENERAL) continued. 
 
Cardiac left ventricular 
function 
CHF responsive to treatment 
Severe or refractory CHF or 
requiring intubation 
Cardiac troponin I (cTnI) 
Levels consistent with unstable 
angina as defined by the 
manufacturer 
Levels consistent with myocardial 
infarction as defined by the 
manufacturer 
Cardiac troponin T (cTnT) 
 0.1 - <0.2 ng/mL 
 0.2 ng/mL 
Hypotension 
 
  
Requiring therapy and sustained 
medical attention, but resolves 
without persisting physiologic 
consequences 
Shock (associated with acidemia and 
impairing vital organ function due to 
tissue hypoperfusion) 
Myocarditis  
CHF responsive to treatment 
Severe or refractory CHF 
Pericardial effusion/ 
pericarditis 
With physiologic consequences 
Tamponade (drainage or pericardial 
window required) 
Syncope (fainting) is 
graded in the 
NEUROLOGY category.   
- 
- 
Thrombosis/embolism 
Deep vein thrombosis, requiring 
anticoagulant therapy 
Embolic event including pulmonary 
embolism 
Vein/artery operative 
injury is graded as 
Operative injury of 
vein/artery in the 
CARDIOVASCULAR 
(GENEARL) category. 
 
 
Cardiovascular/General – 
Other  
(Specify, ___________) 
Severe 
Life-threatening or disabling 
 


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APPENDIX P (continued) 
 
 
 
Grade 
Adverse Event 
3 
4 
COAGULATION 
 
DIC (disseminated 
intravascular coagulation) 
Also consider Platelets.   
Note:  Must have increased 
fibrin split products or D-dimer 
in order to grade as DIC. 
Laboratory findings present 
with no bleeding 
Laboratory findings and 
bleeding  
Coagulation - Other  
(Specify, _______________) 
Severe 
Life-threatening or disabling  
CONSTITUTIONAL SYMPTOMS 
 
Weight gain associated with 
Veno-Occlusive Disease 
(VOD) for BMT studies, if 
specified in the protocol.   
Also consider Ascites Edema, 
Pleural effusion (non-
malignant). 
>10% or as ascites 
>10% or fluid retention 
resulting in pulmonary failure 
DERMATOLOGY/SKIN 
 
Erythema multiforme (e.g., 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis) 
Severe or requiring IV fluids 
(e.g., generalized rash or 
painful stomatitis) 
Life-threatening (e.g., 
exfoliative or ulcerating 
dermatitis or requiring enteral 
or parenteral nutritional 
support) 
 
 


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APPENDIX P (continued) 
Grade 
Adverse Event 
3 
4 
DERMATOLOGY/SKIN continued 
 
Rash/desquamation associated 
with graft versus host disease 
(GVHD) for BMT studies, if 
specified in the protocol. 
Symptomatic generalized 
erythroderma or symptomatic 
macular, papular or vesicular 
eruption, with bullous 
formation, or desquamation 
covering 50% of body surface 
area 
Generalized exfoliative 
dermatitis or ulcerative 
dermatitis or bullous formation 
 
GASTROINTESTINAL 
 
 
 
Ascites(none-malignant) 
Symptomatic, requiring 
therapeutic paracentesis  
Life-threatening physiologic 
consequences 
Colitis  
 
 
 
Also consider 
Hemorrhage/bleeding with 
grade 3 or 4 thrombocytopenia, 
Hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
Melena/GI bleeding, Rectal 
bleeding/hematochezia, 
Hypotension.   
Abdominal pain, fever, change 
in bowel habits with ileus or 
peritoneal signs, and 
radiographic or biopsy 
documentation 
Perforation or requiring surgery 
or toxic megacolon 
Diarrhea associated with graft 
versus host disease (GVHD) 
for BMT studies, if specified in 
the protocol. 
 
For pediatric BMT studies, if 
specified in the protocol. 
 
Also consider 
Hemorrhage/bleeding with 
grade 3 or 4 thrombocytopenia, 
Hemorrhage/bleeding without 
 
>1500mL of diarrhea/day 
 
 
 
>15mL/kg of diarrhea/day 
 
Severe abdominal pain with or 
without ileus 
 
 
 
 
 
 
 


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grade 3 or 4 thrombocytopenia, 
Pain, Dehydration, 
Hypotension. 


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APPENDIX P (continued) 
Grade 
Adverse Event 
3 
4 
GASTROINTESTINAL (continued). 
  
Duodenal ulcer (requires 
radiographic or endoscopic 
documentation) 
Uncontrolled by outpatient 
medical management; requiring 
hospitalization 
Perforation or bleeding, 
requiring emergency surgery 
 
 
 
 
 
 
 
 
Gastric ulcer 
(requires radiographic or 
endoscopic documentation) 
 
 
Also consider 
Hemorrhage/bleeding with 
grade 3 or 4 thrombocytopenia, 
Hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
Bleeding without perforation, 
uncontrolled by outpatient 
medical management; requiring 
hospitalization or surgery 
Perforation or bleeding, 
requiring emergency surgery 
Gastritis 
 
 
Also consider 
Hemorrhage/bleeding with  
grade 3 or 4 thrombocytopenia, 
Hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
Uncontrolled by out-patient 
medical management; requiring 
hospitalization or surgery 
Life-threatening bleeding, 
requiring emergency surgery 
Pancreatitis 
 
Also consider Hypotension. 
 
Note:  Amylase is graded in the 
METABOLIC/LABORATOR
Y category. 
Abdominal pain with pancreatic 
enzyme elevation 
Complicated by shock (acute 
circulatory failure) 


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APPENDIX P (continued) 
 
Grade 
Adverse Event 
3 
4 
GASTROINTESTINAL (continued). 
 
Mucositis 
 
 
Note:  Radiation-related 
mucositis is graded as 
Mucositis due to radiation. 
Painless erythema, edema, or 
ulcers preventing swallowing or 
requiring hydration or 
parenteral (or enteral) 
nutritional support 
Severe ulceration requiring 
prophylactic intubation or 
resulting in documented 
aspiration pneumonia 
Typhlitis 
(inflammation of the cecum) 
 
Also consider 
Hemorrhage/bleeding with 
grade 3 or 4 thrombocytopenia, 
Hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
Hypotension, Febrile 
neutropenia.  
 
Abdominal pain, diarrhea, 
fever, and radiographic or 
biopsy documentation 
Perforation, bleeding or necrosis 
or other life-threatening 
complication requiring surgical 
intervention (e.g., colostomy) 
 
 
 
 
 
 


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APPENDIX P cont’d 
Grade 
Adverse Event 
3 
4 
HEMORRHAGE 
 
Notes:  Transfusion in this section refers to pRBC infusion. 
For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to grading 
severity by grading the site or type of bleeding. 
 
If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of 
bleeding: NS Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding 
with surgery, Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal 
bleeding/hematochezia, Vaginal bleeding. 
Hemorrhage/bleeding with grade 3 or 
4 thrombocytopenia   
 
Also consider Platelets, Hemoglobin, 
Transfusion: platelets, Transfusion: 
pRBCs, site or type of bleeding.  If 
the site is not listed, grade as 
Hemorrhage – Other  
(Specify site, __________). 
 
Note:  This adverse event must be 
graded for any bleeding with grade 3 
or 4 thrombocytopenia. 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Hemorrhage/bleeding without grade 
3 or 4 thrombocytopenia 
 
Also consider Platelets, Hemoglobin, 
Transfusion: platelets, Transfusion: 
pRBCs, Hemorrhage – Other 
(Specify site, ____________). 
 
Note:  Bleeding in the absence of 
grade 3 or 4 thrombocytopenia is 
graded here only if the specific site 
or type of bleeding is not listed 
elsewhere in the HEMORRHAGE 
category.  Also grade as Other in the 
HEMORRHAGE category.   
Requiring transfusion 
Catastrophic bleeding requiring 
major non-elective intervention 


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APPENDIX P (continued) 
 
Grade 
Adverse Event 
3 
4 
HEMORRHAGE (continued) 
 
CNS hemorrhage/bleeding 
Bleeding noted on CT or other 
scan with no clinical 
consequences 
Hemorrhagic stroke or 
hemorrhagic vascular event 
(CVA) with neurologic signs 
and symptoms 
Hemoptysis  
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
 
Melena/GI bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Rectal bleeding/hematochezia 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Vaginal bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Hemorrhage – Other  
(Specify site, _____________)  
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Grade 
Adverse Event 
3 
4 
HEPATIC 
 
Bilirubin  
 
Bilirubin associated with graft 
versus host disease (GVHD) 
for BMT studies, if specified in 
the protocol. 
>3.0 – 10.0 x ULN 
 
>6 - <15 mg/100mL 
>10.0 x ULN 
 
>15 mg/100mL 
 
 


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APPENDIX P (continued) 
 
Grade 
Adverse Event 
3 
4 
 
INFECTION/FEBRILE NEUTROPENIA 
 
Febrile neutropenia (fever of 
unknown origin without clinically or 
microbiologically documented 
infection) 
Present 
Life-threatening sepsis (e.g., septic 
shock) 
Infection/Febrile Neutropenia – Other 
(Specify, _____________) 
Severe 
Life-threatening or disabling 


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APPENDIX P (continued) 
 
Grade 
Adverse Event 
3 
4 
NEUROLOGY 
 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY 
category. 
CNS cerebrovascular ischemia 
Transient ischemic event or 
attack (TIA) 
Permanent event (e.g., cerebral 
vascular accident) 
Leukoencephalopathy 
associated radiological findings 
Severe increase in SAS; severe 
ventriculomegaly; near total 
white matter T2 hyperintensities 
or diffuse low attenuation (CT); 
focal white matter necrosis 
(cystic) 
Severe increase in SAS; severe 
ventriculomegaly; diffuse low 
attenuation with calcification 
(CT); diffuse white matter 
necrosis (MRI) 
Seizure(s) 
Seizure(s) in which 
consciousness is altered  
Seizures of any type which are 
prolonged, repetitive, or difficult 
to control (e.g., status 
epilepticus, intractable epilepsy) 
Grade 
Adverse Event 
3 
4 
PULMONARY 
 
Adult Respiratory Distress 
Syndrome (ARDS) 
- 
Present 
Apnea 
Present 
Requiring intubation 
Carbon monoxide diffusion 
capacity (DLCO) 
>25 - <50% of pretreatment or 
normal value 
<25% of pretreatment or normal 
value 
FEV1 
>25 - <50% of pretreatment or 
normal value 
<25% of pretreatment or normal 
value 
Hypoxia 
Decreased O2 saturation at rest, 
requiring supplemental oxygen 
Decreased O2 saturation, 
requiring pressure support 
(CPAP) or assisted ventilation 


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- 111 - 
APPENDIX P (Continued) 
 
Grade 
Adverse Event 
3 
4 
RENAL/GENITOURINARY 
 
Creatinine  
Note:  Adjust to age-appropriate 
levels for pediatric patients. 
>3.0- 6.0 x ULN 
>6.0 x ULN 
Renal failure 
Requiring dialysis, but 
reversible 
Requiring dialysis and 
irreversible 
SECONDARY MALIGNANCY 
 
Secondary Malignancy – Other 
(Specify type, _____________) 
excludes metastasis from initial 
primary 
- 
Present 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX Q 
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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- 113 - 
†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. 
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. 


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- 114 - 
APPENDIX R 
STAGING OF CLL 
 
Binet staging 
 
Binet stage 
Lymph node areas 
Hemoglobin  
11 g/dl 
Platelet 
 100  109/L 
Survival 
(years) 
A 
  3 
No 
No 
12 
B 
3 or > 
No 
No 
7 
C 
 
Yes 
(or low platelet) 
Yes  
(or low hemoglobin) 
2 
 
  
Modified Rai staging 
Rai 
stage 
Risk category 
Lymphocytosis 
Lymph node 
enlargement 
Spleen/liver 
enlargement 
Hemoglobin 
< 11 g/dl 
Platelet 
<100109/L 
Survival 
(years) 
0 
Low 
Yes 
No 
No 
No 
No 
 10 
I 
Intermediate 
Yes 
Yes 
No 
No 
No 
 7 
II 
Intermediate 
Yes 
 
 
No 
No 
 7 
III 
High 
Yes 
 
 
Yes 
No 
1.5 
IV 
High 
Yes 
 
 
 
Yes 
1.5 
 
 
 


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Appendix S 
 
Weight / Adjusted Body Weight for Drug Dosing 
 
 
 
 
 
 


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FHCRC Current Version 1/13/2016 
- 116 - 
 
 
APPENDIX T 
 
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 


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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 
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 
 

ICF_001.pdf: 
1840.00 A 
Page 1 of 17 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
SEATTLE CHILDREN’S 
 
Consent to Participate in a Research Study Called: 
Nonmyeloablative Conditioning with Pre- and Post-Transplant Rituximab followed by 
Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients with Advanced 
Chronic Lymphocytic Leukemia – a Multi-Center Trial 
 
 
Who is in Charge of This Research Study? 
Principal Investigators:  Fred Hutchinson Cancer Research Center 
Mohamed L. Sorror, MD 
Assistant Member, FHCRC, Assistant Professor of 
Medicine, UW 
667-2765 
David G. Maloney, MD 
Member, FHCRC, Professor of Medicine, UW  
667-5616 
Brenda M. Sandmaier, MD 
Member, FHCRC, Professor of Medicine, UW  
667-4961 
Stanley Riddell, MD 
Member, FHCRC, Professor of Medicine, UW 
667-5249 
Mary E.D. Flowers, MD 
Member, FHCRC,  Professor of Medicine, UW 
667-5115 
Rainer Storb, MD 
Member, FHCRC, Professor of Medicine, UW 
667-4407 
Statistician: 
Barry Storer, Ph.D., Affiliated Associate Professor of Biostatistics, UW, 
Member, FHCRC (667-6533). 
 
Research Nurse:                       Michelle Bouvier, RN (206) 667-6993, pager (206) 995-7658 
 
 
 
Emergency (24 hour) Phone: (206) 598-8902 Fax: (206) 598-4034 
 
Additional Performance Sites 
Investigators 
Emergency Phone Numbers 
Rigshospitalet      
Niels Andersen, MD   
+45 35 45 1134 
City Hlth & Sci - Torino 
Benedetto Bruno, MD 
011-39-0339-1129064 
Veterans Affairs Puget Sound 
Health Care System 
Thomas Chauncey M.D., PhD 
 
(206) 762-1010 for the oncologist on-call 
Mayo Clinic 
William Hogan, MD. 
(507) 284-2511 
 
 
 
 
 
 
 
 
 


1840.00 A 
Page 2 of 17 
➢  What is the purpose of this consent form? 
This form is called a consent form. The purpose of this form is to let you know about a research 
study being done here at the cancer center. It tells you about the purpose, risks and benefits, and 
describes what is involved in the study. It also tells you what other choices you have. 
 
➢  Do I have to take part in this study? 
No, you do not have to take part in this study. It is up to you. To help you decide if you want 
to take part in this study, you should: 
• Read this form. 
• Ask your doctor questions about the study. 
• Write down your questions. 
• Have your doctor (attending physician) explain anything that you do not understand. 
• Discuss it with your family or close friends. 
• Take time to think about whether you want to take part in this study. 
 
➢ Why is this research study being done?  
The reason for doing this study is to determine whether a new method of stem cell transplant 
(nonmyeloablative), is useful in treating patients with chronic lymphocytic leukemia (CLL).  
Nonmyeloablative stem cell transplants use lower doses of chemotherapy and radiation than 
conventional stem cell transplants.  These transplants use stem cells from the blood and appear to be 
less toxic in other cancers of the blood. Stem cells (both those taken from the donor and those of the 
recipient) are the “seeds” necessary to make blood cells. We want to see if using less chemotherapy 
and radiation with drugs that suppress (hold back) the immune system will allow for successful 
treatment with fewer side effects.  
 
Following infusion of donor stem cells, we hope to see a mixture of the patient’s and the donor’s 
stem cells. This mixture of donor and recipient stem cells is called “mixed chimerism.” We hope 
that donor cells will attack the patient’s leukemia. This is called the “graft-versus-leukemia” 
effect. We have added a drug named, Rituximab, which is known to have anti-leukemia activity 
against CLL cells and has been extensively used for treatment of CLL. We hope the addition of 
Rituximab will help in controlling CLL early after transplant till the “graft-versus-leukemia” 
takes control. Further, Rituximab could augment the “graft-versus-leukemia” effect by activating 
donor immune cells and hence improve disease control. In addition, in the event of recurrence of 
cancer after this nonmyeloablative transplant, white blood cells from the patient’s donor may be 
given to enhance the graft-versus-leukemia effect, and hopefully remove all remaining cancer 
cells. There is no guarantee that this procedure will be successful. 
 
 
 
 
 
 


1840.00 A 
Page 3 of 17 
➢ Why have I been asked to take part in this research study, and who is conducting it? 
You are being asked to take part in this study because you have (CLL), a cancer of the blood that 
is treatable with a stem cell transplant. Patients in research studies include only those who choose 
to take part. Please take your time to make your decision. We encourage you to discuss your 
decision with your doctor, family, and friends. This is a multicenter clinical trial coordinated 
through the Fred Hutchinson Cancer Research Center in Seattle, Washington. 
At the present time there are no curative therapies known outside of stem cell transplantation for 
your type of cancer. Because of your age or underlying health status, you may have a higher 
likelihood of experiencing harm from a conventional stem cell transplant. 
 
 
➢ How many people will take part in the study?  
Eighty adult patients with CLL will be enrolled in the study. 
 
➢ What is involved in the study? 
 
Before you begin the study. Before enrollment on the study, you will be checked for suitability 
for the study. You will be asked to give information about your medical history and undergo the 
exams and tests listed below. If you have had any of them recently, your doctor may decide not 
to repeat them. The exams and tests include: 
 
 
• Bone marrow biopsy & aspiration 
• Blood tests 
• Urine tests 
• Chest x-ray 
• Electrocardiogram (ECG)  
• MUGA scan or echocardiogram (test to see how well your heart works)  
• Pulmonary function tests (test to see how well your lungs work 
 
These exams and tests are not experimental; they are routine. They represent good medical care 
even if you do not join the study. If you do join, some of these procedures may be done more 
often than if you were not taking part in the study. The tests may be done on an outpatient basis 
at your doctor’s office or clinic, or in a hospital. If you have no measurable disease at the time of 
pretransplant staging, bilateral (both sides) bone marrow biopsies will be obtained to assess for 
minimal residual disease. 
 
During the study: Any significant new findings that develop during the course of treatment, 
which may affect your willingness to continue participation, will be provided to you. Prior to 
each treatment you will have a physical exam and blood tests. You will have blood tests at least 
three times per week to check blood cell counts and kidney function. Other blood tests, including 
liver function tests, will be done periodically. Blood tests may be required more frequently. In 
addition, a bone marrow aspiration will be requested at various time points. The bone marrow 
aspirations will be evaluated for mixed chimerism and disease. 
 
Additional blood samples will be requested for research purposes. We will use your blood and 
tissue samples for research as described in this consent form. Samples will be stored indefinitely.  


1840.00 A 
Page 4 of 17 
We are also trying to determine the best way of dosing rituximab. This study involves collecting 
blood samples to see how much rituximab is in your body at various times after transplant, so we 
can understand the best way to give the drug. We will also use simple blood tests to look at two 
genes which might help us predict how well rituximab will work on your leukemia cells. 
 
 
 
If we want to use your tissue in the future for a purpose not described in this consent, we must 
first send a request to the Institutional Review Board (IRB) for review and approval for all 
proposed new research. 
 
Procedures that are being tested during the study. 
 
1. 
Low dose treatment and stem cell transplantation. Peripheral blood stem cells will be used 
in this study. Peripheral blood stem cells are collected from the blood after the donor has 
been treated with a drug called growth factor. These cells are then infused into you like a 
blood transfusion. Treatment is the chemotherapy and radiation necessary to establish a 
graft, that is, to allow donor stem cells to grow in the recipient’s marrow for the production 
of blood cells. 
 
We intend to suppress (hold back) your immune system using low dose total body 
irradiation (TBI) and fludarabine (please see below for side effect profile of these 
treatments) to allow your body to accept the donor stem cells. Rituximab will be used to 
control CLL early after transplant till the “graft-versus-leukemia” takes control. Further, 
Rituximab could augment the “graft-versus-leukemia” effect by activating donor immune 
cells and hence improve disease control. The immune suppressing drugs cyclosporine 
(CSP) and mycophenolate mofetil (MMF) will be given after the infusion of donor stem 
cells to ensure continued acceptance of your immune system to the presence of donor stem 
cells and to prevent graft-versus-host disease (GVHD). Since the treatment appears to have 
few serious side effects, we plan for most of your post-transplant course to occur as an 
outpatient. However, about one-half of patients require admission at some point after 
transplant. The average hospital stay is approximately 11 days. Listed below is a table that 
shows the schedule for receiving fludarabine, TBI and the immune suppressing drugs CSP 
and MMF. Days with a minus sign before them indicate the number of days before the 
transplant. Days with a plus sign before them indicate the number of days after the 
transplant. 
 
 
 
 
Sample 
Sample Size 
Timing 
Blood  
Up to 10 ml to 20 ml 
(approximately 4 
teaspoons) 
Before and after transplant, and after you return 
home at approximately Day +10, +24, +38, +60,   
+84, +180, and one year. These samples will be 
requested at the same time as your regularly 
scheduled doctor visits. 


1840.00 A 
Page 5 of 17 
Day number 
-4 
-3 
-2 
-1 
0 
+1 
+10 
+24 
+27 
+38 
+40 
+56 
+96 
+100 
+180 
Fludarabine 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TBI 
 
 
 
 
200 cGy 
 
 
 
 
 
 
 
 
 
 
Rituximab 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
Stem cell 
infusion 
 
 
 
 
Infusion 
 
 
 
 
 
 
 
 
 
 
CSP for 
related 
 
Start 
→ 
→ 
→ 
→ 
→ 
→ 
 
→ 
→ 
TaperA 
→ 
→ 
Stop 
CSP for 
unrelated 
 
Start 
→ → 
→ 
→ 
→ 
→ 
 
→ 
→ 
→ 
→ 
TaperB 
Stop 
MMF for 
related 
 
 
 
 
StartC 
→ 
→ 
→ 
Stop 
 
 
 
 
 
 
MMF for 
unrelated 
 
 
 
 
StartC  
→ 
→ 
→ 
→ 
→ 
TaperD 
→ 
Stop 
 
 
 
2. 
Molecular Test of Disease Response: Certain blood cancers can be monitored by a 
special test that detects the DNA of the tumor cells. This test is called a polymerase 
chain reaction or PCR test. This sensitive test may be used for monitoring the 
response of your cancer to the stem cell transplant. This test will be performed using 
peripheral blood and bone marrow samples. This test will not add to the frequency of 
standard blood or bone marrow tests scheduled to monitor the response of the 
leukemia to the stem cell transplant. Some of these tests are still experimental and, 
therefore, the results of the unapproved tests will not be used for clinical decision 
making and will not be routinely made available to the patient. 
 
3. 
Molecular Test of Donor Engraftment: The percentage of donor cells in your blood 
and marrow can be monitored by special tests (e.g. PCR) that detect the DNA of the 
donor cells. These sensitive tests are used for evaluating the degree of donor 
engraftment after the blood stem cell transplant. This test will be performed using 
peripheral blood and bone marrow samples. This test will not add to the frequency of 
standard blood or bone marrow tests. 
 
4. 
Tests to Study the Recovery of the Immune System: Up to 10mls of blood (less than 
1 tablespoon) will be drawn up to 5 times within the first year post-transplant to 
determine how the immune system has recovered. 
 
➢ How long will I be in the study? 
Your treatment will last approximately 3 and 1/2 months, but could be longer. You will be asked 
to return for follow up at 6 months and every year thereafter. We would like to keep track of 
your medical condition for the rest of your life to look at the long-term effects of the study. 
However, you may be taken off the protocol if one of the following happens: 
•  The study treatment does not work for your cancer; 
•  You develop a serious side effect that you cannot tolerate or that cannot be controlled with 
other medications;  
•  Your health gets worse; 
•  You are unable to meet the requirements of the study (for example, you cannot take the 
medicine as prescribed or you refuse follow-up); 
•  You start other treatments for your cancer; 


1840.00 A 
Page 6 of 17 
•  Other treatments for your cancer become available; 
•  Your request; 
Your decision to participate in this study is voluntary. You may decide not to participate in this 
study at any time, for any reason, without notice. However, early withdrawal from treatment 
during the conditioning regimen without subsequent stem cell transplantation could be fatal. The 
early discontinuation of the immune suppressing drugs, MMF and Cyclosporine, after blood 
stem cell transplant could lead to rejection of the donor blood stem cells or life threatening 
GVHD. We request that you discuss your decision with your primary doctor and if you wish the 
research physician prior to discontinuing the study. 
 
➢  What is long-term follow-up? 
We would like to keep track of your medical condition and health for the rest of your life to look 
at the long-term effects of the study.  Long-term follow-up includes getting information useful 
for your medical care and research.  Results of tests that are done after one year, as needed, help 
your referring physician plan your future care.  We also get information for research by mailing 
questionnaires to you.  The questionnaires will ask how you are doing and if you have any health 
problems.  Research information is entered into our research database. 
 
➢ What are the risks of the study?  
There are risks involved in this study, and there may be side effects. Most of these are listed 
below, but they will vary from person to person. Your doctor may be able to give you other 
medications to make some of the side effects less bothersome. 
 
Side effects that we know about now are described in the table. Side effects are categorized into 
either: 
• Likely side effects: Side effects that may occur in 10% or more of patients (this means 
that 10 or more patients out of 100 might get this). Certain side-effects in this category 
could occur in virtually all patients. 
• Less likely side effects: Side effects that may occur in 3-9% of patients (this means that 
3 to 9 patients out of 100 might get this). 
• Rare side effects: Side effects that do not occur very often, but may occur in less than 
3% of patients (this means that 1 or 2 patients out of 100 might get this).    
 


1840.00 A 
Page 7 of 17 
With any drug or combination of drugs, there may be complications or side effects that we 
do not know about. 
Likely Side Effects  
Less Likely Side Effects  
Rare Side Effects  
Graft-versus-host disease 
Allergic reaction (including 
itching, hives, flushing, 
hypersensitivity, shortness of 
breath, wheezing, chest 
tightness, skin rashes, fever, 
chills, muscle stiffening, 
severe breathing problems) 
Sores in mouth and/or throat 
Nausea 
Jaundice (yellowish 
discoloration of sclera) 
Hair loss 
Vomiting 
Rejection/graft failure 
Skin or nail discoloration 
Diarrhea 
Fluid retention (bloating or 
swelling) 
Nail changes 
Loss of appetite 
Weakness 
Painful burning on the skin of 
the hands and feet 
Fever 
Fatigue 
Irregular menses or stopping 
of menses 
Lowered white blood cell 
counts (may lead to infection) 
Seizure 
Infertility (inability to have 
children) in women or Sterility 
for men 
Lowered platelet counts (may 
lead to bleeding) 
Tremor 
Failure of heart function 
Lowered red blood cell counts 
(may lead to anemia, fatigue, 
shortness of breath) 
Muscle or joint pain 
Failure of liver function 
Infection 
 
Failure of brain function 
 
 
Impairment or failure of 
kidney function 
 
 
Failure of lung function 
 
Stem Cell Transplant. Based on our preliminary studies of patients with various blood cancers, 
we expect the proposed nonmyeloablative stem cell transplant to be associated with fewer side 
effects than are observed with a conventional, high-dose radiotherapy and/or chemotherapy, 
transplant. It is possible that you could experience serious side effects similar to those that occur 
after conventional stem cell transplants that use high doses of chemotherapy and radiation. These 
side effects include low blood counts, infections, bleeding, and failure of donor stem cells to 
grow. Supportive care with red blood cell and platelet transfusions and antibiotic therapy may be 
necessary. Organ damage may also occur as a result of radiation or treatment with drugs that 
suppress the immune system. Although one of the goals of this study is to reduce the risk of 
transplant, the side effects of treatment can be severe enough to cause your death. 
 
For patients receiving unrelated transplants there is an extremely low risk that for reasons beyond 
our control either (i) your unrelated donor will be unable to donate stem cells or (ii) the donation 
will result in a product that cannot be infused safely.  If either of these extremely unlikely events 
were to occur after you receive the conditioning regimen, there is a chance that your own 


1840.00 A 
Page 8 of 17 
marrow cells will not recover.  If your own marrow cells do not recover, the only way to prevent 
your death would be to find a replacement donor.  Finding a replacement donor soon enough to 
prevent death would be very difficult.  Even if another donor is found, the transplant using the 
replacement donor's stem cells might not be successful. 
 
Graft-versus-host disease (GVHD), or inflammation of the skin, liver, and gastrointestinal tract 
(usually of acute onset and short duration) due to donor white blood cells, may occur and require 
treatment with drugs to suppress the immune system. In similar studies, 57% of patients required 
treatment for GVHD that developed within the first 100 days after transplant. One-half of 
patients developed a chronic form of GVHD (gradual onset and long duration) that required 
treatment. Seven percent of patients developed GVHD that was fatal. Severe GVHD and the 
treatment of GVHD may be associated with life-threatening infection. 
 
Rejection of the Graft. There is a small but possible risk that you will reject your donor’s stem 
cells after transplant. In similar studies of nonmyeloablative transplant following fludarabine and 
total body irradiation, 3% of patients had rejection. If this occurs, the dose of chemotherapy and 
radiation given would not be expected to cause a long period of low blood counts, and you would 
be expected to recover your blood counts if they were relatively normal before the transplant. 
Although most patients’ blood counts will recover, there is a small chance that blood counts may 
not recover. Failure to recover blood counts following rejection increases the risk of infection or 
bleeding which may result in death. 
 
Relapse/Disease Progression. The malignancy may not regress or may recur even if the 
transplant is initially successful. The rate of relapse may be increased compared to conventional 
transplants that utilized high dose chemotherapy. You will be monitored closely for evidence of 
relapse or progression of your CLL. Donor lymphocyte infusion and/or other therapies may be 
performed if your CLL progresses.  
 
Total Body Irradiation (TBI) at high doses in conventional transplants may cause nausea, 
vomiting, diarrhea, temporary hair loss, and painful swelling of the parotid gland (a gland under 
the chin) for a few days. TBI may also cause damage to the lining of the mouth, called 
“mucositis” that requires pain medication and temporary administration of fluids and nutrition by 
vein.  TBI may cause diarrhea that lasts for a few days.  In addition TBI can cause damage to the 
lungs and often causes the formation of cataracts many years after its administration.  High dose 
TBI also destroys normal bone marrow cells in addition to malignant cells. The dose of TBI used 
in this protocol is approximately one-sixth of that used in conventional transplant protocols, and 
severe acute side effects have not yet been observed. TBI has been associated with causing 
infertility; however, it is expected that the risk of infertility will be lower than the risk after 
transplants that use higher doses of TBI. Although TBI can theoretically cause abnormalities in 
children born to transplant survivors, the incidence of genetic abnormalities has not been 
reported to be greater than the general population. However, this is a potential risk and birth 
control should be used for at least one year after transplant to minimize risks of conceiving. 
There is a risk that a small percentage of patients may develop a secondary cancer resulting from 
this treatment. There may be some unknown consequences to the patient’s health resulting from 
the administration of total body irradiation. 
 
You will also be receiving diagnostic exams (CT scans, chest x-rays, bone scan, etc) to help 
follow your progress.  These exams will result in a radiation dose to you, but these doses are 


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small in comparison to the therapy dose you will receive.  They are not expected to increase your 
health risk. 
 
Fludarabine is a chemotherapy drug used in the treatment of blood cancer. You have received 
this medicine or one like it in the past as a treatment for your CLL. The fludarabine in this study 
is not intended to treat your CLL. Fludarabine is being used in stem cell transplants to try and 
reduce the risk of graft rejection. Its main side effects include lowering of blood counts and 
increasing the risk of developing infections. In early studies, some patients who received high 
doses experienced nerve damage; however, such side effects would not be expected with the 
doses used in this study. Hemolytic anemia (immune damage to red cells) has occurred in some 
patients with chronic lymphocytic leukemia who received fludarabine.  If you have experienced 
this side effect in the past, there is a possibility that you may again experience severe hemolytic 
anemia when given fludarabine. All possible medical precautions will be taken to ensure your 
safety. 
 
Mycophenolate Mofetil (MMF): MMF is a drug used for suppressing the immune system for 
stem cell transplantation. The drug is reasonably well tolerated by patients who have had 
nonmyeloablative transplants. There are a small number of patients who have received solid 
organ transplants and had reversible fall in their red cell or white cell count while receiving 
MMF. Additionally, cases of Pure Red Cell Aplasia (PRCA) have been reported in some patients 
receiving MMF. PRCA is a condition in which the bone marrow stops producing red blood cells. 
In some instances, PRCA can be reversed by reducing or stopping MMF. Your blood counts will 
be monitored closely and if significant decrease is noted, dose adjustments or stopping your 
MMF may be indicated.  
Cases of progressive multifocal leukoencephalopathy (PML) have occurred in some patients 
receiving MMF. PML is a rare disorder that affects the central nervous system, and is most often 
found in patients with suppressed immune systems. It occurs when the polyomavirus (or JC 
virus) is activated, and can cause neurologic symptoms including weakness on one side of the 
body, lack of emotion, confusion, cognitive difficulties, and loss of coordination. It can cause 
permanent disability and is sometimes fatal. You should notify your doctor immediately if you 
develop any of the above symptoms. 
Other uncommon, though potentially important, side effects include nausea, vomiting, diarrhea, 
and abdominal discomfort. Occasional cases of gastrointestinal bleeding have also been reported 
among patients receiving MMF for long periods of time. 
 
Likely Side Effects  
Less Likely Side Effects  
Rare Side Effects  
• Nausea (feeling sick to 
stomach) 
• Vomiting (throwing up)  
• Diarrhea (loose stools) and 
abdominal discomfort 
• Lower red blood cell count 
that is reversible 
• Lower white blood cell count 
with increased risk of infection 
• Stomach and bowel 
bleeding (blood in stools) 
• Secondary cancers 
 


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MMF has caused birth defects in humans. The United States Food and Drug Administration 
(FDA) requires that women who take part in this study must use two forms of contraception if 
they are fertile and not abstinent. 
 
FOR WOMEN WHO COULD BECOME PREGNANT: Birth defects could occur if you take 
MMF while you are pregnant. As discussed above, you must use 2 effective forms of 
contraception if you are fertile and sexually active. You should talk to your doctor to find out 
which methods of birth control would be most effective for you. You must notify your doctor 
and the coordinating center for the study immediately if you become pregnant while you are 
taking MMF. You should not breast feed while you are taking MMF. 
 
Rituximab is a drug made up of an antibody produced in a laboratory. This antibody attaches to 
a protein on the surface of lymphoma cells and can lead to their destruction. Rituximab can also 
destroy some normal white blood cells called B-lymphocytes. Rituximab is widely used to treat 
lymphoma, and you have likely already received it during your earlier treatment. We are 
studying whether additional doses of rituximab will increase the success of your transplant. 
 
Some patients have an allergic reaction when they receive rituximab. These reactions are 
generally worst with the first few doses, and may go away with subsequent dosing. We use drugs 
like diphenhydramine (Benadryl) to prevent such allergic reactions, though they are not always 
successful. The most common side effects of rituximab are allergic, and include temporary fever, 
chills, and skin rash. Since rituximab can affect normal lymphocytes, it may increase the risk of 
certain infections; you will be screened and monitored closely for these infections after your 
transplant, and you will receive preventive medication against certain infections as part of 
standard transplant care. In rare cases, rituximab has been associated with bowel injuries or with 
a disease called progressive multifocal leukoencephalopathy (PML), both of which can be 
serious, life-threatening, or fatal. 
 
Cyclosporine (CSP) is a drug used for suppressing the immune system. The immediate effects 
of this drug may include nausea or vomiting when given orally. Other possible side effects 
include developing high blood pressure (hypertension), shaking of the hands (tremor), increased 
hair growth, and an effect on mental function. These effects are generally reversible upon 
decreasing the dose of the drug. An occasional patient has had a seizure, but it is unclear whether 
CSP, alone or in combination with other drugs, was responsible.  There is a risk that a small 
percentage of patients may develop a secondary cancer resulting from this treatment. 
 
Some patients given intravenous CSP for the treatment of GVHD have experienced a painful 
sensation in the hands or feet or both. The pain subsided with slowing of the infusion, the 
improvement of the GVHD or when the CSP was switched from the intravenous to the oral form. 
Patients may experience a change of liver or kidney function, in which case, the dose of CSP 
may need to be reduced or possibly withheld. This effect on the kidneys appears to increase 
when other drugs that might cause kidney problems are given at the same time, especially certain 
antibiotics. Occasionally the kidney damage is severe enough to require the use of intravenous 
fluids or even an artificial kidney machine (hemodialysis). If your kidney function is poor prior 
to transplant, there is an increased risk that you may develop kidney failure requiring 
hemodialysis.  
 


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Destruction of red blood cells (hemolysis) often occurs while on CSP, and sometimes CSP needs 
to be withheld or discontinued for this reason. There is a risk of headaches and seizures while 
taking cyclosporine. Episodes of bleeding into the brain have occurred in two patients on similar 
protocols that may be related to CSP therapy. During treatment, CSP blood levels will be 
monitored periodically to determine if there is an increased risk of side effects that warrant 
adjusting the dose. 
 
Central Venous Catheter. A central venous catheter is a hollow tube that is placed in a large 
vein inside the body. It is used to give intravenous medicine and to withdraw blood for lab tests. 
It is placed surgically, often using a local anesthetic (numbing medicine injected into the skin), 
and can cause some discomfort. There has been considerable experience with the use of central 
venous catheters. Complications have included clotting (accumulation of aggregates of blood 
cells that block the lumen of the catheter) and local infection, which sometimes causes an 
infection in the blood. Clotting may require that the catheter is removed or that you receive 
treatment of the clot with a fibrinolytic agent (Tissue Plasminogen Activator [t-PA] - a medicine 
that dissolves blood clots). Occasionally, there has been skin redness at the catheter exit site, 
which may require treatment with an antibiotic. 
 
Bone marrow sampling: All patients will need to have marrow sampling performed. The risks 
of bone marrow sampling include slight pain, the possibility of infection, temporary bruising and 
bleeding around the site of the blood draw. There is a small additional risk of damage to the 
pelvis and nerve damage. 
 
Risk to the Unborn:  You should not become pregnant or father a child while on this study. The 
treatments in this study have NOT been proven to be safe at any stage of pregnancy. Therefore, 
if you are pregnant or nursing, you are not eligible for this study. Women who have the potential 
of becoming pregnant or men who have the potential of fathering a child must use some form of 
effective birth control for one year after transplant. Effective birth control would be defined as 
the following: 1) refraining from all acts of vaginal intercourse (ABSTINENCE); 2) consistent 
use of birth control pills; 3) injectable birth control methods (Depo-Provera); 4) tubal 
sterilization or male partner who has undergone a vasectomy; 5) placement of an IUD 
(intrauterine device); and, 6) use, with every act of intercourse, of a diaphragm with 
contraceptive jelly and/or condoms with contraceptive foam. 
 
Sterility and Future Childbearing Potential for Men and Women: Chemotherapy and/or 
irradiation may affect fertility. Male patients may become sterile (unable to produce sperm). 
Female patients may find that their menstrual cycle becomes irregular or stops permanently. 
However, this DOES NOT MEAN THAT YOU CANNOT BECOME PREGNANT OR 
FATHER A CHILD, and you must use some effective method of birth control for at least one 
year after the transplant. Damage to ovaries and testes may result in birth defects or permanent 
inability to have a child or become pregnant. You should discuss these risks and options in detail 
with your doctor before entering this study. 
 
➢ Are there benefits to taking part in this study?  
The primary possible benefit is that it may provide an effective and potentially curative treatment 
for the patient’s disease without the risks of treatment with high doses of radiation and 
chemotherapy. We cannot and do not guarantee the patient will benefit by taking part in this 
study. The treatment patients receive may even be harmful. Doctors feel that participation in this 


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study will give the patient at least as good a chance of surviving CLL as the patient might expect 
from other treatments. We hope the information learned from this study will benefit other 
patients with this type of leukemia in the future. 
 
➢  What if new information is learned while I am in this study that might affect my health? 
If we learn any important new information that might affect your health, welfare, safety, or 
willingness to stay in the research study, your doctor (attending physician) will tell you.  You 
may be asked to sign another consent form if you wish to stay in the research study at that time. 
 
➢ What other treatment options are there?  
 Instead of being in this study, you can decide to have: 
• No treatment. 
• A conventional allogeneic or autologous stem cell transplant, if eligible. 
• Conventional chemotherapy, if appropriate. 
• Biological (antibody) therapy, if appropriate. 
• Experimental chemotherapy for patients with CLL who fail fludarabine, if eligible.  
 
In general, patients who do not respond to treatment with fludarabine or who have cytogenetic 
abnormality of deletion 17, survive less than 12 months without treatment or with conventional 
chemotherapy. Nearly all patients who experience worsening of their CLL after prior fludarabine 
treatment fail to respond to further treatment with fludarabine or similar medicines. For some 
patients in this situation, antibody therapies can improve symptoms. For other patients, an 
autologous transplantation may get rid of CLL, but it may come back at a later date. For patients 
who are eligible, high-dose chemotherapy with or without radiation followed by receiving stem 
cell transplantation from another individual may get rid of CLL, but this procedure may have 
complications early after the transplant. Please talk with your doctor about these and other 
options before you enter the study.  You may continue to discuss other options that may become 
available during the research study. 
 
➢  Can I change my mind about taking part in this study?  
Yes, you can change your mind.  You have the right to choose whether or not you want to take 
part in this research study.  You may decide to stop taking part in the study once you have 
started.  Leaving the study will not result in any loss of benefits that you already have.   
 
If you withdraw after some of the treatment is given but before you get the stem cells transplant, 
then you might experience some delay in regaining your full marrow function. This might 
require some additional supportive care and transfusion of blood products. However, we 
anticipate that the marrow function will eventually come back after this mild form of treatment.  
 
It is very important to let your doctor (attending physician) know right away if you want to 
stop taking part in this study.  Your doctor will talk with you about your choices. 
 


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➢ How will information about me be kept private?  
We will try to keep your personal information as private as we can. There is no guarantee of 
absolute privacy. Your personal information may be disclosed if required by law. Organizations 
that are listed below may inspect or copy your research records for quality assurance and data 
analysis. Your research records will identify you by name and will include things such as your 
medical history, results of your blood tests and exams, reports from your surgery and treatment, 
reports of your office visits.  
 
➢   Who may see my research information?  
In order to evaluate the results of the study, individuals from the Fred Hutchinson Cancer 
Research Center (FHCRC) may need to review medical records that identify you by name. These 
individuals include investigators directly involved in the study, institutional committees 
responsible for reviewing the safety and progress of studies, and members of the Institutional 
Review Board (this Committee is responsible for protecting the rights of persons taking part in 
research). In order to evaluate the results of this study, individuals from the National Cancer 
Institute might also need to review medical records that identify you by name. 
 
Your research records may be made available to the following organizations: 
• The Fred Hutchinson Cancer Research Center (FHCRC) 
• The University of Washington (UW) 
• The Seattle Cancer Care Alliance (SCCA) 
• National Institutes of Health (NIH) 
• Office for Human Research Protections (OHRP) 
• The Food and Drug Administration (FDA) 
• Institutional Review Board (IRB) 
 
Your identity will not be revealed in any publication or presentation of results. Study records will 
be maintained indefinitely for the purpose of analysis and follow-up. 
 
➢ What are the costs?  
You and/or your insurance company will pay all medical expenses relating to, or arising from, 
this study. You and/or your insurance company will be responsible for all procedures related for 
your treatment under this study. You and/or your insurance company will not be responsible for 
any exceptional research sampling or procedure that is not directly related or necessary for your 
treatment under this study. If you are injured or become ill from taking part in this study, 
emergency medical treatment is available but will be provided at the usual charge. The attending 
physician will authorize medical care. No funds have been set aside to pay you in the event of 
injury. You or your insurance company will be charged for continuing medical care and/or 
hospitalization. You will not be paid for taking part in this study. If you have questions regarding 
your costs, financial responsibilities, and/or medical insurance coverage for this activity, please 
contact the SCCA Patient Financial Services Department at (206) 288-1113. 
 
➢ Do I have to be part of the study?  
Your decision to participate in this study is voluntary. You may choose either to take part or not 
to take part in this research study. You may decide not to participate in this study at any time, for 
any reason, without notice. However, early discontinuation of the drugs that suppress (hold back) 


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the immune system, CSP and MMF, after stem cell transplant could lead to rejection of the donor 
stem cells or life threatening GVHD.  
 
We request that you talk with the research physician and your regular doctor prior to 
withdrawing from the study. You will continue to receive medical care even if you decide to 
discontinue treatment on this study. If you have questions about the study, please talk with your 
physician or one of the investigators listed at the beginning of the consent. Do not sign this form 
unless you have had the chance to ask questions and have received satisfactory answers. You 
may also wish to discuss this matter with a relative or friend. 
 
➢ What are my rights as a study participant?  
Even after you agree to take part in this study, you may withdraw at any time. Before 
withdrawing, you should notify one of the people involved with this research. This will allow 
that person or someone else supervising the research to inform you of the medical risks 
associated with withdrawing. The medical risks may be substantial. You can choose to withdraw 
one of two ways. In the first, you can stop your study treatment, but still allow the study staff to 
follow your care. In the second, you can stop your study treatment and not have any further 
contact with the study staff. Either way, there will be no penalty or loss of benefits that you are 
already entitled to. Your decision will not affect your routine medical treatment, your 
relationship with those treating you, or your relationship with the study staff. If you withdraw 
from study therapy, you will still continue to receive medical care. 
 
➢ Who can I call if I have questions or problems?  
For Questions About 
   Please Contact 
This study and what it involves 
Your doctor (attending physician) or one of the investigators 
listed at the beginning of the consent 
Your rights as a participant in a 
research study 
Karen Hansen, in the Institutional Review Office, FHCRC 
at 206-667-4867 
Your bills and health insurance 
coverage 
Seattle Cancer Care Alliance, Patient Financial Services at 
206-288-1113 
Research use of your blood or 
tissue sample, or research files 
Clinical Research Division, Data Management Office, 
FHCRC/Clinical Research Division at 206-667-4728 
Research related injury 
Your physician or one of the investigators listed at the 
beginning of this consent 
Emergency care 
Emergency (24 hour) phone: (206) 598-8902 
 
 
 
 
 
 
 


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➢What about use of my tissue/blood cells for research? 
An Institutional Review Board (IRB) must also approve any future or new research study using 
your tissue. The IRB is a group of people who review research studies to protect your rights.  
The research that may be done with your tissue is not designed to specifically help you.  It might 
help people who have cancer and other diseases in the future.  Reports about research done with 
your tissue will not be given to you or your doctor.  These reports will not be put in your health 
records.  The research using your tissue will not affect your care. 
 
Your tissue will be used only for research and will not be sold.  The research done with your 
tissue may help to develop new products in the future, but you will not get paid. 
 
The possible benefits of research from your tissue include learning more about what causes 
cancer and other diseases, how to prevent them and how to treat them.  The greatest risk to you is 
the release of information from your health records. The chance that this information will be 
given to someone else is very small.  
 
➢ Where can I get more information about cancer and its treatment?  
You can call the Cancer Information Service at 1-800-4-CANCER or visit the National Cancer 
Institute’s Clinical Trials Web Site at http://cancertrials.nci.nih.gov. You can also get 
information at any time from the doctor in charge of your medical care in this study or one of the 
study investigators. 


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CONSENT TO PARTICIPATE IN THE RESEARCH STUDY 
I have carefully read this consent form.  This study has been explained to me.   I have a 
choice whether to take part or not to take part in this study. I have been told of the risks and 
benefits of taking part in this study. I have had the chance to ask questions about it, and all 
questions were answered to my satisfaction.  I now agree to take part in this research study. 
 
I also give permission to the people and organizations connected with this research study to 
review and copy my research records, both during the research and the long-term follow-up.  
 
Participant Printed Name, Signature, and Date 
 
 
Legally Authorized Representative: If you have read this form (or had it read to you), asked 
any questions, and consent on behalf of the participant, please sign: 
Legally authorized representative / Printed Name, Signature, and Date 
 
Relation to the participant 
 
 
 
MEDICAL STAFF PERSON’S STATEMENT 
I have discussed the above research study, including the study purpose, procedures, risks 
and benefits, and possible alternatives, with the person signing above.  All the elements of 
informed consent were reviewed and discussed with the subject.  Special concerns that the 
participant expressed were noted and appropriately addressed.  I encouraged questions and 
have answered all questions to the best of my ability.  The participant is aware that he/she 
has a choice in taking part in this study.  A signed copy of the consent form will be given 
to the participant.  
  
_________________________________ 
 
 
 
Medical Staff Person’s Signature 
 
  Date 
 
 
 
Printed Name and Title of Medical Staff Person 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Any Additional Staff Person Present During Consent Process (if present) 
  
 


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1840.00A 
Current Version:   12/25/2014 
Previous Version:   4/8/2014 
Copies to: Patient, Medical Records, Research File  
 
Signed Consent MUST be sent to Data Management – LF-229 
FHCRC, 1100 Fairview Ave N, Seattle, WA 98109-1024