Clinical trial NCT01252667
Conditions: Acute Myeloid Leukemia
Sponsor: Fred Hutchinson Cancer Center
Start date: 2011-01-25; Completion date: 2019-03-01
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of clofarabine in combination with 2, 3, or 4 Gy TBI in preparation for hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA)-identical related and HLA-matched unrelated donors in patients with AML. (Part 1)

II. To determine the efficacy of the maximum tolerated dose of clofarabine combined with 2, 3, or 4 Gy TBI in reducing the 6 month relapse rate in patients with AML compared to our historical experience with fludarabine and 2 Gy TBI. A satisfactory improvement will be considered 6 month relapse rate declines from 35% to 20% among high-risk (objective for low risk group terminated August 2014). (Part 2)

SECONDARY OBJECTIVES:

I. Leukemia-free and overall survivals.

II. Non-relapse mortality (NRM) of \< 5% at 100 days.

III. Engraftment rate of \>= 95%.

IV. Prognostic significance of cytogenetics and genetic markers not detected by traditional karyotype analysis, with special respect to tyrosine kinase receptor mutations (such as fms-like tyrosine kinase 3 \[FLT3\]), retrovirus-associated deoxyribonucleic acid (DNA) sequences (RAS)- and nucleophosmin gene mutations along with CCAAT/enhancer binding protein, alpha (C/EBP) mutations.

V. Rigorous monitoring for minimal residual/recurring disease by standard morphologic, flow cytometric, and molecular techniques in order to facilitate early intervention.

VI. To evaluate the pharmacokinetics of clofarabine (pharmacokinetic samples discontinued January 2017).

OUTLINE: This is a dose-escalation study of clofarabine.

CONDITIONING REGIMEN: Patients receive clofarabine intravenously (IV) over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine orally (PO) every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

After completion of study treatment, patients are followed up at 4 months and then every year thereafter.

Arms: arm 1: CONDITIONING REGIMEN: Patients receive 30 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI arm 2: CONDITIONING REGIMEN: Patients receive 40 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI arm 3: CONDITIONING REGIMEN: Patients receive 50 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI arm 4: CONDITIONING REGIMEN: Patients receive 30 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI arm 5: CONDITIONING REGIMEN: Patients receive 40 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI arm 6: CONDITIONING REGIMEN: Patients receive 50 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Clofarabine: Given IV

Cyclosporine: Given PO

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT

Pharmacological Study: Optional correlative studies

Total-Body Irradiation: Undergo TBI
Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Clofarabine intervention 3: Cyclosporine intervention 4: Laboratory Biomarker Analysis intervention 5: Mycophenolate Mofetil intervention 6: Peripheral Blood Stem Cell Transplantation intervention 7: Pharmacological Study intervention 8: Total-Body Irradiation
Intervention descriptions: intervention 1: Undergo allogeneic hematopoietic PBSCT intervention 2: Given IV intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO intervention 6: Undergo allogeneic hematopoietic PBSCT intervention 7: Optional correlative studies intervention 8: Undergo TBI

Protocol documents:
Prot_SAP_000.pdf: 
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FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE, DEPARTMENT OF 
MEDICINE, DIVISION OF ONCOLOGY 
SEATTLE CHILDREN’S 
Current Version: 09/03/2017 
Previous Version: 05/23/2017 
 
 
1. Title of protocol: A Phase II Study of Optimally Dosed Clofarabine in Combination 
with Low-Dose TBI to Decrease Relapse Rates after Related or Unrelated Donor 
Hematopoietic Cell Transplantation in Patients with AML 
 
Investigators: 
 
Brenda M. Sandmaier, MD  
Member, FHCRC, Professor of Medicine, UW (206-667-4961) 
Elizabeth Krakow, MD 
Assistant Member, FHCRC Assistant Professor of Medicine, 
UW (206-667-3410) 
 
 
 
 
 
 
Boglarka Gyurkocza, MD               
FHCRC Affiliate Investigator   
Pamela Becker, MD, PhD 
Affiliate Investigator, FHCRC, Associate Professor of Medicine, 
UW (206-288-6890) 
Marco Mielcarek, MD 
Member, Clinical Research, FHCRC, Professor of Medicine, 
UW (206-667-2827) 
Mohamed L. Sorror, MD/MSc  
Associate Member, FHCRC, Associate Professor of Medicine, 
UW (206-667-2765) 
Ann Woolfrey, MD 
Member, FHCRC; Professor of Pediatrics, UW (206-667-4453) 
Mary E.D. Flowers, MD 
Member, FHCRC, Professor of Medicine, UW (206-667-5115) 
Jerry Radich, MD 
Member, FHCRC, Professor of Medicine, UW (206-667-4118) 
Jeannine S. McCune, PharmD 
Member, FHCRC, Professor, UW (206-543-1412) 
Elihu Estey, MD 
Member, FHCRC, Professor of Medicine, UW (206-288-7176) 
Rainer Storb, MD  
Member, FHCRC, Professor of Medicine UW (206-667-4407) 
 
Radiation Oncologist: Ralph Ermoian, MD., Assistant Professor, Radiation Oncology, UW; 
(206) 598-4100 
Statistician: Barry Storer, Ph.D., Member, FHCRC Affiliate Professor of Biostatistics, UW 
(206)-667-6151, (206)-598-4115 
Research Nurse: Michelle Bouvier, RN (206) 667-6993, pager (206) 995-7658 
 
Additional Performance Sites 
Investigators 
Emergency Phone 
Numbers 
Veterans Affairs Puget Sound 
Health Care System  
Thomas Chauncey MD, PhD      
(206)-762-1010  
 
 
 
Emergency Phone: (206) 598-8902 


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Table of Contents 
 
 
Page 
2. Introduction 
4 
3. Background 
4 
4. Proposal 
8 
5. Objectives 
9 
6. Patient selection 
9 
7. Donor selection 
11 
8. Informed consent 
12 
9. Protocol registration 
13 
10. Plan of treatment 
14 
11. Patient evaluations 
25 
12. Donor evaluations 
31 
13. Drugs and toxicities 
32 
14. Records 
35 
15. Statistical consideration and termination of study 
35 
16. Data safety monitoring plan 
39 
17. Targeted/Planned Enrollment 
41 
18. References 
42 
19. Appendices 
46 
 


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2. INTRODUCTION 
 
The incidence of acute myeloid leukemia (AML) increases nearly exponentially as a 
function of age beyond the third decade of life 1. Patients diagnosed with de novo AML 
who are older than 55 years and receive intensive induction chemotherapy experience 
complete remission (CR) rates of approximately 50%, median survivals of 6-12 months, 
and 5 year survivals of 5-10%. Outcomes are poor even for patients who achieve CR 
and receive intensive consolidation therapy; the median survivals are approximately 10-
12 months 2-6. The feasibility of allogeneic hematopoietic cell transplantation (HCT) to 
improve relapse-free survival in patients with AML in this older age group has 
traditionally been limited by high rates of transplant-related mortality (TRM) due to 
toxicities from typical, intense conditioning regimens7,8. More recently, we have explored 
a minimally toxic nonmyeloablative preparative regimen consisting of fludarabine (90 
mg/m2) and low-dose total body irradiation (TBI; 2 Gy), which permits allogeneic 
engraftment and depends on graft-vs.-leukemia (GVL) effects for eliminating residual 
leukemic cells 9-12. We observed long-term disease-free survival in a significant 
proportion of older patients with AML given either related or unrelated donor HCT 13,14, 
treated on Fred Hutchinson Cancer Research Center Protocols 1225, 1406, 1463, 1533, 
1591, 1596, 1641, 1654, 1668, 1732, 1813, 1898, 1938 and 1959. However, a major 
cause of failure of this approach has been leukemia relapse, seen in 43% of patients at 
5 years after HCT14. Here, we propose to improve outcomes for patients with AML by 
substituting clofarabine for fludarabine in the conditioning regimen under the hypothesis 
that clofarabine, a new generation purine nucleoside analogue, has comparable 
immunosuppressive but better anti-leukemic activities than fludarabine. As a result, we 
anticipate that clofarabine will reduce the leukemic cell burden before transplantation 
without compromising the favorable toxicity profile of this regimen. Reducing the tumor 
burden is likely to increase the success of GVL effects in eliminating the last leukemic 
cells and, thereby, minimizing the relapse risk. Patients older than 55 years with AML in 
morphologic leukemia-free state will be eligible for this study. Younger patients with 
comorbid conditions excluding them from conventional high-risk conditioning regimens 
will also be eligible. The efficacy part of the study will be preceded by a dose finding 
part, aimed at determining the optimal clofarabine dose. Monitoring for minimal residual 
disease (MRD) after HCT will be rigorous, using immunophenotypic, cytogenetic and 
molecular methods. Finally, clofarabine might be less immunosuppressive than 
fludarabine, and graft rejection beyond the historical rate of 5% might become an issue. 
Therefore, graft rejection will be monitored and the TBI dose increased by 1 Gy if more 
than 5% graft rejection is seen. 
 
3. BACKGROUND 
 
Epidemiology and Prognosis 
The prevalence of AML increases with age, with a median patient age of 67 years at 
diagnosis, according to Surveillance, Epidemiology and End Result (SEER) statistics. 
Approximately 35-80% of adult patients with de novo AML achieve complete remissions 
when treated with induction therapy 15,16. These remissions are rarely durable and 
additional therapy is needed for long-term relapse-free survival. Based on a study from 
the Cancer and Leukemia Group B, multiple cycles of high-dose cytarabine have 


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Figure 1. Overall Survival, Relapse/Progression and 
Non-relapse Mortality rates in patients with AML (n=274) 
undergoing non-myeloablative allogeneic HCT. 
become the standard consolidation therapy for patients with favorable and intermediate 
cytogenetic risks under the age of 60 years 17. The biology of AML in the elderly 
appears to differ from that of younger patients, with an increased incidence of 
antecedent dysplasia, poor prognosis karyotypes, and multidrug resistant glycoprotein 
MDR1 18-21. Furthermore, patients over the age of 60 years and those with comorbid 
conditions are usually treated with less intense regimens due to their inability to tolerate 
multiple cycles of high-dose chemotherapy, resulting in low, approximately 10-15% long 
term survival rates 5,22,22. A recent retrospective analysis including 2,444 patients with 
AML, 60 years or older, treated on several SWOG, ECOG and M.D. Anderson protocols 
between 1976 and 2004 reported a 5-year overall survival rate of about 5%23. 
Allogeneic HCT using conventional high-dose conditioning regimens represents a post-
remission therapy option with curative potential; however, these regimens are 
accompanied by prohibitively high regimen-related morbidity and mortality in older 
patients or those with comorbid conditions.  
 
Nonmyeloablative HCT for patients with AML 
The development of nonmyeloablative and reduced-intensity conditioning regimens has 
enabled older and medically infirm patients with myeloid malignancies to undergo 
allogeneic HCT. A number of studies of reduced-intensity conditioning followed by 
allogeneic HCT from HLA-identical siblings or HLA-matched unrelated donors have 
been published 24-28.  
 
Among the largest studies is that from the FHCRC/Seattle Consortium, which has been 
recently updated 14. The study included 274 patients (median age: 60 years) with de 
novo or secondary AML who underwent allogeneic HCT from related (n=118) or 
unrelated donors (n=156) after conditioning with 2 Gy total body irradiation (TBI) with or 
without fludarabine (90 mg/m2) on FHCRC protocols. A calcineurin inhibitor and MMF 
were used for postgrafting immunosuppression. With a median follow-up of 38 months 
in surviving patients, the estimated 
5-year overall survival, 
relapse/progression and non-
relapse mortality (NRM) rates were 
33%, 42% and 26%, respectively 
(Figure 1). Patients in first and 
second complete remission had 
better survivals than patients with 
more advanced disease (37% and 
34% vs. 18%, respectively). 
Patients with HLA-matched related 
or unrelated donors had similar 
survivals. Advanced disease stage 
and unfavorable cytogenetics were 
associated with increased relapse 
and mortality. Chronic GVHD was 
associated with lower relapse risk.  
 


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Table 1. Risk of Relapse/Progression. Multivariate analysis, n=226. 
Not significant: age, donor, HCT-CI, number of pre-HCT high-dose chemotherapy cycles
1.55
No
0.06
1.0
CBC Recovery at HCT: Yes
0.15
> 18 mo
0.81
6 - 18 mo
< 0.0001
1.0
Time between Dx and HCT: < 6 mo
1.18
Undetermined Significance
2.71
Unfavorable
0.001
1.0
Cytogenetic Risk: Favorable/Intermediate
1.07
Yes
0.83
1.0
Minimal Residual Disease: No 
0.99
Secondary
0.97
1.0
AML Etiology: De Novo 
5.89
Not CR1/2
2.51
CR2
< 0.0001
1.0
Stage: CR1
P
HR
Variable
1.55
No
0.06
1.0
CBC Recovery at HCT: Yes
0.15
> 18 mo
0.81
6 - 18 mo
< 0.0001
1.0
Time between Dx and HCT: < 6 mo
1.18
Undetermined Significance
2.71
Unfavorable
0.001
1.0
Cytogenetic Risk: Favorable/Intermediate
1.07
Yes
0.83
1.0
Minimal Residual Disease: No 
0.99
Secondary
0.97
1.0
AML Etiology: De Novo 
5.89
Not CR1/2
2.51
CR2
< 0.0001
1.0
Stage: CR1
P
HR
Variable
Variable
Score
Unfavorable Cytogenetics
+1
CR2
+1
> CR3
+2
Lack of pre-HCT CBC Recovery
+0.5
> 18 months between diagnosis and HCT
-2
Relapse Risk Score < 0: LOW RISK
Relapse Risk Score > 0: HIGH RISK
Table 2. Relapse Risk Score
Despite an encouraging number of long-term leukemia-free survivors, AML relapse 
remained the major cause of 
treatment failure after HCT. Most 
relapses occurred early after HCT; the 
median time to relapse was 84 days. 
The 6-month and 1-year relapse rates 
were 31% and 35%, respectively. 
Relapses occurring beyond 2 years 
were rare.  
 
The finding of early relapse implies 
that regrowth of residual leukemia 
after HCT outpaces GVL effects, 
which may take months to develop. 
Therefore, a strategy that retards the 
regrowth of leukemia after HCT may provide time for potent GVL effects to develop, and, 
thereby, lower the relapse rate and improve survival. To this end, we propose to 
intensify the anti-leukemic efficacy of the current conditioning regimen by substituting 
the anti-leukemic drug clofarabine for fludarabine. 
 
Development of Relapse Risk Score 
In an effort to discriminate patients at high and low risk for relapse/progression within 
this cohort, Cox regression was used to perform univariate and multivariate analyses of 
risk factors (Table 1), treating non-relapse mortality as competing risk. Leukemia stage, 
cytogenetic risk status and time between diagnosis and HCT had statistically significant 
impact on the risk of relapse/progression. 
  
In order to stratify patients with respect to risk of relapse, we developed a simple risk 
score that summarizes the contribution of multiple risk factors.  From a multivariate Cox 
regression model (excluding patients not in remission at the time of HCT), we assigned 
weights based on the relative magnitude of the log hazard ratios associated with the 
principal risk factors.  From a starting score of 0, points are added or subtracted based 
on the following risk factors:  2nd CR, 3rd or later CR, unfavorable cytogenetics, absence 
of pre-HCT peripheral blood cell count recovery and time from diagnosis to HCT > 18 
months (Table 2).  Patients were then stratified according to whether the total risk score 
was ≤0 (low risk) or >0 (high risk), providing a clear separation of relapse rates 
(Figure 2A) and overall survival 
(Figure 2B).  Although this risk 
scoring system has not yet been 
prospectively validated, we believe it 
is adequate for risk stratification in the 
proposed protocol.  While all patients 
enrolled in this study will receive the 
same treatment regimen, the two risk 
groups will be analyzed separately, 
given the differences in the expected 
relapse rates.   


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A
B
Figure 2. Relapse/Progression (A) and Overall Survival (B) rates stratified by 
Relapse Risk Score
%
Years from HCT
Clofarabine to Reduce Relapse Risk 
Clofarabine (2-chloro-9-[deoxy-2’-fluoro--D-arabinofuranosyl] adenine; Cl-F-ara-A; 
CAFdA) is a rationally designed, second generation purine nucleoside analogue. It was 
designed as a hybrid molecule to both overcome the limitations and incorporate the best 
qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA). It was approved in 
December 2004 by the US Food and Drug Administration for the treatment of pediatric 
patients with relapsed or refractory acute lymphoblastic leukemia after at least 2 prior 
regimens, based on the induction of complete responses.  
 
In a phase I study involving pediatric patients with refractory and relapsed leukemia, six 
clofarabine dose levels between 11.25 and 70 mg/m2/day were studied; the maximum 
tolerated dose was found to be 52 mg/m2/day for 5 days, which resulted in complete 
and sustained inhibition of DNA synthesis 29. In addition, clofarabine demonstrated 
efficacy in early phase studies in older or relapsed patients with AML. In phase 2 clinical 
trials, treatment with single agent clofarabine 30 or in combination with cytarabine 31 32, 
demonstrated efficacy as induction therapy as well as salvage therapy in adult patients 
with AML resulting in overall response rates ranging from 41% to 60%. Safety and 
efficacy have not been established in adults (greater than 21 years of age) or patients 
aged 65 years and older (Prod Info Clolar(R) iv injection, 2008). Furthermore, several 
groups of investigators described incorporation of clofarabine into conditioning regimens 
for allogeneic HCT, in combination with a traditionally used alkylating agent such as 
busulfan, melphalan or thiotepa 33-38,38,39. These single institution studies, albeit small, 
showed, that conditioning regimens incorporating clofarabine in various combinations 
(mostly in combination with an alkylating agent), followed by allogeneic HCT were well 
tolerated and safe. The replacement of fludarabine with clofarabine in busulfan-
containing preparative regimens did not seem to impact engraftment. 
 
The anti-tumor activity of clofarabine involves three major mechanisms: inhibition of 
DNA synthesis (through inhibition of DNA polymerase ), inhibition of ribonucleotide 
reductase (RnR) and direct induction of apoptosis 40,41. With respect to inhibition of RnR, 
clofarabine is superior to fludarabine 42, while in inhibiting DNA polymerase , 


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clofarabine and fludarabine are similar and both are superior to cladribine 40. In addition, 
unlike fludarabine, clofarabine can directly induce apoptosis by disrupting the integrity of 
mitochondria and thereby releasing cytochrome c and apoptosis-inducing factor 43, 
which is postulated to be a factor in the potent cytotoxic effects of both clofarabine and 
cladribine toward nondividing lymphocytes. Furthermore, studies have shown that 
inhibiting either RnR or DNA polymerase activity enhances tumor cell radiosensitivity by 
preventing the repair of DNA damage and the ability to overcome replication 
blockage44,45. Indeed, clofarabine has been shown to act as a powerful radiosensitizer 
both in vitro and in vivo by interfering with the DNA damage response, an effect, which 
was comparable to the radiosensitizing effects of 5-FU and gemcitabine46.  These 
properties may be particularly effective not only in enhancing specific anti-leukemia 
effects, but also, promoting allograft engraftment by suppressing host T-lymphocytes in 
the non-myeloablative HCT setting.  
 
We therefore hypothesize that by substituting clofarabine for fludarabine in the 
nonmyeloablative preparative regimen, recurrence rates of AML will be reduced without 
compromising engraftment or the favorable toxicity profile of this transplant approach. 
 
 
4. PROPOSAL 
 
The current multi-institutional protocol’s primary objective is to: Improve the 6 month 
relapse rate of patients with AML who are either > 55 years of age undergoing related or 
unrelated HCT following nonmyeloablative conditioning while maintaining historic rates 
of NRM and engraftment, or patients <55 years of age and are considered to be at high 
risk for serious toxicities associated with a conventional, high-dose preparative regimen. 
The study aim is to reduce the relapse rate to < 20% in high-risk patients and to < 5 % 
in low-risk patients (low risk group terminated August 2014 – see statistical section). We 
plan to achieve this goal by substituting clofarabine, a new generation purine nucleoside 
analogue with both immunosuppressive and anti-leukemic activity for fludarabine in the 
standard low-dose TBI (2, 3, or 4 Gy) regimen. The study will be conducted in 2 parts; 
first, a dose-finding part to determine the optimal dose of clofarabine followed by an 
extended accrual at the “optimal” dose. During Part 1, only patients with a relapse risk 
score > 0 (“high risk”, as described above, in Section 2. Background) will be enrolled.  
We will start by administering clofarabine daily on days -6 to -2 at 30 mg/m2/day (total 
dose: 150 mg/m2). If there is no dose limiting toxicity (DLT; see definition below) when 
the 3rd patient reaches day 14 after HCT (21 days after initiation of clofarabine), the next 
three patients will be treated with clofarabine at 40 mg/m2/day (total dose: 200 mg/m2), 
with the goal to treat the final three patients at 50 mg/m2/day (total dose: 250 mg/m2). 
Once the optimal dose of clofarabine is determined, 33 additional high risk patients and 
30 additional low risk patients (low risk group terminated August 2014 – see statistical 
section) will be treated with clofarabine at the maximum tolerated dose determined in 
Part 1.  Participation in clofarabine pharmacokinetic studies will be offered to patients 
with actual body weight > 15 kg treated at the Fred Hutchinson Cancer Research 
Center, at all dose levels (pharmacokinetic samples discontinued January 2017).  A 
stopping rule for graft rejection will be based on the outcomes in patients. Should that 
stopping rule be triggered, the dose of TBI will be increased by 1 Gy. In addition, a 


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stopping rule is in place for NRM, defined as any death occurring in the absence of 
relapse. If there exists reasonable evidence that the true rate of 100 day NRM exceeds 
5%, the study will be referred to the DSMB for review to determine whether 
modifications are warranted or whether it needs to be terminated due to lack of safety   
 
 
5. OBJECTIVES 
 
Primary Objectives 
 
Part 1: To determine the maximum tolerated dose of clofarabine in combination with 2, 
3, or 4 Gy TBI in preparation for HCT from HLA-identical related and HLA-matched 
unrelated donors in patients with AML. 
 
Part 2: To determine the efficacy of the maximum tolerated dose of clofarabine 
combined with 2, 3, or 4 Gy TBI in reducing the 6 month relapse rate in patients with 
AML compared to our historical experience with fludarabine and 2 Gy TBI. A 
satisfactory improvement will be considered 6 month relapse rate declines from 35% to 
20% among high-risk (objective for low risk group terminated August 2014 – see 
statistical section)  
 
Secondary Objectives 
 
1. Leukemia-free and overall survivals 
 
2. NRM of < 5% at 100 days 
 
3. Engraftment rate of > 95% 
 
4. Prognostic significance of cytogenetics and genetic markers not detected by 
traditional karyotype analysis, with special respect to tyrosine kinase receptor mutations 
(such as FLT3), RAS- and nucleophosmin gene mutations along with C/EBP mutations  
 
5. Rigorous monitoring for minimal residual/recurring disease by standard morphologic, 
flow cytometric, and molecular techniques in order to facilitate early intervention. 
 
6. To evaluate the pharmacokinetics of clofarabine (pharmacokinetic samples 
discontinued January 2017). 
 
6. PATIENT SELECTION 
 
Inclusions 
1. Patients age > 55 years with AML OR patients age < 55 years with AML, who also 
through pre-existing medical conditions or prior therapy are considered to be at high risk 
for serious toxicities associated with a conventional, high-dose preparative regimen. 
Patients must be older than 1 year of age.  
 


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2. Patients must be in morphologic leukemia-free state (marrow blasts < 5%) without 
evidence of extramedullary disease within 21 days of HCT. 
 
3. Only patients with Relapse Risk Score > 0 (“high risk”) will be enrolled during Part 1 
(see Relapse Risk Score system in section 3. Background). Patients with all Relapse 
Risk Scores will be enrolled during Part 2 (low risk group terminated August 2014 – see 
statistical section). 
 
4. HLA-identical related or HLA-matched unrelated donor available.  
 
5. A signed informed consent form or minor assent form 
 
 
 
Exclusions 
1. AML FAB M3 in CR1. 
 
2. Active AML involvement of the central nervous system (CNS) with disease refractory 
to intrathecal chemotherapy (for LP requirement and intrathecal treatment guidelines, 
see Appendix N). 
 
3. Presence of circulating leukemic blasts in the peripheral blood detected by standard 
morphology 
 
4. Patients who are HIV+ (HIV+ patients registered at FHCRC should be offered 
treatment on Protocol 1410). 
 
5. Fertile men and women unwilling to use contraceptive techniques during and for 12 
months following treatment. 
 
6. Organ dysfunction: 
a.  Cardiac: left ventricular ejection fraction < 35% (or, if unable to obtain 
ejection fraction, shortening fraction of < 26%).  Ejection fraction is 
required if age > 50 years or there is a history of anthracycline exposure or 
history of cardiac disease. Patients with a shortening fraction < 26% may 
be enrolled if approved by a cardiologist 
b.   Pulmonary:   
(i) DLCO<40% (corrected), TLC < 40%, FEV1 < 40% and/or receiving 
supplementary continuous oxygen.  
(ii) The FHCRC PI of the study must approve enrollment of all patients 
with pulmonary nodules.   
c.   Liver Function Abnormalities:  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, and the degree of portal hypertension.  
Patients will be excluded if they are found to have fulminant liver failure, 
cirrhosis of the liver with evidence of portal hypertension, alcoholic 
hepatitis, esophageal varices, a history of bleeding esophageal varices, 


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hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction 
evinced by prolongation of the prothrombin time, ascites related to portal 
hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary 
obstruction, chronic viral hepatitis with total serum bilirubin >3mg/dL, or 
symptomatic biliary disease. 
d.  Renal: Serum creatinine should be within normal limits as specified by  
      institutional guidelines. For patients with serum creatinine > upper limit of    
      normal, a 24-hour creatinine clearance will be performed 
and should be equal to or more than the lower limit of normal 
    
7. Karnofsky score < 60 (see Appendix B) or Lansky Score < 50 (see Appendix C)     
 
8. Patients with poorly controlled hypertension and on multiple antihypertensives. 
 
9. Females who are pregnant or breastfeeding. 
 
10. Patients with active non-hematologic malignancies (except non-melanoma skin 
cancers) or those with non-hematologic malignancies (except non-melanoma skin 
cancers) who have been rendered with no evidence of disease, but have a greater than 
20% chance of having disease recurrence within five years. 
 
This exclusion does not apply to patients with non-hematologic malignancies that do not 
require therapy. 
 
11. The addition of cytotoxic agents for “cytoreduction” with the exception of. tyrosine 
kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose 
cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the 
initiation of conditioning. 
 
12. Fungal infections with radiological progression after receipt of amphotericin B or 
active triazole for greater than 1 month.   
 
13. Patients with active bacterial or fungal infections unresponsive to medical therapy. 
 
 
7. DONOR SELECTION 
 
Inclusions 
 
1. FHCRC matching allowed will be Grade 1.0 to 2.1 (Appendix O):  Unrelated donors 
who are prospectively: 
 
a. 
Matched for HLA-A, B, C, DRB1 and DQB1 by high  
 
resolution typing;  
 
b. 
Only a single allele disparity will be allowed for HLA-A, B,  
 
or C as defined by high resolution typing (see Appendix O for other  
 
donor selection details). 
 


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2.  A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion. Donors 
are excluded when preexisting immunoreactivity is identified that would jeopardize 
donor hematopoietic cell engraftment. This determination is based on the standard 
practice of the individual institution. The recommended procedure for patients with 10 of 
10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) 
screens to class I and class II antigens for all patients before HCT. If the PRA shows 
>10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be 
obtained. The donor should be excluded if any of the cytotoxic cross match assays are 
positive.  For those patients with an HLA Class I allele mismatch, flow cytometric or B 
and T cell cytotoxic cross matches should be obtained regardless of the PRA results.  
 
3. Patient and donor pairs homozygous at a mismatched allele are considered a two-
allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of 
mismatch is not allowed.  
 
4. Peripheral blood stem cells (PBSC) only will be permitted as a HSC source on this 
protocol. 
 
Exclusions 
1. Marrow donors. 
 
2. Donors who are HIV-positive and/or medical conditions that would result in increased 
risk to the donor G-CSF mobilization and PBSC collections. 
 
3. Identical twin 
 
4. Any contraindication to the administration of subcutaneous G-CSF at a dose of 16 
mg/kg/day for 5 consecutive days 
 
5. Serious medical or psychological illness 
 
6. Pregnant or lactating females 
 
7. Prior malignancy within the preceding 5 years, with the exception of non-melanoma 
skin cancers 
 
8. Children < 12 years old.   
 
 
8. INFORMED CONSENT 
 
A conference will be held with the patient and family to discuss this study and 
alternative treatments available for the underlying disease.  A separate conference will 
be held for the donor.  The conference will be conducted by the outpatient-attending 
physician.  All potential risks associated with the use of clofarabine, low dose TBI, 
immunosuppressive drugs, HCT, GVHD, infections, rejection, disease 
progression/recurrence, risk of infertility and DLI should be discussed as objectively as 


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possible.  Specifically, the advantages and risks of this approach in comparison to non 
transplant strategies should be discussed.  Informed consent from the patient will be 
obtained using a form approved by the Institutional Review Board (IRB) of the Fred 
Hutchinson Cancer Research Center and the local IRB if the patient is treated in a 
collaborating institution. 
 
9. PROTOCOL REGISTRATION 
 
A. FHCRC patients: Eligible patients will be identified by the Clinical Coordinators Office 
who will register the patient with the Registration Office (206-667-4728) between 8:30 
am and 4:00 pm, Monday through Friday. After hours, the Registration Office can be 
reached by paging (206) 995-7437. 
 
B. Collaborating institutions: Eligible patients will be identified by the principal 
Investigator of the collaborating institution who will register the patient with the FHCRC 
Registration Office. Registration will include completion of the eligibility 
checklist/demographic form (Appendix L). This form and a copy of the signed informed 
consent will be faxed to the Trial Coordinator (206-667-5378). Questions regarding 
eligibility or protocol information should be directed to Brenda Sandmaier, MD (206-667-
4961). 
 
 


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10. PLAN OF TREATMENT 
 
A. Outline of Treatment Plan (Figure 3. Also, please see Appendix T for Plan of 
Treatment in a Flow Chart Format) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. HCT: The hematopoietic graft will be unmodified, G-CSF-mobilized PBSC, collected 
as per NMDP standard, see additional details in section G (Collection and Infusion of 
Donor PBSC). Two 12-liter leukaphereses will be on consecutive days, day –1 and day 
0; cells will be infused together on day 0 following TBI. Refer to institutional practice 
guidelines for methods of infusion. If the CD34+ cell dose is <5.0 x 106/kg after the 
second collection, a third day collection should be added, and extra dose of G-CSF 
should be given to the donor before the final collection. 
 
C. Cytoreduction: Given the high risk of relapse for patients with AML allografted in 
relapse and the poor response to DLI for morphologically relapsed AML after allogeneic 
transplant, morphologic leukemia-free state (marrow blasts < 5%, the absence of 
circulating blasts) must be achieved prior to enrollment. The referring physician may 
administer therapy prior to the patient arriving at the transplant center. No high-dose 
chemotherapy can be given within three weeks (or the interval in which a cycle of 
standard chemotherapy would be administered in a non-transplant setting) prior to 
Protocol 2430
TBI**
HCT
Leukemia/MRD Assessments
-3
56
0
28
84
-4
-2
CLOFARABINE*
-1
180
120
40
Days
-5
-6
*Clofarabine Dose Escalation
(20 mg/m2 x 5, total dose = 100 mg/m2)
Dose Level 1: 30 mg/m2 x 5, total dose = 150 mg/m2
Dose Level 2: 40 mg/m2 x 5, total dose = 200 mg/m2
Dose Level 3: 50 mg/m2 x 5, total dose = 250 mg/m2
**TBI Dose Escalation: 
ONLY for engraftment failure
2 Gy (starting dose)
3 Gy
4 Gy
Figure 3. Protocol Treatment Schema
CSP
MMF
Immunosuppression
CSP: - Related Donors: 5 mg/kg PO q12hrs days -3 to +56, then taper to day +180 
- Unrelated Donors: 5 mg/kg PO q12hrs days -3 to +100, then taper to day +180
MMF: - Related Donors: 15 mg/kg PO q12hrs days 0 to +28, then stop
- Unrelated Donors: 15 mg/kg PO q8hrs days 0 to +40, then taper to day +96


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initiating the nonmyeloablative transplant conditioning. The attending physician will 
determine the need for further cytoreductive therapy.   
 
Tyrosine Kinase Inhibitors must be discontinued on day -7 and not be resumed post 
HCT.     
 
D. CNS leukemia: Patients must be evaluated for CNS leukemia with lumbar puncture, 
cytospin and flow cytometry of the cerebrospinal fluid prior to enrollment. Patients with a 
history of treated CNS leukemia are eligible if there is no evidence CNS leukemia with 
lumbar puncture, cytospin and flow cytometry of the cerebrospinal fluid prior to 
enrollment. Patients with a history of treated CNS leukemia will receive two doses of 
prophylactic intrathecal (IT) chemotherapy (either methotrexate or ara-c) prior to 
conditioning and 6 doses of IT chemotherapy following transplant starting on day +32. 
 
E. Conditioning Regimen (refer to Figure 3):  
The conditioning regimen consists of clofarabine and TBI. 
 
 
Clofarabine will be administered as a 2 hour intravenous infusion once daily for 5 days, 
on days -6, -5, -4, -3 and -2.  
 
Part 1 
 
During Part 1, only patients with a relapse risk score > 0 (“high risk”, as described above, 
in Section 3. Background) will be enrolled.  The study will initially treat three patients 
with clofarabine at 30 mg/m2/day (based on actual bodyweight). If there is no evidence 
of DLT (see DLT below) when the 3rd patient has reached post HCT day 14, the next 
group of three patients will be treated with clofarabine at 40 mg/m2/day (based on actual 
bodyweight), with the goal to treat the final group of three patients at 50 
mg/m2/day(based on actual bodyweight).. 
 
If >1 patient experiences DLTs at a given clofarabine dosage, this will define excessive 
toxicity, and the next lower dose level will be used for Part 2. If only one patient 
experiences DLTs, then 3 additional patients will be treated at that clofarabine dosage. 
If there are no DLTs present in these additional three patients, dose escalation will 
continue. 
 
If excessive toxicity is seen at the starting dose level of 30 mg/m2/day, then de-
escalation to 20 mg/m2/day will occur.   
 
Clofarabine Related Dose-limiting toxicity (DLT) is defined as grade 4 toxicity of the 
a) lungs (not including previous infections),  
b) heart,  
c) liver, not resolving within 48 hours 
d) kidneys, not resolving within 48 hours 
e) gastrointestinal tract  
f) central nervous system  


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as defined by NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE), 
occurring within 21 days of initiation of clofarabine administration (post HCT day 14).  
 
Patients that experience DLTs will have further clofarabine doses held and proceed to 
TBI as previously scheduled.  
 
Part 2 
Once the optimal dose of clofarabine is determined in Part 1, accrual will be extended to 
patients with relapse risk score of < 0 (“low risk”) (low risk group terminated August 
2014 – see statistical section) and > 0 (“high risk”, see description of relapse risk score 
in Section 2. Background). All additional patients will receive the same treatment 
regimen using clofarabine at that dose, but patients at high- and low risk for relapse will 
be analyzed separately (low risk group terminated August 2014 – see statistical section).   
Patients enrolled from Part 1 at the same dose used in Part 2 will be included in this 
analysis. We plan to treat 36 patients in the high-risk group and 30 patients in the low-
risk group (low risk group terminated August 2014 – see statistical section) at this dose 
of clofarabine (see section 15. Statistical Considerations and Termination of Study for 
additional details). 
 
Clofarabine Pharmacokinetics (discontinued January 2017) 
Participation in clofarabine pharmacokinetics studies will be optional and will be offered 
to patients with actual body weight > 15 kg and treated at the FHCRC at the time of 
enrollment.  
 
Following the infusion of the first clofarabine dose, 2-3 ml of blood will be drawn from 
the Hickman venous access line at each of the following time points relative to the 
START of the 2-hour infusion: end of clofarabine infusion (2 hr), 3 hr, 4 hr, 5 hr and 6 hr. 
For the 2nd, 3rd, 4th and 5th doses of clofarabine, 2-3 ml of blood will be obtained 
before EACH dose.. This constitutes a total of 9 pharmacokinetic samples, which will be 
used to obtain data on the levels of clofarabine. 
 
TBI of 2 Gy at 6-15 cGy/min at the patient midplane from a linear accelerator will be 
administered on day 0, followed by PBSC infusion. Regardless of the actual time of TBI 
administration on Day 0, immunosuppression should be given per schedule and prior to 
the infusion of PBSC. 
 
The dose of TBI will be increased by 1 Gy ONLY if there is reasonable evidence that the 
rate of graft rejection exceeds the historical rate of 5% (see section on “Statistical 
Considerations and Termination of Study” for additional details).   
In this event, depending on the current toxicity experience, the dose of clofarabine will 
be left at the same level or reduced one dose level.  In either case, the next 6 patients 
will be monitored for DLT.  If the dose level of clofarabine is reduced, then it will be 
restored to the previous level if no more than one DLT is seen in the next 6 patients.   If 
the dose level is not reduced, and more than one DLT is seen in the next 6 patients, 
then the dose of clofarabine will be reduced one level.  After dose adjustment the next 6 
patients will be monitored for DLT in the same manner. 
 


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F. Immunosuppression (refer to Figure 3.): 
 
Day –3, patients with related donors: Commence CSP at 5.0mg/kg PO q12hrs, continue 
to day +56 and then taper to day +180. CSP should be routinely taken at 9:00 a.m. and 
9:00 p.m. 
 
Day –3, patients with unrelated donors: Commence CSP at 5.0mg/kg PO q12hrs, 
continue to day +100 and then taper to day +180. CSP should be routinely taken at 9:00 
a.m. and 9:00 p.m. 
 
Day 0, patients with related donors: After HCT on day 0, MMF will be given at 15mg/kg 
PO at 4-6 hours after G-PBMC infusion is complete, then to be given at 15mg/kg PO 
q12hrs until day +28 included, then, in the absence of GVHD, stopped without tapering.  
 
Day 0, patients with unrelated donors:  After HCT on day 0, MMF will be given at 
15mg/kg PO at 4-6 hours after G-PBMC infusion is complete, then to be given at 
15mg/kg PO q8hrs until day +40 included, and then taper to day +96.  
 
CSP 
1. 
Starting Dose in Adults:  CSP (Neoral is preferred) is given orally at 5.0 mg/kg 
q12hrs PO (based on adjusted body weight) from day –3 until day +56 to patients 
with related donors and to day +100 to patients with unrelated donors.  Dose 
should be adjusted to maintain a high therapeutic CSP level as discussed below.  
If there is nausea and vomiting at anytime during CSP treatment the drug should 
be given intravenously at the dose that was used to obtain a therapeutic level.  
The conversion from oral CSP (Neoral) to intravenous cyclosporine = oral 
cyclosporine dose divided by 2.5 equals IV dose.  Use CSP levels to further 
adjust the dose.  The formulation of CSP can be changed to Sandimmune if 
nausea and vomiting are persistent. 
 
2.  
Pediatric Dose: Due to the variable and increased metabolism in children, CSP 
will be started intravenously at the following doses at day –3 to be adjusted to 
maintain a therapeutic level as specified below. CSP trough level should be 
obtained on day 0 and CSP dose adjusted to ensure therapeutic levels. The 
patient may be changed to oral CSP after HCT when he or she is able to take 
oral medications. Dose should be adjusted to maintain high therapeutic levels as 
discussed below. If nausea or vomiting occurs at any time during CSP treatment, 
CSP should be administered intravenously at the dose that was used to obtain a 
therapeutic level. The conversion from oral CSP (Neoral) to intravenous 
cyclosporine = oral cyclosporine dose divided by 2.5 equals the IV dose. Use 
CSP levels to further adjust the dose. 
• Age ≤6 years old: 1.6mg/kg IV q8hrs 
• Age >6 years old: 2.0mg/kg po or IV q12hrs. Administration route (po or IV) will 
be left to the discretion of Pediatric Attending. 


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3.  
In the absence of GVHD, for related donor graft recipients: CSP is to be tapered 
from day +56 and discontinued on day + 180; for unrelated donor graft recipients: 
CSP is to be tapered from day +100 and discontinued on day +180. The referring 
physician, who will receive explicit instructions and guidelines for detecting and 
managing GVHD, will manage this. Modifications of the taper schedule may be 
indicated if significant disease progression occurs early post-transplant 
 
4. 
Blood pressure, renal function (serum creatinine, BUN), electrolytes and 
magnesium need to be followed at least three times per week during the first 
month, twice weekly until day +100, then once per week until CSP is stopped, 
unless clinical circumstances suggest the need for more frequent evaluations.   
 
5. 
Dose Adjustments: CSP, whole blood "trough" levels (i.e. 11-12 hours from the 
prior dose) will be evaluated on day “0” of transplant and adjusted if necessary to 
maintain blood levels of 400 ng/ml (upper end of the therapeutic range of the 
FHCRC CSP assay). After day + 28, typical serum CSP transplant levels 
between 120 and 360 will be targeted. The rational for requiring initial high CSP 
doses is extrapolated from the preclinical nonmyeloablative canine studies, which 
used an equivalent dose to establish an allograft. Dose reductions should only be 
made if CSP toxicity (such as renal insufficiency) is present, or levels exceed 
values provided in Table 3.  in the absence of toxicity. Dose reductions for high 
levels with or without toxicity should be conservative e.g. 25%, to avoid 
inadequate immune suppression. A decrease of the GFR by >50% or increase of 
creatinine of 2x baseline values attributable to CSP therapy will be justification for 
a 25% decrease in CSP dose.  However, therapeutic levels of CSP should be 
maintained. 
 
 


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Table 3:  CSP Dose Adjustment by Levels 
 
 
CSP Level to Target 
Using LC-MS/MS 
Method 
CSP Level to Target 
Using Immunoassay 
Method 
Day “0” – Day +28 
Whole blood “trough” (11-12 hrs 
from prior dose) 
 
400 ng/ml 
 
500 ng/ml 
(upper end therapeutic 
range for this method) 
 
 
 
After Day +28  
120-360 ng/ml 
 
150 - 450 ng/ml 
 
Levels >480 ng/ml by LC-MS/MS 
Method 
• with or without CSP toxicity 
• decrease GFR> 50% 
• increase creatinine 2x 
baseline due to CSP 
 
 
 
25% dose reduction 
 
 
 
N/A 
Levels >600 ng/ml by 
Immunoassay Method 
• with or without CSP toxicity 
• Decrease GFR >50% 
• increase creatinine 2x 
baseline due to CSP 
 
 
N/A 
 
 
25% dose reduction 
Patients on Hemodialysis 
320 ng/ml 
400 ng/ml 
 
6. 
CSP Monitoring:  Further CSP determinations should be performed on a twice 
weekly basis for the first month and then weekly until day +100 unless high levels 
are detected (see Table 3), or toxicity is suspected in which case more frequent 
monitoring will be performed as clinically indicated.  Routine monitoring of CSP 
may follow institutional guidelines beyond day +140. 
 
 


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7.  
Drugs Interactions: Drugs that may affect CSP levels are shown in Table 4. 
 
 
Table 4:  Drugs Affecting CSP Level 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
*Discontinuation of fluconazole, voriconazole or itraconazole may lower CSP levels, and if used as 
antifungal prophylaxis changes in these drugs should be avoided during the first month post-
transplant. 
MMF 
1. 
Initiating MMF Therapy:  Oral administration of MMF will be given based on 
adjusted body weight at 15 mg/kg (45 mg/kg/day) from the evening of day 0 (i.e. 
first dose to follow 4-6 hours after HCT).  Patients with related donors will receive 
subsequent doses q12hrs, patients with unrelated donors q8hrs. Doses will be 
rounded to the nearest 250mg (capsules are 250mg).  If there is nausea and 
vomiting at any time preventing the oral administration of MMF, MMF should be 
administered intravenously based on adjusted body weight at 15mg/kg every 12 
or 8 hrs, depending on donor type, as above. 
 
2. 
Tapering of MMF:  Patients with related donors will receive MMF 15mg/kg q12hrs 
through day +28; then, in the absence of GVHD, MMF will be stopped without 
tapering.  
 
Patients with unrelated donors will be given MMF daily at 15mg/kg q8hrs through 
day +40 post transplant, and then in the absence of GVHD, MMF should be 
tapered on day +41 by 11%/week x 8 weeks and discontinued on day +96. 
 
3. 
Maintaining MMF:  Markedly low (<40%) donor T-cell chimerism after HCT may 
indicate impending graft rejection. MMF should be continued at full dose or, if 
MMF taper has been initiated, reinstitution of full dose MMF should occur.  
Consideration of graft salvage with use of pentostatin + DLI (as per protocol 1825) 
should be considered.  
Decrease CSP Levels 
Increase CSP Levels 
Enhance Potential for 
Nephrotoxicity 
Carbamazepine 
metoclopramide 
nafcillin 
octreotide 
phenobarbital 
phenytoin 
primidone 
rifampicin 
sulfonamides 
trimethoprim 
azithromycin 
alcohol 
acetazolamide 
caspofungin 
clarithromycin 
colchicine 
diltiazem 
doxycycline 
erythromycin 
fluconazole*                       
fluoroquinolones 
imipenem 
itraconazole* 
ketoconazole 
nicardipine 
nifedipine 
verapamil 
voriconazole* 
Aminoglycosides 
Loop diuretics (furosemide) 
Amphotericin formulations 


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4. 
Guidelines for MMF dose adjustment due to drug toxicity:  
If in the clinical judgment of the attending physician the observed toxicity is 
related to MMF administration, a dose adjustment may occur.  The 
discontinuation of MMF at any point should be discussed with the Study PI and 
should be documented in the permanent medical record and all Case Report 
Forms (CRF). 
 
Gastrointestinal Toxicity.  Severe gastrointestinal toxicities such as 
gastrointestinal hemorrhage have been very rare after nonmyeloablative HCT. In 
the event of gastrointestinal toxicity that requires medical intervention including 
medication for control of persistent vomiting or diarrhea that is considered to be 
due to MMF after day +28, a 20% dose reduction will be made or the drug may 
be given IV. If severe refractory diarrhea or overt gastrointestinal bleeding occurs, 
MMF may be temporarily stopped. Then MMF should be restarted at 20% 
reduced dose when the underlying toxicity subsides. 
 
Neutropenia.  Based on previous experience in patients after nonmyeloablative 
HCT, dose adjustments are likely to occur because of hematopoietic adverse 
effects, in particular neutropenia.  A thorough evaluation of neutropenia should 
occur including peripheral blood chimerism studies, marrow aspiration and 
review of marrow suppressive medications (e.g. bactrim, ganciclovir).  If all other 
potential causes of marrow toxicity are ruled out, dose adjustments will only be 
made for grade IV neutropenia that persists after day +28 post-transplant. Dose 
reductions should be conservative (20%).  After day +21, the use of G-CSF will 
be permitted for neutropenia. For severe toxicity related to MMF (grade IV 
neutropenia > 5 days refractory to G-CSF), MMF may be decreased and if 
neutropenia persists, MMF can be stopped.  The MMF should be restarted at 20% 
reduced dose when the underlying toxicity subsides.  
 
 
G. Collection and Infusions of Donor PBSC: 
1. G-CSF Administration to Donors: All related donors will receive G-CSF 16 ug/kg/day 
for 5 consecutive days from day -4 to day –0 (Table 5). G-CSF will be administered by a 
subcutaneous daily injection. These doses will be administered before 10:00 a.m. each 
day in the Outpatient Department (OPD). The schedule of G-CSF administration and 
PBSC collections can only be ascertained once day 0 is identified. Once a treatment 
regimen schedule has been fixed and the schedule of G-CSF administration and PBSC 
collections made, the plan has to be confirmed with the personnel in the apheresis room. 
 
Timing of PBSC collection from unrelated donors is prearranged through the NMDP. 
Day 0 should be fixed on a Monday-Thursday when possible. G-CSF will be 
administered by subcutaneous injection to the unrelated donor starting 5 days prior to 
the day of HCT (see Table 3) as per NMDP protocol. Donors will receive approximately 
16 μg/kg of GCSF each day of mobilization. A 12 liter apheresis will be obtained on day 


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–1 and on day 0 for a total of 12 to 24 liters of apheresis collection that will be infused 
on day 0. 
 
a. Immunophenotyping of the PBSC product will be performed by the cellular therapy 
laboratory and will include T-cells and their subsets, monocytes, and NK cells. 
 
b. Collection of DLI. Donor lymphocytes will be collected from unrelated donor PBSC 
products prior to transplant for potential future use of DLI on other protocol or treatment 
plans. A portion of the PBSC product from unrelated donors will be frozen according to 
standard cryopreservation for DLI.  
 
Table 5.  Treatment Schema for Donor 
Day 
-5 
-4 
-3 
-2 
-1 
0 
G-CSF (~16 g/kg) 
X 
X 
X 
X 
X 
X 
PBSC collection 
 
 
 
 
X 
X 
 
 
2. PBSC Collection: related donors will preferably undergo vein-to-vein collections or 
may receive an appropriate catheter inserted on or before day of apheresis. PBSC will 
be collected in the afternoon of day -1, stored in the refrigerator at 4ºC overnight. A 
second collection will be performed the following afternoon and both collections will be 
transfused on day 0. If < 5 x 106 CD34+ cells/kg are collected an additional day of 
collection will be performed. If PBSCs cannot be collected by a vein-to-vein technique, a 
percutaneous Mahurkar catheter will be inserted. General procedures will include the 
use of a standard apheresis machine (COBE Spectra, Lakewood Colo.), and processing 
up to 24 liters of whole blood during the collection. The plan for PBSC collection is 
shown in Table 5. 
 
PBSC Collection: for unrelated donors scheduling and collection is arranged through 
unrelated donor registries. The schedule of G-CSF administration and collection of 
PBSC is determined as per NMDP protocol. The physician responsible for PBSC 
collection will obtain informed consent from the donor. 
 
3. PBSC infusion: All patients will receive unmodified PBSC infusion on day 0 of the 
treatment regimen (Refer to institutional practice guidelines for methods of infusion). 
 
H. ABO Incompatibility 
All patients with ABO incompatibility should be evaluated and treated according to the 
standard practice of the individual institution. Recommendations are provided in 
Appendix D. It should be noted that two cases of recipient hemolysis have been 
documented in patients with minor ABO mismatch with their donor47. The suspected 
cause is donor anti-host hemagglutinin production from “passenger lymphocytes” in the 
donor PBSC that may expand post transplant. Therefore, patients should be monitored 
and treated aggressively when there is any evidence of hemolysis. 
 


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I. Post-HCT Growth Factors 
Patients should in general not receive post-transplant growth factors during the first 3 
weeks after HCT. Growth factors should not be given unless neutropenia develops or 
persists past day 21 post transplants (ANC < 500/μL). 
J. Infection Prophylaxis 
Recommended prophylaxis for PCP, VZV, and HSV are listed in Appendix E with the 
modification that PCP, VZV, and antifungal prophylaxis should be continued if the 
patient is receiving treatment for chronic GVHD. To the extent possible, use of 
nephrotoxic (eg, vancomycin, amphotericin B, etc) and hepatotoxic (eg, voriconazole, 
etc) agents is to be avoided during clofarabine administration.  
 
During clofarabine administration and for the following 3 days (until day +1) Micafungin 
will be used as antifungal prophylaxis due to possible liver toxicity. Prophylactic adult 
dosing is 50 mg IV daily. Prophylactic pediatric dosing is: Age 2-8 years old: 
2mg/kg/dose per day max of 50mg daily.  Age >8-28 years old: 1mg/kg/dose per day 
max 50mg daily. Following that, since antifungal prophylaxis strategies are evolving, 
patients may receive antifungal prophylaxis as per the standard practice of the 
treatment institution.  Standard CMV monitoring and prophylaxis should commence at 
the time of transplant and should continue as per standard practice.  Patients who reject 
their graft can discontinue this infection prophylaxis. 
 
IgG levels and IVIG Supplemental replacement will be monitored per Institutional 
Practice.   
 
K. Endpoint/Treatment Failure 
 
Disease progression will be defined as  
a. Persistence or appearance of aberrant blasts on a bone marrow aspirate by flow 
cytometry  
b. Persistence or reappearance of a previously described cytogenetic or molecular 
abnormality. 
 
Relapse will be defined as the presence of >5% blasts by morphology on a marrow 
aspirate or the presence of circulating blasts in the peripheral blood.  
 
Evidence of disease progression or relapse at any time point following HCT will be 
considered a treatment failure, and consideration will be given to withdrawal of 
immunosuppression, chemotherapy and/or DLI on another protocol. Such treatment will 
be at the discretion of the attending physician. Patients who are considered treatment 
failures will still be followed for outcomes. 
 
L. Modifications of Immunosuppression for Disease Progression/Relapse and Low 
Donor T-cell Chimerism: This section provides guidelines for management of patients 
with AML progression/relapse and low donor chimerism.   
 
 


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1. Progression/Relapse 
Evidence of AML progression/relapse will be an indication for therapeutic intervention.  
In part, this will be dependent on where a patient is relative to the standard tapering 
schedule.  If the attending physician believes that the patient requires very aggressive 
therapy, the case will be presented to the institutions’ patient review committee.  
 
In the absence of GVHD priority should be given to rapid reduction of 
immunosuppression, the details of which will be left to the discretion of the attending 
physician. One possible approach is to discontinue MMF if it’s still being taken, and 
taper CSP over 2 weeks. Bone marrow aspirate and blood chimerism studies should be 
repeated when off immunosuppression after 2 weeks. An alternative approach that can 
be considered, especially, when there is a concern of an acute GVHD flare is the abrupt 
discontinuation of both CSP and MMF followed by administration of weekly low dose 
(10 mg/m2) methotrexate. 
 
DLI will not be given for progressive or relapsed disease on this protocol, and patients 
with relapse or progression would be eligible for other ongoing intervention protocols or 
treatment plans (i.e. re-induction, DLI, hypomethylating agents, TK inhibitors, etc), 
according to the attending physician’s preference.  
 
2. Low Donor T-Cell chimerism 
Definition of mixed donor/host chimerism, engraftment, graft failure and rejection. For 
the purposes of this protocol, mixed chimerism will be defined as the detection of donor 
T-cells (CD3+) and granulocytes (CD 33+), as a proportion of the total T-cell and 
granulocyte population, respectively, of greater than 5% and less than 95% in the 
peripheral blood.  Full donor chimerism is defined as > 95% donor CD3+ T-cells. Mixed 
or full donor chimerism will be evidence of donor engraftment.  Increasing donor 
chimerism is defined as an absolute increase of 20% of CD3+ donor T-cells over the 
previous chimerism evaluation. Decreasing donor chimerism is defined as an absolute 
decrease of 20% of CD3+ T-cell chimerism over the previous evaluation.  Low donor 
chimerism is defined as < 40% CD3+ donor T-cells after HCT.  Low donor chimerism 
should always be confirmed with repeat peripheral blood T-cell and granulocyte 
chimerism analysis.  A DNA-based assay that compares the profile of amplified 
fragment length polymorphisms (ampFLP) (or FISH studies or VNTR) of the patient and 
donor will be used to quantitate chimerism of sorted peripheral blood T-cells (CD3+) and 
granulocytes (CD 33+). The same assay should be used in a given patient for repeated 
studies of chimerism.  This DNA-based analysis will also be performed on the whole 
nucleated cell fraction from marrow aspirates. Therapeutic decisions (e.g. pentostatin + 
DLI as per protocol 1825) will be made based on the results of sorted T-cell studies of 
peripheral blood. For the purposes of this protocol, graft rejection is defined as the 
inability to detect or loss of detection of greater than 5% donor T-cells (CD3+) as a 
proportion of the total T-cell population, respectively, after nonmyeloablative HCT.  Also 
for the purposes of this protocol, graft failure is defined as grade IV thrombocytopenia 
and neutropenia after day +28 that lasts > 2 weeks and is refractory to growth factor 
support. TBI dose escalation in this protocol will be based on graft rejection.  
 


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Evaluation of chimerism.  Patients will have peripheral blood and whole bone marrow 
evaluations for chimerism at various time points through one year post transplant. If the 
patient has not obtained > 95% donor chimerism in CD+3 by one year continue to 
evaluate through 5 years post transplant as clinically indicated.  Peripheral blood will be 
sorted to evaluate T-cell (CD+3), granulocyte (CD+33), and/or NK cell (CD56) 
compartments. (See Patient Post Transplant Evaluation section for instructions and 
exceptions). 
 
Decreasing Donor Chimerism and Graft Rejection. Decreasing donor chimerism after 
day +28 may indicate that graft rejection is occurring. DLI alone does not appear to 
reverse this process. The patient’s case should be discussed with the 
FHCRC principal investigator of the study. Patients who reject their grafts will not be 
offered DLI on this protocol and may be eligible for a second allograft on another 
protocol. 
 
11. PATIENT EVALUATIONS 
 
A. Patient Pretransplant/Baseline Evaluation.  
 
Work-up should include the following: 
 
1. History: A complete history with full details of the patient’s prior treatment and 
response. 
 
2. Careful physical exam with determination of Karnofsky score (Appendix B) or 
Lansky Play-Performance Score (Appendix C), and scoring according to the HSCT-CI 
Score (Appendix Q). 
 
3. CBC/differential, creatinine, BUN, uric acid, Na+, K+, Cl_, Bun, creatinine, glucose, 
liver function tests, ABO/Rh typing, hepatitis screen, CMV, and toxoplasmosis serology, 
anti-HIV serology, and serum LDH 
 
4. Obtain serum creatinine approximately 72 hours before clofarabine administration.  If 
serum creatinine > upper limit of normal, obtain 24-hour urine collection to measure 
creatinine clearance. 
 
5. Pulmonary function tests with corrected DLCO. 
 
6. Chest x-ray (CXR), PA and lateral views. 
 
7. MUGA scan or echocardiogram for patients > 50 years of age, or history of cardiac 
disease or anthracycline exposure. 
 
 
 
 
 


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8. Evaluation and prophylaxis of CNS disease.  
Please refer to Appendix N for recommendations for intrathecal diagnostic 
evaluation and prophylaxis for specific malignant diseases. If patients undergo 
intrathecal diagnostic evaluation, cerebral fluid should be sent for cell count and 
differential, cytospin, cytology, total protein, and glucose. 
 
9. Immunophenotyping of the PBSC graft.  
Immunophenotyping of the PBSC product will be performed by the Cellular Therapy 
Laboratory and will include CD34, CD3/4 and CD3/8 cells.  The residual specimen will 
be sent to the Heimfeld lab to do phenotypic characterization of cellular subsets  
 
 
Additionally, see the following table (Table 6) for AML pre-transplant evaluations. 
 
Table 6: Pre-Transplant Evaluation 
 
Note: All bone marrow aspirates and biopsies are unilateral and must be collected 
within 21 days of treatment. See Tables 7-8 for post-transplant evaluations and 
additional lab instructions. 
Specimen / Test / Imaging 
Clinical / Research 
Comment 
Bone marrow aspirate 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics- *see comment 
Clinical 
*If abnormal pre-
transplant 
FISH for clonal abnormalities - 
*see comment 
Clinical 
*If abnormal pre-
transplant 
PCR  
Research – Specimen 
Processing  
 
Peripheral Blood 
Storage for chimerism analysis 
Clinical 
 
PCR - *see comment 
Research – Specimen 
Processing  
*Only if marrow sample 
is not available 
 
 
10. Retrospective Specimens: unstained bone marrow aspirate slides, core biopsy 
specimens (fixed in formalin) and/or peripheral blood samples and/or slides obtained at 
diagnosis or confirmed relapse of AML will be requested from outside institutions and 
will be used for cytogenetic and molecular studies (with special respect to tyrosine 
kinase receptor mutations, such as FLT3, RAS- and nucleophosmin gene mutations 
along with C/EBP mutations). Send specimens to Specimen Processing (FHCRC E1-
305), label samples “Protocol #2430”. 
 
 
 


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B. Patient Post-transplant Evaluation 
See Table 7 for AML post-transplant evaluation on day +28, +56, +84, etc. This is a 
recommended evaluation schedule.   
 
Additionally, include the following: 
1. CBC three times a week, or more often if clinically indicated, from day 0 until day +28, 
and twice weekly until 2 months post-transplant or later if clinically indicated. 
 
2. Electrolyte panel (sodium, potassium, chloride, CO2, glucose, BUN, creatinine, 
calcium, magnesium, phosphorus and albumin) 3 times per week and liver function 
tests (ALT, AST, ALK Phos, total bilirubin, direct bilirubin, total protein, albumin and 
LDH) 2 times per week until day +28 and then weekly. 
 
3. Patients should be assessed for the need of IVIG monitoring and replacement 
therapy per Institutional Guidelines 
 
4. GVHD Evaluation at Departure from Transplant Center 
This evaluation should occur on the week of day + 84. 
 
GVHD evaluation guidelines: 
a. History and physical exam, attention to evaluation of chronic GVHD (Appendix G) 
b. Complete blood count, serum IgG, and serum total bilirubin, alkaline phosphatase, 
ALT, and AST 
c. Skin biopsy 
d. Schirmer's tear test 
e. Pulmonary function test 
f. Oral exam 
g. Dietician assessment 
h. Gynecological assessment (adult female) 
 
See Section 13.F for diagnosis and treatment guidelines for acute and chronic GVHD. 
 
 
 


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Table 7: Post-Transplant Evaluation (See text for pre-transplant evaluations) 
This is a recommended evaluation schedule.  See Table 8 for  
additional lab instructions. 
Specimen/ Test/ 
Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual 
x 5 
years 
28 
56 
84 
120 
180 
1 
1.5 
 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained 
based on clinical judgment 
 Chimerism 
Clinical 
 
 
 
x 
 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal 
pre-
transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal 
pre-
transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
PCR for FLT3-
ITD, RAS, NPM1 
and C/EBP 
mutations and 
t( 8;21), 
inversion 16; 
t(15;17) 
Research - 
Specimen 
Processing, 
E1-305 
*If 
molecular 
marker 
present pre-
transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
Peripheral blood 
 Chimerism 
(CD3+) 
Clinical 
*Days 56 
and 180 
only if <50% 
on day 28 
x 
*See 
comment 
x 
 
*See 
comment 
x 
 
 
Chimerism 
(CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
 
Chimerism  (NK 
CD56+) 
Clinical 
Optional for 
outside 
institutions 
x 
 
 
 
 
 
 
 
PCR for FLT3-
ITD, RAS, NPM1 
and C/EBP 
mutations and 
t( 8;21), 
inversion 16; 
t(15;17) 
Research - 
Specimen 
Processing, 
E1-305 
*If 
molecular 
marker 
present pre-
transplant 
AND 
marrow 
sample is 
not 
available 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
GVHD evaluation 
Clinical 
See text for 
details 
 
 
x 
 
 
 
 
 
 
 
 


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Table 8: Additional Lab Instructions 
Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. All 
instructions apply to both pre- and post-transplant evaluations unless identified otherwise. 
 
Off-site providers may use local facilities for the tests. 
 
Volumes represent desired amounts. 
 
Specimen / 
Test 
Type 
Instructions 
 
Lab Name 
Contact Information 
Bone marrow 
 
Chimerism  
Clinical 
1-3mL bone 
marrow in green-
top tube 
Clinical 
Immunogenetics 
Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-7700 
Pathology 
(aspirate) 
Clinical 
2mL bone marrow 
in EDTA/ formalin 
SCCA Pathology 
Lab 
Seattle Cancer Care 
Alliance 
(206) 288-1355 
Pathology 
(biopsy) 
Clinical 
1cm bone marrow 
in formalin OR 
mounted in paraffin 
SCCA Pathology 
Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-1355 
Flow Cytometry 
Clinical 
2mL bone marrow 
in green-top tube 
UW 
Hematopathology 
Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-7060 
Cytogenetics 
Clinical 
3mL bone marrow 
in green-top tube 
SCCA 
Cytogenetics Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-1390 
FISH 
Clinical 
2mL bone marrow 
in green-top tube 
SCCA 
Cytogenetics Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-1390 
PCR 
Research 
3mL bone marrow 
in lavender-top 
tube 
Label “protocol 
2430” 
Specimen 
Processing 
FHCRC E1-305 
(206) 667-4645 
Peripheral blood 
 
Chimerism  
(CD3+), (CD33+) 
NK(CD56+) 
Clinical 
10mL blood in 
green-top tube for 
Flow sorting, then 
to CIL 
UW 
Hematopathology 
Lab, routed to 
Clinical 
Immunogenetics 
Lab 
Mailstop G7-800 825 
Eastlake Ave, East 
Seattle, WA 98109 
(206) 288-7060 
Flow Cytometry 
Clinical 
10mL blood in 
green-top tube 
UW 
Hematopathology 
Lab 
Seattle Cancer Care 
Alliance 
 (206) 288-7060 
PCR  
Research 
7mL blood in 
lavender-top tube 
Label “Protocol 
2430” 
Specimen 
Processing 
FHCRC E1-305 
(206) 667-4645 
Outside institutions may use VNTR analysis (sex- matched transplants) or sex 
chromosome FISH-analysis (sex-mismatched transplants) for chimerism analysis. 


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Table 9:  Retrospective Specimens 
Note:  Samples obtained at diagnosis of AML or first indication of relapse from outside 
centers 
Specimen / 
Test 
Type 
Instructions 
Lab Name 
Contact Information 
Bone marrow 
 
PCR 
Research 
3mL bone marrow in 
lavender-top tube 
AND/OR unstained 
slides 
Label “protocol 2430” 
Radich Lab 
FHCRC D4-385 
(206) 667-2592 
Peripheral blood 
 
PCR 
Research 
7mL blood in lavender-
top tube AND/OR 
unstained slides, 
ONLY if marrow is not 
available 
Label “protocol 2430” 
Radich Lab 
FHCRC D4-385 
(206) 667-2592 
 
 
12. DONOR EVALUATIONS 
 
1. Complete history and physical examination. 
 
2. Lab tests: CBC with reticulocytes and platelet counts, serum sodium, potassium, 
chloride, CO2, BUN, creatinine, uric acid, LDH, calcium, magnesium, phosphate, 
alkaline phosphatase, AST, ALT, hepatitis screen, CMV, syphilis, HIV and HTLV I 
serologies and ABO Rh blood typing.  If the donor has antibodies against red cell 
antigens of the recipient, the titers will be determined. Cytotoxic crossmatch between 
patient and donor will be performed (HLA Laboratory). 
 
3. No placement of a central line is necessary for PBSC collection unless it is 
determined that the donor has poor venous access. If necessary, a temporary apheresis 
(e.g. Mahurkar) catheter will be placed at the time of leukapheresis. 
 
4. A CBC will be checked prior to and after leukapheresis collection, and daily while on 
G-CSF. CBCs will be checked thereafter if clinically indicated. 
 
5. The donor will be reevaluated with a directed history and physical examination the 
day after the apheresis is completed. 
 
6. To subsequently determine the origin of relapse, heparinized blood will be sent from 
the donor to CIL (FHCRC: 206-288-7700) for a DNA-based assay that compares the 
profile of amplified fragment length polymorphisms (ampFLP) of the patient and donor. 
 
7. For females of child bearing age, serum pregnancy qualitative [PGSTAT] within 72 
hours prior to initial dose of filgrastim (G-CSF). Results must be available prior to 
filgrastim (GCSF) dose. 
 


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13. DRUGS AND TOXICITIES 
 
Cyclosporine, MMF and clofarabine are all commercially available. They should be 
stored and mixed according to manufacturer's recommendations. 
 
A. For the purposes of this protocol, toxicity will be graded using the modified NCI 
common toxicity scale (Appendix P). 
 
B. Clofarabine See section 10.E Conditioning Regimen for information about 
administration and dosage adjustments. 
Chemical Name:  
2-chloro-9-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-9H-purine-6-amine 
Other names:  
CLOLAR, clofarabine; CAFdA; Cl-F-ara-A; 
2-chloro-2′-fluoro-deoxy-9-β arabinofuranosyladenine 
2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine (Cl-F-ara-A) 
2-chloro-2′-arabino-fluoro-2′-deoxyadenosine 
2-chloro-2′-ara-fluorodeoxyadenosine (CAFdA) 
2-chloro-2′-fluorodeoxyadenosine (CAFdA) 
 
Physical and Chemical Characteristics: 
Clofarabine is a white to off-white solid with a melting point of 228°C to 230°C and a 
molecular weight of 303.5. The drug substance is very stable in the dry state, and 
aqueous solutions are stable to heat treatment. Clofarabine is freely soluble in water 
(1.5 mg/mL) or buffered solutions at room temperature. Clofarabine is not less than 97% 
pure on a dried basis by high performance liquid chromatography (HPLC) analysis. 
Clofarabine is formulated at a concentration of 1 mg/mL. Clofarabine is supplied in 1 vial 
size: a 20-mL clear, glass vial with gray stopper and blue flip off seal. The 20-mL vials 
contain 20 mL (20 mg) of sterile solution. The pH range of the solution is 4.5 to 7.5. The 
solution is clear and practically colorless, preservative free, and free from foreign matter. 
 
Toxicity (IV Studies): 
1. Adult Patients 
Drug-related adverse events (AE) observed in at least 10% of adult patients treated with 
clofarabine in previous clinical trials include myelosuppression, nausea, vomiting, 
infections, fatigue, headache, diarrhea, rigors, dermatitis, anorexia, febrile neutropenia, 
myalgia, asthenia, petechiae, transient elevated liver enzymes, stomatitis, mucositis, 
pyrexia, flushing, constipation, edema, dehydration, nervousness, stomach pain, 
insomnia, depression, dry skin, back pain, and decreased weight. 
 
Adverse events reported in <10% of adult patients include tumor lysis syndrome, 
capillary leak syndrome/SIRS, palmar plantar erythrodysesthesia, pancreatitis, seizures, 
irregular heartbeat, edema, pericardial effusion, multi-organ failure, and death. 
 
 
 


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2. Pediatric Patients 
The most common side effects observed in previous clinical studies of pediatric patients 
treated with clofarabine 52 mg/m2 include vomiting NOS, nausea, febrile neutropenia, 
diarrhea, headache, pruritus, pyrexia, dermatitis, fatigue, rigors, abdominal pain, 
tachycardia, anorexia, petechiae, epistaxis, pain in limb, hypotension, anxiety, cough, 
constipation, erythema, mucosal inflammation, NOS, pain, flushing, edema, and 
hematuria. 
 
Pediatric patients have also experienced increased liver enzymes and increased 
creatinine. Moderate neurological changes have been reported in some patients. 
Infections were reported in almost half of the patients treated with clofarabine. 
Other potential severe AEs include pericardial effusion, LVSD, tumor lysis syndrome, 
SIRS, and capillary leak syndrome. 
 
3. Management of Capillary Leak Syndrome 
In pediatric studies, during or shortly after IV clofarabine administration a few patients 
developed signs and symptoms consistent with capillary leak syndrome. In these 
heavily pretreated patients, it has been difficult to separate potential drug-related cases 
of capillary leak syndrome from concurrent medical conditions such as infection/sepsis, 
progressive disease, or other underlying problems resulting from prior antileukemic 
therapies. 
 
For these reasons, during and after each dose of clofarabine investigators are to assess 
patients for the onset of the following signs or symptoms ≥ grade 2: 
− Tachypnea or other evidence of respiratory distress; 
− Unexplained hypotension; and/or 
− Unexplained tachycardia. 
If one or more of these signs or symptoms occurs during clofarabine infusion, 
clofarabine administration is to be interrupted or held as clinically indicated. It is 
recognized that the total infusion time for this clofarabine dose in this circumstance may 
exceed 2 hours. Thus, if the patient’s condition stabilizes or improves, clofarabine 
administration may resume. 
Pretreatment with steroids (e.g. hydrocortisone 100 mg/day or its equivalent or 
dexamethasone 20 mg/day as part of an anti-emetic regimen) is recommended for all 
subsequent doses during the remainder of clofarabine treatment. 
 
4. Management of liver toxicity  
Severe and fatal hepatotoxicity has occurred with the use of clofarabine. In clinical 
studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during 
treatment with clofarabine at the following rates: elevated aspartate aminotransferase 
(AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 
44% of patients. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 
events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment 
discontinuation and one patient had multi-organ failure and died. Monitor hepatic 
function and discontinue clofarabine for Grade 3 or greater liver enzyme elevations and 
contact PI to discuss modification of conditioning. 
 


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C. TBI: TBI will be given in one 200, 300, or 400 cGy fraction from linear accelerator at 
a rate of 6 - 7 cGy/min. Dosimetry calculations are performed by the radiation therapist. 
At the dosage used, side effects are not expected. Nevertheless, there may be fever, 
alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects 
including cataract formation, growth retardation, pulmonary damage, carcinogenesis, 
and sterilization. 
 
D. CSP: See section 10.F. Immunosuppression for information about administration 
and dosage adjustments. Side effects are generally reversible and may include renal 
insufficiency and failure, hypomagnesemia, paresthesias, tremor, seizures, visual 
disturbances, paresis, disorientation, depression, confusion, somnolence, coma, 
nausea, hypertension, hemolytic-uremic syndrome, hyperglycemia, gynecomastia, and 
hypertrichosis. See standard practice manual for additional information about 
administration, toxicity and complications. 
 
E. MMF: See section 10.F. Immunosuppression for information about administration 
and dosage adjustments. Mycophenolate mofetil (MMF): is supplied in 250mg hard 
gelatin capsules. Capsules may be stored at room temperature. 
 
1. Precautions: previous clinical studies suggested that the principal adverse reactions 
associated with the administration of MMF include leukopenia, sepsis, vomiting and 
diarrhea. Patients will be monitored for the development of these complications. 
 
2. Adverse Events: administration of MMF may be associated with vomiting, diarrhea, 
anemia, leukocytopenia and infection. In the setting of marrow transplantation, however, 
several etiologic factors may contribute to these symptoms. MMF has an increased 
incidence of digestive system adverse events, including GI tract ulceration, and 
hemorrhage (3% of patients receiving MMF). GI tract perforations have rarely been 
observed. Up to 2% of patients receiving MMF for prevention of rejection developed 
severe neutropenia (ANC <500). The development of neutropenia may be related to 
MMF itself, concomitant medications, viral infections or some combination of these 
causes. MMF dose adjustments will be made if clinically indicated if, in the opinion of 
the attending physician, no other cause is thought to be causative for the abnormality. 
These adjustments should be discussed with the principal investigator. 
 
F. GVHD: 
1. Diagnosis: Skin involvement will be assessed by biopsy with percentage of body 
surface area involved recorded. GI symptoms suspicious for GVHD will be evaluated by 
biopsy as indicated. Acute GVHD and chronic GVHD will be graded according to 
established criteria (Appendix F and G). 
2. Treatment: 
Details of GVHD treatment will be left to the discretion of the attending physician. 
Patients may also be eligible for institutional trials of GVHD therapy. 
 
G. Myelosuppression 
Grade IV myelosuppression will be defined as a decrease in ANC to <500/uL and/or 
platelet count to ≤ 20,000/uL. If myelosuppression occurs beyond day +28, a bone 


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marrow aspirate and biopsy should be considered to exclude disease progression. 
Samples should be sent for chimerism analysis by a DNA-based assay that compares 
the profile of amplified fragment length polymorphisms (ampFLP) (or FISH studies or 
VNTR) of the patient and donor. Myelosuppression may occur in this patient population 
for a number of reasons such as direct toxic effect of drugs (clofarabine, MMF, 
ganciclovir etc.), rejection, relapse or after DLI.  Patients who are > 21 days after HCT 
with an ANC of <500/uL may receive G-CSF 5μg/kg/day S.C. Thrombocytopenic 
patients will receive platelet transfusion as per standard care. 
 
 
 


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14. RECORDS 
 
Clinical records will be maintained as confidentially as possible by all collaborating 
institutions. Collection of Case Report Forms (CRF) at standard intervals is the primary 
method of collecting data from collaborating centers. Clinical Statistics at FHCRC 
maintains a patient database to allow storage and retrieval of patient data collected from 
a wide variety of sources. The principal investigator will ensure that data collected 
conform to all established guidelines for coding collection, key entry and verification. 
These data are then entered into a secure dedicated database operated by a data 
manager. Any publication or presentation will refer to patients by a unique patient 
number and not by name to assure patient confidentiality. The licensed medical records 
department, affiliated with the institution where the patient receives medical care, 
maintains all original inpatient and outpatient chart documents. At the FHCRC, patient 
research files are kept in a locked room. They are maintained by the FHCRC data 
collection staff that is supervised by an A.R.T. Access is restricted to personnel 
authorized by the Division of Clinical Research. 
 
 
15. STATISTICAL CONSIDERATIONS AND TERMINATION OF STUDY 
 
Part 1: dose escalation 
The primary objective of Part 1 is to determine the highest dose of clofarabine that can 
be tolerated safely in conjunction with nonmyeloablative HCT. During Part 1, only 
patients with a risk score > 0 (“high risk” as described above, in Section 2. Background) 
will be enrolled.  A standard 3+3 dose escalation scheme will be employed starting at a 
dose of 30 mg/m2/day x 5 days (total dose 150 mg/m2), as described above.  If 3 
patients are successfully transplanted without DLT, then escalation to the next dose 
level will occur.  If 1 of 3 patients experiences DLT, then an additional 3 patients will be 
treated at the same dose, and dose escalation will only occur if no additional patient 
experiences DLT.  A second DLT in either 3 or 6 patients will define excessive toxicity, 
and the next lower dose level will be used for Part 2.  If the highest dose level, 50 
mg/m2/day (total dose of 250 mg/m2) has acceptable toxicity, then that dose level will be 
used for Part 2. The operating characteristics of this dose escalation rule are defined in 
this table. If excessive toxicity is seen at the starting dose level of 30 mg/m2/day, then 
de-escalation to 20 mg/m2/day will occur.   
 
True rate of DLT 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
Probability of escalation 
91% 71% 49% 31% 17% 
8% 
3% 
1% 
<1% 
 
During Part 1, a second occurrence of graft rejection in up to 6 patients at a given 
clofarabine dose level will lead us to be at least 90% confident that the true rate of graft 
rejection exceeds the historical rate of 5%.  If a single engraftment failure is observed in 
the first 3 patients at a given dose level, then an additional 3 patients must be enrolled 
at the same level without an additional engraftment failure before dose escalation can 
continue.  If a second engraftment failure occurs, then the dose of TBI will be increased 
by 1 Gy.  Dose escalation will restart at the current clofarabine dose, provided that 


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clofarabine dose escalation would have been permitted according to the criteria above; 
otherwise, the clofarabine dose will be decreased one level. 
 
Part 2: efficacy analysis 
The primary objective of Part 2 is to evaluate whether the substitution of clofarabine for 
fludarabine can improve the 6 month rate of disease relapse/progression, as defined in 
Section 9.K, compared to our historical experience with a Flu/TBI non-myeloablative 
conditioning regimen followed by HCT.  The historical rates are approximately 35% at 6 
months after HCT in a high risk group (risk score > 0), and approximately 15% at 6 
months after HCT in a low risk group (risk score ≤ 0 (low risk group terminated August 
2014)).  The risk score for a patient is determined by the following scoring system, as 
described Section 2. Background: 2nd CR, +1; 3rd or later CR, +2; unfavorable 
cytogenetics, +1; lack of peripheral blood cell count recovery (platelet count > 
100,000/l; neutrophils > 1,000/l), +0.5; greater than 18 months from diagnosis to 
transplant, -2. 
 
All patients will receive the same treatment regimen, but the two risk groups will be 
analyzed separately.   Patients enrolled from Part 1 at the same dose used in Part 2 will 
be included in this analysis. 
 
In the high risk group, 36 patients will provide 83% power to detect a 15 percentage 
point improvement in the relapse/progression rate, to 20%, with a 1-sided alpha level of 
0.13.  A successful outcome will be defined by relapse within 6 months of HCT in 9 or 
fewer patients. 
 
In the low risk group, 30 patients will provide 81% power to detect a 10 percentage point 
improvement in the relapse/progression rate, to 5%, with a 1-sided alpha level of 0.15.  
A successful outcome will be defined by relapse within 6 months of HCT in 2 or fewer 
patients. (low risk group terminated August 2014) 
 
With the termination of the low risk group as of August 2014, total enrollment will be 44 
patients.  We expect to enter approximately 10 patients per year, so the study will take 7 
years to complete enrollment. 
 
Low risk group terminated. As of August, 2014, accrual of low risk patients in Part 2 
was halted with only 2 patients accrued.  All statistical considerations pertaining to the 
high risk group as described herein are unchanged. 
 
Futility stopping rule (Part 2 patients, and part 1 patients at maximum tolerated 
dose) 
.  If there is reasonable evidence that the rate of relapse/progression within a risk group 
is not improved over the historical benchmark, then accrual to that risk group will be 
terminated.  Reasonable evidence will be taken to mean that the lower bound of a 1-
sided 80% confidence interval for the true rate of relapse/progression exceeds 35% for 
the high risk group or 15% for the low risk group.  Operationally, this rule will be 
triggered by: 


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• High Risk Group: 6/10, 10/20, or 14/30 patients with relapse progression 
• Low Risk Group: 3/10 or 5/20 patients with relapse progression (low risk 
group terminated August 2014) 
 
 
Safety stopping rules (Part 1 Patients, part 1 patients at maximum tolerated dose, and 
Part 2 patients) 
 
Stopping rules will be imposed for non-relapse mortality, defined as any death occurring 
in the absence of documented relapse or progression, and engraftment failure.   The 
historical experience is that the NRM rate at 100 days post-HCT in this patient 
population is only 5%.  We will halt the study for safety review by the DSMB at any time 
that there exists reasonable evidence that the true rate of NRM exceeds 5%.  
Reasonable evidence will be taken to mean that the lower bound of a 1-sided 90% 
confidence interval for the true rate of day 100 NRM exceeds 5%.  Operationally, this 
rule will be evaluated at least every 10 patients as follows: 
 
• NRM (5% threshold): 2/10, 3/20, 4/30, 5/40 
 
Patients may continue to be enrolled pending evaluation of the day 100 endpoint, but 
the outcome in subsequently enrolled patients cannot override the rule if triggered in a 
lesser number.  The operating characteristics of the rule are summarized in the table 
below. 
Therefore, stopping rules will be imposed for: 
 
• NRM > 5% at day 100 
 
The stopping rule will be evaluated separately within each risk group.  Should the rule 
be triggered, accrual to that risk group will be suspended, pending a review of data by 
our DSMB.  This review will consider the possible relationship of the NRM to clofarabine, 
and whether a possibly increased risk of NRM could be tolerated in light of available 
data on the risk-benefit ratio. 
 
Operating characteristics of the stopping rules. 
 
True rate 
of NRM 
Probability of 
triggering  rule1 
(high risk/low 
risk2) 
Average N 
before stopping1 
(high risk/low 
risk2) 
True rate of 
graft 
rejection 
Probability 
of triggering  
rule1 
Average N 
before 
stopping1 
5% 
17% / 14% 
32 / 28 
5% 
19% 
61 
10% 
54% / 48% 
26 / 23 
10% 
70% 
41 
15% 
83% / 75% 
19 / 18 
15% 
95% 
25 
20% 
95% / 91% 
14 / 14 
20% 
>99% 
17 
1 based on 10,000 Monte Carlo simulations 
2 low risk group terminated August 2014 
 


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We will also continue to monitor the occurrence of graft rejection for evidence that the 
rate of graft rejection exceeds the historical rate of 5%.  A stopping rule for graft 
rejection will be based on the combined risk groups, and the confidence limit will be set 
to 90% in order to avoid excessive risk of falsely stopping: 
 
• Graft rejection >5%   
 
The criteria for triggering the rule will be the same as for NRM for the first 40 patients as 
follows:  
 
• Graft rejection(5% threshold): 6/50-60, 7/70 
 
Should the stopping rule be triggered, we will increase the dose of TBI by 100 cGy.  
Depending on the current toxicity experience, the dose of clofarabine will be left at the 
same level or reduced one dose level.  In either case, the next 6 patients will be 
monitored for DLT.  If the dose level of clofarabine is reduced, then it will be restored to 
the previous level if no more than one DLT is seen in the next 6 patients.  If the dose 
level is not reduced, and more than one DLT is seen in the next 6 patients, then the 
dose of clofarabine will be reduced one level.  After dose adjustment the next 6 patients 
will be monitored for DLT in the same manner. 
 
A revision to the TBI dose during Part 2 naturally could impact the evaluation of primary 
and secondary endpoints.  A decision as to whether to extend accrual to accommodate 
this revision will depend on the number of patients already accrued, the preliminary 
results at the time of revision, and the feasibility of extended accrual.  If extended 
accrual is appropriate and feasible, a protocol modification will be submitted for that 
purpose. 
 
Additional analysis 
Although the analysis of Part 2 will be stratified by risk group, comparison to historical 
rates is always complicated by variation in patient characteristics.  Regardless of the 
formal outcome of the trial as defined in Part 2, we would plan to perform a more 
comprehensive analysis of post-transplant endpoints using our historical database as a 
comparator. Although obviously not a substitute for a randomized trial, it will help us to 
determine whether the results stratified on risk score are robust to variation in other 
patient characteristics.   
 
These analyses will employ Cox regression models to compare patients in the current 
study to patients from our historical database for time-to-event endpoints, and will 
evaluate non-relapse and overall mortality, relapse and relapse-free survival, as well as 
acute and chronic GVHD.  Although the overall sample size for the current study will be 
relatively modest, it will also enable us to perform preliminary validation of the scoring 
system for relapse risk that we have developed from our historical data. 
 
Due to limited sample size, the evaluation of genetic markers in the secondary 
objectives will be largely exploratory in nature.  The table below presents some 


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approximate power calculations indicating the magnitude of hazard ratios that could be 
detected using only patients in the current study.  
 
 


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Power to detect association of genetic markers with relapse rate 
Proportion 
with marker 
 
Hazard ratio 
 
Power1 
20% 
2.5 
61% 
33% 
2.0 
47% 
33% 
2.5 
77% 
40% 
2.0 
51% 
40% 
2.5 
78% 
1 assuming n=75, 2-sided alpha=0.05, 
3 years of accrual and 1 year additional follow-up, 
relapse rate profile similar to historical 
 
 
16. DATA SAFETY AND MONITORING PLAN 
 
1. Monitoring the progress of trials and the safety of participants 
Protocol 2430 is a multi-institutional clinical trial that is monitored by the principal 
investigator (PI), Dr. Brenda Sandmaier, with oversight by a Data Safety and Monitoring 
Board (DSMB), the Data Safety Monitoring Committee (DSMC) and the Institutional 
Review Board (IRB). The PI reviews outcome data with the protocol mentor for each 
individual patient at a minimum of 3 months after unrelated donor HCT and the updated 
data are presented at Mixed Chimerism Meetings (includes co-investigators). Please 
see Appendix I and J for definitions of adverse events, serious adverse events (SAE) 
and serious and unexpected events as well as mechanisms for reporting these events. 
SAEs are reported to the trial coordinator. The trial coordinators at collaborating centers 
or the local PIs will fax an official report of an SAE to the coordinating center (FHCRC) 
within ten days. The SAE report is reviewed by the PI. If the SAE meets the FHCRC 
criteria for expedited reporting then an official signed report is submitted to the FHCRC 
Institutional Review Office (IRO). All deaths, regardless of the cause, are reported to the 
IRB. Protocol 2430 will have a dedicated independent DSMB responsible for monitoring 
patient safety on this clinical trial. The DSMB will meet at approximately six month 
intervals for this protocol and all outcome data will be reviewed including all adverse 
events and SAEs reported to the coordinating center (FHCRC) along with those 
officially reported to the FHCRC IRO. The DSMB will confirm that the trial has or has not 
met any stopping rules and reviews any patient safety problems necessitating 
discontinuation of the trial. A report from the DSMB is submitted to the FHCRC IRB as 
well as the trial coordinators/local PIs of this protocol. The DSMB will discontinue the 
review of outcomes when this protocol is closed to accrual and the last patient treated is 
past day +180. Furthermore, the FHCRC also has a DSMC that reviews the progress of 
the protocol with respect to the monitoring plan at the time of each annual renewal. As 
with initial review, annual IRB review and approval will also be required. Flow of 
information concerning clinical trial participants will originate with the clinicians and 
nurses in the clinic or referring clinicians at other institutions and is transmitted to the 
trial coordinator. At the FHCRC, health care providers and rotating attending physicians 
assess patients and record their observations regarding toxicity and response outcomes 


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in the medical record. This documentation is extracted by the study nurse within 140 
days +/- after HCT via chart review and collection of copies of source documents and 
entered into a hard copy or electronic Case Report Form (CRF). The PI reviews the 
official CRF and primary source documents. When the CRFs are verified, they are 
signed by the PI.. Thus, multiple health care providers provide independent 
observations and participate in monitoring this trial. The PI may be a clinician for some 
patients entered on this trial. However, assessments are the sum total of the primary 
health care provider (fellow or physician assistant), floor or outpatient nurse and the PI 
or other attending clinician involved with the patient averting possible conflict of interest 
having the PI as the attending clinician for protocol patients. If determination of adverse 
events is controversial, co-investigators will convene on an ad hoc basis as necessary 
to review the primary data and render a decision. Protocol 2430 will be a multi-
institutional protocol and all collaborating centers sign an agreement with the FHCRC 
stating that data generated from patients from the protocol will be reported accurately in 
a timely manner to the FHCRC. All centers have IRBs that review the protocol and who 
local PIs contact when an adverse event on the protocol occurs. Most of the centers 
have internal auditing mechanisms that assure accurate assessment of clinical 
outcomes. Clinical outcome data will be summarized and transmitted from collaborating 
centers as CRFs. When possible, primary source documents regarding patient 
outcomes will be collected with patients’ names removed and replaced by Unique 
Patient Numbers (UPNs). The CRFs are generated from the collaborating centers at 
defined time points (100 days, 6 months, and yearly). The local PI reviews the official 
CRF and primary source documents. When the CRFs are verified, they are signed and 
data will be entered into a central database managed by the trial coordinator. 
 
2. Plans for assuring compliance with requirements regarding the reporting of Serious 
Adverse Events SAEs 
The adverse event reporting in this multi-institutional clinical trial will follow the FHCRC 
Guidelines for SAE reporting. These guidelines (attached in Appendix I.) detail the 
expedited reporting requirements, definitions of particular events. All SAEs that meet 
expedited reporting criteria are reported to the IRO within 10 days by the investigator, 
trial coordinator, or research nurse upon learning of the event. A completed SAE report 
form, signed by the PI, must be received by the IRO within 10 calendar days. The PI 
reviews all SAEs and annual reports at the time of submission. For patients being cared 
for at the FHCRC, health care providers communicate with the PI, trial coordinator or 
research nurses as events occur triggering subsequent reporting. For patients not being 
cared for at FHCRC the outside facilities communicate with the PI, trial coordinator, or 
research nurse for these reporting purposes. All other deaths and expected serious 
adverse events are reported to the IRB at the time of annual renewal and at the 
biannual mixed chimerism meeting. The PI for a study is responsible for this reporting 
and the IRO assures adverse event reporting on an annual basis. The PI in the annual 
application for grant continuation will summarize reports of toxicities. Furthermore, an 
additional safeguard for adverse event analysis and reporting in this protocol is provided 
by stopping rules that are monitored at least every 10 patients in each arm. All 
collaborating PIs have fulfilled all NIH requirements for training in human subjects’ 
protection. 
 


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3. Plans for assuring that any action resulting in a temporary or permanent suspension 
of an NCI-funded clinical trial is reported to the NCI grant program director responsible 
for the grant 
This clinical research trial uses commercial agents and there is no associated 
Investigational New Drug (IND) or Investigational Device Exemption (IDE). Any 
temporary or permanent suspension, as determined by the PI, IRB, or DSMC, of this 
clinical research trial will be reported to the NCI grant program director by the PI. 
 
4. Plans for assuring data accuracy and protocol compliance 
Collaborating sites will send signed consents, eligibility forms, and CRFs with source 
documents demonstrating eligibility, treatment, and serious adverse events (if 
applicable) to the study staff. These are reviewed for eligibility, adherence to the 
protocol, accuracy, and completeness by the study staff. Queries are sent to the 
collaborating investigators if CRFs are inaccurate or incomplete. The study will be 
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. 
 
 
17. TARGETED/PLANNED ENROLLMENT 
 
Ethnic Category 
Gender 
 
 
 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
18 
24 
42 
Ethnic Category Total of All Subjects 
19 
25 
44 
Racial Categories 
 
 
 
American Indian / Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
1 
1 
2 
White 
17 
23 
40 
Racial Categories:  Total of All Subjects 
19 
25 
44 
 
 
 


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activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. PNAS 
1992;89(7):2970-2974. 
 42.  Lotfi K, Mansson E, Spasokoukotskaja T, et al.  Biochemical pharmacology and resistance to 2-
chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human 
leukemic cells. Clin Cancer Res 1999;5(9):2438-2444. 
 43.  Genini D, Adachi S, Chao Q, et al.  Deoxyadenosine analogs induce programmed cell death in 
chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the 
mitochondria. Blood 2000;96(10):3537-3543. 
 44.  Sutton MD, Walker GC.  Managing DNA polymerases: coordinating DNA replication, DNA repair, 
and DNA recombination (Review). PNAS 2001;98(15):8342-8349. 
 45.  Lin ZP, Belcourt MF, Carbone R, et al.  Excess ribonucleotide reductase R2 subunits coordinate the 
S phase checkpoint to facilitate DNA damage repair and recovery from replication stress. 
Biochem Pharmacol 2007;73(6):760-772. 
 46.  Cariveau MJ, Stackhouse M, Cui XL, et al.  Clofarabine acts as radiosensitizer in vitro and in vivo 
by interfering with DNA damage response. Int J Radiat Oncol Biol Phys 2008;70(1):213-
220. 
 47.  Salmon JP, Michaux S, Hermanne JP, et al.  Delayed massive immune hemolysis mediated by 
minor ABO incompatibility after allogeneic peripheral blood progenitor cell transplantation. 
Transfusion 1999;39(8):824-827. 
 
 


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APPENDICES - Table of Contents 
Appendix A  
Eligibility Guidelines for Donor PBSC Apheresis for Transfusion 
Appendix B  
Karnofsky Performance Status Scale 
Appendix C  
Lansky Play-Performance Scale 
Appendix D  
ABO Incompatibility 
Appendix E  
Infectious Disease Guidelines 
Appendix F  
Acute Graft-Versus-Host Disease Grading 
Appendix G  Chronic Graft-Versus-Host Disease Grading 
Appendix H  
Evaluation of Disease Response 
Appendix I  
Study Coordinator Manual (includes procedures for reporting adverse events) 
Appendix J  
Adverse Event Report 
Appendix K  
Notice of Death Form 
Appendix L  
Patient Demographics and Eligibility Form 
Appendix M  Core Case Report Forms 
Appendix N  
Intrathecal Therapy Administration 
Appendix O  HLA Matching Requirements For Unrelated Donors 
Appendix P  
Adapted Common Toxicity Criteria 
Appendix Q  Hematopoietic Cell Transplant-Comorbidity Index 
Appendix R  
Weight / Adjusted Body Weight for Drug Dosing 
Appendix S  
Coordinating Center Functions 
Appendix T  
Plan of Treatment in a Flow Chart Format 
Appendix U 
Radiotherapy Treatment Guidelines 


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


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


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Appendix C 
LANSKY PLAY-PERFORMANCE SCALE 
(for use with persons ages 1-6 years) 
 
 
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 quiet play activities 
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 D 
 
ABO INCOMPATIBILITY 
 
Red Blood Cell - Incompatibility (Major): 
Occasional patients may have antibodies directed against red blood cell antigens found on the 
donor's cells. These are generally ABO or Rh antigens, although incompatibility with other red 
cell antigens identified by donor-recipient crossmatch may occur. Although the volume of red 
blood cells (RBC) in most PBMC products will only be 2-5% of the product volume before 
infusion, the small quantity may cause a hemolytic transfusion reaction. According to the 
FHCRC policy it is generally acceptable to infuse a volume of about 10ml RBCs per product. If 
the recipient shows an anti-donor titer of ≥ 1:32 or the RBC volume is greater than 10ml (or 
>20ml in two products combined) the PBMC components should be RBC depleted by Starch 
Sedimentation (flowsheet below). Refer to the Clinical Coordinator's Patient Information Sheet 
for instructions regarding management of a specific patient. 
Post transplant blood component support will be according to Standard Practice 
Guidelines. 
 
Timing: Every attempt should be made to infuse red cell depleted PBMC products within 2 
hours of depletion. 
 
Expected Results: Red blood cell depleted PBMC products will contain < 10ml of red blood 
cells and ≥ 90% nucleated cell recovery. 
 
Red Blood Cell - Incompatibility (Minor): Occasional donors may have antibodies directed 
against red blood cell antigens (ABO, Rh, or other antigen system) found on the recipient's cells. 
The risk of hemolysis of recipient red cells immediately after transplant is not of very much 
clinical import. Due to the high number of lymphocytes in the PBMC inoculum, recipients may 
be at much greater risk for a delayed type of hemolysis that can be severe. PBMC products 
contain < 200ml of plasma according to FHCRC policy and no deleterious effects have been 
observed so far. However, if donors show an anti-recipient titer ≥ 1:256, the PBMC component 
should be plasma depleted (see flowsheet below). Refer to the Clinical Coordinator's Patient 
Information Sheet for instructions regarding management of a specific patient. 
Post transplant blood component support will be according to Standard Practice 
Guidelines. 
 
Timing: Every attempt should be made to infuse plasma-depleted PBMC within 2 hours of 
depletion. 
 
Expected Results: The plasma depletion should not affect the nucleated cell recovery. 
 
Red Blood Cell – Bidirectional Incompatibility: Patients undergoing transplants for 
bidirectional RBC incompatibility should be managed according to both algorithms shown below. 
Most red cell depletion techniques also deplete plasma from the PBMC component with no 
additional cell loss. Refer to the Clinical Coordinator's Patient Information Sheet for instructions 
regarding management of a specific patient. 
Post transplant blood component support will be according to Standard Practice 
Guidelines. 


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


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Appendix E 
INFECTIOUS DISEASE GUIDELINES 
 
Please note that the content of these PDFs is from the Fred Hutchinson Clinical Research 
Division Standard Practice Manual and does not contain research related procedures. 
 
 
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment 
hsv-vzv.pdf
 
 
 
CMV Prevention: Surveillance and Preemptive Therapy 
cmvprevention.pdf
 
 
 
 
Antifungal Therapy Guidelines 
Please see Section 9.J on recommendations on antifungal prophylaxis while patients are 
receiving clofarabine. 
antifungal_therapy.p
df
 
 
 
Pneumonia / Pneumocystis Carinii Prophylaxis 
pneumocystisjiroveci
.pdf
 
 
 
 
Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic 
GvHD Requiring Immunosuppressive Therapy and Vaccinations 
antibioticprophylaxisf
orencapsulatedbacter


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


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Appendix G 
CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) 
 
 
Chronic GVHD in allogeneic transplant recipients resembles autoimmune disorders 
such as scleroderma, Sjogren syndrome, primary biliary cirrhosis, lichen planus, 
wasting syndrome, bronchiolitis obliterans among others manifestations (see below). 
Approximately 50% of patients will develop this complication within 6 months after the 
transplant despite continued treatment with immunosuppressive medications. Close 
monitoring is recommended during the first 2 years after allogeneic stem cell 
transplantation so that appropriate treatment can be instituted promptly in patients who 
develop chronic GVHD. Debilitation, joint contractures and profound 
immunosuppression resulting in recurrent bacterial infections are prominent 
characteristics of untreated chronic GVHD. 
 
A. Classification of Chronic GVHD 
The purpose of this classification is to identify patients with cGVHD who need long-term 
systemic immunosuppression according to clinical and laboratory findings and risk 
factors at the time of initial diagnosis. In addition, a morbidity scale has been developed 
to help grade the severity of manifestation of chronic GVHD (Appendix D) at the time of 
diagnosis, when changes in treatment are made and when assessing treatment 
response. 
 
1. Chronic GVHD not requiring systemic treatment: mild abnormalities involving a       
single site, with platelet count >100,000 and no steroid treatment at the onset of   
chronic GVHD.   
a) Oral abnormalities consistent with cGVHD, a positive skin or lip biopsy, and no 
other manifestations of cGVHD. 
b) Mild liver test abnormalities (alkaline phosphatase ≤2 x upper limit of normal, AST 
or ALT ≤3 x upper limit of normal and total bilirubin ≤1.6) with positive skin or lip 
biopsy, and no other manifestations of cGVHD 
c)  Less than 6 papulosquamous plaques, macular-papular or lichenoid rash 
involving <20% of body surface area (BSA), dyspigmentation involving <20% BSA, 
or erythema involving <50% BSA, positive skin biopsy, and no other manifestations 
of cGVHD 
d)  Ocular sicca (Schirmer’s test ≤5mm with no more than minimal ocular 
symptoms), positive skin or lip biopsy, and no other manifestations of cGVHD 
e)  Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations 
of cGVHD 
 
2. Chronic GVHD requiring systemic treatment: more severe abnormalities or 
involvement of multiple sites, or platelet count <100,000, or steroid treatment at 
the onset of chronic GVHD 
a) Involvement of two or more organs with symptoms or signs of cGVHD, with 
biopsy documentation of cGVHD in any organ 


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b) ≥15% base line body weight loss not due to other causes, with biopsy 
documentation of cGVHD in any organ 
c) Skin involvement more extensive than defined for clinical limited cGVHD, 
confirmed by biopsy 
d) Scleroderma or morphea 
e) Onycholysis or onychodystrophy thought to represent cGVHD, with 
documentation of cGVHD in any organ 
f) Decreased range of motion in wrist or ankle extension due to fasciitis caused by   
cGVHD 
g) Contractures thought to represent cGVHD 
h) Oral involvement with functional impairment, refractory to topical treatment 
i) Vaginal involvement with functional impairment, refractory to topical treatment 
j) Bronchiolitis obliterans not due to other causes 
k) Positive liver biopsy; or abnormal liver function tests not due to other causes with 
alkaline phosphatase >2 x upper limit of normal, AST or ALT >3 x upper limit of 
normal, or total bilirubin >1.6, and documentation of cGVHD in any organ 
l) Positive upper or lower GI biopsy 
m) Fasciitis or serositis thought to represent cGVHD and not due to other causes 
 
B. Physical manifestations of Chronic GVHD 
Manifestations that are distinctive for chronic GVHD can begin before day 100 after the 
transplant, and manifestations that are typical of acute GVHD can persist long after day 
100. For this reason, the differential diagnosis between acute and chronic GVHD cannot 
be made solely according to the time interval from transplant. The diagnosis of chronic 
GVHD requires at least one manifestation that is distinctive for chronic GVHD (identified 
by italic print below) as opposed to acute GVHD. In all cases, infection and others 
causes must be ruled out in the differential diagnosis of chronic GVHD. Karnofsky or 
Lansky Clinical Performance scores <60%, ≥15% weight loss, and recurrent infections 
are usually signs of clinical extensive chronic GVHD. Abnormalities that could indicate 
chronic GVHD are categorized by organ system are listed below (italic print identifies 
manifestation more distinct of chronic GVHD): 
 
 
Skin 
Erythema, dryness, pruritis, macular-papular or urticarial rash, pigmentary 
changes (i.e., hyperpigmentation, vitiligo), mottling, papulosquamous or 
lichenoid plaques, hyperkeratosis, exfoliation (ichthyosis), nodules, 
scleroderma, morphea (one or several circumscribed, indurated and 
shiny lesions). The extent of skin involvement and the skin thickness 
score for patients with scleroderma needs to be recorded at the time of 
diagnosis, when changes in treatment are made and when assessing 
treatment response. Medical photos are also useful for assessing the 
extent of skin involvement and response to treatment. 
Nails 
 
B.     Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying (scalp hair, eyelashes, eyebrows), thinning scalp hair, 
alopecia, decreased body hair 


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Mouth 
Dryness, burning, gingivitis, mucositis, striae, dryness, atrophy, erythema, 
lichenoid changes, ulcers, labial atrophy or pigmentary changes, 
tightness around the mouth, sensitivity to acidic, strong flavors, heat or 
cold, tooth decay 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vulva Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or 
lichenoid changes not induced by ovarian failure or other causes 
Liver 
Jaundice and elevated liver function tests not due to other causes (see 
laboratory tests) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, 
dyspnea on exertion, history of recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, diarrhea, malabsorption, dysphagia, 
odynophagia 
Myofascial 
Stiffness and tightness with restriction of movement, occasionally with 
swelling, pain, cramping, erythema and induration, most commonly 
affecting the forearms, wrists and hands, ankles, legs and feet, inability to 
extend the wrists without flexing the fingers or the elbows, contractures 
Muscle 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 
Serosal 
Unexplained effusions involving the pleural, pericardial, or peritoneal 
cavities not due to venocclusive disease of the liver, cardiac insufficiency, 
malignancy, infection, GM-CSF toxicity or other causes 
 
C. Laboratory Testing and Diagnostic Indicators of Chronic GVHD 
 
Eye 
Schirmer’s test with a mean value ≤ 5 mm at 5 minutes, or values of 6-10 
mm in patients who have sicca symptoms, or keratitis detected by slit 
lamp examination 
Liver 
Elevated liver function tests not due to other causes (alkaline 
phosphatase ≥2 x upper limit, of normal, AST or ALT >3 x upper limit of 
normal or total serum bilirubin ≥1.6) 
Lung 
New obstructive lung defect defined as an FEV1 <80% of predicted with 
either an FEF 25-75 <65% of predicted or RV >120% of predicted, or a 
decrease of FEV1/FVC by >12% within a period of less than 1 year, 
thought not to be caused by an infectious process, asthma or recurrent 
aspiration from the sinuses or from gastroesophageal reflux. In the 
absence of GVHD in any other organ, the diagnosis of bronchiolitis 
obliterans requires negative microbiological tests from bronchoalveolar 
lavage, evidence of air trapping by high resolution end-expiratory and 
end-inspiratory CAT scan of the lungs, or confirmation by thoracoscopic 
biopsy. 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by 
barium swallow, endoscopy or manometry 
Intestine 
Endoscopic findings of mucosal edema and erythema or focal erosions 
with histological changes of apoptotic epithelial cells and crypt cell drop 


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out. Patients with unresolved acute GVHD may have more severe 
intestinal mucosal lesions including ulcers and mucosal sloughing. 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis with 
biopsy revealing no other etiological process 
Blood 
Thrombocytopenia (usually 20,000-100,000/l), eosinophilia (> 0.4 x 
103/uL), hypogammaglobulinemia. Hypergammaglobulinemia and 
autoantibodies occur in some cases. 
 
 
D. Guidelines for Treatment of Chronic GVHD after allogeneic HSCT 
 
We strongly recommend that you consult the LTFU office before beginning treatment for 
chronic GVHD and before making changes in immunosuppressive treatment. Clinical 
trials should always be considered because current standard therapies are associated 
with high morbidity and decreased survival for patients with high risk chronic GVHD  
 
Standard treatment of chronic GVHD usually begins with administration of 
glucocorticoids (1mg/kg/day) followed by taper to eventually reach an alternate-day 
regimen, with or without daily cyclosporine or tacrolimus (FK506). Other medications 
used for treatment of corticosteroid-resistant chronic GVHD are summarized on the next 
page. Telephone consultation with the LTFU medical team is available to you, seven 
days a week, to discuss appropriate treatment and provide other follow up 
recommendations. In addition to immunosuppressive treatment, antibiotic prophylaxis 
for encapsulated bacterial infections and PCP must be given to all patients being 
treated for chronic GVHD (see Appendix E). 
 
The duration of systemic immunosuppressive treatment of chronic GVHD varies but 
requires at least one year of therapy. Approximately 80% of patients require systemic 
immunosuppressive for 2 years and 40% of them requires therapy for at least 4 years. 
 
 
Adapted From: Long-Term Followup After Hematopoietic Stem Cell Transplant General Guidelines For 
Referring Physicians, Fred Hutchinson Cancer Research Center Standard Practice Manual, Section X, 
Chronic Graft Versus Host Disease (GVHD), Nov/2003 Version 
 


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Appendix H 
EVALUATION OF DISEASE RESPONSE 
 
 
Based on Cheson et al. “Revised Recommendations of the International Working Group 
for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
standards for Therapeutic Trials in Acute Myeloid Leukemia”  
in JCO, Vol 21, No 24 (December 15), 2003: pp 4642-4649 
 
 
Morphologic Leukemia-free state:  
• 
< 5% blasts in a marrow aspirate with marrow spicules and with a count of at least 200 
nucleated cells 
• 
No blasts with Auer rods 
• 
No extramedullary disease 
 
Morphologic Complete remission (CR): 
Morphologic Leukemia-free state, AND 
• 
Absolute neutrophil count (ANC) > 1,000/L 
• 
Platelets > 100,000/μL 
 
Morphologic Complete remission with incomplete count recovery (CRi):  
The presence of morphologic CR, except  
• 
ANC < 1,000/L or 
• 
Platelets < 100,000/L 


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


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research and (3) serious or suggests that the research places research participants or 
others at a greater risk of physical or psychological harm than was previously known or 
recognized must be submitted to the IRB within ten (10) calendar days of becoming 
aware of the event. 
 
Definitions 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, medical treatment or procedure and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
medical treatment or procedure whether or not considered related to the medicinal product. 
 
Related or Possibly Related Adverse Event:  An adverse event is “related or possibly related 
to the research procedure” if in the opinion of the principal investigator, it was more likely than 
not caused by the research procedures. Adverse events that are solely caused by an 
underlying disease, disorder or condition of the subject or by other circumstances unrelated to 
either the research or any underlying disease, disorder or condition of the subject are not 
“related or possibly related.” If there is any question whether or not an adverse event is related 
or possibly related, the adverse event should be reported.  
 
Serious Adverse Event: An adverse event that results in any of the following outcomes: Death, 
a life-threatening adverse event (real risk of dying), inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity/or change in psychosocial 
status, a congenital anomaly or, requires intervention to prevent permanent impairment or 
damage.  
 
Unexpected Adverse Event – An adverse event is “unexpected” when its nature (specificity), 
severity, or frequency are not consistent with (a) the known or foreseeable risk of adverse 
events associated with the research procedures described in the protocol-related documents, 
such as the IRB-approved research protocol, informed consent document and other relevant 
sources of information such as product labeling and package inserts; and are also not 
consistent with (b) the characteristics of the subject population being studied including the 
expected natural progression of any underlying disease, disorder or condition or any 
predisposing risk factor profile for the adverse event.  
 
To ensure no confusion or misunderstanding exist of the differences between the terms “serious” 
and “severe,” which are not synonymous the following note of clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) or a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory obligations. 
 
For example, hospitalization, in general, will not be considered a serious adverse event as 
approximately half of evaluable MRD patients AND the majority of evaluable URD patients 
receiving non-myeloablative transplants were hospitalized.  Hospitalization will be considered a 
serious adverse event if it fulfills the criteria for a serious and unexpected adverse event as 
described above. 


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Serious events, including deaths, due to GVHD and/or infections will not be reported on an 
expedited basis.  These are well documented, expected, post transplant complications and will 
be reported biannually to the DSMB 
 
FHCRC is acting as the Coordinating Center for this multi-institutional study, and it is the 
responsibility of the FHCRC Principal Investigator (or designee) to complete the FHCRC 
Serious Adverse Event Report for all serious adverse events that meet the expedited reporting 
requirements that are received from the participating sites.  It is the responsibility of the FHCRC 
Principal Investigator to notify the sponsor, NIH, FDA or other agencies of serious adverse 
events as required in the protocol. 
 
Procedure for Reporting Serious and Unexpected Adverse Events from Participating 
Sites 
Regulations defining the responsibilities for reporting serious and unexpected adverse reactions 
are defined above. SAEs or any death regardless of cause (serious, unexpected, and 
related/possibly related) within 180 days after HCT must be reported to the FHCRC Investigator 
within 10 days of learning of the event.  The immediate telephone report must be followed by 
faxed comments to the FHCRC Trial Coordinator at (206) 667-5378. This will be followed by 
detailed written report (See Appendix J) within 10 working days. The report must include the 
date and time of onset, severity and duration of the event, the relationship to the study, the 
treatment given and eventual outcome. Follow-up information to a SAE report must be 
submitted as soon as the relevant information is available. 
 
Obligation of Investigators 
All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur 
between start of any protocol intervention and day 100 during the study will be recorded on the 
Case Report Form (Appendix M). These adverse events which are observed by the 
Investigator or reported by the patient, whether or not attributed to the study, will be reported on 
the Case Report Form using the  selected (for this protocol) NCI Common Toxicity Criteria(NCI-
CTC) version 4  (Appendix P). Attributes will include a description, date of onset, maximum 
severity, and assessment of relationship to the study agent or other suspect agent(s). These 
grade 3 or 4 adverse events will be reported to the DSMB as part of the biannual review of the 
protocol. The DSMB report is submitted with the annual IRB renewal.  
 
Reporting of Unanticipated Problems that Involve Risk to Research Participants or 
Others:  
Any incident, experience, or outcome that meets both of the following criteria:  
• 
Unexpected (in terms of nature [specificity], severity, or frequency) given (a) 
the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
• 
Indicates that the research places research participants or others at a 
greater risk of harm (including physical, psychological, economic, or social 
harm) than was previously known or recognized.  
 
These must be reported to the FHCRC Investigator within 10 days of learning of the event as 
described above for reporting of SAE. 
 
 
 


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V. Case Report Forms 
Clinical outcome data are summarized and transmitted from collaborating centers as CRFs.  
Case report forms must be completed for all patients registered onto the protocols and 
submitted to the FHCRC data coordinating center. When possible, primary source documents 
regarding patient outcomes are collected with patients’ names removed and replaced by Unique 
Patient Numbers (UPNs).  The CRFs are generated from the collaborating centers at defined 
time points (day 28, 56, 84, 100, 6 months, 1 year, 18 months and annually).  The local PI 
reviews the official CRF and primary source documents. For Outside Centers, case report forms 
are expected to be submitted no later than 30 days following the scheduled follow up date. 
When the CRFs are verified, the data is entered into a central database managed by the trial 
coordinator. 
 
VI. Protocol Monitoring 
As the coordinating center, FHCRC will monitor accrual at the outside institutions. The 
guidelines below are intended to guide the reviewers in their assessment of items that 
significantly alter the clinical effectiveness of the treatment or the evaluation of its toxicity. 
 
A. Registration/Randomization 
1. Patient was registered prior to treatment and approval by FHCRC PI occurs prior to 
randomization. 
2. Information given at registration represents actual data in medical records (stage, diagnosis, 
cell type, etc.) 
 
B. Informed Consent/IRB Approval Dates 
1. The consent was signed prior to registration 
2. The consent is in language was approved by the institution’s IRB. IRB approval and 
reapproval are documented including appropriate use of full-board review and proper review of 
appropriate amendments or revisions 
3. Consent was dated and has written witness signature. IRB approval was obtained prior to the 
patient signing the consent form and start of treatment. 
 
C. Patient Eligibility 
1. Eligibility criteria and exclusion criteria were met 
2. Treatment/Intervention Administration 
3. Doses were modified according to protocol 
4. Accurate documentation of drug administration 
 
D. Study Tests/Evaluation 
1. Protocol specified laboratory tests or diagnostic studies are available 
2. Appropriate record of protocol intervention is documented. 
 
E. Study Events/Adverse Drug Experience 
1. Serious Adverse Evens reported according to protocol specifications 
 
F. Follow-Up 
1. Disease status assessed according to the required protocol guidelines documenting response 
to treatment. 
2. Accurate determination of cancer progression 
 
  


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


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


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Appendix K 
NOTICE OF DEATH 
 
 
Patient ID: ________________ Date of Death: _________________ 
Place of Event: ____________________________________________ 
Apparent cause of death (Please be specific. Attach hospital summary or death summary when 
possible): 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
___________________________________________________________________________________ 
Form completed by: __________________________________________ Date: __________________ 


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Appendix L 
PROTOCOL 2430 
PATIENT DEMOGRAPHICS AND ELIGIBILITY FORM 
Protocol 2430 Patient Demographics and Eligibility Form 
Please Fax this completed form to (206)-667-5378 for patient registration. 
Questions regarding eligibility should go to Brenda Sandmaier, MD, 206-667-4961 
UPN: _____________ 
Patient Name: 
_______________________________ 
(Last) 
________________________ 
(First) 
_____  
(MI) 
Date of 
Birth: 
_____ / _____ / __________  Age:________ 
 (Mo)    (Day)         (Year) 
Gender (choose one): 
 Male    
 Female   
 Unknown 
Patient Diagnosis: 
______________________________________   
Status at Transplant: 
 
Planned Day 0: 
_____/______/_____ 
 
(Mo) 
(Day)  (Year) 
Ethnicity (choose one):  Instruct the patient to select one of the following. 
 Hispanic (A person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race.  Term “Spanish Origin” can also be used in addition to 
“Hispanic” or “Latino”.) 
 Not Hispanic or Latino 
 
 Declined to Report 
Race (check all that apply):  Instruct the patient to select one or more of the following. 
 American Indian/Alaska Native (A person having origins in any of the original peoples of 
North, Central, or South America, and who maintains tribal affiliations or community attachment). 
 Asian (A person having origins in any of the original peoples of the Far East, Southeast, Asia, or 
the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand and Vietnam). 
   Black/African American (A person having origins in any of the black racial groups of Africa). 
 Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of 
Hawaii, Guam, Samoa or other Pacific Islands). 
 White (A person having origins in any of the original peoples of Europe, the Middle East or North 
Africa). 
 Research subject does not know race 
 Declined to report 
 
 
 


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Protocol 2430 Eligibility 
 
Inclusion Criteria:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
 Yes 
 No  
Patient signed and dated consent form.   
 
 
 
 
 
Date:  ___________ 
 
 
 
 
Date of IRB approval of consent form: ___________ 
 
 
 
 
 
IRB file:  ___________ 
 
 
TBI DOSE LEVEL  
 
1st dose level: 200 cGy  
 
2nd dose level: 300 cGy  
 
3rd dose level:  400 cGy  
 
 
Signature of Local Principal Investigator:  
__________               Date:                  
            
 
 
Transplant Center: 
___________________________________________________________________ 
 
 
Signature of FHCRC Principal Investigator   
_________________Date:                       
  
 
 
Relapse Risk Score 
Variable                                                                            Patient Score                            PI Initial and Date 
Score 
Unfavorable Cytogenetics 
+1
CR2 
+1 
> CR3 
+2
Lack of pre-HCT CBC Recovery 
+0.5
> 18 months between diagnosis and HCT 
-2
Relapse Risk Score ≤  0: LOW RISK (low  risk group terminated August 2014– see statistical section) 
Relapse Risk Score > 0: HIGH RISK
                                                  Total Risk Score 


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All of the following questions (2-5) must be marked “Yes” for the patient to enter the study.  
(Pediatric Attending will determine eligibility of pediatric patients based on criteria outlined in 
sections “Inclusions” and “Exclusions”)   
 
2a. 
 Yes 
 No   
Patient age ≥ 55 with AML 
 
 
 
 
 
--OR-- 
 
 
2b. 
 Yes 
 No        Patient age is >1 and < 55 with AML, who also through pre-existing 
medical conditions or prior therapy are considered to be at high risk for 
serious toxicities associated with a conventional, high-dose preparative 
regimen.   
 
3.  
 Yes 
 No        Patient is in morphologic leukemia-free state (marrow blasts < 5%) 
without evidence of extramedullary disease within 21 days of HCT.     
 
 
 
 
4.  
 Yes 
 No        HLA-identical related or HLA-matched unrelated donor is available 
 
5.  
 Yes 
 No 
 N/A      Unrelated donors who are prospectively: 
a. Matched for HLA-A,B,C, DRB1 and DQB1 alleles by high 
resolution typing           
     
 
AND 
b. Only a single allele disparity will be allowed for HLA-A, B, or C 
as defined by high resolution typing (See appendix O for other 
 
 
 
 
     donor selection details) Exclusion Criteria 
 
 
 
 
   
Patient 
 
 
 
 
 
A: ________ 
A:_________ 
C:_________ 
C:_________ 
B:_________ 
B:_________ 
DRB1:______ 
DRB1:______ 
DQB1:_____ 
DQB1:_______ 
 
 
Donor 
 
 
 
 
 
A:_________ 
A:_________ 
C:_________ 
C:________ 
B:_________ 
B:_________ 
DRB1:______ 
DRB1:_______ 
DQB1:_______ 
DQB1:_______ 
 
 
 
 
c.  Yes 
  No 
 
Have a negative anti-donor cytotoxic  
 
 
 
 
 
crossmatch 
                                NA 
        Cytotoxic crossmatch not done as patient 
and donor are phenotypically identical 
by molecular methods 
      
d.  Yes 
  No 
 
Patient and donor pairs must not be homozygous at    
 
 
 
 
mismatched allele              
 
 
 


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Exclusion Criteria  
Each of the following questions must be marked “No” Or “NA” for the patient to enroll on 2430. 
 
1.  
 Yes 
 No     
AML FAB M3 in CR1 
 
2.  
 Yes 
 No        Fungal infections with radiological progression after receipt of  
                                  amphotericin B or active triazole for greater than 1 month.   
 
3.  
 Yes 
 No      Active AML involvement of the central nervous system (CNS) with       
                                   disease refractory to intrathecal chemotherapy.  (For LP requirement and        
 
 
 
  
    intrathecal treatment guidelines, see Appendix N).                        
                                      
4.  
 Yes 
 No       Presence of circulating leukemic blasts (in the peripheral blood) detected 
by standard morphology.                                          
 
5.  
 Yes 
 No 
 NA 
Fertile men or women unwilling to use contraceptive techniques  
  
 
                    during and for 12 months following treatment. 
 
6.  
 Yes 
 No       Patient is HIV positive   
 
 
7.  Yes 
 No 
       Organ dysfunction. Please check yes if patient meets any of the      
following. 
  
 
 
 
     
Yes 
 No 
 
Cardiac: left ventricular ejection fraction < 35% (or if 
unable to obtain ejection fraction, shortening fraction of 
< 26%).  Ejection fraction is required if age > 50 years 
or there is a history of anthracycline exposure or 
history of cardiac disease. 
NOTE: If shortening fraction is <26%, a cardiology consult 
is required.  The PI of the study must approve eligibility  
 
  
 
 
 
  
 
  
 PI Signature:  
_____________Date: __ 
__ 
 
  
 
 
 
  
Yes 
 No 
 
Pulmonary: DLCO < 40% (corrected), TLC <40%, 
FEV1 <40% and/or receiving supplementary 
continuous oxygen.  
NOTE: The FHCRC PI of the study must approve of 
enrollment of all patients with pulmonary nodules.  
                                       
      
  
 
 
 
  
 
  
 
 PI Signature:  
_______________Date:     
_____ 
 
 
 
Yes 
 No 
 
 Liver Function Abnormalities: Patients with clinical 
or laboratory evidence of liver disease would be 
evaluated for the cause of liver disease, its clinical 
severity in terms of liver function, and the degree of 
portal hypertension.  Patients will be excluded if they 
are found to have fulminant liver failure, cirrhosis of the 
liver with evidence of portal hypertension, alcoholic 
hepatitis, esophageal varices, a history of bleeding 


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esophageal varices, hepatic encephalopathy, 
uncorrectable hepatic synthetic dysfunction evinced by 
prolongation of the prothrombin time, ascites related to 
portal hypertension, bridging fibrosis, bacterial or 
fungal liver abscess, biliary obstruction, chronic viral 
hepatitis with total serum bilirubin >3 mg/dL, or 
symptomatic biliary disease.  
  
 
 
    
 
Yes 
 No 
 
Renal: Serum Creatinine is outside of the normal limits    
                                           as specified by institutional guidelines. For patients with 
 
 
 
 
 
      serum creatinine > upper limit of normal, a 24-hour  
 
 
 
 
 
      creatinine clearance will be performed and should be  
 
 
 
 
 
      equal to or more than the lower limit of normal 
 
 
 
 
 
     
 
 
 
 
 
      Creatinine Clearance:  __________Date:     _____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI Signature:  _______________      Date:     
__ 
 
 
8.  
 Yes 
 No 
 NA  
Female who is pregnant or breastfeeding. 
 
9.  
 Yes 
 No 
The addition of cytotoxic agents for “cytoreduction” with the exception of 
tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, 
hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be 
allowed within three weeks of the initiation of conditioning.  
 
10. 
 Yes 
 No        Patient with poorly controlled hypertension and on multiple  
antihypertensives. 
  
11. 
 Yes 
No 
Karnofsky score < 60 (see Appendix B) or Lansky Score <50 (see 
Appendix C)     
 
12. 
 Yes 
 No  
Patients with active non-hematologic malignancies (except non-  
melanoma skin cancers) or those with non-hematologic malignancies 
(except non-melanoma skin cancers) who have been rendered with no 
evidence of disease, but have a greater than 20% chance of having 
disease recurrence within five years.   This exclusion does not apply to 
patients with non-hematologic malignancies that do not require therapy. 
  
13. 
 Yes 
 No    
Patient has active bacterial or fungal infection unresponsive to medical 
treatment.   
 
 
Note – the HCT-Comorbidity score (see Appendix Q) is:  _______________ 
 
Signature of person completing form: __________________________ 
Date: ____________ 
 
Signature of Principal Investigator: __________________________ 
Date: ____________ 


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Appendix M 
CORE CASE REPORT FORMS 
 
CRFsVersion3.pdf
 
 
 


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Appendix N 
INTRATHECAL THERAPY ADMINISTRATION 
 
Please note that the content of this PDF is from the Fred Hutchinson Clinical Research Division 
Standard Practice Manual and does not contain research related procedures. 
 
intrathecaltherapy-c
ombined.pdf
 


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Appendix O 
HLA Testing of Donors and Recipients Prior to Hematopoietic Stem Cell 
Transplantation 
 
hla_testing_donors-r
ecipients.pdf
 
 
 
 


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


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


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


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Allergic reaction 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Immune system disorders 
- Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
INFECTIONS AND INFESTATIONS 
 
Enterocolitis infectious 
IV antibiotic, antifungal, 
or antiviral intervention 
indicated; radiologic, 
endoscopic, or operative 
intervention indicated; 
profuse watery diarrhea 
with signs of 
hypovolemia;  bloody 
diarrhea; fever; severe 
abdominal pain; 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Infections and infestations 
- Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 
Aspartate 
aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 


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


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


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


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


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


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


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Appendix R 
Weight / Adjusted Weight for Drug Dosing 
 
weight_for_drug_do
sing.pdf
 


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


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


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Relapse Risk Score
Variable
Score
Unfavorable Cytogenetics
+1
CR2
+1
> CR3
+2
Lack of pre-HCT CBC Recovery
+0.5
> 18 months between diagnosis and HCT
-2
Relapse Risk Score < 0: LOW RISK
Relapse Risk Score > 0: HIGH RISK
Day -6 - -2: Clofarabine 30 mg/m2/day (total dose=150 
/
2)
3 patients reach Day 14: Evaluate for Dose Limiting Toxicities (DLT) and graft 
rejection 
Day 0: TBI 2 Gy, then HCT 
Graft rejection rate 
>5% 
(6/50-60, 7/70) 
(See TBI Dose Escalation for 
Engraftment Failure on next page) 
Graft rejection rate ≤5% 
No change to TBI dose 
Graft Rejection 
Dose Limiting 
No DLT 
1 patient with 
DLT 
>1 patient with 
DLT 
Next 3 patients treated with 
clofarabine 40 mg/m2/day 
(total dose=200 mg/m2) 
3 patients reach Day 14: 
Repeat “Clofarabine Dose 
Escalation” steps. 
Next 3 patients treated with 
clofarabine 50 mg/m2/day 
(total dose=250 mg/m2) 
3 patients reach Day 14: 
Repeat “Clofarabine Dose 
Escalation” steps. 
Next 3 patients treated with 
same dose.  
3 patients reach Day 14: 
Repeat “Clofarabine Dose 
Escalation” steps until Part 
II is reached. 
Go to Part II: Subsequent 
patients will be treated with 
next lower dose (If occurring 
at 30 mg/m2/day dose, drop to 
20 mg/m2/day) 
Go to Part II 
Patient who develops DLT stops 
clofarabine 
PART II: Accrual extended to patients with relapse risk ≤0 (low-risk) (low risk group terminated August 
2014 – see statistical section) and >0 (high-risk). Analyze as separate groups. 
Patients who already received 
treatment at determined optimal 
Patients who have not yet 
received treatment 
Include in analysis 
Treat at determined optimal dose 
level and include in analysis 
Patients who received treatment at 
a non-optimal dose 
Not included in further analysis 
Appendix T 
Plan of Treatment in a Flow Chart Format 
 


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Graft rejection rate >5% 
(6/50-60, 7/70) 
Increase TBI dose to 3 Gy for 
subsequent patients 
TBI Dose Escalation for Engraftment Failure 
Current patients evaluated for 
DLT  
≤1 patient with DLT 
>1 patient with DLT 
Next 6 patients treated 
with same dose of 
clofarabine 
Next 6 patients treated 
with next lower dose of 
clofarabine 
6 patients reach Day 14: 
Evaluate for DLT  
6 patients reach Day 14 
Evaluate for DLT  
≤1 patient with DLT 
>1 patient with 
DLT 
≤1 patient with 
DLT 
>1 patient with DLT 
Go to Clofarabine 
Dose Escalation Part I 
 
Next 6 patients 
treated with lower 
dose 
Next 6 patients 
treated with higher 
dose 
Repeat “TBI Dose 
Escalation for 
Engraftment Failure” 
6 patients reach Day 14: 
Evaluate for DLT  


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Appendix U 
Radiotherapy Treatment Guidelines per Standard Practice 
 
TBI_Adult_Non_Myel
oablative.pdf
                 
TBI_Pediatric_NON_
Myeloablative.pdf