Clinical trial NCT00723099
Conditions: Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Aggressive Non-Hodgkin Lymphoma Chronic Myelogenous Leukemia Chronic Phase Chronic Myelogenous Leukemia Indolent Non-Hodgkin Lymphoma Lymphoma Mixed Phenotype Acute Leukemia Myelodysplastic Syndrome Myeloproliferative Neoplasm Recurrent Chronic Lymphocytic Leukemia Recurrent Follicular Lymphoma Recurrent Lymphoplasmacytic Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Plasma Cell Myeloma Recurrent Small Lymphocytic Lymphoma Recurrent T-Cell Non-Hodgkin Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Chronic Myelogenous Leukemia Refractory Follicular Lymphoma Refractory Hodgkin Lymphoma Refractory Lymphoplasmacytic Lymphoma Refractory Mantle Cell Lymphoma Refractory Small Lymphocytic Lymphoma T-Cell Non-Hodgkin Lymphoma
Sponsor: Fred Hutchinson Cancer Center
Start date: 2008-06-25; Completion date: 2018-07-31
Enrollment: 73 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (TBI) before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from an unrelated donor, that do not exactly match the patient's blood, are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

Detailed description:
PRIMARY OBJECTIVES:

I. Estimate probability of one year survival.

II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin (ATG) based conditioning regimen. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

* Absence of 3 consecutive days with neutrophils \>= 500/ul combined with host cluster of differentiation (CD)3 peripheral blood chimerism \>= 50% at day 42
* Absence of 3 consecutive days with neutrophils \>= 500/ul under any circumstances at day 55
* Death after day 28 with neutrophil count \< 100/ul without any evidence of engraftment (\< 5% donor CD3)
* Primary autologous count recovery with \< 5% donor CD3 peripheral blood chimerism at count recovery and without relapse

SECONDARY OBJECTIVES:

I. Six month non-relapse mortality.

II. Overall incidence of graft failure/rejection. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

* Absence of 3 consecutive days with neutrophils \>= 500/ul combined with host CD3 peripheral blood chimerism \>= 50% at day 42
* Absence of 3 consecutive days with neutrophils \>= 500/ul under any circumstances at day 55
* Death after day 28 with neutrophil count \< 100/ul without any evidence of engraftment (\< 5% donor CD3)
* Primary autologous count recovery with \< 5% donor CD3 peripheral blood chimerism at count recovery and without relapse

III. Kinetics of chimeric reconstitution.

IV. Incidence of neutrophil engraftment by day 42.

V. Incidence of platelet engraftment by six months.

VI. Incidence of grade II-IV and III-IV acute graft-versus-host disease (GvHD) at day 100.

VII. Incidence of one year chronic GvHD.

VIII. Incidence of clinically significant infections at 6 months, 1 year, 2 years.

IX. Probability of one and two year survival.

X. Incidence of one and two year relapse or disease progression.

XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune reconstitution, with both functional and quantitative assays.

XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of total-body irradiation (TBI) on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days 0 to +96.

After completion of study treatment, patients are followed periodically for up to 2 years.

Arms: arm 1: CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Cyclophosphamide intervention 3: Cyclosporine intervention 4: Fludarabine Phosphate intervention 5: Laboratory Biomarker Analysis intervention 6: Mycophenolate Mofetil intervention 7: Total-Body Irradiation intervention 8: Umbilical Cord Blood Transplantation
Intervention descriptions: intervention 1: Undergo umbilical cord blood transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV or PO intervention 7: Undergo TBI intervention 8: Undergo umbilical cord blood transplant

Protocol documents:
Prot_SAP_000.pdf: 
2239.00 	
IRO REC'D MAR 27 2019 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
SEATTLE CHILDREN'S 
Current version: 3/26/19 
Previous version: 12/12/17 
Transplantation of Umbilical Cord Blood in Patients with Hematological Malignancies Using a 
Reduced-intensity Preparative Regimen 
Investigator 
Rachel Salit, MD 
Colleen Delaney, MD, MSc 
Fred Appelbaum, MD 
Brenda Sandmaier, MD 
Rainer Storb, MD 
Stanley Riddell, MD 
Filippo Milano, MD, PhD 
Ann Dahlberg, MD 
Professional Title 
Principal Investigator 
Assistant Member, FHCRC 
Assistant Professor, UW 
Affiliate, FHCRC 
Associate Professor of Pediatric 
Hematology/Oncology, UW 
Member, FHCRC 
Professor of Medicine, UW 
Member, FHCRC 
Professor of Medicine, UW 
Member, FHCRC 
Professor of Medicine, UW 
Member, FHCRC 
Professor of Medicine, UW 
Assistant Member, FHCRC 
Assistant Professor of Medicine, UW 
Assistant Member, FHCRC 
Assistant Professor of Pediatric 
Hematology/Oncology, UW 
Area Code (206) 
667-1317 
667-1385 
667-4412 
667-4961 
667-4407 
667-5249 
667-5925 
667-1959 
Biostatistician: 
Ted Gooley, PhD 	
Member, FHCRC 	
667-6533 
Research Staff: 
Nancy Anderson, RN 
Denise Ziegler 
MaryJoy Lopez 
Research Nurse 
Research Coordinator 
Data Coordinator 
667-6264 
667-5762 
(Fax) 667-2324 
667-6139 
(Fax) 667-2324 
(Fax) 667-2324 
FHCRC Emergency (24 hour) Phone: (206) 598-8902; Fax: (206) 598-4034 
FHCRC IRB Approval 
MAR 29 2019 
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1. 
Introduction 
Conventional myeloablative allogeneic hematopoietic stem cell transplantation (HCT) is limited by 
lack of rapidly available HLA matched donors and excess transplant related mortality (TRM). 
Umbilical cord blood (UCB) is an alternative hematopoietic stem cell (HSC) source with the 
advantages of relative tolerance of HLA disparity [1-5] and rapid availability [6]. UCB transplantation 
(UCBT) is a standard therapy for pediatric leukemia [2-5] and is now being investigated in adults [7-
10]. Many older patients, or those with extensive prior therapy or serious comorbidities, are unable to 
tolerate conventional myeloablative conditioning. Therefore, reduced intensity conditioning (RIC) 
regimens have been developed to extend the possibility of curative transplantation to these populations. 
The use of either related or unrelated volunteer donors as a graft source for RIC is well established [11-
19]. However, for older or infirm patients lacking a suitable related or unrelated donor, UCB is an 
attractive graft source. 
Emerging data suggests that RIC is feasible in the UCB setting [20-25]. Multiple centers have reported 
pilot studies of UCB RIC, and the University of Minnesota has recently published outcomes in a larger 
cohort of 110 patients [26]. Optimal conditioning regimen and post-transplantation 
immunosuppression designed to minimize graft failure and TRM, however, have not yet been defined. 
This protocol will help clarify these questions by replacing ATG in the conditioning regimen of our 
current UCB RIC Protocol (FHCRC 2012) with alternative intensification of therapy and by prolonging 
mycophenolate mofetil (MMF) treatment in the post-transplantation period. 
2. 
Background 
At the FHCRC, our conditioning regimen for UCB RIC for patients with advanced or high risk 
hematologic malignancies has been identical to that of the recently published Minnesota cohort, and we 
have performed 13 transplants to date. Conditioning includes a single dose of cyclophosphamide 
(CY) 50 mg/kg on Day —6, fludarabine (FLU) 40 mg/m2 daily x 5 days (Days —6 to —2), and a single 
dose of 2 Gy of total body irradiation (TBI) (Day —1) (CY/FLU/TBI). Equine anti-thymocyte globulin 
(ATG) is administered 30 mg/kg daily on Days —3 to —Ito patients at high risk for graft rejection 
(those patients who have not undergone autologous transplant within the last year and who have not 
received combination chemotherapy in the preceding 4 months or have received only a single induction 
regimen for leukemia or MDS prior to transplantation). Our post-grafting immunosuppression is 
modified from the Minnesota regimen. Both regimens include cyclosporine (CSA) from Day -3 
through Day +100 then tapered 10% per week to be discontinued no sooner than 6 months post-
transplant. However, in contrast to Minnesota, which has reported on using MMF only twice daily 
from Days -3 to 30, the FHCRC regimen includes MMF one gram three times daily from Day 0 to 30. 
The Minnesota group developed its current RIC regimen through clinical experience. Its initial RIC 
regimen included busulfan (BU) 2mg/kg every 12 hours x 4 (Days -8 to -7), FLU 40 mg/m2 daily x 5 
days (Days —6 to —2), and a single dose of 2 Gy of total body irradiation (Day —1) (BU/FLU/TBI). 
Twenty-one patients were treated on this regimen. Forty-three percent received two cord units at 
transplant and median infused cell dose was 2.6 total nucleated cells (TNC)x107/kg (range 1.6-3.8). 
The regimen resulted in prolonged neutropenia, and four patients who had experienced no 
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chemotherapy in the four months preceding RIC experienced donor graft failure. In an attempt to 
achieve equivalent or greater immunosuppression with less myelosuppression, BU was replaced with a 
single dose of CY resulting in the CY/FLU/TBI regimen. The change resulted in a significant decrease 
in median time to neutrophil recovery (9.5 days (range 5-28 days)) and only one graft failure among the 
first 21 evaluable patients. Sixty-eight percent received two cord units at transplant and median 
infused cell dose was 3.2 TNCx107/kg (range 1.1-5.1). The single CY/FLU/TBI patient with graft 
failure had advanced myelofibrosis without prior combination chemotherapy [20]. As a result of these 
observations, ATG was added to the conditioning regimen for patients without combination 
chemotherapy in the preceding 4 months or with only a single induction regimen for AML prior to 
transplant. Since the introduction of ATG, engraftment in this high risk group has increased from 64% 
to 84% in Minnesota's experience [personal communication]. 
In the recent report of 110 patients using the current CY/FLU/TBI +/- ATG regimen, Minnesota reports 
92 percent neutrophil recovery at a median of 12 days (range 0-32) and primary and secondary graft 
failure in 7 and 8 patients respectively. For the entire cohort, the cumulative incidence of sustained 
engraftment (neutrophil recovery with complete chimerism) was 85% (95%CI 77-92). Eighty-five 
percent of patients received two units and the median infused cell dose was 3.7 TNCx107/kg (range 
1.1-5.3). Three year survival was 45% (95%CI 34-56) and three year event free survival was 38% 
(95%CI 28-48). Transplant related mortality was 19% (95%CI 12-26%) at day 180 and 26% (95%CI 
18-34) at three years. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at day 
100 were 59% (95%CI 49-69%) and 22% (95%CI 14-30). Cumulative incidence of chronic GVHD 
was 23% (95%CI 15-31) at 1 year. In Cox regression analysis; patients with pre-existing high risk 
clinical features and grade III-IV acute GVHD had a significantly higher relative risk of death (relative 
risk 3.0 (1.7-5.2, p<0.01) and 1.9 (1.0-3.5, p=0.04) respectively). In Cox regression analysis, absence 
of ATG in conditioning regimen was associated with a higher risk of GVHD (relative risk 2.2 (1.2-4.0, 
p<0.01), while in univariate analysis use of ATG was associated with a higher risk of TRM at 180 days 
(38% vs. 12%, p=0.02)[26]. 
Our limited experience (13 patients to date) makes drawing conclusions based on our own data 
difficult. With an average follow-up of 463 days among survivors, 4/13 (31%) remain alive, and all 
results appear consistent with those reported in the larger Minnesota series. Our experience combined 
with Minnesota's data raise important questions about possible treatment regimen changes that may 
improve outcomes in RIC UCBT. ATG was originally added to the Minnesota regimen to decrease 
graft failures in high risk patients, but a number of considerations raise questions about the importance 
of ATG in the regimen. Four of the first five graft failures in the Minnesota RIC experience occurred 
following BU/FLU/TBI conditioning. Recent data from Duke and MD Anderson suggest that BU/FLU 
is associated with unexpectedly high rates of graft failure in the UCBT setting [27, personal 
communication]. Early graft failures in the Minnesota RIC setting may, therefore, have been a result of 
the BU/FLU/TBI regimen, and it is unclear the extent to which ATG added to CY/FLU/TBI has 
enhanced engraftment. In addition, UCB unit selection strategies and post-transplantation 
immunosuppression practiced at the FHCRC may enhance engraftment rates as compared to the 
Minnesota experience. Though Minnesota did not report infused cell doses associated with graft 
failures in their pre-ATG patients, infused cell dose has been established as critical to engraftment 
rates. To ensure adequate cell doses we have developed a conservative algorithm at the FHCRC such 
that single unit CBT is allowed only for units matched for 4/6 HLA with TNC dose of at least 6.0 
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x107/kg, for 5/6 HLA with TNC dose of at least 4.0 x107/kg or for 6/6 HLA with TNC at least 3.0 
x107/kg. If these criteria are not met, double unit RIC transplants are performed with a minimum TNC 
of at least 3.0 x107/kg. In addition, at the FHCRC we perform pre-transplant panel reactive antibody 
(PRA) screening followed, in positive cases, by analysis of individual HLA antigens to identify patients 
at risk for antibody mediated rejection of cord units. To our knowledge this process is not widely 
performed at other centers, and in 36 patients treated in our recent protocols, four patients have been 
identified as having units at risk for antibody rejection. For two patients, at-risk units were 
successfully replaced with alternative safe donor units. For one patient, no safe units could be 
identified and the patient's donor was switched to a B allele mismatched unrelated donor. The fourth 
patient was infused one safe unit and one at-risk unit because no alternative donors were available. 
Though engraftment of the safe unit occurred, the at-risk unit was never seen on post-transplant 
chimerism analysis, possibly as a result of immediate rejection by an antibody mediated process. 
Finally, in contrast to Minnesota, at the FHCRC we dose MMF three times daily. Previous data from 
our center in the unrelated RIC setting has demonstrated a decreased risk of graft rejection when MMF 
is administered three times rather than twice daily [28]. Using this approach, we have observed one 
graft failure in 10 evaluable RIC UCB patients and no graft failures in 29 evaluable myeloablative 
UCBT patients. The RIC patient who experienced graft failure was an AML patient who received 
ATG during conditioning. She was successfully salvaged with a second double cord transplant using 
FLU 200mg/m2, CY 50mg/kg, and 4 GY TBI for conditioning. Eight of thirteen RIC patients have 
received ATG in their conditioning regimen. 
While stringent requirements for cell dose, careful assessment of risk for antibody mediated rejection, 
and three times daily MMF through Day 30 likely contribute to the high rates of engraftment in our 
collective UCBT experience, RIC patients at high risk for graft failure still may require more 
significant immunosuppression in their conditioning regimen. For several reasons, however, we 
believe that ATG poses a particular hazard to this population. ATG is well documented to delay T cell 
recovery following transplantation and to increase risk of viral infection. Even in the absence of ATG, 
cord blood patients are known to experience delayed immune reconstitution [29]. Furthermore, our 
three times daily MMF dosing schedule increases risk of infection compared to Minnesota's twice 
daily schedule [28]. In the recent Minnesota series, ATG was, in univariate analysis, associated with a 
higher risk of TRM at 180 days. Among UCBT patients receiving RIC conditioning, ATG has been 
specifically associated with an increased risk of EBV post-transplant lymphoproliferative disorder 
(PTLD) [30]. Though anecdotal, in our center's UCBT experience, our only death from CMV 
(pneumonia) and our only case of HHV6 encephalitis occurred in patients receiving RICs which 
included ATG in conditioning. In addition, we have observed 100% early CMV reactivation in all 
UCBT recipients who were seropositive prior to transplant, and ATG likely exacerbates this problem. 
ATG may also abrogate nascent GVL effects. Finally, ATG is a toxic drug associated with high rates 
of infusion associated reactions and serum sickness, and though again anecdotal, in our experience one 
patient scheduled for UCBT RIC died of a myocardial infarction and multi-system organ failure on Day 
-3 following an adverse reaction to ATG. 
For these reasons we propose a stepwise alternative conditioning escalation strategy that does not 
include ATG for patients at high risk for rejection. Limited literature from several Japanese pilot 
studies confirms the feasibility of non-ATG based conditioning regimen. Reported regimens include 
150 mg/m2 FLU, 80 mg/m2 melphalan (MEL), and 4 Gy TBI as well as 50 mg/kg CY, 200 mg/m2 
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FLU, and 3 Gy TBI regimen[21,24]. Both of these regimen have been associated with reasonable 
engraftment, but infused cell doses and post-grafting immunosuppression were varied, and details of 
outcomes of patients at high risk for rejection were not reported. 
We propose a strategy similar to that of FHCRC Protocol 1949 in the unrelated RIC setting. We will 
replace ATG with an increase in TBI from 200 cGy to 300 cGy. 
The removal of ATG from our conditioning regimen does raise concerns about the possibility of 
increased GVHD and, possibly, subsequent increased mortality. In the Minnesota series, ATG was 
associated with decreased GVHD, and Grade III/IV GVHD was a risk factor for increased mortality. 
However, the Minnesota post-transplantation immunosuppression regimen may not be optimal. 
Patients on the Minnesota regimen received MMF 1 gram twice daily from Days —3 to 30. As 
described above, we have incorporated three times daily MMF into our post-transplantation 
immunosuppression regimen. In addition to promoting engraftment, data from Minnesota suggests that 
TID dosing may decrease the risk of GVHD (though we have not observed this finding in our clinical 
experience) [31,28]. We also propose extending MMF treatment to Day +40 post-transplantation with 
a subsequent 12% dose reduction every one week with a stop date anticipated approximately day +96. 
In our RIC UCBT experience to date, 7/9 evaluable patients have developed grade II-IV GVHD and 
3/9 patients developed grade III-IV GVHD. 4/9 evaluable patients discontinued MMF on day 30 with 
no evidence of GVHD, but three subsequently developed acute GVHD before day 100. Notably, two 
developed symptoms within a week of stopping MMF. We believe, therefore, that extended MMF may 
decrease incidence of acute GVHD. Our proposed regimen is consistent with the current unrelated 
donor RIC MMF schedule under investigation in protocol 1641. In addition, due to possible added 
toxicity without benefit, MMF dosing will be changed from starting on Day 0 to starting 4-6 hours after 
infusion of stem cells on Day 0. 
Patients deemed at higher risk for graft failure will be enrolled. This group includes patients who have 
received <2 cycles of multiagent chemotherapy and patients who have received no multiagent 
chemotherapy within the 3 months previous to UCBT. Patients experiencing graft failure following 
previous allogeneic transplant will also be included. Patients who have had previous autologous 
transplant within 12 months of UCBT are excluded regardless of history of recent treatment. 
3. 	
Objectives 
The primary objective of this protocol is to better assess efficacy of RIC UCBT as measured by 
probability of 1 year survival. In addition, a primary objective is to optimize a non-ATG based 
conditioning regimen. The proposed conditioning regimen will continue to use CY 50mg/m2 and FLU 
200 mg/m2, but the initial TBI dose will be increased from 200 cGy to 300 cGy. 
A. 	
Primary Objective: 
I. 	
Estimate probability of one year survival 
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2. 	
Demonstrate equivalent or improved engraftment rates with a non-ATG based 
conditioning regimen. Patients will be considered graft failure/rejections provided they 
meet any of the criteria listed below: 
i. Absence of 3 consecutive days with neutrophils >500/u1 combined with host 
CD3 peripheral blood chimerism? 50% at day 42 
ii. Absence of 3 consecutive days with neutrophils >500/u1 under any 
circumstances at day 55 
iii. Death after day 28 with neutrophil count <100/u1 without any evidence of 
engraftment (< 5% donor CD3) 
iv. Primary autologous count recovery with < 5% donor CD3 peripheral blood 
chimerism at count recovery and without relapse 
B. 	
Secondary Objectives: 
1. 	
Six month non-relapse mortality 
2. 	
Overall incidence of graft failure/rejection. Patients will be considered graft 
failure/rejections provided they meet any of the criteria listed below: 
i. Absence of 3 consecutive days with neutrophils >500/u1 combined with host 
CD3 peripheral blood chimerism? 50% at day 42 
ii. Absence of 3 consecutive days with neutrophils >500/u1 under any 
circumstances at day 55 
iii. Death after day 28 with neutrophil count <100/u1 without any evidence of 
engraftment (< 5% donor CD3) 
iv. Primary autologous count recovery with < 5% donor CD3 peripheral blood 
chimerism at count recovery and without relapse 
3. 	
Kinetics of chimeric reconstitution 
4. 	
Incidence of neutrophil engraftment by Day 42 
5. 	
Incidence of platelet engraftment by six months 
6. 	
Incidence of grade II-IV and III-IV acute GvHD at day 100 
7. 	
Incidence of one year chronic GvHD 
8. 	
Incidence of clinically significant infections at 6 months, 1 year, 2 years 
9. 	
Probability of one and two year survival 
10. 	
Incidence of one and two year relapse or disease progression 
11. 	
Kinetics of immune reconstitution, with both functional and quantitative assays 
12. 	
Examination of possible immunologic factors leading to emergence of a dominant unit 
4. 	
Patient Selection 
A. 	
Inclusions 
1. Age, Organ Function and Performance Status Criteria (all patients) 
a. 	
Patients must be <70 years old. Patients > 70 may be considered if Performance 
Status > 80% or ECOG <1 and Comorbidity Score < 3 (Appendix V). These 
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patients must be discussed with the PI, Rachel Salit (phone 206-667-1317, pager 
206-314-2845, prior to enrollment. 
b. 	
Adequate cardiac function defined as absence of decompensated congestive 
heart failure, or uncontrolled arrhythmia and: 
i. left ventricular ejection fraction > 35% or 
ii. fractional shortening >22% 
c. 	
Adequate pulmonary function defined as DLCO > 30% predicted, and absence 
of 02 requirements. 
d. 	
Adequate hepatic function. Patients with clinical or laboratory evidence of liver 
disease will be evaluated for the cause of liver disease, its clinical severity in 
terms of liver function, histology, and the degree of portal hypertension. Patients 
with fulminant liver failure, cirrhosis with evidence of portal hypertension or 
bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding 
esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic 
dysfunction evidenced by prolongation of the prothrombin time, ascites related 
to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic 
viral hepatitis with total serum bilirubin > 3mg/dL, and symptomatic biliary 
disease will be excluded. 
e. 	
Adequate renal function defined as creatinine < 2.0 mg/di (adults) or creatinine 
clearance > 40 ml/min (pediatrics). All adults with a creatinine > 1.2 or a history 
of renal dysfunction must have estimated creatinine clearance > 40 ml/min. 
f. 	
Performance status score: Kamofsky (for adults) > 60 or ECOG 0-2; Lansky (for 
children) score 50 (Appendix I) 
g. 	
If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease. 
h. 	
Second hematopoietic cell transplant: Must be > 3 months after prior 
myeloablative transplant. 
i 	
Patients who have received <2 cycles of multiagent chemotherapy and patients 
who have received no multiagent chemotherapy within the 3 months previous to 
UCBT as well as patients experiencing graft failure following previous 
allogeneic transplant. 
2. Disease Criteria 
The following diseases will be permitted although other diagnoses can be considered if 
approved by PCC and the principal investigators. 
a. 
Acute Myeloid Leukemia/Acute Lymphoblastic Leukemia, including 
Biphenotypic Acute Leukemia or Mixed-Lineage Leukemia: Must have < 5% 
morphologic marrow blasts in an evaluable marrow (>25% of normal cellularity 
for age) collected less than one month prior to start of conditioning. Patients 
persistently aplastic for greater than one month since completing last 
chemotherapy are also eligible with the approval of the PI or designee. 
b. 
Chronic myelogenous leukemia: All types, except refractory blast crisis. Chronic 
phase patients must have failed or been intolerant to Gleevec or other tyrosine 
kinase inhibitors. At time of transplant, patients must have <5% blasts in an 
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evaluable marrow (>25% of normal cellularity for age) by morphology within 
the bone marrow 
c. 
Myelodysplastic syndrome (MDS): Any subtype. Morphologic blasts must be 
less than 5% in an evaluable marrow (>25% of normal cellularity for age). If 
blasts are 5% or more, patient requires induction chemotherapy pre-transplant to 
reduce blast count to less than 5%. Patients who have a hypocellular marrow in 
the absence of excess blasts that is related to the underlying disease or as a result 
of treatment for MDS may also be eligible with the approval of the PI or 
designee. 
d. 
Large-cell lymphoma and aggressive T-cell lymphoma: With chemotherapy 
sensitive disease that has failed autologous transplant or patients who are 
ineligible for an autologous transplant. Chemotherapy sensitive disease is 
defined as? 50% reduction in the size of the tumor with the chemotherapy 
regimen immediately preceding transplant. 
e 	
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL):  Must 
be refractory to fludarabine or fail to have a complete or partial response after 
therapy with a regimen containing fludarabine (or another nucleoside analog, 
e.g. 2-CDA, pentostatin) or experience disease relapse within 12 months after 
completing therapy with a regimen containing fludarabine (or another nucleoside 
analog). 
f. 
Hodgkin Disease: Must have received and failed frontline therapy. 
g. 
Follicular lymphoma, marginal zone B-Cell lymphoma, lymphoplasmacytic  
lymphoma, mantle-cell lymphoma, and indolent T-cell lymphomas: Must have 
progressed with the most recent remission duration being <6 months. Patients 
with bulky disease should be considered for debulking chemotherapy before 
transplant. Patients with refractory disease are eligible, unless they have bulky 
disease and an estimated tumor doubling time of less than one month. 
h. 
Multiple Myeloma: Must have received prior chemotherapy. Consolidation of 
chemotherapy by autografting prior to nonmyeloablative HCT is permitted. 
i. 
Myeloproliferative syndromes  
B. 	
Exclusions 
1. 
Patients with an available 5-6/6 HLA-A, B, DRB I matched sibling donor. 
2. 
Pregnancy or breastfeeding. 
3. 
Evidence of HIV infection or known HIV positive serology. 
4. 
Uncontrolled viral or bacterial infection at the time of study enrollment. 
5. 
Active or recent (prior 6 month) invasive fungal infection without ID consult and 
approval. 
6. 
Active central nervous system malignancy 
7. 
Patients who have received? 2 cycles of multiagent chemotherapy within the 3 months 
previous to UCBT. Patients who have had previous autologous transplant within 12 
months of UCBT are excluded regardless of history of recent treatment. 
5. 	
Donor Selection 
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CB donor selection will be based on institutional guidelines and in general should be selected to 
optimize both HLA match and cell dose. Additionally, CB grafts shall consist of one or two CB donors 
based on, but not exclusively determined by, cell dose (TNC/kg and CD34/kg), HLA matching and 
disease status and indication for transplant. Attending preference will be allowed for single versus 
double unit as well as the degree of mismatching based on patient specific factors, as long as the 
following minimum criteria are met: 
A. HLA matching: 
i. 	
Minimum requirement: The CB graft(s) must be matched at a minimum at 4/6 HLA-A, 
B, DRB1 loci with the recipient. Therefore 0-2 mismatches at the A or B or DRB1 loci 
based on intermediate resolution A, B antigen and DRB1 allele typing for determination 
of HLA-match is allowed. 
HLA-matching determined by high resolution typing is allowed per institutional 
guidelines as long as the minimum criteria (#A.i., above) are met. 
B. Selection of two CB units is mandatory when a single cord blood unit does not meet the 
following criteria in the table below. 
• 
Single Unit Allowed for: 
Match 
Grade 
TNC Dose 
6/6 
? 2.5 x 107/kg 
5/6, 4/6 
> 4.0 (+ 0.5) x 107/kg 
If two CB units are used, the total cell dose of the combined units must be at least 3.0 x 
107  TNC per kilogram recipient weight based on pre-cryopreservation numbers, with each CB 
unit containing a MINIMUM of 1.5 x 107 TNC/kg. 
C. The minimum recommended CD34/kg cell dose should be 2 x 105 CD34/kg, total dose from a 
single or combined double. 
D. The unmanipulated CB unit(s) will be FDA licensed or will be obtained under a separate 
IND, such as the National Marrow Donor Program (NMDP) Protocol 10-CBA conducted 
under BB IND-7555 or another IND sponsored by (1) a participating institution or (2) an 
investigator at FHCRC. 
E. Up to 5% of cord blood product, when ready for infusion, may be withheld for research 
purposes as long as thresholds for infused TNC dose are met. Thresholds for single unit 
transplantation are described in 5.B.4. Threshold for double unit transplantation is? 3.0 x 
107/kg. These products will be used to conduct studies involving the immunobiology of 
double cord transplantation and kinetics of engraftment. 
UCB Unit Exclusions 
A. 	
Any cord blood units with <1.5 x 107 total nucleated cells per kilogram recipient weight. 
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B. 	
Any cord blood units without full maternal testing and negative results for hepatitis A, B, C, 
HIV, and HTLV-1 viruses. Any additional available virology results on the unit itself will be 
reviewed but are not mandated, complete or always available. Cord blood units are presumed to 
be CMV negative regardless of serologic testing due to passive transmission of maternal CMV 
antibodies. 
6. 
Evaluation and Counseling of Patient 
The patient and donor units will be completely evaluated. The protocol will be discussed thoroughly 
with patient and caregivers, and all known risks to the patient will be described. The procedure and 
alternative forms of therapy will be presented as objectively as possible and the risks and hazards of the 
procedure explained to the patient or, in the case of minors, to the patient's responsible family 
members. 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. 
7. 
Protocol Registration 
Eligible patients will be identified by the Clinical Coordinators Office. Patients will be registered with 
the Registration Office (206-667-4728) between 8:30 am and 4:00 p.m. Pacific time, Monday through 
Friday. After hours, the Registration office can be reached by paging (206) 995-7437. 
8. 
Plan of Treatment, Drug Administration 
A. 	
Conditioning Regimen 
-6 
Fludarabine 40 mg/m2 IV over 1 hour 
Cyclophosphamide 50 mg/kg IV 
-5 
Fludarabine 40 mg/m2 IV over 1 hour 
-4 
Fludarabine 40 mg/m2 IV over 1 hour 
—3 
Fludarabine 40 mg/m2 IV over 1 hour 
—2 
Fludarabine 40 mg/m2 IV over 1 hour 
—1 
TBI 300 cGy 
0 
UCB transplant 
1. 	
Cyclophosphamide administration. 
a. 
Cyclophosphamide will be given at 50 mg/kg on Day -6. Doses? 5000 mg are 
infused IV over 2 hours. Lower doses usually are administered over one hour. 
Adjusted body weight should be used for calculating initial doses if patient's 
actual weight is > 100% of ideal body weight. 
b. 
MESNA will be given for bladder prophylaxis according to institutional 
guidelines. 
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2. 	
Fludarabine administration. 
a. 
Fludarabine will be administered at a dose of 40 mg/m2 IV over one hour once 
daily on each of 5 consecutive days for a total dose of 200 mg/m2. Patients > 
120% of ideal weight, BSA will be calculated using adjusted weight. 
b. 
Fludarabine dose for adult patients (>18 years old) with renal impairment 
(defined as CrC1 < 70mL/minute per 24-hour) is 35 mg/m2 daily for five 
consecutive days given as noted above. 
c. 
Fludarabine dose may also be reduced to 35 mg/m2 daily if there is prior 
malignancy involvement of the central nervous system with intrathecal 
chemotherapy and/or cranio-spinal irradiation. 
3. 	
Total Body Irradiation (TBI) 
See Appendix II for radiation guidelines. 
B. 	
Immunosuppressive Therapies 
Patients will receive prophylaxis for GVHD with 2 drugs as follows: 
1. 	
Cyclosporine A 
a. 
Patients will receive cyclosporine A (CSA) therapy beginning on Day -3 
maintaining a trough level between 200 and 400 ng/mL by HPLC analysis (250 
and 500 ng/ml by immunoassay). For adults the initial dose will be 2.5 mg/kg IV 
over 1 hour every 12 hours. For children <40 kg the initial dose will be 2.5 
mg/kg IV over 1 hour every 8 hours. 
b. 
Dose adjustments will be made on the basis of toxicity and low CSA levels with 
a trough level of <200 mg/L (HPLC). Once the patient can tolerate oral 
medications, CSA will be converted to an oral form. CSA dosing will be 
monitored and altered as clinically appropriate. 
c. 
Patients will receive CSA until Day +100. If no GVHD, the dose will then be 
tapered 10% per week starting on Day +101 and discontinued no sooner than 6 
months post-transplant. 
2. 	
Mycophenolate mofetil (MMF) 
a. 
Patients will receive MMF at the dose of 15 mg/kg IV (based on adjusted 
weight) every 8 hours with a maximum of 1 gram/dose starting 4-6 hours after 
infusion of UCBT on Day 0. If actual body weight is < ideal weight, calculation 
based on actual weight is allowed. Rounding of the dose to the nearest 250 mg 
capsule size is also allowed. Once the patient can tolerate oral medications, 
MMF may be converted to an oral form. 
b. 
MMF will be given every 8 hrs daily until day 40 post-transplant and then in the 
absence of GVHD, tapered by 12%/week with MMF discontinued after day + 
96. 
c. 
MMF dosing to be monitored and altered as clinically appropriate. 
d. 
Markedly low (<40%) donor T cell chimerism after UCBT may indicate 
impending graft rejection. MMF should be continued at full dose or, if MMF 
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taper has been initiated, reinstitution of full dose MMF should occur. If MMF 
has been discontinued, MMF should be reinitiated at full dose. 
C. 	
Umbilical Cord Blood Transplant (UCBT)  
1. 
Procedures for requesting, receiving and characterizing the cord blood unit for infusion 
will be according to institutional protocol. 
2. 
The cord blood unit should be thawed and infused per FHCRC standard practice 
guidelines. Cord blood products should be infused without delay as soon as the product 
arrives on the unit. 
a. 
The thawed product (either one or two units) will be delivered to the patient 
floor/bedside where the product is double-checked by a nurse with the 
technologist from the Cellular Therapy Laboratory. Visual inspection of the 
product is also made at this time. The unit(s) is verified according to 1) the 
infusion order sheets, 2) the patient's identification number on the cell product, 
3) the product (cell) identification number and 4) the patient wrist band. 
b. 
If the cord blood unit(s) fail to pass inspection or if there is insufficient 
information to verify the cell product for the patient, notify the Cell Therapy Lab 
and the PI, Rachel Salit ((206) 667-1317, pager 206-314-2845 immediately. 
c. 
The goal infusion time of each cord blood unit is 30 minutes, as clinically 
possible. Pre-medications (if any) prior to cord blood infusion will be at the 
discretion of the attending. Under no circumstances is the cord blood to be 
irradiated. No medications or fluids should be given piggyback through the 
catheter lumen that is being used for cord blood infusion. 
d. 
The product is infused via IV drip directly into the central line according to 
standard practice with gravity filtered tubing. 
e. 
Vital signs should be monitored before beginning the infusion and periodically 
during administration. Notify the attending physician, fellow or PA immediately 
if the patient exhibits signs or symptoms of a reaction. 
f. 
Benadryl, epinephrine, and hydrocortisone should be available at the bedside for 
emergency use if necessary. Oxygen with nasal prongs for standby use should be 
present in the room. 
g. 
If the patient is a double cord blood recipient, the two units may be given 
consecutively with no wait between infusion of the units. However, infusion of 
the second unit will not begin until any acute toxicities from the first unit have 
been controlled. The start and stop time of each unit should be recorded on the 
infusion record. 
D. 	
Supportive Care  
Patients will receive transfusions, infection prophylaxis, and therapy according to institutional 
guidelines (Appendix III for FHCRC infection guidelines). 
E. 	
Growth Factor Support 
Patients will be started on G-CSF support at 5mcg/kg (IV/SQ)(round to vial size) beginning on Day +1 
after the UCB infusion and continued daily until ANC > 2500/4 for 2 consecutive days. Once a 
patient has met these criteria, the ANC will be monitored and G-CSF restarted if ANC falls to < 1000. 
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F. 	
Management of Pre-engraftment Immune Reactions 
A well recognized clinical entity consisting of skin rash, fever, and, often, loose stools and respiratory 
distress has been noted to occur prior to engraftment among cord blood patients, generally between 
Days +7 and +21. This clinical syndrome likely involves cytokine activation, and though clinically 
similar to acute or hyperacute graft versus host disease, it appears to be a distinct entity, "pre-
engraftment syndrome." This syndrome is often controlled with brief steroid bursts, thus avoiding a 
commitment to extended steroid exposure. Patients should be monitored carefully for this syndrome. 
If patients have moderate to severe symptoms as described above and alternative etiologies (i.e., 
infection) have been excluded or are being appropriately evaluated, recommendations for management 
are: 
1. 
For patients not on steroid therapy when the syndrome occurs: methylprednisolone 
should be given at 1 mg/kg IV q day for three days. If symptoms have abated, steroids 
should be stopped. If symptoms persist, 1 mg/kg can be continued through six days 
then stopped if symptoms have abated. If symptoms persist for more than six days, the 
patient should be considered to have acute/hyperacute GVHD and should be treated 
with prolonged steroids as deemed appropriate. 
2. 
For patients already on steroids for other reasons when the syndrome occurs: 
methylprednisolone should be given at a dose of 3-5 mg/kg IV (max dose 500 mg) q 12 
hours x 48 hours, followed by a rapid taper to 1 mg/kg IV q 12 hours. Patients should 
be weaned after response as tolerated. 
9. 	
Evaluation 
Refer to FHCRC/SCCA Standard Practice Manual for Pre-Transplant Evaluation Guidelines for 
Allogeneic Transplant (results of tests and/or procedures conducted as per standard of care for pre-
transplant workups may be used for eligibility determination if conducted within an appropriate 
window prior to screening). See Appendix IV for schedule of study evaluations. 
A. 	
Patient Pre-Study Screening and Evaluation Procedures 
1. 
Medical history, allergies, previous chemotherapy, prior radiotherapy, hormonal or 
immunotherapy and response to treatment, end-organ toxicity and infections. 
2. 
Kamofsky/ECOG or Lansky performance status (Appendix I). 
3. 
Physical examination. 
4. 
Complete blood and platelet count with leukocyte differential. 
5. 
Basic metabolic and hepatic function panels. 
6. 
Urinalysis. 
7. 
Pregnancy test (blood or urine) in females of childbearing potential. 
8. 
Viral titers (HSV, CMV, HIV, HBsAg, HBcAb, HCV, HTLV1/2). 
9. 
PCR for CMV DNA must be done within 2 weeks prior to the start of conditioning. 
10. 
Bone marrow aspirate (and biopsy as clinically indicated) within 30 days prior to 
conditioning. 
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11. 
Electrocardiogram, MUGA or echocardiography with measurement of the left 
ventricular ejection fraction (LVEF). 
12. 
Chest radiograph and pulmonary function tests. CXR not required if chest CT 
performed (see 9.A.15). 
13. 
DNA specimen from patient and from UCB unit(s) submitted to Clinical 
Immunogenetics Laboratory (CIL) for chimerism studies. 
14. 
X-rays and other disease marker evaluations as appropriate for patient diagnosis 
(Appendix IX). 
15. 
A chest CT without contrast to exclude occult fungal infection prior to transplant for 
patients with a history of the following: 
• history of MDS or a history of 2 or more consecutive inductions/re-inductions 
to treat acute leukemia 
• CML blast crisis 
• prolonged neutropenia of at least 2 months immediately preceding transplant 
16. 
Pediatric pretransplant evaluation considerations: for children that are not able to 
cooperate to have a MUGA and/or pulmonary function tests, an echocardiogram should 
be attempted and pulse oximetry with exercise tolerance obtained. If not possible at all, 
it should clearly be documented in the physician's note. 
17. 
Comorbidity Index score to be completed by research staff (Appendix V). 
18. 
Clinical immune reconstitution studies (see section 9.F). 
19. 
Lymphocytes subset enumeration (T cell subset with B and NK cells) 
21. 
Blood Samples for Host and Donor Immunologic Interaction Studies (see section 9.E). 
22. 
Immune Reconstitution Research Study (see section 9.F) 
B. 	
Patient Evaluations from Day 0 until Engraftment (through Day 30) 
1. 
Physical examinations daily or as clinically indicated. 
2. 
Complete blood and platelet count daily, or as clinically indicated, until the absolute 
neutrophil count (ANC) >5 X 108/L for 3 consecutive measurements. Leukocyte 
differential is to be performed daily if WBC count > 500. 
3. 
Basic metabolic panel daily or as clinically indicated (at least twice weekly). 
4. 
CMV PCR surveillance as clinically indicated per institutional guidelines (Appendix 
III). 
5. 
Urinalysis as clinically indicated. 
6. 
Chest radiographs as clinically indicated. 
7. 
Bone marrow aspirate (+/- biopsy, as clinically indicated) on Day 28 for assessment of 
underlying disease and UCB engraftment. Day 28 BM specimen submitted for whole 
bone marrow chimerism studies. Please note if patient is a double cord blood recipient. 
Other tests on BM that are disease appropriate on Day 28. 
8. 
Day 28 peripheral blood for chimerism studies (as possible sorted for CD3, CD14, 
CD33, CD56 cells). 
9. 
Peripheral blood for chimerism studies (sorted for CD3, CD14, CD33, CD56 cells) on 
Day 28. 
10. 
GVHD evaluation (Appendix VI) weekly or as clinically indicated. 
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11. 
Additional tests (e.g., X-rays and tumor markers) as clinically appropriate for 
assessment of underlying malignancy on Day 28 (Appendix IX). 
12. 
Clinical immune reconstitution studies (see section 10.F). 
13. 
Blood samples for Host and Donor Immunologic Interaction Studies (see section 9.E) 
14. 
Immune Reconstitution Research Studies (see section 9.F) 
C. 	
Patient Evaluations from Engraftment to Day 100 
1. 
Physical examinations weekly ancUor as clinically indicated. 
2. 
Karnofsky/ECOG/Lansky performance once between Day 80 and Day 100 (App.I). 
3. 
Complete blood and platelet count with leukocyte differential at least weekly and/or as 
clinically indicated. 
4. 
Basic metabolic panel at least weekly and as clinically indicated. 
5. 
CMV PCR surveillance as clinically indicated per institutional guidelines (Appendix 
III). 
6. 
Urinalysis as clinically indicated (at least once prior to d/c with urine creatinine/albumin 
ratio). 
7. 
Chest radiographs as clinically indicated. 
8. 
Peripheral blood for chimerism studies (as possible sorted for CD3, CD33, CD56) on 
Days 56 and 80. 
9. 
Bone marrow aspirate and biopsy on Day 80 (or prior to departure) for all patients for 
assessment of disease relapse, chimerism and UCB engraftment. Please note if patient is 
a double cord blood recipient. Other tests on BM that are disease appropriate on Day 80 
(Appendix XI). 
10. 
GVHD evaluation (Appendix VI) weekly and as clinically indicated. 
11. 
Clinical immune reconstitution studies (see section 9.F). 
12. 
Blood samples for Host and Donor Immunologic Interaction Studies (see section 9.E). 
13. 
Immune Reconstitution Research Studies (see section 9.F). 
D. 	
Patient Evaluations at 6 months, 1 year and 2 years 
1. 
Physical examinations at 6 months, 1 year and 2 years. 
2. 
Karnofsky/ECOG or Lansky performance status (Appendix I) at 6 months, 1 year and 2 
years. 
3. 
Complete blood count with leukocyte differential and serum chemistry at 6 months, 1 
year and 2 years and as clinically indicated. 
4. 
CMV surveillance as clinically indicated per institutional guidelines (Appendix III). 
5. 
Chest radiographs as clinically indicated. 
6. 
Peripheral blood for chimerism studies (as possible sorted for CD3, CD33, CD56) at 6 
months, 1 year and 2 years. 
7. 
Bone marrow aspirate (+/- biopsy, as clinically indicated) at 1 year and, as clinically 
indicated, at 2 years for assessment of UCB engraftment and evidence of recurrent 
disease. DNA BM specimen submitted for chimerism studies. Please note if patient is a 
double cord blood recipient. Other tests that are disease appropriate (Appendix IX). 
8. 
GVHD evaluation (Appendix VI) at 6 months, 1 year and 2 years. 
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9. 
Other tests as clinically appropriate for restaging assessment of underlying malignancy 
at 6 months, 1 year and 2 years and as clinically indicated (Appendix IX). 
10. 
Autopsy report, if available, if death occurs before the 2 year follow-up. 
11. 
Clinical immune reconstitution studies (see section 9.F). 
12. 
Immune Reconstitution Research Studies at 6 months, 1 year, and 2 years (see section 
9.F). 
E. 	
Host and Donor Immunologic Interaction Studies 
For patients 21-30 kg 
1. 
Prior to the start of conditioning (and after consent obtained): 20 ml of peripheral blood 
will be collected in green top tubes to generate EBV transformed LCL lines from the 
patient for research studies evaluating donor/host immunologic reactions. 
2. 
Post transplantation on up to five occasions, 20 ml of peripheral blood may be collected 
in green top tubes to assay for immune mediated responses occurring between the host 
and donors. The timing of sample collection will be at investigator discretion and 
research staff will initiate the orders. Once individual engraftment has occurred and to 
avoid obtaining samples if patients have been placed on steroids for treatment of a 
GVHD (steroids interfere with the studies). 
3. 
Please send samples to the Delaney Lab D2-335; contact Denise Ziegler (206) 667-5762 
4. 
Samples should be drawn on MONDAY through FRIDAY ONLY. 
For patients larger than 30 kg 
1. 
Prior to the start of conditioning (and after consent obtained): 30 ml of peripheral blood 
will be collected in green top tubes to generate EBV transformed LCL lines from the 
patient for research studies evaluating donor/host immunologic reactions. 
2. 
Post transplantation on up to five occasions, 30 ml of peripheral blood may be collected 
in green top tubes to assay for immune mediated responses occurring between the host 
and donors. The timing of sample collection will be at investigator discretion and 
research staff will initiate the orders. Once individual engraftment has occurred and to 
avoid obtaining samples if patients have been placed on steroids for treatment of a 
GVHD (steroids interfere with the studies). 
3. 
Please send samples to the Delaney Lab D2-335; contact Denise Ziegler (206) 667-5762 
4. 
Samples should be drawn on MONDAY through FRIDAY ONLY. 
F. 	
Immune Reconstitution after UCBT 
Clinical Studies (to be performed as possible): 
1. 
Quantitative immunoglobulin levels (IgG, IgA, IgM) will be assessed at Day 28, 56, 
100, 6 months, 1 year and 2 years. 
2. 
Lymphocytes subset enumeration (T cell subset with B and NK cells) will be assessed 
pre-transplant and at Day 28, 56, 100, 6 months, 1 year and 2 years. 
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Research Studies (research blood samples may be used interchangeably, and amount of blood 
to be drawn may be reduced at the investigator/attending physician's discretion and as dictated 
by patient safety): 
1. 	
Samples will be collected for assessment of post-transplant immune reconstitution 
baseline prior to the start of conditioning, and then on Day 28, 56, 100, 6 months, 1 
year, and 2 years. FHCRC: We will collect blood in a 10mL tube (green top Na Heparin 
tube will be sent to the Digel Lab). Participating centers: One green top Na Heparin tube 
will be collected at all time points as possible. Days 28-100 will be batched for 
shipment at day 100 to FHCRC for analysis. Later time points will be shipped at time of 
collection. Samples should be shipped MONDAY through THURSDAY only. Main 
contact: Denise Ziegler, 206-667-5762. 
NOTE: In certain clinical circumstances (e.g., relapse or terminal illness) study tests may be 
omitted at the physician's or PI's discretion. 
G. 	
Study Evaluation Windows 
The target dates for post-transplant study evaluations are outlined in the table below: 
Evaluation Date Post Transplant 	Window 
Day +21 
+/-3 days 
Day +28 
+/-3 days 
Day +42 
+/- 7 days 
Day +56 
+/- 7 days 
Day +80 
+/- 7 days 
Day +100 
+1-7 days 
Day +180 
+/-30 days 
1 year 
* 
 
2 year 
* 
 
*Every effort will be made to complete the I and 2 year evaluations as close to these dates as possible, 
taking into consideration patient's circumstances at these time points. 
10. 	
Drugs, Irradiation and Cord Blood Administration - Toxicities and Complications. 
Refer to Appendix X for a list of potential adverse events associated or expected with hematopoietic 
cell transplantation. 
A. 	
Treatment-Related Toxicities  
For the purposes of this protocol, toxicity will be graded using the modified NCI common 
toxicity scale (Appendix VII) 
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I. 	
Potential toxicities associated with the Conditioning Regimen 
C clo hos hamide 
Common 
Less Frequent 
Uncommon 
Occurs in 21-100 people 
out of every 100 
Occurs in 5-20 people out of 
every 100 
Occurs in <5 people out of every 100 
Nausea/vomiting 
Mucositis 
Sterility 
Severe suppression of 
blood counts 
Diarrhea 
Fluid weight gain/edema 
Alopecia 
Hemorrhagic cystitis 
Cardiomyopathy 
Skin rash 
SIADH (Syndrome of Inappropriate 
Anti-diuretic Hormone) 
Fludarabine 
Common 
Less Fre 1 uent 
Uncommon 
Occurs in 21-100 people 
out of 100 
Occurs in 5-20 people out of 
every 100 
Occurs in <5 people out of every 100 
Severe suppression of 
Chills 
Neurotoxicity 
blood counts 
Fever 
Agitation and confusion 
Diarrhea 
GI bleeding 
Blurred vision 
Anorexia 
Peripheral edema 
Peripheral neuropathy 
Mucositis 
Hearing loss 
Nausea/vomiting 
Headache 
Stomatitis 
Cerebellar syndrome 
Osteoporosis 
Blindness 
Dysuria 
Coma 
Weakness 
Depression 
Insomnia 
Hemorrhagic cystitis (except in FA) 
Abnormal renal function test 
Autoimmune hemolytic anemia 
Deep venous thrombosis 
Aneurysms 
Pruritic skin rash 
Abnormal liver function/Liver failure 
Constipation 
Transient ischemic attack 
Dysphagia 
Myalgia 
Arthralgia 
Renal failure 
Total Body Irradiation (TB!) 
At the 200 and 300 cGy, side effects are not expected. Nevertheless, there may be fever, 
alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including 
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cataract formation, growth retardation, pulmonary damage, carcinogenesis, and sterilization. 
Those side effects might be more frequently seen in patients given 400 cGy or 450 cGy. 
2. 
Toxicities potentially associated with the infusion of the UCB graft 
Potential toxicities associated with the infusion include DMSO toxicity and side effects 
from red cells. DMSO toxicity and side effect of red cells may include changes in heart 
rate, rhythm or function, changes in blood pressure, changes in oxygenation, fever, 
chills, sweats, nausea/vomiting, diarrhea, abdominal cramping, headache, allergic 
reaction, presence of DMSO taste and odor, hemoglobinuria, and acute renal failure. 
3. 
Potential toxicities associated with Immunosuppressive Therapies 
C clos orine A 
Nephrotoxicity 
Thrombotic thrombocytopenic purpura 
Seizures 
Electrolyte imbalances 
Hypertension 
Paresthesias/neuropathy 
Hirsutism 
Gingival hyperplasia 
Increased risk of relapse 
Increased risk of opportunistic infection 
M co henolate Mofetil MMF 
Pancytopenia 
Hypertension 
Headache 
Dizziness 
Insomnia 
Hyperglycemia 
Rash 
Electrolyte imbalances 
Leg cramps/bone pain 
Nausea/diarrhea 
Spontaneous abortion 
Birth defects 
Progressive multi focal 
leukoencephalopathy 
Toxicities associated with Growth Factor G-CSF, Neu o en 
Bone pain 
Insomnia 
Headaches 
Dyspnea 
Body aches 
Rash 
Fatigue 
Edema 
Nausea/vomiting 
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11. 
Protocol Enrollment and Special Considerations 
Projected Target Accrual 
ETHNIC AND GENDER DISTRIBUTION CHART 
TARGETED! PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
4 
8 
Not Hispanic or Latino 
34 
34 
68 
Ethnic Category Total of All Subjects* 
38 
38 
76 
Racial Categories 
American Indian / Alaska Native 
2 
2 
4 
Asian 
4 
4 
8 
Native Hawaiian or Other Pacific Islander 
1 
I 
2 
Black or African American 
4 
4 
8 
White 
27 
29 
56 
Racial Categories: Total of All Subjects* 
38 
38 
76 
12. Guidelines for Serious Adverse Event Reporting 
A.  Monitoring the Progress of Trial and the Safety of Participants 
This is a Phase 2 clinical trial that is monitored by the principal investigator (PI), Rachel Salit, M.D. 
and a Data Safety and Monitoring Board (DSMB). For FHCRC patients, the PI reviews the outcome of 
the date for each individual patient on an ongoing basis. The PI of the study will have primary 
responsibility for ensuring that the protocol is conducted as approved by the Scientific Review 
Committee and Institutional Review Board. The PI will ensure that the monitoring plan is followed, 
that all data required for oversight of monitoring are accurately reported to the DSMB and Protocol and 
Data Monitoring Committee, that all adverse events are reported according to the protocol guidelines, 
and that any adverse reactions reflecting patient safety concerns are appropriately reported. The PI will 
personally review with the Research Nurse the clinical course of all the enrolled patients at least twice 
monthly. 
Until October 2018, this was a multi-institution trial with FHCRC serving as the Coordinating Center. 
In this capacity, the PI obtained copies of all IRB approvals and had the responsibility for receiving the 
information required for adverse event reporting and safety monitoring from outside sites, and 
disseminating that information to the appropriate Consortium committees. Written agreements were 
obtained from all participating sites acknowledging their responsibilities for data and adverse event 
reporting and agreement to provide records, files, case report forms or any other documents needed to 
verify compliance. The PI reviewed outcome data for each individual patient at a minimum of 3 
months after UCBT. Clinical outcome data were summarized and transmitted from collaborating 
centers as case report forms (CRFs). When possible, primary source documents regarding patient 
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outcomes were collected from the collaborating centers. The CRFs were generated from the 
collaborating centers at defined time points (day 28, day 100, day 180, 1 year and 2 years post-
transplant). The local PI reviewed the official CRF and primary source documents. When the CRFs 
were verified, the data were entered into a central database managed by the FHCRC Coordinating 
Center. 
The DSMB discontinued the review of outcomes when this protocol closed to accrual in August 2018. 
A dedicated independent DSMB monitored patient safety. The DSMB met at six-month intervals and 
all outcome data were reviewed including all adverse events reported to the FHCRC along with those 
officially reported to the FHCRC IRB. The DSMB confirmed whether the trial met any stopping rules 
and reviewed any patient safety problems necessitating discontinuation of the trial. Reports from the 
DSMB were submitted to the FHCRC IRB. 
B. 	
Reporting of Adverse Events  
Adverse events will be collected and graded according to the modified (for HSCT) NCI Common 
Toxicity Criteria (Appendix VII). Grade 3 or 4 adverse events (or highly unusual grade 2 adverse 
events), which occur from the start of study treatment (pre-transplant conditioning) through Day +100 
post-transplant will be collected on the Case Report Form (CRF). These adverse events, which are 
observed by the Investigator or reported by the patient, whether or not attributed to the study, will be 
reported on the CRF. 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 according to CTCAE criteria. Association or relatedness to the study 
agent will be graded as follows: 1 = unrelated, 2 = unlikely, 3 = possibly related, 4 = probably related, 
and 5 = definitely related. 
If a patient experiences relapse or graft failure and goes on to further treatment off protocol, adverse 
events will no longer be collected with the exception of death. The adverse event reporting in this 
clinical trial will comply with current FHCRC reporting policy (see Appendix VIII). 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. Toxicities meeting the study stopping rule 
criteria will be reported to the IRB within 10 days of study staff awareness. All other SAEs and deaths, 
not meeting the expedited reporting criteria, will be reported to the IRB as part of the annual 
continuation review report to the IRB. Hospitalization, in general, will not be considered a serious 
adverse event as the majority of patients receiving reduced intensity transplants are hospitalized. 
Hospitalization will be considered a serious adverse event if it is unexpected or the duration of the 
hospital stay is unexpected. 
Refer to Appendix X for a list of potential adverse events associated or expected with hematopoietic 
cell transplantation. PI and the research study team have fulfilled all NIH requirements for training in 
human subjects protection. 
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C. 
Plans for assuring data accuracy and protocol compliance  
For study enrollment, a signed consent form and eligibility checklist with source documents must 
demonstrate study eligibility. Fred Hutch Cord Blood Program research staff review CRFs for 
adherence to the protocol, accuracy, and completeness. 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. . 
D. 
Oversight and Review of Safety Monitoring 
An annual review of the progress of the study with respect to the monitoring plan will be performed by 
a Data and Safety Monitoring Committee (DSMC). As part of the annual renewal process, the PI will 
submit an accounting of patient enrollment and outcomes defining the monitoring plan in sufficient 
detail as to permit verification of the report through chart audit. The IRB provides a final level of 
annual review. Approval by the DSMC is a necessary but not sufficient condition for final approval by 
the IRB. The IRB will review the same continuation application and materials that are reviewed by the 
DSMC, and make an independent assessment of the progress of the trial and determine whether the 
perceived risk-benefit ratio continues to be acceptable. 
13. Records 
Clinical Statistics maintains a patient database at Fred Hutch to allow storage and retrieval of patient 
data collected from a wide variety of sources. The investigator will ensure that data collected conform 
to all established guidelines for coding, collection, key entry and verification. Each patient is assigned 
a unique patient number to assure patient confidentiality. Patients will not be referred to by this 
number, by name, or by any other individual identifier in any publication or external presentation. The 
licensed medical records department, affiliated with the institution where the patient receives medical 
care, maintains all original inpatient and outpatient chart documents. Patient research files are kept in a 
locked room. They are maintained and supervised by the FHCRC Cord Blood Program. Access is 
restricted to personnel authorized by the Cord Blood Program. 
14. 
Statistical Considerations 
A. 	
Statistical Analyses 
The goal of this study is to gain experience in UCBT with the proposed conditioning regimen. One-
year overall survival will be considered to be our primary endpoint, but only for purposes of 
estimation, not hypothesis testing. Given the population of patients being treated, there does not exist a 
treatment to which this group can be compared since patients will receive the current approach due to 
the lack of a suitable alternative donor. The primary objective of the current study is therefore not to 
compare outcome to a benchmark value, but rather to obtain a reasonably precise estimate of one-year 
survival. The results of this trial will then form the basis for potential future changes. 
We propose to enroll 76 patients to the current study. This sample size was not chosen based on any 
statistical grounds, but represents a balance between the number of patients that can be accrued in a 
reasonable time frame and a number that will provide meaningful data upon which future trials can be 
built. 
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Secondary endpoints will be evaluated and include overall survival (i.e., beyond one year); non-relapse 
mortality (at 6 months, one year, and overall); incidence of graft failure/rejection; neutrophil and 
platelet engraftment; acute and chronic GVHD; relapse; progression-free survival; clinically significant 
infections. 
Kaplan-Meier and cumulative incidence estimates will be used to summarize all time-to-event 
endpoints as appropriate. 
15. Termination of study 
The study is now permanently closed to accrual and activities are limited to data analysis. 
Page 23 of 49 


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16. 	
References 
1. 
Kurtzberg, J., M. Laughlin, M.L. Graham, et al., Placental blood as a source of hematopoietic 
stem cells for transplantation into unrelated recipients. N Engl J Med, 1996. 335(3): 157-66. 
2. 
Gluckman, E., V. Rocha, A. Boyer-Chammard, et al. Outcome of cord-blood transplantation 
from related and unrelated donors. Eurocord Transplant Group and the European Blood and 
Marrow Transplantation Group. N Engl J Med, 1997. 337(6): 373-81. 
3. 
Rubinstein, P., C. Carrier, A. Scaradavou, et al., Outcomes among 562 recipients of placental-
blood transplants from unrelated donors. N Engl J Med, 1998. 339(22): 1565-1577. 
4. 
Rubinstein, P., J. Kurtzberg, F. Loberiza, et al., Comparison of Unrelated Cord Blood and 
Unrelated Bone Marrow Transplants for Leukemia in Children: A Collaborative Study of the 
New York Blood Center and the International Bone Marrow Transplant Registry. Blood, 2001. 
98: 814a. 
5. 
Wagner, J.E., J.N. Barker, T.E. DeFor, et al., Transplantation of unrelated donor umbilical 
cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell 
dose and HLA disparity on treatment-related mortality and survival. Blood, 2002. 100(5): 
1611-8. 
6. 
Barker, J.N., T.P. Krepski, T.E. DeFor, et al., Searching for Unrelated Donor Hematopoietic 
Stem Cells: Availability and Speed of Umbilical Cord Blood versus Bone Marrow. Biol Blood 
Marrow Transplant, 2002. 8: 257-260. 
7. 
Laughlin, M.J., J. Barker, B. Bambach, et al., Hematopoietic engraftment and survival in adult 
recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001. 344(24): 1815-
22. 
8. 
Laughlin, M.J., M. Eapen, P. Rubinstein, et al., Outcomes after transplantation of cord blood 
or bone marrow from unrelated donors in adults with leukemia. N Engl J Med, 2004. 351(22): 
2265-75. 
9. 
Long, G.D., M. Laughlin, B. Madan, et al., Unrelated umbilical cord blood transplantation in 
adult patients. Biol Blood Marrow Transplant, 2003. 9(12): 772-80. 
10. 
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Transplantation of Two Partially HLA -Matched 
Umbilical Cord Blood Units To Enhance Engraftment in Adults with Hematologic Malignancy. 
Blood, 2005. 105: 1343-1347. 
11. 
Giralt, S., E. Estey, M. Albitar, et al., Engraftment of allogeneic hematopoietic progenitor cells 
with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without 
myeloablative therapy. Blood, 1997. 89(12): 4531-6. 
12. 
Slavin, S., Nagler, A., Naparstek, E., et al, Nonmyeloablative Stem Cell Transplantation and 
Cell Therapy as an Alternative to Conventional Bone Marrow Transplantation with Lethal 
Cytoreduction for the Treatment of Malignant and Nonmalignant Hematologic Diseases. 
Blood, 1998. 91(3): 756-763. 
13. 
Childs, R.e.a., Engraftment Kinetics after Nonmyeloablative Allogeneic Peripheral Blood Stem 
Cell Transplantation: Full Donor T-Cell Chimerism Precedes Alloimmune Responses. Blood, 
1999. 94(9): 3234-3241. 
14. 
Giralt, S., P.F. Thai!, I. Khouri, et al., Melphalan and purine analog-containing preparative 
regimens: reduced-intensity conditioning for patients with hematologic malignancies 
undergoing allogeneic progenitor cell transplantation. Blood, 2001. 97(3): 631-7. 
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15. 
McSweeney, P.A., D. Niederwieser, J.A. Shizuru, et al., Hematopoietic cell transplantation in 
older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with 
graft-versus-tumor effects. Blood, 2001. 97(11): 3390-400. 
16. 
Chakraverty, R., K. Peggs, R. Chopra, et al., Limiting transplantation-related mortality 
following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning 
regimen. Blood, 2002. 99(3): 1071-8. 
17. 
Niederwieser, D., M. Mans, J.A. Shizuru, et al., Low-dose total body irradiation (TBI) and 
fludarabine followed by hematopoietic cell transplantation (HCT) from HLA -matched or 
mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and 
mycophenolate mqfetil (MMF) can induce durable complete chimerism and sustained 
remissions in patients with hematological diseases. Blood, 2003. 101(4): 1620-9. 
18. 
Mans, M.B., D. Niederwieser, B.M. Sandmaier, et al., HLA-matched unrelated donor 
hematopoietic cell transplantation after nonmyeloablative conditioning for patients with 
hematologic malignancies. Blood, 2003. 102(6): 2021-30. 
19. 
Giralt, S., B. Logan, M. Zhang, et al., Non-Ablative or Reduced Intensity Conditioning 
Regimens With Volunteer Unrelated Donor Progenitor Cell Transplantation: An Analysis from 
the Center for International Blood and Marrow Transplant Research 
Sergio Giralt, I, Brent Logan, 1*, Mei-Jie Zhang,1*, Olivia McGaha,1*, Karen Ballen, 1, 
Christos Emmanouilides,l, Rajneesh Nath,1*, Pablo Parker,], David Porter, 1, Brenda 
Sandmaier, 1, Edmund Waller, l, Juliet Barker, 1 , Steven Pavletic, 1, and Daniel Weisdorf 1. 
Blood, 2004. 
20. 
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Rapid and complete donor chimerism in adult 
recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity 
conditioning. Blood, 2003. 102(5): 1915-1919. 
21. 
Misawa M, Kai S, Okada M, et al. Reduced-intensity conditioning followed by unrelated 
umbilical cord blood transplantation for advanced hematologic malignancies. Int J Hematol. 
2006;83:74-79. 
22. 
Chao, N.J., Koh LP, Long GD, et al., Adult recipients of umbilical cord blood transplants 
aft ernonmeyloablative preparative regimens. Biol Blood Marrow Transplant, 2004;10:569-575. 
23. 
Komatsu T, Narimatsu H, Yoshimi A, et al. Successful engraftment of mismatched unrelated 
cord blood transplantation following reduced intensity preparative regimen using fludarabine 
and busulfan. Ann Hematol. 2007;86:49-54. 
24. 
Miyalcoshi, S., K. Yuji, M. Kami, et al., Successful engraftment after reduced-intensity 
umbilical cord blood transplantation for adult patients with advanced hematological diseases. 
Clin Cancer Res, 2004. 10(11): 3586-92. 
25. 
Ballen KK, Spitzer TR, Yeap BY, et al. Double unrelated reduced-intensity umbilical cord 
blood transplantation in adults. Biol Blood Marrow Transplant. 2007;13:82-89. 
26. 
Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after non-
myeloablative conditioning: impact on transplant outcome in I/O adults with hematological 
disease. Blood. Epub ahead of print, June 2007. 
27. 
Horwitz M, Chute J, Gasparetto C, et al. Myeloablative intravenous busulfan/fludarabine 
conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in 
adult recipients. Blood 2007;110:a2007. 
28. 
Mans MB, Sandmaier BM, Storer BE, et al. Unrelated donor granulocyte colony-stimulating 
factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative 
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conditioning: the effect of postgrafiing mycophenolate mofetil dosing. Biol Blood Marrow 
Transplant. 2006;12:454-465. 
29. 
Komanduri KV, St. John LS, de Lima M, et at. Delayed immune reconstitution after cord 
blood transplantation is characterized by impaired thymopoiesis and late memory T cell 
skewing. Blood. Epub ahead of print, August 2007. 
30. 
Brunstein CG, Weisdorf DJ, DeFor T, et al. Increased risk of Epstein-Barr virus associated 
post-transplant lymphoproliferative disorder after anti-thymocyte globulin non-myeloablative 
conditioning for umbilical cord blood transplantation. Blood, 2005;105:a3235. 
31. 
Jacobson P, Rogosheske J, Barker JN, et al. Relationship of mycophenolic acid exposure to 
clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther. 2005 
Nov;78(5):486-500. 
32. 
Consoli U, El-Tounsi I, Sandoval A, et al. Differential induction of apoptosis by fludarabine 
monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia. Blood 
1998;91(5):1742-8. 
33. 
Gamberale R, Galmarini CM, Fernandez-Calotti P, et at. In vitro susceptibility of CD4+ and 
CD8+ T cell subsets to fludarabine. Biochem Pharmacol 2003;66(11):2185-91. 
34. 
Giaccone L, McCune JS, Mans MB, et al. Pharmacodynamics of mycophenolate mofetil after 
nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood 
2005;106(13):4381-8. 
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APPENDIX I: 	
Performance Status Scales 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
Lansky Play Performance Scale 
Score 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both, greater restrictions of, and less time spend in play activities 
60 
Up and around, but minimal active play, keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play; able to participate in all 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
Unresponsive 
0 
Dead 
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APPENDIX II: 	
Guidelines for Total Body Irradiation 
All patients who have had previous radiation therapy or TBI will be seen by Radiation Oncology prior 
to entrance on the protocol for approval for additional TBI. TBI may be delivered by local guidelines 
provided the effective dose is equivalent to what is recommended in the TBI Guidelines. 
Patients ineligible for this protocol include those who have had previous irradiation to areas of the 
body such that the Radiation Oncologist feels that even a relatively small dose of total body irradiation 
(TBI) cannot safely be given. 
If the patient has previously had total body irradiation (TBI), the radiation oncologist will have the 
option of deciding whether the patient is still eligible to receive additional TBI. Based on the 
recommendation of the treating Radiation Oncologist, the patient may be eligible for this protocol with 
modifications to the beam such that the lungs and or kidneys are partially shielded from the radiation 
beam. No other organs may be shielded. 
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Equipment: 
Modality: 
High-energy photons with energy? 6MV photons should be utilized. Although there is no upper limit 
on the energy as long as the skin dose requirements can be met, it is recommended that 18MV or lower 
be used. The selection of energy is determined by the dose uniformity criterion. 
Target Volume: 
The total body will be treated including the head and feet in one field (except in certain circumstances). 
Care should be taken to ensure that the patient is entirely within the 90% isodose decrement line of the 
beam (i.e., not in the penumbra region of the beam). 
Target Dose: 
The prescription point is defined as the point along the longitudinal axis of the patient at the midline at 
the level of the umbilicus (see Point 5). No tissue inhomogeneity correction will be made in 
the calculation of dose to the prescription point. The absorbed dose along the patient's head to toe axis 
(line formed by the intersection of the midsagittal plane and the midcoronal plane) shall be within 10% 
of the prescribed dose. The dose at selected anatomical points shall be calculated and these calculations 
are to be submitted as part of the quality assurance. Measurements of patient dimensions needed for the 
calculation of the prescription dose will be made at the time of the simulation for lung blocks. 
Measurement and calculations of required monitor units necessary for each treatment will be performed 
for both the expected upright treatment position (AP-PA fields) and the reclining, lateral decubitus 
position (AP-PA fields). In the event the patient proves too ill to receive a fraction in the upright 
position, dose calculation will have been pre-calculated to permit treatment in the lateral decubitus 
position). 
Prescription Point: 
1. Head (Point 1): this reference point is defined along the longitudinal axis of the skull at the greatest 
mid-separation (immediately superior to the nasal bridge). The depth should be taken as midway 
between the entrance and exit points of the opposed radiation beams. 
2. Neck (Point 2): this reference point is defined along the patient's longitudinal axis at the level of 
C3/C4 (approximate mid-neck, but chosen for the thinnest mid-separation of the neck). The point is 
taken to be midway between the entrance and exit point of the beam. 
3. Upper Mediastinum (Point 3): this reference point is defined along the patient's longitudinal axis 
at the level of the angle of Louis. The reference point is midway between the entrance and the exit 
points of the opposed beams. 
4. Lower Mediastinum (Point 4): this reference point is defined along the patient's longitudinal axis 
at the level of the xiphisternal notch. The reference point is midway between the entrance and exit 
points of the opposed beams 
5. Umbilicus (Point 5): THE PRESCRIPTION POINT is defined along the patient's longitudinal axis 
at the level of the umbilicus. The prescription point is midway between the entrance and exit points of 
the opposed beams. 
6. Knee (Point 6): this reference point is defined along the midline in the midplane of the knee at the 
level of the patella. 
7. Ankle (Point 7): this reference point is defined along the midline at the midplane of the ankle at the 
level of the lateral malleolus. 
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8. Shielded Lung Dose (Point 8): this reference point is located on the right chest wall under the lung 
block. It is centered (both medial/lateral and cephalocaudad) under the lung block as projected on the 
patient's skin. The depth should be taken as midway between the entrance and exit points of the 
opposed radiation beams. Dose measurements at this location will be taken during a fraction with lung 
shielding in place. 
9. Unshielded Lung Dose (Point 9): This reference point is the same as point 8. Dose measurements 
at this location will be taken during a fraction without lung shielding in place. The depth should be 
taken as midway between the entrance and exit points of the opposed radiation beams. 
Dose Definition: 
The absorbed dose is specified as centigray (cGy)-to-muscle. 
The total dose shall be 300 cGy given in a single fraction. 
Dose Rate: 
A mid-plane dose rate of between 6 and 15 cGy per minute is required. 
Dose Uniformity: 
The objective is to keep the dose throughout the body, defined to extend to within 2 mm of the skin 
surface, to at least 90% of the prescription dose. In addition, the brain dose shall not exceed 107% of 
the prescription dose. For AP/PA treatments, partial transmission lung blocks will be used to limit the 
overall total lung dose. The dose at the midpoint of the thickest part of the body while in the treatment 
position should be determined and if necessary, modifications made to the treatment to raise the dose in 
this region to at least 90% of the prescription dose. 
In order to satisfy the requirement that the skin dose at a depth of 2 mm is within at least 90% of the 
prescription dose, beam spoilers or other equally effective devices should be used. The field size shall 
be such that no part of the patient extends into the portion of the penumbra region where the dose is 
less than 90% of the central axis dose. 
Treatment Technique: 
Patients will be treated using AP/PA fields in an upright seated or standing position in a TBI 
positioning device. Treatment will be delivered with equally weighted parallel opposed portals, with 
each treatment including both AP and PA fields. If the patient is unable to tolerate the upright position, 
acceptable alternate arrangements will include equally weighted AP-PA parallel opposed fields 
delivered to the patient in a lateral decubitus position on a treatment couch or gurney. 
Changes in patient positioning after the patient has started TBI are discouraged. When unavoidable, to 
ensure compliance to the overall dose and lung shielding parameters, appropriate changes in lung 
blocking and dose recalculation will be required. 
Young patients requiring anesthesia will be treated in an AP/PA configuration at extended distance. If 
more than a single field is needed to accomplish treatment, the field junction should occur at the level 
of the thighs and be shifted every 2 fractions. 
Dose Calculation for the Prescription Point: 
The calculation of the treatment time or the monitor units for the prescribed dose can be carried out 
using standard techniques. However, TBI presents special problems relative to the routine treatment 
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situation in that the field sizes are much larger and the treatment distances much longer. The TBI 
percent depth dose (PDD) or Tissue Maximum Ratio (TMR) and output factors should be measured 
under TBI treatment conditions for a range of phantom sizes to establish the database for TBI beam-on 
time calculations or to validate the calculation methodology. 
Typically, a calculation methodology will be adopted which uses PDD or TMR and output factors 
measured under standard conditions but then modified to account for the larger treatment distance. For 
example, modified values for inverse square corrected percentage depth dose or tissue-air ratios and 
tissue phantom ratios are necessary for some treatment units when the patient is positioned at a long 
distance from the photon source and near the floor or one wall of the room. Also, some deviation from 
an exact inverse square decrease with distance has been demonstrated for certain geometries. 
Measurements of dose at the center of a phantom about the size of the typical patient should be 
performed and compared to the calculated dose. If differences are found, additional correction factors 
should be introduced to the calculation method. 
Critical Organ Dose Points: 
The required dose calculations should be performed for the 9 points referenced above. The midline 
dose at these locations should be recorded on the TBI Summary Form. The dose can be calculated 
based on the thickness at each location and factors appropriate to the TBI treatment conditions. 
It is recommended that entrance and exit TLDs or diodes be placed on the patient at each required dose 
assessment location. The midline dose can be calculated from these measurements making the 
appropriate corrections to the readings and then averaging the corrected values. 
In younger patients it is also recommended that TLDs or diodes be placed underneath the lung blocks 
to document the transmission dose and scatter dose. 
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APPENDIX III: Infection Treatment and Prophylaxis Guidelines 
CMV screening and pre-emptive treatment 
C MV. pdf 
Anti-fungal treatment 
Ant rf u nga I_The ra py 
pdf 
PCP prophylaxis 
4.0 
PCP. pdf 
HSV and VZV prophylaxis and treatment 
HSV and VZV. pdf 
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APPENDIX IV: 	
Schedule of Study Evaluations 
Activity 
Screen 
Day Ito engraftment 
Days 31-100 
Long Term Follow up 
daily 
Weekly 
Day 28 
(±3 days) 
weekly 
Day 42 
(±7 days) 
Day 56 
(±7 days) 
Day 80 
(±7 days) 
Day 100 
(±7 days) 
6 months 
(± 30 days) 
1 year 
2 years5  
Informed consent 
X 
Medical history 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X (Day 
80-100) 
X 
X 
X 
Height/Weight 
X 
X 
GVHD evaluation 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
CRC with diff 
X 
x' 
x 
x 
x 
X 
Basic Metabolic Panel 
X 
X 
X 
X 
X 
X 
Hepatic Function Panel 
X 
As clinically indicated or per standard practice 
Viral screening 
Including CMV PCR 
Per standard practice 
CMV Surveillance by PCR 
Per standard practice 
Pregnancy test 
X 
Bone marrow bx/asp* 
X 
X 
X 
X 
Chimerism — BM 
X 
X 
X 
X 
Chimerism — Pli 
X 
X 
X 
X 
X 
X 
Host/donor studies (FI1CRC) 
X 
Investigator discretion as described in 9.E 
Urinalysis 
X 
As clinically indicated or per standard practice 
EKG 
X 
As clinically indicated or per standard practice 
MUGA or echo 
X 
As clinically indicated or per standard practice 
Chest x-ray or CT 
X 
As clinically indicated or per standard practice 
PFT's 
X 
As clinically indicated or per standard practice 
Disease evaluation 
X 
X 
(and as defined in Appendix IX) 
X 
X 
X 
X 
IgG, IgA, IgM (as possible) 
X 
X 
X 
X 
X 
X 
Lymphocyte panel (as possible) 
X 
X 
X 
X 
X 
X 
lmmunophenotypic evaluation 
X 
X 
X 
X 
X 
X 
X 
Check Section 9: Evaluation for details. Every effort will be made to complete the 1- and 2-year evaluations as close to these dates as possible, taking into consideration patient's circumstances at these 
time points*Bone marrow biopsy as clinically indicated. 
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APPENDIX V: The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 
Instructions: Circle applicable scores and provide actual value or cause of co-morbidity. 
Comorbidities 
Definitions 
HCT-CI weighted 
scores 
Actual Lab 
Values/Comments 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, 
and ventriuclar arrhythmias 
1 
Cardiac 
Coronary artery disease, congestive heart 
failure, myocardial infarction, or EF<50% 
1 
Inflammatory bowel 
disease 
Crohn's disease or ulcerative colitis 
I 
Diabetes* 
Requiring treatment with insulin or oral 
hypoglycemics, but not diet alone 
1 
Cerebro-vascular 
disease 
Transient ischemic attack or cerebro-vascular 
Accident 
1 
Psychiatric 
Disturbance 
Depression anxiety requiring psychiatric consult 
or treatment 
1 
Hepatic -mild* 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, 
or AST/ALT >ULN-2.5XULN 
1 
Obesity* 
Patients with a body mass index > 35kg/ m2  
1 
Infection* 
Requiring continuation of anti-microbial 
Treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD 
.  Polymyalgia rheumatica 
2 
Peptic ulcer* 
Requiring treatment 
2 
Moderate/severe 
renal* 
serum creatinine>2mg/d1, on dialysis, or prior 
renal transplantation 
2 
Moderate 
pulmonary* 
DLCO and/or FEV, >65%-80% or 
Dispend on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient's past 
3 
history, excluding non-melanoma skin cancer 
Heart valve disease* 
Except mitral valve prolapse 
3 
Severe pulmonary* 
DLCO and/or FEVI  <65% or 
dyspnea at rest requiring oxygen 
3 
Moderate/severe 
Hepatic 
Liver cirrhosis, Bilirubin>1.5XULN or 
AST/ALT>2.5XULN 
3 
Please provide 
()CPS): 
Karnofksy performance Score=  
% 
Total Score 
 
= 
Completed by (print):  
Date completed:  
 
Signature:  
 
*Comorbidity is currently active or patient requires medical treatment + 
;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 erythematosus; RA, rheumatoid arthritis; CTD, connective tissue disease; 
DLCO, diffusion capacity of carbon monoxide; FEVI, forced expiratory volume in one second; AST, aspartatc aminotransfcrase; ALT, alanine 
aminotransferase 
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APPENDIX VI: 	
GVHD Staging and Grading 
ACUTE GVHD ASSESSMENT 
Staging by Individual Organ Involvement 
SKIN: 	
measured by rash first appearing generally between 10 and 70 days after transplant. (excludes rashes 
of known viral or other origin) 
Stage 
Description 
1 
Maculopapular rash <25% BSA 
2 
Maculopapular rash 25 — 50% BSA 
3 
Generalized erythroderma 
4 
Generalized erythroderma with 
bullous formation and desquamation 
LIVER*: measured by total serum bilirubin 
Stage 
Description 
1 
2.0 — 2.9 mg/dL 
2 
3.0 — 5.9 mg/dL 
3 
6.0— 14.9 mg/dL 
4 
> 15.0 mg/dL 
GUT**: 	
includes only diarrhea occurring after Day +21 
Score 
Adult 
Pediatric*** 
1 
upper GI (anorexia, nausea, vomiting) 
with diarrhea of <1000 mL/day 
upper GI (anorexia, nausea, vomiting) 
with diarrhea of <555 mL/m2/day 
2 
1000— 1499 mL/day diarrhea 
556-833 mUm2/day diarrhea 
3 
> 1500 mL/day diarrhea 
>833 mUm2/day diarrhea 
4 
severe abdominal cramping, bleeding or ileus caused by GVHD 
In cases where another cause of hyperbilirubinemia antedated the onset of rash, the liver score should be 
decreased by one stage. 
** In cases where peak GI symptoms are exacerbated by a cause other than GVHD, the gut score should be 
decreased by one stage. 
*** Pediatric patients <17 years of age 
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ACUTE GVHD ASSESSMENT 
Overall Grade 
The determination of an overall GVHD grade should be based on the organ stage, response to treatment and 
whether GVHD was a major cause of death. 
Overall 
Grade 
Organ Stage 
Qualifying Conditions 
Additional Qualifying Conditions 
I 
Stage 1 -2 skin 
No liver or gut 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD. 
II 
Stage 3 skin 
or 
Stage 1 liver 
or 
Stage 1 gut 
N/A 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD, but glucocorticoid treatment after 
the onset of GVHD was generally sufficient 
to control the disease. 
III 
Stage 4 skin 
or 
Stage 2-4 liver 
or 
Stage 2-4 gut 
without GVHD as a major 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD and that additional treatment after 
the onset of GVHD did not readily control 
the disease. 
contributing cause of death 
IV 
Stage 4 skin 
Or 
Stage 2-4 liver 
or 
Stage 2-4 gut 
with GVHD as a major 
GVHD was resistant to both the 
prophylactic immunosuppressive regimen 
and any additional treatment after the onset 
of the disease. 
contributing cause of death 
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GVHD Staging and Grading (continued) 
CHRONIC GVHD 
In the past, any manifestation of GVHD that was present (or continued) at 100 days after HCT or 
thereafter was arbitrarily defined as chronic GVHD even if the clinical manifestation was 
indistinguishable from that of acute GVHD. Advances in HCT practice in the past 2 decades have 
profoundly altered the presentation and natural history of both acute and chronic GVHD and bring 
previous definitions into question. For instance, acute GVHD may present beyond 3 months in patients 
who have received reduced-intensity conditioning whereas manifestations of acute and chronic GVHD 
can be present simultaneously. Therefore, the current consensus is that clinical manifestations, and not 
the time to symptomatic onset after transplantation, determine whether the clinical syndrome of GVHD 
is considered acute or chronic.' 
Chronic GVHD will therefore be defined according to the National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Diagnosis of 
chronic GVHD will require the presence of at least l diagnostic clinical sign of chronic GVHD or 
presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests after 
the exclusion of other possible diagnoses. Chronic GVHD will be described as mild, moderate, or severe 
as graded according to the attached Organ Scoring Sheet. Symptoms developing after day 100 but 
consistent with acute GVHD only will be considered persistent, recurrent, or late-onset acute GVHD. 
Symptoms consistent with both chronic and acute GVHD occurring after day 100 will be considered 
overlap chronic GVHD syndrome. 
1 	
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host-disease: I. 
Diagnosis and Staging Working Group Report. Bio Blood and Marrow Transplant 
2005;11:945-955. 
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Chronic GVHD Organ Scoring Sheet 
SCORE 0 
SCORE I 
SCORE 2 
SCORE 3  
_J 
PERFORMANCE SCORE: 
0 Asymptomatic 
and fully active 
(ECOG 0; KPS or 
LPS 100%) 
O Symptomatic, fully 
ambulatory, restricted only in 
physically strenuous activity 
(ECOG 1, KPS or LPS 80-90%) 
0 Symptomatic, 
ambulatory, capable of 
self-care, >50% of 
waking hours out of bed 
(ECOG 2, KPS or LPS 
60-70%) 
0 Symptomatic, limited self-care, 
>50% of waking hours in bed 
(ECOG 3-4, KPS or LPS <60%) 
KPS ECOG LPS 
0 <18% BSA with disease 	
0 19-50% BSA OR 
0 >50% BSA OR deep sclerotic 
SKIN  
0 No Symptoms 
Clinical features: 	
signs but NO sclerotic features 
CI Maculopapular rash 
0 Lichen planus-like 
features 
O Papulosquamous 
lesions or ichthyosis 
o Hyperpigmentation 
El Hypopigmentation 
O Keratosis pilaris 
0 Erythema 
El Erythroderma 
O Poikiloderma 
O Sclerotic features 
O Pruritus 
0 Hair involvement 
O Nail involvement 
% BSA 
Involved 
O Abnormality present but NOT thought to represent GVHD 
involvement with 
superficial sclerotic 
features "not hidebound" 
(able to pinch) 
features "hidebound" (unable to 
pinch) OR impaired mobility, 
ulceration or severe pruritus 
MOUTH 
Diagnostic/distinctive 
features  
O Present 
O Absent 
0 No symptoms 
O Mild symptoms with disease 	
0 Moderate symptoms 	
0 Severe symptoms with disease 
signs but not limiting oral intake with disease signs with 	
signs on examination with major 
significantly 	
partial limitation of oral 	
limitation of oral intake 
intake 
O Abnormality present but NOT thought to represent GVHD 
EVES 
Mean tear test (mm): 
El > I 0 
O 6-10 
O <5 
O Not done 
0 No symptoms 
0 Mild dry eye symptoms not 
affecting ADL (requiring 
eyedrops < 3 x per day) OR 
asymptomatic signs of 
keratoconjunctivitis sicca 
0 Moderate dry eye 
symptoms partially 
affecting ADL (requiring 
drops > 3 x per day or 
punctal plugs), 
WITHOUT vision 
impairment 
0 Severe dry eye symptoms 
significantly affecting ADL (special 
eyeware to relieve pain) OR unable 
to work because of ocular 
symptoms OR loss of vision caused 
by keratoconjunctivitis sicca 
O Abnormality present but NOT thought to represent GVHD 
GI TRACT  
0 No symptoms 	
O Symptoms such as nausea, 
vomiting,anorexia,dysphagia, 
abdominal pain or diarrhea 
without significant weight loss 
(<5%) 
O Abnormality present but NOT thought to represent GVHD 
0 Symptoms associated 	
0 Symptoms associated with 
with mild to moderate 	
significant weight loss >15%, require 
weight loss (5-15%) 	
nutritional supplement 
for most calorie needs OR esophagea 
dilation 
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LUNGS 
LI PFTs not done 
FEV1 
DLCO 
Weight loss 
0 Esophageal stricture or web 
o Nephrotic syndrome 
1=1 Malabsorption 
Bronchiolitis obliterans 	
0 Bronchiolitis obliterans with organizing pneumonia 
0 Pericardial Effusion 	
0 Pleural Effusion(s) 	
o Ascites (serositis) 
0 Peripheral Neuropathy 	
0 Myasthenia Gravis 	
o Polymyositis 
0 Coronary artery involvement 	
0 Cardiomyopathy 
O 
None 
0 Cardiac conduction defects 
0 Eosinophilia >500/microliter 0 Other: 	
 
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Page 2 of 2 
SCORE 0 	
SCORE I 
SCORE 2 	
SCORE 3 
LIVER 	
0 Normal I,FT 	
0 Elevated Bilirubin, 
AP*, AST or ALT <2 x 
ULN 
O Abnormality present but NOT thought to represent GVHD 
El Bilirubin >3 mg/di or 
Bilirubin, enzymes 2-5 x 
ULN 
0 Bilirubin or enzymes > 5 x ULN 
El No symptoms 
0 Severe symptoms (shortness 
of breath at rest; requiring 02) 
0 Mild symptoms 
(shortness of breath after 
climbing one flight of 
steps) 
0 Moderate symptoms 
(shortness of breath after 
walking on flat ground) 
0 FEVI > 80% OR 	III FEVI 60-79% OR 
FEV1 40-59% OR 
LFS 6-9 	
0 FEVI <39% OR 
LFS=2 	
LFS 3-5 	
LFS 10-12 
Li Abnormality present but NOT thought to represent GVHD 
JOINTS AND FASCIA 
0 No symptoms 	
0 Mild tightness of 	
0 Tightness of arms or legs 0 Contractures WITH significant 
arms or legs, normal 
or mild decreased 
range of motion 
(ROM) AND not 
affecting ADL 
OR joint contractures, 
erythema thought due to 
fasciitis, moderate decrease 
ROM AND mild to 
moderate limitation of ADI., 
decrease of ROM AND significant 
limitation of ADL (unable to tie 
shoes, button shirts, dress self etc.) 
O Abnormality present but NOT thought to represent GVHD 
GENITAL TRACT 	
CI No symptoms 	
CI Symptomatic with 	
0 Symptomatic with 
Diagnostic/ 	
mild signs on exam 	
moderate signs on exam 
Distinctive features: 	
AND no effect on 	
AND with mild dyspareunia 
Present 	
coitus and minimal 	
or discomfort with 
0 Absent 	
discomfort with 	gynecologic exam 
H Not examined 	
gynecologic exam 
- 	
- 	
- 	
- 
Symptomatic WITH advanced 
signs (stricture, labial agglutination or 
severe ulceration) AND severe pain 
with coitus or inability to insert 
vaginal speculum 
O Abnormality present but NOT thought to represent GVHD 
Other indicators, clinical manifestations or complications related to chronic GVHD (check all that apply): 
Biopsy obtained: Dyes 0No Organ system(s) biopsied: 	
GVHD confirmed by histology: Dyes 0No 
OVERALL severity of GVHD: 	
0 No GVHD 0 Mild 	 0 Moderate 	
0 Severe 
Change from previous evaluation: 0 No GVHD 0 Improved 	
0 Stable 	
0 Worse 	
0 N/A (baseline) 
Completed by (print): 	
Date completed: 	
 
Signature: 	
 
f Pulmonary scoring should be performed using both the symptom and pulmonary function testing (PFT) scale whenever possible. When discrepancy exists between 
pulmonary symptom or PFT scores the higher value should be used for final scoring. Scoring using the Lung Function Score (LFS) is preferred, but if DLCO (carbon 
monoxide diffusion capacity corrected for hemoglobin) is not available, grading using LTV] (forced expiratory volume) should be used. The LFS is a global 
assessment of lung function after the diagnosis of bronchiolitis obliterans has already been established.n The percent predicted FEVI and DLCO (adjusted for 
hematocrit but not alveolar volume) should be converted to a numeric score as follows: > 80% = 1; 70-79% = 2; 60-69% = 3; 50-59% = 4 40-49% = 5; <40% = 6. 
'The LFS = FEVI score + DLCO score, with a possible range of 2-12. 
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APPENDIX VII: Adapted from COMMON TOXICITY CRITERIA (CTC) 
ALLERGY/IMMUNOLOGY 
Adverse Event 
Grade 3 
Grade 4 
Allergic reaction/ hypersensitivity 
(including drug fever) 
Symptomatic bronchospasm, requiring 
parenteral medication(s), with or 
without urticaria; allergy related 
edema/angioedema 
Anaphylaxis 
Vasculitis Requiring steroids 
Requiring steroids 
Ischemic changes or requiring amputation 
Allergy/Immunology — Other 
(specify): 
Severe 
Life-threatening or disabling 
BLOOD/BONE MARROW 
Adverse Event 
Grade 3 
Grade 4 
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 
CARDIOVASCULAR - ARRHYTHMIA 
Adverse Event 
Grade 3 
Grade 4 
Cardiovascular/Arrhythmia - 
Other (specify): 
Symptomatic, and requiring 
treatment of underlying cause 
Life-threatening (e.g., arrhythmia 
associated with CHF, hypotension, 
syncope, shock) 
CARDIOVASCULAR — GENERAL 
Adverse Event 
Grade 3 
Grade 4 
Cardiac left ventricular function 
CHF responsive to treatment 
Severe or refractory CHF or requiring 
intubation 
Cardiac troponin 1 (cTnI) 
Levels consistent with unstable 
angina as defined by the 
manufacturer 
Levels consistent with myocardial 
infarction as defined 
Cardiac troponin T (cTnT) 
> 0.1 - <0.2ng/mL 
> 0.2ng/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 vain thrombosis, requiring 
Embolic event including 
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Adverse Event 
Grade 4 
Grade 3 
DIC (disseminated intravascular 
coagulation) 
Also consider 
Platelets. 
Note: Must have increased fibrin 
split products or D-dimer in order 
to grade as DIC  
Thrombotic microangiopathy 
(e.g., thrombotic thrombocytopenic 
purpura/TTA or 
hemolytic uremic syndrome/HUS) 
Also consider 
Hemoglobin, platelets, creatinine. 
Note: Must have microangiopathic 
changes on blood smear (e.g., 
schistocytes, helmet cells, red cell 
fragments).  
Coagulation - Other (specify): 
Laboratory findings present with 
no bleeding 
Laboratory findings present 
without clinical consequences 
Evidence of RBC destruction with 
creatinine (>3 x ULN) not 
requiring dialysis 
Severe 
Laboratory findings and bleeding 
Laboratory findings and clinical 
consequences, (e.g., CNS 
hemorrhage/bleeding or 
thrombosis/embolism or renal failure) 
requiring therapeutic intervention 
Evidence of RBC destruction with renal 
failure requiring dialysis and/or 
encephalopathy. 
Life-threatening or disabling 
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pulmonaryembolism 
anticoagulant therapy 
Vein/artery operative injury is 
graded as Operative injury of 
vein/artery in the 
Cardiovascular (general) 
category. 
Other (specify): 	
 
Cardiovascular/General — 
Severe 
Life-threatening or disabling 
COAGULATION 
CONSTITUTIONAL SYMPTOMS 
Adverse Event  
Grade 3  
Grade 4 
Weight gain associated with 	>10% or as ascites 	
>10% or fluid retention resulting in 
Veno-Occlusive Disease (VOD) 	
pulmonary failure 
for BMT studies, if specified in 
the protocol. 
Also consider  
Ascites Edema, Pleural effusion 
(non-malignant).  
DERMATOLOGY/SKIN 
Adverse Event 
Grade 4 
Grade 3 
Life-threatening (e.g., exfoliative or 
ulcerating dermatitis or requiring 
enteral or parenteral nutritional support) 
Erythema multiforme (e.g., 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis) 
Rash/desquamation associated 
with graft versus host disease 
(GVHD) for BMT studies, if  
Severe or requiring IV fluids (e.g., 
generalized rash or painful 
stomatitis) 
Symptomatic generalized 
erythroderma or symptomatic 
macular, papular or vesicular 
Generalized exfoliative dermatitis or 
ulcerative dermatitis or bullous formation 
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specified in the protocol. 
eruption, with bullous formation, 
or desquamation covering >50% of 
body surface area. 
GASTROINTESTINAL 
Adverse Event 
Grade 3 
Grade 4 
Ascites (none-malignant) 
Symptomatic, requiring therapeutic 
paracentesis 
Life-threatening physiologic 
consequences 
Colitis 
Also consider 
Abdominal pain, fever, change in bowel 
habits with ileus or 
peritoneal signs, and radiographic or 
biopsy documentation 
Perforation or requiring surgery or toxic 
megacolon 
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
melena/GI bleeding, rectal 
bleeding/hematochezia, 
hypotension. 
Diarrhea associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
For pediatric BLOT studies, if 
specified in the protocol. 
Also consider 
>1500mL of diarrhea/day 
>15mL/kg of diarrhea/day 
Severe abdominal pain with or without 
ileus 
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
pain, dehydration, hypotension. 
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 
Bleeding without perforation, 
uncontrolled by outpatient medical 
management; requiring 
hospitalization or surgery 
Perforation or bleeding, requiring 
emergency surgeryv 
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
Gastritis 
Also consider 
Uncontrolled by out-patient 
medical management; requiring 
hospitalization or surgery 
Life-threatening bleeding, requiring 
emergency surgery 
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
Pancreatitis 
Also consider 
Abdominal pain with pancreatic 
enzyme elevation 
Complicated by shock (acute 
circulatory failure) 
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Hypotension. 
Note: Amylase is graded in 
theA4ETABOLIC/LABORATORY 
category. 
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 
Abdominal pain, diarrhea, fever, 
and radiographic or biopsy 
documentation 
Perforation, bleeding or necrosis or other 
life-threatening complication 
requiring surgical intervention (e.g., 
colostomy) 
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
hypotension, febrile neutropenia. 
HE MORRHAGE 
Notes: 
infusion. 
(<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
Transfusion: pRBCs, and Transfusion: platelets in addition to grading severity 
is listed, also use the grading that incorporates the site of bleeding: NS 
Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI 
into skin), Rectal bleeding/ hematochezia, Vaginal bleeding. 
Transfusion in this section refers to pRBC 
For any bleeding with grade 3 or 4 platelets 
thrombocylopeni6. Also consider Platelets, 
by grading the site or type of bleeding. 
If the site or type of Hemorrhage/bleeding 
Hemorrhage/bleeding, Hematuria, Hematemesis, 
bleeding, Petechiae/purpura (Hemorrhage/bleeding 
Adverse Event 
Grade 3 
Grade 4 
Hemorrhage/bleeding with grade 
3 or 4 theombocytopenia 
Also consider 
Requiring transfusion 
Catastrophic bleeding, requiring major 
non-elective intervention 
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. 
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/G1 bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring major 
non-elective intervention 
Rectal bleeding/hematochezia 
Requiring transfusion 
Catastrophic bleeding, requiring major 
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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 
HEPATIC 
Adverse Event 
Grade 3 
Grade 4 
Bilirubin 
Bilirubin associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
>3.0 — 10.0 x ULN 
>6 - <15mg/100mL 
>10.0 x ULN 
>15mg/100mL 
INFECTION/FEBRILE NEUTROPENIA 
Adverse Event 
Grade 3 
Grade 4 
Febrile neutropenia (fever or 
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 
NEUROLOGY 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Adverse Event 
Grade 3 
Grade 4 
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 (MR.I) 
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) 
PULMONARY 
Adverse Event 
Grade 3 
Grade 4 
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 02 saturation at rest, 
Decreased 02 saturation, 
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requiring supplemental oxygen 
requiring pressure support 
(CPAP) or assisted 
ventilation 
RENAL/GENITOURINARY 
Adverse Event 
Grade 3 
Grade 4 
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 
Adverse Event 
Grade 3 
Grade 4 
Secondary Malignancy — Other 
(specify type): 
- 
Present 
Excludes metastasis from initial 
primary. 
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PPENDIX VIII: FHCRC IRE Policies 
http://extranet.fhorc.org/EN/sections/iro/irb/policy/index.html  
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Appendix IX: Recommended Additional Disease Specific Evaluations 
Pre-transplantation  
Multiple Myeloma (*Waldenstrom's Macroglobulinemia patients, same as below 
with no skeletal survey, or MRI): 
• Complete skeletal survey including skull and long bones 
• MRI of skeleton 
• Quantitative serum immunoglobulin levels 
• Serum protein electrophoresis and immunofixation 
• 24hr urine collection to determine creatinine clearance and protein excretion, urine protein 
electrophoresis and immunofixation 
• Serum cryoglobulins 
• C-reactive protein 
• Serum 132 microglobulin 
• Serum viscosity for patients with > 3.0 mg/di of IgM monoclonal protein or > 4.0 mg/di of IgA or 
IgG protein 
• FISH probes for chromosome 13 abnormalities. 
Lymphoma and CLL: 
. CT scans of chest, abdomen and pelvis (and neck if clinically indicated) 
. Peripheral blood for flow cytometry (CLL and NHL only) 
• Quantitative serum immunoglobulin 
• Serum 132 microglobulin 
• Serum LDH 
. Patients with CLL should have FISH probes for deletion of chromosome 13, 11q, trisomy 12, and 
p53 analysis. 
Post-transplantation  
MM (*Waldenstrom's Macroglobulinemia patients, same as below with no skeletal 
survey, or MRI): 
• Quantitative serum immunoglobulin levels on day 80. Repeat at 6, 12, 18 and 24 months and then 
annually x 5 years post-transplant. 
• Serum protein electrophoresis and immunofixation on day 80. Repeat at 6, 12, 18 and 24 months and 
then annually x 5 years. 
• All patients will have twenty-four hour urine collection for protein, creatinine clearance, urine 
protein electrophoreis (UPEP) and immunofixation (IFX) at 12 months. Patients with an abnormal 
UPEP/IFX pretransplant, will have additional twenty-four hour urine collection for protein, 
creatinine clearance, UPEP, and IFIX at day +80, then 6, 12, 18 and 24 months, and then annually x 
5 years. 
• Complete skeletal survey, including skull and long bones at 12 months and then annually x 5 years. 
MRI of skeleton at 12 months and then annually x 5 years. 
• Serum [32 microglobulin at 6, 12, 18 and 24 months and then annually x 5 years. 
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NHL, HD and CLL: 
• CT scans of chest, abdomen and pelvis (neck if clinically indicated) at day 56 if abnormal 
pretransplant and day 80 for all patients. Repeat at 6, 12, 18, and 24 months and then annually x 5 
years post-transplant. 
• Patients with CLL and NHL with peripheral blood involvement with lymphoma pretransplant: flow 
cytometry analysis on day 28, 56, 80. Repeat at 6, 12, 18, and 24 months and then annually x 5 
years. 
• For CLL patients, quantitative serum immunoglobulin levels on day 80. Repeat at 6, 12, 18 and 24 
months and then annually x 5 years. If abnormal pre-transplant. 
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Appendix X: Potential Adverse Events Associated or Expected with Hematopoietic Cell Transplantation 
1. Graft versus host disease. GVHD is a major toxicity associated with the infusion of allogeneic donor stem 
cells. GVHD may be acute or chronic and may affect multiple organ systems, including the skin, liver, and GI 
tract. 
2. Opportunistic infections, including viral and fungal infections, can result in severe pulmonary, neurologic, 
hepatic and other organ dysfunction, and possible death. 
3. Gastrointestinal toxicity. Nausea and vomiting can be anticipated during the entire course of ablative therapy. 
Mucositis and diarrhea should be expected. Prednisone can cause GI bleeding. 
4. Cardiac toxicity. Cardiotoxicity (congestive heart failure, pericardial effusion, EKG changes) is uncommonly 
associated with the chemotherapy agents and TBI used in the regimen and these sequelae may prove lethal. 
5. Pulmonary toxicity. Diffuse interstitial pneumonitis of unknown etiology and diffuse alveolar hemorrhage 
occurs with some regularity after BMT and interstitial fibrosis occurs much more rarely. Both are well-described 
complications of intensive chemotherapy and TBI regimens and may prove lethal. 
6. Hepatic toxicity. Veno-occlusive disease of the liver is a common toxicity of high-dose chemoradiotherapy and 
may result in death. Cyclosporine may cause elevation of ALT/AST. 
7. Renal dysfunction. Chemoradiotherapy may uncommonly cause renal dysfunction. More commonly, 
nephrotoxicity results from cyclosporine and generally responds to dose reduction. Rarely, idiopathic or 
calcineurin inhibitor-associated hemolytic-uremic syndrome may occur and may be progressive and fatal. A 
syndrome of moderate renal insufficiency and hemolysis has been seen 5-7 months post HSCT after intensive 
multi-agent conditioning plus TBI. 
8. Hemorrhagic cystitis. manifested either as gross or microscopic hematuria, is a common toxicity after high-
dose chemoradiotherapy, but usually associated with regimens that include cyclophosphamide. Hemorrhagic 
cystitis may predispose to a long-term increased risk of bladder cancer. 
9. Central nervous system toxicity. Radiation and chemotherapy can cause CNS toxicity, including seizures, 
depressed mental status, or leukoencephalopathy. Calcineurin inhibitors can cause seizures or other CNS toxicity. 
10. Marrow aplasia. Severe neutropenia, thrombocytopenia, and anemia, is expected to occur for a period of 7 to 
42 days following infusion of marrow. Transfusion of platelets and red blood cells is expected as supportive care. 
Transfusion of blood products may be associated with acquisition of HIV or a hepatitis virus. Neutropenia may 
increase the risk for acquiring serious infection. Thrombocytopenia may increase the risk of life-threatening 
hemorrhage. Hemorrhagic or infectious complications during the expected period of aplasia may result in death. 
11. Miscellaneous. Alopecia and sterility are expected complications of the program as a whole. Cataract 
development is possible after TBI and/or steroids. Deficiencies of growth hormone, thyroid hormone, and sex 
hormones are possible after TBI. Calcineurin inhibitors can cause transient gingival hyperplasia, tremor, seizure, 
hypertension, headache, dysesthesia and hirsutism. Steroid therapy can also contribute to fluid retention, easy 
bruising, hypertension, aseptic necrosis of bone and increased susceptibility to infection. MMF can cause 
spontaneous abortions and birth defects. Hospitalization during conditioning and recovery period is expected to 
be 5-9 weeks in duration. 
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