Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)
Phase: PHASE2
Conditions: Hemophagocytic Lymphohistiocytosis, Chronic Active Epstein-Barr Virus Infection, Chronic Granulomatous Disease, HIGM-1, Leukocyte Adhesion Deficiency, IPEX
Sponsor: Medical College of Wisconsin

 
 
REDUCED-INTENSITY CONDITIONING FOR CHILDREN AND 
ADULTS WITH HEMOPHAGOCYTIC SYNDROMES OR 
SELECTED PRIMARY IMMUNE DEFICIENCIES (RICHI) 
(Posted on clinicaltrials.gov as NCT01998633) 
 
BMT CTN PROTOCOL 1204 
VERSION 4.0 
 
Study Chairpersons 
Carl Allen, MD, PhD1   and   Michael Pulsipher, MD2 
 
Protocol Team 
 
K. Scott Baker, MD, MS3 
Catherine Bollard, MD4 
Lauri Burroughs, MD3 
Lisa Filipovich, MD5 
Stephen Grupp MD, PhD6 
Rabi Hanna, MD7 
Leslie Kean, MD, PhD3 
Sung-Yun Pai, MD8 
Alyssa Ramirez9 
Philip Roehrs, MD10 
Kirk Schultz, MD11 
Shalini Shenoy, MD12 
Julie-An Talano, MD13 
Peter Dawson, PhD9 
Pam Budnick14 
Mary Eapen, MD, MS13
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1Texas Children’s Cancer and Hematology 
Centers 
2University of Utah School of Medicine 
3Fred Hutchinson Cancer Research Center 
4Children’s National Medical Center 
5Cincinnati Children’s Hospital 
  6Children’s Hospital of Philadelphia 
7Cleveland Clinic Foundation 
 
8Boston Children’s Hospital 
9The EMMES Corporation 
10University of North Carolina at Chapel Hill 
11BC Children’s Hospital 
12Washington University School of Medicine 
13Medical College of Wisconsin 
14National Marrow Donor Program 
 
 
 
___________________________________________  
________________________________________ 
Approval Signature (Protocol Chair/Officer)  
 
Approval Signature (Protocol Chair/Officer) 

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Core Study Participants: 
Alfred I. DuPont Hospital for Children – Nemours 
Wilmington 
All Children’s Hospital 
Ann and Robert H. Lurie Children’s Hospital of 
Chicago 
Baylor College of Medicine 
British Columbia Children’s Hospital – Vancouver 
CancerCare Manitoba 
Children’s Healthcare of Atlanta 
Children’s Hospital & Research Center, Oakland 
Children’s Mercy Hospital and Clinics 
Children’s National Medical Center 
Cincinnati Children’s Hospital Medical Center 
City of Hope National Medical Center 
Cleveland Clinic Foundation 
Cook Children’s Medical Center 
DFCI/Brigham & Women’s Hospital 
DFCI/Children’s Hospital of Boston 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
Hackensack University Medical Center 
Johns Hopkins/SKCCC 
Karmanos Cancer Institute – Children’s Hospital 
of Michigan 
Medical College of Wisconsin 
Memorial-Sloan Kettering Cancer Center 
Nemours Children’s Clinic - Jacksonville 
Oregon Health & Science University 
Penn State College of Medicine – The Milton S. 
Hershey Medical Center 
Phoenix Children’s Hospital 
Primary Children’s Medical Center – Utah BMT 
Riley Hospital for Children – Indiana University 
Roswell Park Cancer Institute 
UCLA – Mattel Children’s Hospital 
University of Alabama at Birmingham 
University of Florida College of Medicine 
(Shands) 
University of Iowa Hospitals and Clinics 
University of Louisville – Kosair Children’s 
Hospital 
University of Michigan Medical Center 
University of Minnesota 
University of North Carolina Hospital at Chapel 
Hill 
University of Rochester Medical Center 
University of Texas Southwestern Medical 
Center 
University of Texas/MD Anderson Cancer 
Research Center 
University of Wisconsin Hospital and 
Clinics 
Virginia Commonwealth University 
Washington University in St. Louis – St. 
Louis Children’s Hospital 

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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #1204  
 
Reduced-Intensity Conditioning for Children and Adults with Hemophagocytic Syndromes 
or Selected Primary Immune Deficiencies (RICHI) 
 
Study Chairpersons:  
Carl Allen, MD, PhD and Michael Pulsipher, MD  
 
Primary Objective: 
To prospectively determine the 1-year overall survival in subjects 
treated for hemophagocytic syndromes or primary immune 
deficiencies (CGD, HIGM1, IPEX, and severe LAD-I) using a 
standardized, reduced-intensity conditioning protocol consisting of 
fludarabine, melphalan and intermediate timing of alemtuzumab 
(Day -14).  
 
Secondary Objectives:  
Secondary objectives for the study include measurement of 
sustained engraftment, incidence of HLH and CAEBV reactivation 
and death from disease, immune reconstitution and functional 
immune recovery at 1-year, cumulative incidence (CI) of grade II-
IV and III-IV acute GVHD and chronic GVHD, transplant-related 
complications (VOD, CNS toxicity), infectious complications 
including reactivation of CMV, adenovirus, EBV, invasive fungal 
infection or bacterial sepsis, and overall survival and rate of 
sustained engraftment of specific disease subsets. 
 
Study Design: 
This study is designed as a Phase II multi-center trial. The study 
population includes patients with HLH, HLH-related disorders, 
and selected primary immune deficiencies: CGD, HyperIgM 
Syndrome (HIGM1), IPEX Syndrome, or severe LAD-I with 
indications for HCT receiving a bone marrow transplant from a 
related or unrelated donor (see HLA typing requirements in 
eligibility criteria below). 
 
Accrual Objective: 
The trial will accrue a minimum of 35 HLH patients. 
 
Accrual Period:  
The estimated accrual period is 3 years. 
 
Eligibility Criteria: 
Eligible patients are > 3 months and ≤ 45 years of age with 
Lansky/Karnofsky performance status ≥ 50% who have HLH or 
related disorders or selected immune deficiencies with an 
indication for HCT. Patients must have adequate organ function 
(cardiac, renal, hepatic, pulmonary).  Only bone marrow donors 
are allowed on this study. The donor must be: 
• 
An unaffected sibling donor who is a 6/6 match at HLA–A 
and –B (intermediate or higher resolution) and –DRB1 (at 
high resolution using DNA-based typing) OR 

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• 
An unaffected related donor (other than sibling) who is a 
7/8 or 8/8 match for HLA–A, –B, –C (at intermediate or 
higher resolution), and –DRB1 (at high resolution using 
DNA-based typing) OR 
• 
An unrelated donor who is a 7/8 or 8/8 match at HLA–A, –
B, –C, and –DRB1 (at high resolution using DNA-based 
typing). 
 
Treatment Description: 
All eligible patients undergoing bone marrow HCT will receive 
reduced-intensity conditioning (RIC) with fludarabine, melphalan 
and alemtuzumab beginning on Day -14. 
 
Study Duration: 
Patients will be followed for 1 year post-HCT.  
 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Background .................................................................................................................... 1-1 
1.1.1. 
An Opportunity to Improve Survival of Patients with HLH and Selected Primary 
Immune Deficiencies (PID) ........................................................................................ 1-1 
1.1.2. 
Challenges with Rejection of Cord Blood in Patients with HLH/PID ........................ 1-1 
1.2. 
Hemophagocytic Lymphohistiocytosis ......................................................................... 1-2 
1.2.1. 
Diagnostic Criteria for HLH ....................................................................................... 1-2 
1.2.2. 
Initial Therapy for HLH .............................................................................................. 1-3 
1.2.3. 
Salvage Strategies for Recurrent/Refractory HLH ..................................................... 1-3 
1.2.4. 
Fully Ablative Conditioning with Hematopoietic Cell Transplant and HLH ............. 1-4 
1.2.5. 
Reduced Intensity Conditioning Hematopoietic Cell Transplantation for HLH ........ 1-4 
1.2.6. 
Optimizing RIC HCT for HLH Syndromes ................................................................ 1-5 
1.2.7. 
HLH-Related Syndrome:  Chronic Active EBV Disease ........................................... 1-5 
1.2.8. 
Diagnosis of CAEBV .................................................................................................. 1-5 
1.2.9. 
CAEBV and HCT ....................................................................................................... 1-6 
1.3. 
Selected Primary Immune Deficiencies ....................................................................... 1-6 
1.3.1. 
Chronic Granulomatous Disease ................................................................................. 1-6 
1.3.2. 
Hyperimmunoglobulin M Syndrome .......................................................................... 1-8 
1.3.3. 
IPEX Syndrome .......................................................................................................... 1-8 
1.3.4. 
Leukocyte Adhesion Deficiency ................................................................................. 1-9 
1.4. 
Summary ....................................................................................................................... 1-10 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Study Objectives ................................................................................. 2-1 
2.2.1. 
Primary Hypothesis ..................................................................................................... 2-1 
2.2.2. 
Primary Objective ....................................................................................................... 2-1 
2.2.3. 
Secondary Objectives .................................................................................................. 2-2 
2.3. 
Patient Eligibility ........................................................................................................... 2-2 
2.3.1. 
Patient Inclusion Criteria............................................................................................. 2-2 
2.3.2. 
Patient Exclusion Criteria ........................................................................................... 2-4 
2.3.3. 
Donor Selection Criteria ............................................................................................. 2-5 
2.3.4. 
Donor Exclusion Criteria ............................................................................................ 2-5 
2.4. 
Treatment Plan............................................................................................................... 2-6 
2.4.1. 
Alemtuzumab (Campath-1H) ...................................................................................... 2-7 
2.4.2. 
Fludarabine .................................................................................................................. 2-8 
2.4.3. 
Melphalan .................................................................................................................... 2-8 
2.4.4. 
Infusion of Hematopoietic Stem Cells ........................................................................ 2-9 
2.5. 
GVHD Prophylaxis ........................................................................................................ 2-9 
2.5.1. 
Cyclosporine (CSA) .................................................................................................... 2-9 
2.5.2. 
Methylprednisolone/Prednisone ................................................................................ 2-10 

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2.6. 
Managing Chimerism .................................................................................................. 2-10 
2.7. 
Supportive Care (Recommended) .............................................................................. 2-11 
2.7.1. 
Engraftment Syndrome ............................................................................................. 2-11 
2.7.2. 
Venous Access .......................................................................................................... 2-11 
2.7.3. 
Growth Factor ........................................................................................................... 2-11 
2.7.4. 
Blood Products .......................................................................................................... 2-11 
2.7.5. 
Treatment of Fever/Infections ................................................................................... 2-12 
2.7.6. 
Blood Pressure Monitoring and Control ................................................................... 2-12 
2.7.7. 
Infection Surveillance and Prophylaxis .................................................................... 2-12 
2.8. 
Toxicities ....................................................................................................................... 2-14 
2.8.1. 
Conditioning: Pancytopenia ...................................................................................... 2-14 
2.8.2. 
Alemtuzumab ............................................................................................................ 2-14 
2.8.3. 
Fludarabine ................................................................................................................ 2-14 
2.8.4. 
Melphalan .................................................................................................................. 2-15 
2.8.5. 
Hematopoietic Cell Infusion ..................................................................................... 2-15 
2.8.6. 
Cyclosporine ............................................................................................................. 2-15 
2.8.7. 
Tacrolimus................................................................................................................. 2-15 
2.8.8. 
Dexamethasone, Methylprednisolone and Prednisone ............................................. 2-15 
2.8.9. 
Filgrastim (G-CSF) ................................................................................................... 2-15 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
Sustained Engraftment (sustained donor lymphoid and myeloid chimerism) ............ 3-1 
3.2.2. 
HLH and CAEBV Reactivation .................................................................................. 3-1 
3.2.3. 
Immune Reconstitution and Functional Immune Recovery........................................ 3-2 
3.2.4. 
Cumulative Incidence of Neutrophil and Platelet Engraftment .................................. 3-2 
3.2.5. 
Grade II-IV and Grade III-IV Acute GVHD............................................................... 3-3 
3.2.6. 
Chronic GVHD ........................................................................................................... 3-3 
3.2.7. 
Frequency of Transplant-related Complications ......................................................... 3-3 
3.3. 
Correlative Biology Studies ........................................................................................... 3-3 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1. 
Screening and Eligibility Procedures .......................................................................... 4-1 
4.2. 
Study Monitoring ........................................................................................................... 4-1 
4.2.1. 
Follow-up Schedule .................................................................................................... 4-1 
4.2.2. 
Adverse Event Reporting ............................................................................................ 4-3 
4.2.3. 
Patient Evaluations Prior to Enrollment ...................................................................... 4-3 
4.2.4. 
Patient Evaluations Prior to Conditioning .................................................................. 4-6 
4.2.5. 
Required Post-Transplant Evaluations (Follow evaluation windows listed in Table 
4.2.3) ........................................................................................................................... 4-6 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 

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5.1. 
Study Design ................................................................................................................... 5-1 
5.2. 
Accrual ............................................................................................................................ 5-1 
5.3. 
Study Duration ............................................................................................................... 5-1 
5.4. 
Randomization ............................................................................................................... 5-1 
5.5. 
Primary Objective .......................................................................................................... 5-1 
5.6. 
Sample Size and Power Considerations ....................................................................... 5-1 
5.7. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.8. 
Demographic and Baseline Characteristics ................................................................. 5-4 
5.9. 
Analysis of Primary Endpoint ...................................................................................... 5-4 
5.10. Analysis of Secondary Endpoints ................................................................................. 5-4 
5.11. Safety Analysis ............................................................................................................... 5-5 
 
 
LIST OF APPENDICES 
 
APPENDIX A 
HUMAN SUBJECTS 
APPENDIX B 
CONSENT FORM 
APPENDIX C  
LABORATORY PROCEDURES 
APPENDIX D 
LANSKY PERFORMANCE STATUS SCALE 
APPENDIX E  
RECOMMENDATIONS FOR HLH THERAPY PRIOR TO HCT 
FOR HLH SALVAGE THERAPY, AND FOR HLH CNS THERAPY 
APPENDIX F 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
APPENDIX G 
BLOOD PRESSURE LEVELS BY AGE AND HEIGHT 
PERCENTILE 
APPENDIX H 
REFERENCES 
 
 

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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
Hematopoietic cell transplant (HCT) is required for long-term survival in many patients with 
primary defects of the immune system.  The major obstacles to long-term survival with high 
quality of life in these patients, many of whom have significant morbidities at the time of 
transplant, are treatment-related mortality (TRM) and durable immune reconstitution.  Reduced-
intensity conditioning protocols have significantly improved outcomes in patients with immune 
deficiencies such as hemophagocytic lymphohistiocytosis (HLH) (Marsh et al., 2011).  However, 
the decrease in treatment-related morbidity and mortality comes with increased risk of 
inadequate durable engraftment, though a portion of patients with unstable chimerism or graft 
loss may be rescued with subsequent lymphocyte infusions or repeat HCT (Marsh et al., 2010).  
In an institutional case series of patients with HLH and related disorders, “intermediate” (Day  
-14) timing of alemtuzumab administration maintained excellent survival rates with improved 
stable engraftment (Marsh et al., 2013b).  In this study, we will test the efficacy of Intermediate-
Timed Alemtuzumab Reduced Intensity Conditioning (Intermediate RIC) in a multi-center 
setting in patients with HLH and other primary immunodeficiencies. 
 
1.1.1. An Opportunity to Improve Survival of Patients with HLH and Selected Primary Immune 
Deficiencies (PID) 
 
Although outcomes after related and unrelated donor HCT have improved dramatically in the 
past decade, survival in patients with diseases of immune dysfunction has lagged behind.  
Myeloablative (MA) approaches have been plagued with high rates of early treatment related-
mortality (section 1.2.4), but even patients transplanted with RIC approaches have not had ideal 
outcomes.  A review of CIBMTR data between 2008 and 2010 illustrates this challenge.  A total 
of 77 HLH patients received unrelated BM/PBSC, 22 related BM/PBSC, and 57 unrelated cord 
blood (CB) transplants during this three-year period.  One third received various RIC approaches 
and 2/3 MA approaches.  Overall survival (OS) at 1-year was 70% in those who received either 
related or unrelated BM/PBSC and 67% in recipients of unrelated CB.  One-year OS of patients 
with immune deficiencies included in this protocol (XLP, Chediak-Higashi, CGD, HIGM1, 
IPEX, and LAD-I) receiving URD RIC approaches was similarly poor at 74% (personal 
communication, Mary Eapen, CIBMTR).  Single-center experiences with fludarabine, 
melphalan, and alemtuzumab describe overall survival as high as 90% in HLH patients, 
demonstrating a clear opportunity to improve survival in this patient population (Cooper et al., 
2008; Marsh et al., 2010). 
 
1.1.2. Challenges with Rejection of Cord Blood in Patients with HLH/PID 
 
Very little data on outcomes of cord blood transplantation in this population has been published.  
Early experience with use of cord blood following the Flu/Mel/Alem approach led to a high 
number of rejections.  This anecdotal experience is borne out by CIBMTR data.  Between 2008-

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2010, of the 56 who underwent cord blood transplantation for HLH (2/3 MA, 1/3 RIC), 13 had 
primary and 7 had secondary graft failure for an overall graft failure rate of 36%.  One-year 
survival was poor, at 67%.  Patients with immune deficiencies undergoing cord blood procedures 
during these three years rejected 35% and 34% of the time with RIC (n= 31) and MA (n=68) 
approaches, respectively.  Over the same time period, rejection occurred in 5% of MA 
procedures 
for 
immune 
deficiencies 
who 
received 
unrelated 
BM/PBSC 
(personal 
communication, Mary Eapen, CIBMTR).  There is clearly a major problem with cord blood 
engraftment in these non-malignant disorders that will need to be addressed by a different 
approach.  Relative delay in immune reconstitution with cord grafts and difficulty generating 
cytotoxic T cell therapy from donor cells are also challenges in this population with frequent 
infectious complications.  With these data in mind, most investigators will choose a 7/8 or 8/8 
HLA matched unrelated donor over a cord blood for these disorders.  For patients who do not 
have a 7-8/8 matched unrelated donor available, enrollment on pilot studies aimed at improving 
engraftment using UCB or haploidentical donors is encouraged.   
 
1.2. 
Hemophagocytic Lymphohistiocytosis 
 
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation 
characterized by clinical signs and symptoms of extreme inflammation caused by dysregulation 
of immune effector function.  Without prompt initiation of immunochemotherapy, active familial 
HLH is almost universally fatal (Janka, 1983).  “Primary” inherited and presumed “secondary” 
acquired HLH are impossible to differentiate in the acute clinical setting, and distinctions 
between these groups are becoming increasingly blurred.  In the last Histiocyte Society trial, 
HLH-94, there was no significant difference in outcomes between patients with presumed 
familial or presumed secondary HLH with overall 3-year survival of 55% (Henter et al., 2002).  
 
1.2.1. Diagnostic Criteria for HLH 
 
The current resource most clinicians use to define HLH is the Histiocyte Society HLH-2004 
research protocol that requires either identification of recognized mutations in HLH-associated 
genes (including PRF1, MUNC13-4, STX11, STXBP2 (Munc18-2), SH2D1A (XLP1), BIRC4 
(XLP2), LYST (Chediak-Higashi Syndrome), or RAB27a (Griscelli Syndrome))  or five out of 
eight clinical criteria: fever; splenomegaly; cytopenias in 2/3 lineages; hypertriglyceridemia 
and/or hypofibrinogenemia; hemophagocytosis in bone marrow/spleen/lymph node/liver; 
decreased NK-cell activity; elevated ferritin; and elevated soluble CD25 (also called soluble IL-2 
receptor alpha) (Henter et al., 2007). (See Table 1.2.) 
 
 
 

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TABLE 1.2: DIAGNOSTIC CRITERIA FOR HLH USED IN THE HLH-2004 TRIAL* 
 
The diagnosis of HLH may be established by: ** 
A.   A molecular diagnosis consistent with HLH:  Pathologic mutations of PRF1, UNC13D (MUNC13-2), 
STXBP2 (Munc18-2), Rab27a, STX11, SH2D1A, or BIRC4  
-OR- 
 
B. Five out of the eight criteria listed below are fulfilled: 
1. Fever ≥ 38.3°C 
2. Splenomegaly 
3. Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood):  
Hemoglobin < 9 g/dL (in infants < 4 weeks: hemoglobin < 10 g/dL)  
Platelets < 100X103/mL 
Neutrophils < 1X103/mL 
4. Hypertriglyceridemia (fasting, > 265 mg/dL) and/or  
    hypofibrinogenemia (< 150 mg/dL)  
5. Hemophagocytosis in bone marrow or spleen or lymph nodes or liver 
6. Low or absent NK-cell activity 
7. Ferritin > 500 ng/mL 
8. Elevated Soluble CD25 (soluble IL-2 receptor alpha)*** 
 
Notes:  
*  
Adapted from Henter et al. 2007  
**  
Additionally, in the case of familial HLH, no evidence of malignancy should be apparent.  
*** 
Elevations above age-adjusted, laboratory-specific normal levels (defined as > 2 SD from the mean) appear more 
meaningful than the original designation of ‘> 2,400 U/mL’, because of variations between laboratories and 
age groups. 
 
1.2.2. Initial Therapy for HLH 
 
Without therapy, survival of patients with active familial HLH is approximately 2 months 
(Henter et al., 1991). The first international treatment protocol for HLH was organized by the 
Histiocyte Society in 1994 and led to reported survival of 55%, with a median follow-up of 3.1 
years (Henter et al., 2002).  The HLH-94 protocol included an 8 week induction therapy with 
dexamethasone, etoposide, and intrathecal methotrexate in patients with CNS inflammation.  The 
principal goal of induction therapy is to suppress the life-threatening inflammatory process that 
underlies HLH.  At the end of 8 weeks, patients who can be weaned off of dexamethasone and 
etoposide without recurrence, recover normal immune function, and have no identified HLH-
associated gene defects may stop therapy.  HCT is generally recommended in patients with CNS 
involvement, recurrent/refractory disease, persistent NK cell dysfunction or proven 
familial/genetic disease (Jordan et al., 2011).  
 
1.2.3. Salvage Strategies for Recurrent/Refractory HLH 
 
A significant number of patients with HLH will either fail to respond adequately to current 
therapies or have disease recurrence prior to HCT.  Approximately 50% of patients treated on the 
HLH-94 study experienced a complete resolution of HLH, while 30% experienced a partial 
resolution, and approximately 20% died prior to HCT (Henter et al., 2002).  Notably, most 

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deaths occurred during the first few weeks of treatment and may reflect either pre-existing 
morbidities or primary refractory disease.  While it is hoped that some patients will fare better 
with more prompt diagnosis of HLH, others remain unresponsive to standard therapy. Initial 
treatment with anti-thymocyte globulin (Thymoglobulin, rabbit ATG) has been reported to give 
higher complete response rates, but due in part to higher recurrence rates, long term outcomes do 
not appear superior (Ouachee-Chardin et al., 2006).  
 
At present there is little data regarding potential second line therapies. Case reports exist 
describing the use of infliximab, daclizumab, alemtuzumab, anakinra, vincristine, and other 
agents as salvage therapies for HLH (Bruck et al., 2011; Henzan et al., 2006; Imashuku et al., 
1999; Kobayashi et al., 2007; Olin et al., 2008; Strout et al., 2010; Tomaske et al., 2002).  Due to 
the increasing recognition of the critical role of T cells in driving HLH pathogenesis, 
alemtuzumab has been increasingly used as a salvage therapy.  A recent retrospective analysis of 
25 patients found that alemtuzumab has significant activity against refractory HLH (Marsh et al., 
2013a).  Though refractory HLH typically has a dismal prognosis, approximately 70% of 
patients in this series survived.  In contrast to refractory patients, those patients who initially 
respond well to standard therapy but then recur as treatment is tapered or withdrawn often 
respond to reintensification of therapy with standard agents. 
 
1.2.4. Fully Ablative Conditioning with Hematopoietic Cell Transplant and HLH 
 
For patients with refractory or inherited HLH, HCT is the only curative therapy currently 
available.  In the HLH-94 protocol, consisting primarily of matched related and matched 
unrelated donors, 3-year survival was 64% (Horne et al., 2005).  A retrospective evaluation of 
HLH patients undergoing HCT with unrelated matched donors through the National Marrow 
Donor Program (Baker et al., 2008) and a single-institution study from Necker Hospital which 
included many haploidentical donors (Ouachee-Chardin et al., 2006) both reported similar 
outcomes with long-term survival for patients receiving ablative conditioning for HLH at  ~55%.  
Most of the patients in these reports treated with ablative conditioning received busulfan, 
cytoxan and etoposide with or without ATG.  A significant finding in all of these studies is a 
very high rate of TRM > 30% (Baker et al., 2008; Horne et al., 2005; Ouachee-Chardin et al., 
2006).  Causes of death were multifactoral, including infection, veno-occlusive disease, 
hemorrhage, and multi-system organ failure.  Primary graft failure was reported in 9-22%.  
Ouachee-Chardin et al. attributed 50% of the TRM to reactivation of HLH, and Horne et al. 
correlated active disease at the time of transplant with primary graft failure.  These poor Day 
+100 outcomes with standard myeloablative conditioning regimens highlight the need for an 
alternative approach to transplantation for these patients, many of whom come to transplant with 
pre-existing organ dysfunction, infection and persistent pathologic inflammation. 
 
1.2.5. Reduced Intensity Conditioning Hematopoietic Cell Transplantation for HLH  
 
Several recent series have demonstrated decreased TRM and improved overall survival with 
reduced-intensity conditioning strategies that include alemtuzumab (Cooper et al., 2006; Cooper 
et al., 2008; Marsh et al., 2010). In the long-term, protection from HLH reactivation requires 
stable donor chimerism greater than 10-20% (Ouachee-Chardin et al., 2006), and donor T cells 
alone may be sufficient to protect against HLH reactivation (Cooper et al., 2008).  The immune 

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deficiencies described below require similar levels of chimerism for disease correction.  In a 
single-institution study, survival for HLH patients receiving RIC was significantly superior to 
survival for patients receiving myeloablative conditioning (92% vs. 43%) (Marsh et al., 2010).  
There were no deaths before Day +100 in the RIC group.  However, while survival was 
significantly improved, patients undergoing RIC HCT in this series had extremely high rates of 
post transplantation mixed chimerism (65%).  Other series also report high rates of mixed 
chimerism in patients treated with alemtuzumab-based RIC for HLH (Cooper et al., 2008).   
 
1.2.6. Optimizing RIC HCT for HLH Syndromes  
 
The improved survival reported for RIC strategies for HCT for HLH may be due to decreased 
toxicity of fludarabine/melphalan compared to myeloablative busulfan/cyclophosphamide.  
Additionally, it is possible that alemtuzumab-mediated depletion of T cells and antigen-
presenting cells ameliorates inflammation prior to transplant.  Investigators from Cincinnati 
Children’s Hospital reported that the timing of alemtuzumab administration appeared to 
influence sustained engraftment with 65% of patients having mixed chimerism: 29% of patients 
who received “distal” alemtuzumab (starting Day -22) and 79% of patients who received 
“proximal” alemtuzumab (start day range -12 to -8).  Most of the patients with mixed chimerism 
in this study ultimately received lymphocyte infusion or second stem cell infusion.  
Alemtuzumab persists at cytotoxic levels in patients following RIC for up to 60 days (Morris et 
al., 2003), with an estimated half-life of 15-21 days (Rebello et al., 2001).  While a RIC 
approach for HLH appears to be effective, the optimal dose and timing of alemtuzumab and 
other therapeutic agents used in conditioning to achieve maximum survival with improved 
engraftment remains to be defined.    
 
Recent data from Cincinnati Children’s Hospital suggests that intermediate timing (starting Day  
-14) of alemtuzumab significantly improved engraftment rates (87% Day +100 stable 
engraftment without donor lymphocyte infusion (DLI)) while maintaining improved overall 
survival (90% at one year).  The cumulative incidence of mixed chimerism was also significantly 
better in the Intermediate RIC (31%) compared to patients who received “proximal” 
alemtuzumab (72%) (Marsh et al., 2013b). 
 
1.2.7. HLH-Related Syndrome:  Chronic Active EBV Disease 
 
While over 90% of the adult population is infected with EBV, rare individuals develop a life-
threatening condition of chronic active EBV disease (CAEBV), characterized by highly elevated 
EBV levels in blood and tissue and often associated with hemophagocytic syndrome.  EBV 
typically infects B cells and CAEBV may arise as a B-cell lymphoproliferation.  However, in 
most cases of CAEBV in Asians or Native Americans, very high levels of EBV are detected in T 
or NK cells (Reviewed in (Cohen et al., 2011)).   
 
1.2.8. Diagnosis of CAEBV  
 
CAEBV is defined as prolonged systemic symptoms of inflammation associated with 
uncontrolled EBV infection of B, T or NK cells.  Unlike post-transplant lymphoproliferative 

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disorder, CAEBV arises in people without known immune dysfunction or iatrogenic immune 
suppression.  Clinical Definition of CAEBV requires all of the following (Cohen et al., 2011):  
1. Severe progressive illness of > 6 months duration, usually with fever, lymphadenopathy 
and splenomegaly that either began as primary EBV infection or was associated with 
markedly elevated antibody titers to EBV viral capsid antibody (≥ 1:5120) or early 
antigen (≥ 1:640), or markedly elevated EBV DNA in the blood; 
2. Infiltration of tissues (e.g., lymph nodes, liver, lungs, CNS, bone marrow, eye, skin) with 
lymphocytes; 
3. Elevated EBV DNA, RNA or proteins in affected tissues; and, 
4. The absence of any other immunosuppressive condition. 
 
1.2.9. CAEBV and HCT 
 
CAEBV is infrequently reported in North America.  In a 28-year series at the NIH and Baylor 
College of Medicine, 19 patients with EBV were evaluated.  In this North American cohort, 
immunosuppressive agents, rituximab, autologous cytotoxic T cells, cytotoxic chemotherapy or 
autologous HCT achieved only short-term responses.  The only cures were achieved with 
allogeneic HCT, with 5/8 alive 2-11 years after transplantation, including 2 of 3 who underwent 
subablative HCT (Cohen et al., 2011).  From 57 other cases of CAEBV who underwent HCT 
reported in the literature, overall survival was 72%.  Factors associated with survival from these 
cases include younger age (14.4 years vs. 21.2 years), shorter time to transplant from onset of 
disease (3.5 years vs. 6.5 years), and non-myeloablative conditioning (69% vs. 38%) (Cohen et 
al., 2011). 
 
1.3. 
Selected Primary Immune Deficiencies 
 
HLH is caused by defects in effector immune function resulting in uncontrolled immune 
activation and pathologic inflammation.  Defects in other regulatory pathways also cause 
diseases due to dysfunctional immune mechanisms, including chronic granulomatous disease, 
hyper IgM syndrome, IPEX syndrome, and leukocyte adhesion deficiency.  HCT corrects defects 
in all of these primary immune deficiencies and sustained partial chimerism may be sufficient for 
cure.  HCT with myeloablative conditioning is associated with high rates of TRM in these 
patients due to pre-existing infections and organ dysfunction in many patients at the time of 
transplant (Filipovich, 2008). 
 
1.3.1. Chronic Granulomatous Disease 
 
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by ineffective 
function of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in 
impaired microbicidal activity of reactive oxygen in neutrophils, macrophages and eosinophils.  
Patients with NADPH oxidase deficiency are susceptible to recurrent, life-threatening infections 
by bacteria and fungi (reviewed in (Kang et al., 2011; Seger, 2010b)).  CGD is a heterogeneous 
disease with significant phenotypic variability.  The production of residual oxygen intermediates 
(ROIs) is determined by the specific NADPH mutation, and is a predictor of survival in patients 

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with CGD (Kuhns et al., 2010).  However, even among patients with similar NADPH mutations, 
there is variability in clinical outcomes.  Therefore, the specific genetic defect, the patient’s 
infection history, the presence of active inflammation or infection and other co-morbidities are 
important clinical variables in risk/benefit considerations for different therapeutic options.  
 
1.3.1.1. Diagnosis of CGD 
 
CGD is diagnosed by clinical history of recurrent infections, classically including 
Staphylococcus aureus (lymphadenitis, liver abscess), Burkhoderia (necrotizing pneumonia, 
sepsis), Serratia marcescens (sepsis, skin ulcers, osteomyelitis), Nocardia and Aspergillus spp. 
(pneumonia, brain, bone infections), Actinomyces spp. (cervicofacial, pulmonary or abdominal 
infections), 
Granulibacter 
bethesdensis 
(lymphadenitis), 
Mycobacterium 
tuberculosis  
(pulmonary and extrapulmonary infections), and Leishmania infantum (intracellular protozoal 
infection) (Reviewed in (Seger, 2010a)).  Front-line diagnostic tests are based on measurement 
of phagocyte NADPH oxidase (Phox) activity.  The flow-cytometry-based dihydrorhodamine-
1,2,3 (DHR) test measures the ability of stimulated phagocytes to oxidize DHR interacellularly, 
and is a sensitive screening study (Vowells et al., 1995).  Definitive diagnosis is made by 
protein- or DNA-based study of the five Phox components: gp91phox (X-linked), p47phox, p67phox, 
p22phox and p40phox (Rada and Leto, 2008). 
 
1.3.1.2. HCT for CGD 
 
While survival has improved with the use of prophylactic antimicrobials and earlier diagnosis, 
the only cure for CGD currently available is allogeneic hematopoietic cell transplantation.  To 
date, fewer than 200 transplants have been reported, with most data as case reports.  A survey of 
European centers (n=27 patients) reported 85% survival with myeloablative conditioning and 
primarily matched-sibling donors (Seger et al., 2002).  Two series including matched unrelated 
donor (MUD) transplants for CGD (n=19) with ablative conditioning reported cumulative 84% 
survival (Schuetz et al., 2009; Soncini et al., 2009). Reduced intensity conditioning strategies for 
HCT in CGD are feasible.  One study from the NIH reported 70% survival (n=10 patients) with 
allogeneic matched related donor (MRD) transplants with non-myeloablative conditioning 
(cyclophosphamide/fludarabine/ATG) (Horwitz et al., 2001).  Similarly, a European consortium 
reported successful MRD/MUD transplants with non-myeloablative busulfan- and fludarabine-
based conditioning regimen with ATG, with durable engraftment, survival to 1 year, and 
normalized superoxide production in all three patients (Gungor et al., 2005).  A CIBMTR survey 
(through 2009) found 59 patients who had undergone allogeneic transplant for CGD with 71% 
overall survival (Seger, 2010b).  In CGD, patients with stable mixed chimerism recover 
neutrophil Phox function (Martinez et al., 2012; Horwitz et al., 2001).  To date, the limited data 
available make it difficult to determine what the most optimal conditioning regimen is for this 
disease, however, a reduced-intensity conditioning transplant strategy is particularly attractive in 
CGD, where many patients have significant co-morbidities including severe infections at the 
time of transplant.  
 
 

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1.3.2. Hyperimmunoglobulin M Syndrome 
 
Hyper-IgM syndrome includes a heterogeneous group of conditions characterized by defects in 
class-switch recombination (CSR).  As a result, serum IgM accumulates with reduced or absent 
levels of IgG, IgA and IgE.  The most common genetic form of hyper-IgM syndrome, HIGM1, is 
caused by defects in the gene encoding CD40 ligand (CD40L) on the X chromosome.  In 
addition to defective humoral immunity and lack of germinal centers in peripheral lymphoid 
tissue, patients with hyper-IgM may also have neutropenia, anemia, impaired delayed-type 
hypersensitivity reactions to recall antigens, and decreased T cell proliferation in vitro 
(Reviewed in (Davies and Thrasher, 2010)).  More than 50% of boys with HIGM1 develop 
symptoms by one year, and more than 90% are symptomatic by four years (Winkelstein et al., 
2003).  Symptoms include recurrent respiratory tract bacterial infections, opportunistic 
infections, chronic diarrhea, neutropenia, thrombocytopenia and anemia.  Opportunistic 
infections from Pneumocystis jeroveci and Cryptosporidium parvum are also common (Lee et 
al., 2005).  The median survival of patients with HIGM1 without HCT is less than 25 years 
(Levy et al., 1997; Winkelstein et al., 2003). 
 
1.3.2.1. Diagnosis of HIGM1 
 
HIGM1 should be considered in boys with recurrent bacterial and opportunistic infections.  Lab 
criteria include decreased serum IgG (2 or more SD below normal for age) with a mutation in 
CD40LG or a family history of maternally related males with HIGM1 [ESID Working Party 
2005: http://www.esid.org/workingparty.php?party=3&sub=2&id=73#Q16]. 
 
1.3.2.2. HCT for HIGM1 
 
Allogeneic HCT is the only curative treatment currently available for HIGM1.  The largest 
published case series is a European survey which reported HCT for 38 patients, with 68% long-
term survival and immune reconstitution with cure in 58%.  Pre-existing lung disease correlated 
with poor outcome and all deaths in this series were associated with infection (Gennery et al., 
2004).  Outcomes for MRD and MUD were not statistically different.  There were some patients 
conditioned with non-ablative strategies but too few to analyze separately (Gennery et al., 2004).  
However, the cases included in the survey by Gennery et al. as well as other case series support 
feasibility of reduced-intensity conditioning strategies (Kikuta et al., 2006; Jasinska et al., 2013; 
Gennery et al., 2004).  The co-morbidities of this population prior to transplant and associated 
risks of TRM also support investigation of a RIC approach in patients with HIGM1. 
 
1.3.3. IPEX Syndrome 
 
IPEX refers to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked 
inheritance.  The syndrome is a rare X-linked disorder that typically presents with a triad of 
enteropathy, autoimmune polyendocrinopathy and dermatitis (Powell et al., 1982).  Most patients 
present with the characteristic constellation of symptoms in early infancy.  IPEX is caused by 
defects in the inhibitory regulatory helper T cells (Tregs) due to dysfunctional or absent FOXP3 
transcription factor (Wildin et al., 2001; Chatila et al., 2000).  Disease manifestations are due to 
immune dysregulation from absent or dysfunctional Tregs.  Disease-causing mutations in FoxP3 

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have been described in each of the main coding regions of the gene, as well as in some non-
coding regions (Campbell and Ziegler, 2007).    
 
1.3.3.1. Diagnosis of IPEX Syndrome 
 
IPEX should be considered in male infants with chronic diarrhea, failure to thrive and/or onset of 
type 1 diabetes in infancy.  The other clinical manifestations discussed above are also supportive.  
Definitive diagnosis is established by absent or functionally defective FOXP3+ CD4+ T cells or 
by mutational analysis of FoxP3 (Hannibal and Torgerson, 1993).     
 
1.3.3.2. HCT for IPEX Syndrome 
 
HCT is the only curative therapy for IPEX currently available.  Infections and co-morbidities are 
common in patients at the start of transplant.  Literature is limited to case reports, including 
examples demonstrating feasibility of reduced intensity conditioning strategies and resolution of 
disease symptoms even with mixed chimerism (Burroughs et al., 2010; Dorsey et al., 2009; Rao 
et al., 2007; Seidel et al., 2009; Zhan et al., 2008). 
 
1.3.4. Leukocyte Adhesion Deficiency 
 
Leukocyte adhesion deficiency is a primary immune disorder caused by defects in migration of 
immune cells.  It typically presents in infancy with delayed umbilical cord separation with 
omphalitis, deep tissue infections, impaired pus formation, and poor wound healing.  LAD-I is an 
autosomal recessive disorder caused by mutations in the common chain (CD18) of the  -
integrin family, resulting in deficiency of 3 integrins with functions in leukocyte function: 
lymphocyte function associated antigen-1 (LFA-1, CD11a/CD18), Mac-1 (CD11b/CD18), and 
gp 150/95 (CD11c/CD18) (Reviewed in (Etzioni, 2010)).  The severity of LAD-I is related to the 
degree of CD18 deficiency: severe deficiency is observed in patients with less than 2% of normal 
surface expression of CD18; mild to moderate deficiency is observed in patients with greater 
than 2-30% of normal surface expression of CD18 (Fischer et al., 1988).  Clinical management 
of LAD-I depends on clinical severity.  Mild to moderate disease can usually be managed with 
antibiotic therapy while this is generally inadequate for patients with severe disease (Etzioni, 
2010). 
 
1.3.4.1. Diagnosis of LAD-I 
 
Definitive diagnosis of severe LAD-I can be made in male or female patients with decreased 
intensity of expression of CD18 on neutrophils (< 5% of normal for age) with mutation of the 2 
integrin gene and/or absence of 2 integrin mRNA in leukocytes (Conley et al., 1999). 
 
1.3.4.2. HCT for LAD-I 
 
HCT is the only curative therapy for patients with severe LAD-I currently available.  The largest 
published series reported 36 children who underwent HSC transplant with 75% overall survival 
(Qasim et al., 2009).  Reduced-intensity conditioning was used in 8 patients, with no deaths in 
this sub-group, and mixed-donor chimerism was sufficient to correct the symptoms of LAD. 

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1.4. 
Summary 
 
HLH, HLH-related disorders, CGD, HIGM1, IPEX and severe LAD-I represent primary immune 
disorders that are typically fatal without HCT.  However, transplant is often complicated by 
inflammation, infection and other co-morbidities.  In addition, these disorders have been shown 
to be cured with partial chimerism, making them an ideal target for the use of reduced intensity 
approaches, where a portion of patients may not achieve full donor chimerism, but instead 
achieve stable mixed chimerism.  Reduced-intensity conditioning strategies have demonstrated 
improved survival with decreased TRM in institutional series for patients with HLH (Cooper et 
al., 2006; Marsh et al., 2010; Marsh et al., 2011).  However, graft loss and unstable chimerism 
remain challenges.  An institutional case series from Cincinnati Children’s Hospital 
demonstrated full or high-level chimerism and improved durable engraftment using intermediate 
(Day -14) timing alemtuzumab (Marsh et al., 2013b).  This study aims to test the efficacy of the 
Intermediate RIC strategy in a prospective multi-center study including HLH as well as other 
primary immunodeficiencies where allogeneic transplant with RIC has been shown to be feasible 
and stable chimerism is curative. 
 
 

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CHAPTER 2 
 
 
2. 
STUDY DESIGN  
 
2.1. 
Study Overview 
 
The primary goal of this Phase II clinical trial is to determine the one-year overall survival of 
patients treated for immune deficiencies including HLH, HLH-like disorders, CGD, HIGM1, 
IPEX syndrome, and severe LAD-I with MRD/MUD bone marrow transplant using a reduced-
intensity conditioning strategy including intermediate-timing of alemtuzumab.  The patient’s 
donor must be willing and able to give bone marrow stem cells and be: 
• 
An unaffected sibling donor who is a 6/6 match at HLA-A and –B (intermediate or higher 
resolution) and –DRB1 (at high resolution using DNA-based typing) OR 
• 
An unaffected related donor (other than a sibling) who is a 7/8 or 8/8 match for HLA-A,  
-B, -C (at intermediate or higher resolution) and –DRB1 (at high resolution using DNA-
based typing) OR 
• 
An unrelated donor who is a 7/8 or 8/8 match at HLA-A, -B, -C, and –DRB1 (at high 
resolution using DNA-based typing). 
 
The transplant conditioning regimen will include fludarabine, melphalan, and alemtuzumab 
starting at Day -14 (Flu/Mel/Alem).  GVHD prophylaxis will consist of cyclosporine and 
corticosteroids through engraftment.  Post-transplant supportive care will include infection 
surveillance and prophylaxis, and disease-specific supportive care. 
 
2.2. 
Hypothesis and Study Objectives 
 
2.2.1. Primary Hypothesis 
 
Allogeneic HCT with MRD/MUD using RIC conditioning (fludarabine, melphalan) and 
intermediate timing of alemtuzumab (Day -14) in patients with hemophagocytic syndromes or 
selected primary immune deficiencies including CGD, HIGM1, IPEX syndrome, and severe 
LAD-I will result in a one year overall survival rate of 90%.   
 
2.2.2. Primary Objective 
 
To prospectively determine the one year overall survival in subjects treated for hemophagocytic 
syndromes or selected primary immune deficiencies (CGD, HIGM1, IPEX, and severe LAD-I) 
using a standardized, reduced-intensity conditioning protocol consisting of fludarabine, 
melphalan and intermediate timing of alemtuzumab (Day -14).  
 
 

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2.2.3. Secondary Objectives 
 
Secondary objectives are to determine the impact of HCT on clinical and laboratory 
manifestations of hemophagocytic syndromes and selected primary immune deficiencies and the 
incidence of HCT complications.  Secondary clinical outcomes to be collected include: 
1. Rates of sustained engraftment: Donor engraftment > 5% (unfractionated blood and T 
cells) at one year without infusion of stem cell products after the original transplant.  
Incidence and timing of primary graft failure (< 5% donor cells by Day +42), infusion of 
second stem cell product, or graft loss (< 5% donor cells at any time from initial 
engraftment through Day +365), all of which are considered failures of sustained 
engraftment, will be analyzed. 
2. Incidence of HLH and CAEBV reactivation and death from disease. 
3. Immune reconstitution and functional immune recovery. 
4. The cumulative incidence of neutrophil and platelet engraftment. 
5. The cumulative incidence of grade II-IV and III-IV acute GVHD and chronic GVHD. 
6. Transplant-related complications including hepatic veno-occlusive disease (VOD) and 
CNS toxicity. 
7. Rates of reactivation of CMV and EBV and infection with adenovirus, invasive fungal 
infection, or bacterial sepsis. Prospective collection of peripheral blood at specific time-
points, in order to study pharmacokinetics of alemtuzumab, engraftment, and immune 
reconstitution with clinical correlation in a companion biology study. 
8. Overall survival and rate of sustained engraftment at one year of specific disease subsets 
(HLH-related diseases and selected immune deficiencies). 
 
2.3. 
Patient Eligibility 
 
2.3.1. Patient Inclusion Criteria 
1. Patient is ≥ 3 months and ≤ 45 years of age at time of enrollment. 
2. Meets criteria for one of the following immune disorders (2A-2F) requiring HCT: 
2A. HLH or related disorder with indication for HCT:  
a. Inherited gene mutation associated with HLH: PRF1, UNC13D (MUNC13-2), 
STXBP2 (MUNC18-2), STX11, RAB27A (Griscelli syndrome, type 2), SH2D1A 
(XLP1), XIAP (XLP2), LYST (Chediak-Higashi syndrome).  
– OR – 
b. Meets clinical criteria for HLH (Table 1.2), refractory to therapy according to HLH-
94 or HLH-2004 (dexamethasone/etoposide), or recurrent episodes of hyper-
inflammation.    
– OR – 
c. Meets clinical criteria for HLH (Table 1.2), without identified gene defects, with 
affected sibling – OR – decreased or absent NK cell function at the last evaluation,  

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– OR – a history of CNS inflammation as evidenced by pleocytosis in CSF or MRI 
evidence of hyper-inflammation in the CNS. 
2B. CAEBV: Patients with chronic EBV infection (CAEBV) with or without associated 
lymphoma (in complete remission) or active HLH.  Note that this diagnosis is distinct 
from 
post-transplant 
lymphoproliferative 
disorder/ 
EBV-associated 
lymphoproliferative disease (PTLD/LPD).  Patients must meet all of the following: 
a. Severe progressive illness, usually with fever, lymphadenopathy and splenomegaly 
that either began as primary EBV infection or was associated with markedly elevated 
antibody titers to EBV viral capsid antibody (≥ 1:5120) or early antigen (≥ 1:640), or 
markedly elevated EBV DNA in the blood; 
– AND – 
b. Infiltration of tissues (e.g., lymph nodes, liver, lungs, CNS, bone marrow, eye, skin) 
with lymphocytes; 
– AND – 
c. Elevated EBV DNA, RNA or proteins in affected tissues; 
– AND – 
d. The absence of HIV or post-transplant lymphoproliferative disorder. 
2C. Chronic granulomatous disease with indication for HCT: 
a. Oxidative burst < 10% normal with dihydrorhodamine (DHR) assay  
– AND –  
b. Documented CGD mutation(s) in gp91phox, p47phox, p67phox, p22phox or p40phox   
– AND –  
c. Severe disease as evidenced by one or more of the following: 
i. history of one or more potentially life-threatening infections 
ii. inflammatory bowel disease 
iii. failure to thrive with height <10% for age (unless parent(s) height <10%)  
iv. autoimmune complication felt to be linked to CGD 
2D. X-linked Hyper IgM Syndrome (HIGM1): 
a. Decreased serum IgG (more than 2 standard deviations below normal for age)  
– AND –  
b. Mutation in CD40LG – OR – family history of maternally related males with HIGM1. 
2E. IPEX Syndrome: 
a. Absent FOXP3+ CD4+ T cells – OR – abnormal function of FOXP3+CD4+ T cells  
– AND – 
b. Disease-associated mutation in FoxP3 (bi-allelic in females) – OR – family history of 
maternally related males with clinical diagnosis of IPEX. 
2F. Severe Leukocyte Adhesion Deficiency, type I (LAD-I): 
a. Decreased CD18 expression on neutrophils (<5% normal for age)  
– AND – 
b. Mutation of ITGB2 – OR – absence of ITGB2 mRNA in leukocytes 
3. Lansky or Karnofsky performance status ≥ 50%. 
4. The patient’s donor must be willing and able to give bone marrow stem cells and be: 

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• An unaffected sibling donor who is a 6/6 match at HLA-A and –B (intermediate or 
higher resolution) and –DRB1 (at high resolution using DNA-based typing) OR 
• An unaffected related donor (other than sibling) who is a 7/8 or 8/8 match for HLA-
A, -B, -C (at intermediate or higher resolution) and –DRB1 (at high resolution using 
DNA-based typing) OR 
• An unrelated donor who is a 7/8 or 8/8 match at HLA-A, -B, -C, and –DRB1 (at high 
resolution using DNA-based typing). 
5. Patient must have adequate organ function as measured by: 
a. Cardiac: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction 
(LVSF) > 26% by echocardiogram. 
b. Renal: Calculated or radioisotope GFR > 50 mL/min/1.73m2 
c. Hepatic: Adequate liver function: serum conjugated (direct) bilirubin < 2x upper limit 
of normal for age as per local laboratory (with the exceptions of isolated 
hyperbilirubinemia due to Gilbert’s syndrome, or hyperbilirubinemia as the result of 
liver inflammation in the setting of persistent, active HLH); ALT and AST < 10x 
upper limit of normal as per local laboratory (with the exception of elevated 
transaminase levels as the result of liver inflammation in the setting of persistent, 
active HLH).   
d. Pulmonary: Patient may not be on mechanical ventilation support or have progressive 
pulmonary infection at the time of transplant; Pulmonary Function Testing (PFT) 
with FEV1 > 50% of normal and DLCO corrected for Hgb > 50% of normal.  Patients 
unable to undergo PFTs should have stable respiratory status with SaO2 > 90% on a 
maximum of 2L/min supplemental oxygen. 
6. Signed informed consent. 
 
2.3.2. Patient Exclusion Criteria  
1. Hematopoietic stem cell transplant within 6 months of enrollment. 
2. Uncontrolled bacterial, viral or fungal infection (currently receiving appropriate 
antimicrobials and experiencing progression or no clinical improvement) at time of 
enrollment.  We recognize that patients with CAEBV may have ongoing EBV viremia at 
the time of initiating transplant therapy, but other patients should have no uncontrolled 
bacterial, viral or fungal infections at the time of enrollment (or prior to initiating the 
preparative regimen).  
3. Pregnant or breastfeeding. 
4. Seropositive for human immunodeficiency virus (HIV). 
5. Alemtuzumab within 2 weeks of enrollment. 
6. History of prior or current malignancy, especially malignancies with a likelihood of 
relapse and progression, with the exception of (1) EBV-associated lymphomas related to 
immune deficiency or lymphomas associated with X-linked LPD in a good remission, as 
they are unlikely to relapse after treatment; (2) Resected basal cell carcinoma or treated 

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cervical carcinoma in situ. Cancer treated with curative intent will not be allowed unless 
approved by the Protocol Officer or one of the Protocol Chairs. 
 
2.3.3. Donor Selection Criteria 
1. Related donors will be identified according to institutional guidelines. 
2. HLA typing of a sibling donor must be a 6/6 match for HLA–A and –B (intermediate or 
higher resolution) and –DRB1 (at high resolution using DNA-based typing). 
3. HLA typing of a related donor other than a sibling must be a 7/8 or 8/8 match for HLA-
A, -B, -C (at intermediate or higher resolution) and –DRB1 (at high resolution using 
DNA-based typing).  
4. Unrelated donors will be identified through the National Marrow Donor Program 
(NMDP) or equivalent donor search organization. 
5. HLA typing of an unrelated donor must be a 7/8 or 8/8 match for HLA–A, –B, –C and 
DRB–1 (at high resolution using DNA-based typing). 
6. Donors must be willing and able to donate bone marrow stem cells. 
7. For HLH or related disorders: If donor is a relative of a recipient with known HLH-
associated gene mutations, the donor must not have the same HLH-causing gene 
mutations as the recipient (a sibling with a heterozygous mutation of an autosomal 
recessive HLH-associated gene would be acceptable, as would a female sibling or other 
female relative who is a carrier of an X-linked HLH-associated gene mutation). If donor 
is a relative of a recipient with unknown genetic cause of HLH, the donor must not have 
medical history concerning for HLH or laboratory values suggestive of significant 
immune dysfunction (for example, highly elevated ferritin or absent NK cell function). 
8. For CGD, HIGM1, IPEX Syndrome, and LAD-I: If donor is a sibling, the donor must not 
meet diagnostic criteria for the immune deficiency for which the patient is receiving 
HCT. 
9. A donor who is EBV IgG positive is recommended for recipients with history of EBV 
exposure, and strongly recommended for patients with CAEBV.  Similarly, a donor who 
is CMV IgG positive is recommended for recipients with history of CMV exposure. 
 
2.3.4. Donor Exclusion Criteria 
1. Donors will be excluded if they are an identical twin of the recipient. 
2. Females who are pregnant (positive serum β-HCG) or uninterruptedly breastfeeding will 
be excluded. 
3. HIV seropositive donors will be excluded. 
4. Donors receiving experimental therapy or investigational agents will be excluded unless 
approved by the protocol chairs and protocol officer. 
 
 

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2.4. 
Treatment Plan 
 
If an infection occurs or a pre-existing infection worsens between the day of enrollment and the 
day the preparative regimen is scheduled to begin, the infection must be controlled and the 
patient clinically improved prior to initiating the preparative regimen. We recognize that patients 
with CAEBV may have ongoing EBV viremia at the time of initiating pre-transplant therapy, but 
other patients should have no uncontrolled bacterial, viral or fungal infections at the time of 
initiation of the transplant preparative regimen. 
 
Patients will receive Intermediate RIC with Flu/Mel/Alem (Table 2.4). The experimental design 
is outlined in Figure 2.4. 
 
 
 
Figure 2.4: Trial Design 
 
 
TABLE 2.4: Flu/Mel/Alem(-14) 
Day 
Treatment 
(adults and children > 15kg) 
Treatment 
(children 10 to 15 kg) 
Treatment 
(children < 10 kg) 
-14 
Alemtuzumab* 3mg test dose 
Alemtuzumab 0.2 mg/kg 
Alemtuzumab 0.2 mg/kg 
-13 
Alemtuzumab*  (max 21.75 mg) Alemtuzumab 0.2 mg/kg 
Alemtuzumab 0.2 mg/kg 
-12 
Alemtuzumab*  (max 21.75 mg) Alemtuzumab 0.2 mg/kg 
Alemtuzumab 0.2 mg/kg 
-11 
Alemtuzumab*  (max 21.75 mg) Alemtuzumab 0.2 mg/kg 
Alemtuzumab 0.2 mg/kg 
-10 
Alemtuzumab*  (max 21.75 mg) Alemtuzumab 0.2 mg/kg 
Alemtuzumab 0.2 mg/kg 
-9 
Rest 
Rest 
Rest 
-8 
Fludarabine 30 mg/m2 
Fludarabine 30 mg/m2 
Fludarabine 1 mg/kg  
-7 
Fludarabine 30 mg/m2 
Fludarabine 30 mg/m2 
Fludarabine 1 mg/kg  
-6 
Fludarabine 30 mg/m2 
Fludarabine 30 mg/m2 
Fludarabine 1 mg/kg  
-5 
Fludarabine 30 mg/m2 
Fludarabine 30 mg/m2 
Fludarabine 1 mg/kg  
-4 
Fludarabine 30 mg/m2 
Fludarabine 30 mg/m2 
Fludarabine 1 mg/kg  
-3 
Melphalan 140 mg/m2 
Melphalan 140 mg/m2 
Melphalan 4.7 mg/kg 
-2 
Rest 
Rest 
Rest 
-1 
Rest 
Rest 
Rest 
0 
Stem cell infusion 
Stem cell infusion 
Stem cell infusion 
 
Alemtuzumab dose is 1 mg/kg for the entire treatment course (including the test dose on Day -14) in adults 
and children > 15 kg.  
 
Calculation for Alemtuzumab daily dose for Day-13, Day-12, Day-11, Day-10 for a patient 15kg-90kg: 
((1mg/kg x (patient weight in kg)) – 3mg)/4 
 
The maximum cumulative Alemtuzumab dose for any patient is 90 mg, making the maximum daily dose of 
Alemtuzumab from Day-13 to Day -10, 21.75 mg = (90mg – 3mg)/4 

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2.4.1. Alemtuzumab (Campath-1H) 
 
If a patient cannot receive the complete dose due to intolerance, the choice of conditioning 
regimen modifications (if any) will be left to the institution; however, the patient will be 
followed per protocol. 
 
For information about the Campath Distribution Program and how to procure Campath, please 
visit the following website: http://www.campath.com/index.html 
 
2.4.1.1. Premedication 
 
Premedication should be commenced 30 minutes prior to each infusion of alemtuzumab, 
including the first dose, and should be continued as needed for at least 48 hours after the last 
dose of alemtuzumab. 
 
Recommended pre-medication includes the following combination of medications: 
Acetaminophen: 15 mg/kg PO pre-therapy, then as needed every 6 hours for signs of 
allergic reaction (maximum 4 grams per day) 
Diphenhydramine: 1 mg/kg IV or PO pre-medication, then every 6 hours as needed for 
signs of allergic reaction (maximum 50 mg/dose) 
Meperidine: 0.5 mg/kg IV every 6 hours as needed for rigors 
Hydrocortisone: 1 mg/kg IV pre-medication, then 1-2 mg/kg IV as needed for signs of 
allergic reaction. For patients on scheduled corticosteroids for control of HLH, 
dexamethasone or methylprednisolone may substitute for hydrocortisone. 
 
2.4.1.2. Alemtuzumab administration 
 
First day:  test dose: 
Day -14:  The first day children ≤ 15kg will receive a dose of 0.2 mg/kg subcutaneously.  
Children or adults > 15 kg will receive a maximum of 3 mg subcutaneously.  Subcutaneous route 
of administration for alemtuzumab is required on this protocol. 
 
If the first dose is not tolerated: 
If the patient has a severe, life-threatening or fatal adverse reaction to alemtuzumab (e.g., severe 
hypotension, severe bronchospasm), the adverse event meets the expedited reporting 
requirements (within 24 hours for life-threatening or fatal events or within 3 days for severe 
events) through the expedited AE reporting system via AdvantageEDCSM (see Section 4.2.2).   
 
If the first dose is tolerated: 
Alemtuzumab will be given subcutaneously each day for the next four days (-13 to -10).  The 
total dose will be 1 mg/kg with a maximum cumulative dose of 90 mg.  For children ≤ 15 kg, the 
dose will be 0.2 mg/kg each day.  For children or adults > 15kg the dose will be the total dose 
(1mg/kg) minus the 3 mg test dose divided evenly over the four days.  For example, if the 

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patient weighs 40 kg, they will receive 3 mg on Day -14 and 40 mg (total dose) – 3 mg (test 
dose) = 37 mg/4 daily doses or 9.25 mg daily Day -13 to Day -10. (Table2.4) 
 
Day -13 to Day -10: (total dose (1 mg/kg) – test dose (3 mg))/4 mg given daily subcutaneously 
(max cumulative dose: 90 mg, max daily dose (90 mg – 3 mg)/4 or 21.75 mg for any patient ≥ 
90kg). (Table 2.4) 
 
Alemtuzumab dilution guidelines:  For ≤ 3 mg, drug is diluted to 3 mg/mL concentration. For 
doses > 3 mg undiluted 30 mg/mL concentration is used. 
 
2.4.2. Fludarabine 
 
Fludarabine will be administered IV, on Day -8 to Day -4 (for a total of 5 days) given over a 
minimum of 30 minutes daily.  (Table 2.4) The infusion can take longer per institutional 
guidelines. 
 
 
For patients ≥ 10kg, Dose:  30 mg/m2/day IV (cumulative dose 150 mg/m2) 
For children < 10kg, Dose:  1 mg/kg/day IV (cumulative dose 5 mg/kg) 
 
Preparation, administration and monitoring will be according to institutional standard practice. 
 
Dose Adjustment of Fludarabine for Patients Whose Weight Exceeds > 125% IBW 
Fludarabine will be dosed based on actual weight for patients ≤ 125% IBW. Those > 125% IBW 
will be dosed based upon adjusted ideal body weight as follows: 
 
Adjusted ideal body weight = IBW + 0.25(Actual weight – IBW)  
 
The following formulas for pediatric and adult IBW calculations are recommended, but IBW 
may be calculated according to institutional SOPs. 
 
Recommended Ideal Body Weight Calculation for Children Age 1-17 years 
IBW = (Height (cm)2 x 1.65)/1000 
 
Recommended Ideal Body Weight Calculation for Adults 
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg 
IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg 
 
2.4.3. Melphalan 
 
Melphalan will be given IV on Day -3 (Table 2.4). It is recommended to be given over a 
minimum of 30 minutes; however, the infusion can be shorter or longer per institutional 
guidelines. 
 
 
For patients ≥ 10kg, Dose:  140 mg/m2 IV 
 
For children < 10 kg, Dose:  4.7 mg/kg IV 
 

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2.4.4. Infusion of Hematopoietic Stem Cells 
 
Under no circumstances is the stem cell product to be irradiated.  Vital signs should be 
monitored before beginning the infusion and periodically during administration.  Pre-
medications and hydration prior to stem cell infusion will be administered per institutional 
procedures.   
 
2.5. 
GVHD Prophylaxis 
 
Patients will receive the regimen as described in Table 2.5 
 
TABLE 2.5: GVHD PROPHYLAXIS REGIMEN 
 
Day 
Dosage (HLH Patients) 
Dosage (Non-HLH Patients) 
-3 
Cyclosporine dosed to maintain appropriate 
level.  Given through Day +100, then taper 
to Day +180. 
Cyclosporine 
dosed 
to 
maintain 
appropriate level.  Given through Day 
+100, then taper to Day +180. 
-2 
Methylprednisolone 2 mg/kg/day IV 
(if patient is already on corticosteroids for 
HLH control, adjust to this amount) 
-- 
-1 
Methylprednisolone 2 mg/kg/day IV 
-- 
0 
Stem cell infusion 
Methylprednisolone 1 mg/kg/day  
(ongoing  through Day +28, then taper over 
1 month; may substitute PO Prednisone 1.2 
mg/kg/day) 
Stem cell infusion 
Methylprednisolone 1 mg/kg/day  
(ongoing  through Day +28, then taper 
over 1 month; may substitute PO 
Prednisone 1.2 mg/kg/day) 
 
2.5.1. Cyclosporine (CSA) 
 
Cyclosporine administration will commence on Day -3 and dosing per institutional standard will 
be adjusted to maintain a level of 250-500 ng/mL by TDX method (or 200-350 ng/mL by 
Tandem MS or equivalent level for other CSA testing methods).  CSA can be administered by 
continuous or intermittent infusion per institutional guidelines.  Patients who are on CSA at the 
time of starting conditioning will continue on the pre-HCT dose, with adjustment to goal levels 
beginning on Day -3. Either brand name (Sandimmune) or generic cyclosporine will be allowed. 
 
Dose adjustments will be made on the basis of toxicity and CSA levels.  Once the patient can 
tolerate oral medications and has a normal gastro-intestinal transit time, CSA will be converted 
to an oral form per institutional standards.  CSA dosing will be monitored and altered as 
clinically appropriate.  
 

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Patients will receive CSA until Day +100 and CSA will be tapered between Days +100 to +180.  
If there is no GVHD, the dose will be tapered by approximately 10% per week beginning on Day 
+100. 
 
In the event of toxicity, tacrolimus may be substituted for cyclosporine. Tacrolimus 
administration will commence on Day –3, and doses will be adjusted to maintain a level of 8-12 
ng/mL by the IMx immunoassay technique (Abbott Diagnostics) or a level of 5-8 ng/mL if 
measured by a LC-tandem mass-spectrometric assay.  If using another method to measure levels 
then dose should be adjusted to maintain appropriate levels per institutional standards.  
Tacrolimus can be administered by intermittent infusion or by continuous infusion to maintain 
therapeutic levels per institutional guidelines.  
 
Dose adjustments will be made on the basis of toxicity and tacrolimus levels.  Once the patient 
can tolerate oral medications and has a normal gastro-intestinal transit time, tacrolimus will be 
converted to an oral form. Tacrolimus dosing will be monitored and altered as clinically 
appropriate. 
 
From Day +100 to +180, tacrolimus will be gradually tapered in patients without significant 
acute or chronic GVHD (taper approximately 10% per week). 
 
2.5.2. Methylprednisolone/Prednisone 
 
On Day -2, methylprednisolone 2 mg/kg/day IV in two divided doses will be started as GVHD 
prophylaxis as well as prophylaxis against reactivation of HLH and adrenal insufficiency for 
patients with HLH.  For patients who remain on corticosteroids for HLH control, this will be 
continued and unchanged through conditioning until Day -2, when previous corticosteroids will 
be replaced with methylprednisolone.  On Day 0, the methylprednisolone dose will decrease to 1 
mg/kg/day for patients with HLH and continue at that dose until Day +28. For patients without 
HLH, they will start methylprednisolone at Day 0 at 1mg/kg/day. All patients will continue at 
that dose until Day +28.  In the absence of GVHD, methylprednisolone will be tapered and 
discontinued over 1 month.  Oral prednisone may substitute for methylprednisolone at 1.2 
mg/kg/day after Day 0. 
 
2.6. 
Managing Chimerism  
1. Donor chimerism studies (T cell and whole blood) are required monthly starting at Day 
+28 through Day +100, then at Day +180 and Day +365. An optional chimerism study at 
Day +21 is recommended if neutrophil engraftment occurs before Day +28.  
Additionally, donor chimerism studies are required at Day +42 if prior chimerism results 
are equivocal (donor chimerism < 20%). Additional donor chimerism studies are 
recommended at Day +70. Monitoring chimerism outside of the required studies can be 
performed by whole blood or T-cell chimerism or both, by center preference.   
Recommendation: If chimerism falls by > 25% after engraftment, we recommend that 
immune suppression be rapidly tapered (over 0-14 days) with more frequent (weekly) 
chimerism monitoring.  If chimerism continues to fall despite withdrawal of immune 
suppression, DLI can be given according to center preference.  If the patient has falling 

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chimerism in the face of clinically active, significant GVHD, full withdrawal of immune 
suppression may not be clinically feasible. 
2. Patients with donor engraftment < 5% by Day +42 will be considered primary graft 
failures.   
Recommendation:  It is recommended that these patients undergo a second transplant.  
 
2.7. 
Supportive Care (Recommended) 
 
Institutional standard care practice guidelines will be followed after transplantation for 
nutritional support, treatment of infections, and blood product support.  Supportive guidelines are 
detailed below. 
 
2.7.1. Engraftment Syndrome 
 
Engraftment syndrome is a clinical diagnosis.  The most frequently reported manifestations are 
transient fever, rash, and respiratory symptoms not attributable to infection or GVHD.  The 
pathophysiology is multifactoral mediated by cellular, complement and cytokine components.  
Diagnostic criteria include fever (temperature > 38.5o C) without an identifiable infectious cause 
within 4 days of the start of neutrophil recovery and/or an erythematous rash not attributable to 
GVHD or medications and/or capillary leak (weight gain, edema, ascites, effusions) or 
respiratory symptoms not attributable to IPS.  Mild symptoms may not require therapy due to the 
self-limiting nature of this syndrome.  For progressive symptoms, methylprednisolone at  
2 mg/kg/day is recommended for 2-5 days.  If recurrent, prolonged, or unusually severe, 
investigation for HLH reactivation and GVHD is recommended. 
 
2.7.2. Venous Access 
 
Recipients will have appropriate long-term central venous access placed, per institutional 
standard practice, prior to beginning the conditioning regimen.  The placement of a double lumen 
tunneled catheter is recommended. 
 
2.7.3. Growth Factor 
 
Granulocyte colony stimulating factor (G-CSF) may be used at the treating physician’s 
discretion.  Granulocyte-monocyte colony stimulating factor (GM-CSF) is generally not 
recommended for patients with HLH. 
 
2.7.4. Blood Products 
 
The hemoglobin level is recommended to be maintained over 8.0 g/dL for at least 100 days post-
transplant.  Due to specific bleeding risks in HLH patients, the platelet count should be 
maintained > 50,000/ul, and transfused per institutional guidelines in patients with other immune 
defects.  Irradiated blood products should be administered universally. 
 

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2.7.5. Treatment of Fever/Infections 
 
Patients should be monitored closely for clinical manifestations of infection and treated per 
institutional guidelines with broad spectrum antibacterial, antiviral and antifungal agents.  Since 
patients receive alemtuzumab, they are especially susceptible to bacterial and viral infections in 
the early post-transplant period. 
 
2.7.6. Blood Pressure Monitoring and Control 
 
Blood pressure should be strictly controlled to prevent CNS toxicity. Patients with HLH often 
have experienced renal toxicity prior to HSCT. This in combination with high doses of steroids 
and Calcineurin inhibitors used both before and after HSCT puts these patients at risk for 
posterior reversible encephalopathy syndrome (PRES). Blood pressure should be monitored 
closely and elevations in systolic and/or diastolic pressure(s) should be treated promptly to 
maintain blood pressure within 10% above the baseline age-related median systolic and diastolic 
pressure (see Appendix G). 
 
PRES is characterized by headache, seizures, and visual loss, as well as an abrupt increase in 
blood pressure.  If PRES is suspected or diagnosed, symptom-directed treatment should be 
maintained until the condition is reversed by control of hypertension or other instigating factors. 
A negative MRI is required to exclude PRES. 
 
2.7.7. Infection Surveillance and Prophylaxis 
 
2.7.7.1. HSV prophylaxis 
 
Valacyclovir or acyclovir prophylaxis is recommended for 6 months for patients who are 
seropositive for HSV or VZV. 
 
2.7.7.2. Pneumocystis jirovecii pneumonia (PJP) prophylaxis 
 
Trimethoprim-sulfamethoxazole or an equivalent drug should be administered beginning after 
neutrophil recovery and continued post-transplant for 1 year. 
 
2.7.7.3. Fungal prophylaxis 
 
Due to the level of prolonged immune suppression, anti-fungal prophylaxis against Aspergillus 
sp. is recommended with agents such as itraconazole, voriconazole, posaconazole or other 
appropriate agents until Day +180.   
 
2.7.7.4. Bacterial prophylaxis 
 
May consider bacterial prophylaxis per institutional guidelines. 
 
2.7.7.5. CMV surveillance 
 

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All recipients must be tested weekly for CMV from plasma using the PCR method beginning a 
week after commencing alemtuzumab (starting Day -7) until Day +100, then at Day +180 and 
Day +365.  Antiviral therapy for CMV reactivation should commence if CMV testing reveals a 
high or rising viral load, according to institutional practice guidelines. 
 
2.7.7.6. EBV surveillance 
 
Patients will have EBV DNA quantitative PCR testing on plasma or peripheral blood cells every 
week after commencing alemtuzumab (starting Day -7) until Day +100, then at Day +180 and 
Day +365. In the event of persistent EBV viremia or signs/symptoms consistent with EBV-
related PTLD, therapy is recommended according to institutional practice guidelines. 
 
2.7.7.7. Adenovirus surveillance 
 
Testing for adenovirus infection in the blood by PCR is recommended in the event of symptoms 
suspicious for an infection, including diarrhea, hepatic dysfunction or respiratory symptoms.  If 
an active systemic infection is diagnosed, therapy should be instituted according to institutional 
practice guidelines. 
 
2.7.7.8. Intravenous immune globulin 
 
Intravenous immune globulin may be administered according to institutional practice guidelines. 
 
2.7.7.9. HLH surveillance  
a. HLH recurrence should be evaluated in patients who develop unexplained fever (> 2 
days) or organ dysfunction.  Markers of inflammation include sIL2Rα, ferritin, LDH and 
d-dimers.  Recommendations for pre-transplant management of inflammation in HLH are 
discussed in Appendix E.  Patients with HLH may have exaggerated engraftment 
syndrome.  However, systemic HLH typically does not recur in the absence of graft loss. 
b. All patients with history of CNS involvement by HLH (pleocytosis, elevated protein, 
abnormal MRI, or hemophagocytosis in CSF) should undergo diagnostic LP prior to 
transplant, at Day +28 (+ 3 days), at Day +100 (+ 14 days) or at any time of mental status 
change.  Brain MRI may be substituted for LP if patients are not able to tolerate the 
procedure.  CNS reactivation of HLH (as evidenced by pleocytosis or hemophagocytosis 
in CSF, or MRI consistent with HLH-associated inflammation) pre- or post-transplant 
may be treated with intrathecal therapy.  Isolated CNS inflammation may be seen despite 
engraftment in patients without systemic symptoms of inflammation. 
c. Patients who have reactivation of HLH, either isolated CNS or systemic (fever, highly 
elevated ferritin and soluble IL2R, end-organ damage) may receive salvage therapy per 
treating physician.  Stable engraftment > 20% is typically sufficient to prevent symptoms 
of HLH, though isolated CNS inflammation is occasionally observed (Jordan et al., 
2011).  See Appendix E for recommendations for HLH salvage therapy. 
 

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2.7.7.10. Guidelines for infusing a second stem cell product or donor cellular infusion 
 
Refer to Section 2.6 for guidelines for managing unstable chimerism and graft loss.   
 
2.8. 
Toxicities 
 
2.8.1. Conditioning: Pancytopenia 
 
The administration of Flu/Mel/Alem is expected to produce pancytopenia for at least a week in 
most patients.  Most patients will require transfusions of red blood cells and platelets during this 
period. In addition, many patients will develop fever and approximately 30% will develop a 
documented infection during the period of neutropenia.  Complications related to pancytopenia 
may be life-threatening or fatal. 
 
2.8.2. Alemtuzumab  
 
Administration can cause fevers, rigors, nausea, vomiting, bleeding, hypotension, fatigue, rash, 
local irritation at injection site, urticaria, arrhythmias, dyspnea, headache, cough, pruritis, throat 
inflammation, diarrhea, pain, anorexia, increased perspiration, sepsis, myalgia, asthenia, 
hypertension, pharyngitis, abdominal pain, back pain, dizziness, anemia, infections, neutropenia 
and thrombocytopenia. 
 
Fever and chills: These are regularly observed, particularly during initial doses.  They 
probably result from breakdown of cells binding the antibody. 
 
Skin rash and itching: A complication that is probably due to allergic reactions to the 
antibodies.  These symptoms will usually be prevented by or controlled with anti-histamines 
as well as with concomitant administration of corticosteroids. 
 
Anaphylaxis: A rare but severe allergic reaction which may cause a life-threatening drop in 
blood pressure, wheezing and difficulty breathing and severe hives or skin exfoliation.  This 
complication may be treated with anti-histamines and steroids. 
 
Platelet and white cell count depression: These are frequently observed and are probably 
caused by the binding of the antibody to human blood elements.  Platelet transfusions should 
be administered to reduce the chance of bleeding or life-threatening hemorrhage. 
 
2.8.3. Fludarabine 
 
Administration can cause hemolytic anemia, neutropenia, thrombocytopenia, low blood counts 
secondary to bone marrow suppression, bleeding, infection, pneumonia, nausea, vomiting, 
anorexia, diarrhea, oral ulcers, stomatitis, pain, skin rash, pneumonitis, edema, fever, rigors, 
fatigue, weakness, blurred vision, peripheral neuropathy, agitation/nervousness, confusion, 
difficulty breathing, coma, renal damage, decreased immunity and rarely encephalopathy (in 
very high doses). 
 

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2.8.4. Melphalan 
 
Administration can cause neutropenia, thrombocytopenia, anemia, infection, bleeding, nausea, 
vomiting, anorexia, weakness, weight loss, hypotension, diarrhea, oral ulcers, decreased 
immunity, sterility, interstitial pneumonitis, lung fibrosis, allergic reactions, skin breakdown (if 
drug leaks from vein), temporary hair loss, excessive perspiration, cancer of bone marrow cells, 
hepatic damage, cardiac arrest and rarely seizures (with very high doses). 
 
2.8.5. Hematopoietic Cell Infusion 
 
Infusion of allogeneic BM cells can result in shortness of breath, fever, hemolysis with renal 
dysfunction and back pain or anaphylaxis.  To reduce the risk of reactions to product infusion, 
patients will be hydrated before and after administration of allogeneic BM, and will be 
monitored closely before, during and after infusion as per institutional practice. 
 
2.8.6. Cyclosporine 
 
Administration may cause nephrotoxicity, seizures, tremors, headaches, abdominal pain or 
indigestion, edema, confusion, muscle cramps, dizziness, hemolytic anemia, hypertension, 
hirsutism, thrombotic microangiopathy, electrolyte imbalances, paresthesia/neuropathy, gingival 
hyperplasia, hypertrygliceridemia, diarrhea, transient blindness, renal dysfunction and hepatic 
dysfunction. 
 
2.8.7. Tacrolimus 
 
Administration may cause hypertension, hyperglycemia, anemia, hyperkalemia, hypokalemia, 
hypomagnesemia, hypocalcemia, anorexia, diarrhea, nausea, fever, headache, hair loss, vomiting, 
peripheral neuropathy, pruritis, rash, abdominal pain, confusion, joint pain, increased light 
sensitivity, changes in vision, insomnia, infection, jaundice, renal injury, and seizures. 
 
2.8.8. Dexamethasone, Methylprednisolone and Prednisone 
 
Corticosteroids can cause predisposition to infection, overeating, abnormal hormone production, 
hyperglycemia, slowed growth, decreased bone density, headaches, poor wound healing, 
hypertension, stomach ulcers, muscle weakness, cataracts, increased intraocular pressure, 
worsening of diabetes, pancreatitis, disturbance of bone calcium, electrolyte disturbances, 
gastritis, GI bleeding, insomnia and mental status changes, fluid retention, edema, fat 
accumulation causing a change in facial appearance, and aseptic necrosis. 
 
2.8.9. Filgrastim (G-CSF) 
 
Administration can cause bone pain, increased levels of liver enzymes and uric acid in the blood, 
thrombocytopenia, headaches, fatigue, local irritation at injection site, nausea, bleeding, fever, 
allergic reaction, splenomegaly or rupture of the spleen, worsening of pre-existing skin rashes, 
temporary 
hair 
loss, 
and 
inflammation 
of 
a 
blood 
vessel 
in 
the 
skin.

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3-1 
CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. 
Primary Endpoint 
 
The primary endpoint will be overall survival at one year post-transplant in patients who receive 
at least one dose of the preparative regimen. 
 
3.2. 
Secondary Endpoints  
 
Secondary endpoints are evaluations of the effects of HCT on clinical and laboratory 
manifestations of immune deficiency at one year and evaluation of other transplant-related 
outcomes.  These will include the following: 
 
3.2.1. Sustained Engraftment (sustained donor lymphoid and myeloid chimerism) 
 
Sustained engraftment will be considered to have occurred in the absence of: 
1. Primary graft failure: < 5% donor chimerism by Day +42 
2. Second stem cell infusion: DLI (except in the case of donor CTLs given for infection 
control) or second HCT following original HCT 
3. Secondary graft failure: < 5% donor chimerism following original engraftment 
 
Overall as well as T cell (CD3+) chimerism will be evaluated at least every month following 
engraftment until Day +100, then at Day +180 and Day +365, as well as when clinically 
indicated.  
 
3.2.2. HLH and CAEBV Reactivation 
 
3.2.2.1. Systemic HLH reactivation 
 
HLH reactivations are difficult to define since the transplant process alters many of the 
diagnostic criteria (Henter et al., 2007).  Post-transplant HLH reactivation is defined by clinical 
and lab evidence of pathologic inflammation (persistent fever, progressive cytopenias, rising 
ferritin and soluble IL2Rα, decreasing fibrinogen, hepatosplenomegaly, end-organ damage) not 
attributable to other causes.   
 
3.2.2.2. CNS HLH reactivation 
 
Reactivation of CNS inflammation in patients with HLH may present with or without altered 
mental status and is defined by pleocytosis in CSF or an MRI consistent with CNS inflammation 
not attributable to other causes.   
 

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3.2.2.3. CAEBV reactivation 
 
In a patient with known CAEBV, CAEBV reactivation is defined as detection of recipient EBV+ 
lymphocytes in tissue (peripheral blood lymphocytes or tissue biopsy) following engraftment. 
 
3.2.3. Immune Reconstitution and Functional Immune Recovery 
 
3.2.3.1. Recovery of lymphocyte subpopulations 
 
Absolute number of CD3, CD4, CD8, CD16+56 and CD19 cells will be measured by flow 
cytometry.  Immunoglobulin levels (IgG, IgA and IgM) will also be quantified (at baseline prior 
to conditioning, Day +100 and Day +365). B cell reconstitution is defined as an IgG of > 500 
mg/dL more than 12 weeks from the last IVIg infusion. 
 
3.2.3.2. Correction of Immune Defects 
 
The following will be tested prior to conditioning, on Day +100 and Day +365, per underlying 
diagnosis. 
Disease-specific studies:  
i. 
HLH: NK cell function 
ii. 
HLH (with PRF1 mutation): Perforin expression by flow cytometry 
iii. 
XLP: SAP expression by flow cytometry 
iv. 
CAEBV: EBV qPCR  
v. 
HIGM: CD40L expression on activated CD4+ T cells by flow cytometry (if available) 
vi. 
CGD: DHR assay 
vii. 
IPEX: Quantitative Treg analysis by flow cytometry; Functional Treg assay (if 
available) 
viii. 
LAD: CD18 expression on granulocytes by flow cytometry 
 
3.2.4. Cumulative Incidence of Neutrophil and Platelet Engraftment 
 
Neutrophil Engraftment: Time to ANC engraftment is defined as the first of three measurements 
on different days that the patient has an absolute neutrophil count of ≥ 500/uL following 
conditioning regimen induced nadir. 
 
Platelet Engraftment: Platelet engraftment is defined as the first day of a minimum of three 
measurements on different days that the patient has achieved a platelet count > 20,000 AND the 
patient is platelet transfusion independent for a minimum of seven days following conditioning 
regimen induced nadir. 
 
Subjects must not have had platelet transfusions during the preceding 7 days after the day of 
engraftment, unless the platelet transfusion is being given specifically to achieve a platelet 
threshold to allow an elective invasive procedure. 
 

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3.2.5. Grade II-IV and Grade III-IV Acute GVHD 
 
The cumulative incidence of grade II-IV and grade III-IV acute GVHD will be assessed 
according to the BMT CTN Manual of Procedures (MOP). 
 
3.2.6. Chronic GVHD 
 
Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP. 
 
3.2.7. Frequency of Transplant-related Complications 
 
3.2.7.1. Veno-occlusive disease 
 
Veno-occlusive disease (VOD) is diagnosed by the presence of two or more of the following 
with no other identifiable cause for liver disease (McDonald et al., 1993): 
1. Jaundice (direct bilirubin > 2 mg/dL or > 34 umol/L) 
2. Hepatomegaly with right upper quadrant pain 
3. Ascites and/or weight gain (> 5% over baseline) 
 
3.2.7.2. CNS toxicity  
 
CNS toxicity is defined as a patient experiencing seizures, CNS hemorrhage, or posterior 
reversible encephalopathy syndrome (PRES). 
 
3.2.7.3. Infection 
 
Infection is defined as documented infection with or reactivation of viruses, including CMV 
reactivation, adenovirus infection, or EBV reactivation; invasive fungal infections; and systemic 
bacterial infections.  CMV and EBV will be followed by PCR weekly.  Other pathogens will be 
evaluated as clinically indicated. 
 
3.2.7.4. Disease Group Specific Outcomes 
 
The above endpoints will be analyzed within disease subgroups, specifically HLH patients 
versus patients entering with other primary immune deficiencies.   
 
3.3. 
Correlative Biology Studies  
 
Optional peripheral blood samples will be collected for correlative biology studies and shipped 
to the BMT CTN Research Sample Repository within 14 days prior to start of conditioning (Day 
-28 to Day -14), on Day -7, Day -1, Day +1, Day +14, Day +28, Day +42, Day +70, Day +100, 
Day +180 and Day +365. As samples must be collected and shipped the same day and only on 
Monday through Thursday, there is some flexibility in these specific days as shown below 

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(Table 3.3).  Blood samples will be used in correlative biology studies, including correlation of 
clinical variables with alemtuzumab pharmacokinetics, engraftment, and immune reconstitution. 
 
TABLE 3.3: OPTIONAL PERIPHERAL BLOOD SAMPLES FOLLOW-UP SCHEDULE 
Visit 
Window 
Prior to start of conditioning Day -28 to Day -14 
Day -7 
Day -8 to Day -6 
Day -1 
Day -2 to Day 0 
Day +1 
Day +1 to Day +3 
Day +14 
Day +12 to Day +16 
Day +28 
Day +26 to Day +30 
Day +42 
Day +39 to Day +45 
Day +70 
Day +60 to Day +80 
Day +100 
Day +90 to Day +110 
Day +180 
Day +160 to Day +200 
Day +365 
Day +335 to Day +395 

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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. 
Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  The following procedures should be followed: 
1. The transplant coordinator at the transplant center should proceed with their institution’s 
standard procedure to identify a sibling donor, if applicable.  If an unrelated donor search 
is to be pursued, then the coordinator should inform the transplant center’s assigned 
NMDP (or other appropriate donor search organization) coordinator through the standard 
procedure for any unrelated donor. 
2. Within the 14 days prior to initiation of the conditioning regimen, an authorized user at 
the transplant center should enter the patient demographics and complete the Segment 0 
Enrollment Form in AdvantageEDC.  The Segment 0 form includes a question 
confirming that the patient (or legally authorized representative) signed the informed 
consent.  The patient will be assigned a study number at this time.  Additionally, Segment 
0 requires completion of the HLA-typing form (patient and donor) to confirm that the 
HLA-typing meets protocol criteria.  Upon successful completion of the two Segment 0 
forms, the authorized user will proceed to Segment A and complete the Segment A 
enrollment form to verify eligibility and capture proposed start date of conditioning.  The 
Segment A enrollment form must be completed prior to initiation of conditioning 
regimen. 
 
4.2. 
Study Monitoring 
 
4.2.1. Follow-up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.2.1.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide.  The Data 
Management Handbook, including the Forms Submission Schedule, is available on the 
homepage of the Internet data entry system. 
 
4.2.1.1. Follow-up visits 
 
Follow-up visits will begin as soon as patients are enrolled onto the study.  The follow-up period 
is 12 months. 
 
 

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TABLE 4.2.1: FOLLOW-UP SCHEDULE 
Study Visit 
Target Day 
(+ 3 Days to Day +42 Post-HCT) 
(+ 7 Days to Day +60) 
(+ 14 Days to Day +100) 
(+ 28 Days After Day +100) 
1 week 
7 days 
2 week 
14 days 
3 week 
21 days 
4 week 
28 days 
5 week 
35 days 
6 week 
42 days 
7 week 
49 days 
8 week 
56 days 
9 week 
63 days 
10 week 
70 days 
11 week 
77 days 
12 week 
84 days 
13 week 
91 days 
100 day 
100 days 
6 month 
180 days 
12 month 
365 days 
 
4.2.1.2. Criteria for forms submission 
 
Criteria for timeliness of submission for all study forms are detailed in the Data Management 
Handbook and User’s Guide.  Forms that are not entered into AdvantageEDCSM within the 
specified time will be considered delinquent.  A missing form will continue to be requested 
either until the form is entered into AdvantageEDCSM and integrated into the Data and 
Coordinating Center’s (DCC) master database or until an exception is granted and entered into 
the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
4.2.1.3. Reporting patient deaths 
 
Recipient Death Information must be entered into AdvantageEDCSM within 24 hours of 
knowledge of the patient’s death on the Death Form and the Unexpected, Grade 3-5 Adverse 
Event Form.  If the cause of death is unknown at that time, the cause of death field may be left 

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blank.  However, once the cause of death is determined, the form must be updated in 
AdvantageEDCSM.   
 
4.2.1.4. CIBMTR data reporting 
 
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all 
consecutive hematopoietic stem transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR).  
Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database 
(SCTOD) (Note: Federal legislation requires submission of these forms for all US allotransplant 
recipients).  Enrollment of BMT CTN #1204 must be indicated on the SCTOD pre-transplant 
registration form.  Additionally, CIBMTR pre- and post-transplant Report Forms must also be 
submitted for all patients enrolled on this trial.  CIBMTR forms will be submitted directly to the 
CIBMTR at the times specified on the Form Submission Schedule.   
 
4.2.1.5. Weekly GVHD monitoring 
 
GVHD should be monitored in accordance with BMT CTN guidelines as specified in the Manual 
of Procedures.  Patients should be assessed weekly until Day +100 post-transplant for GVHD.  
After Day +100, patients will be assessed at each follow-up visit for the presence of GVHD 
through 12 months.  For scheduling, a target day range has been provided in Table 4.2.1. 
 
4.2.2. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) and all deaths will be reported through an expedited 
AE reporting system via AdvantageEDCSM.  Additionally, any occurrence of posterior reversible 
encephalopathy syndrome (PRES) or reversible posterior leukoencephalopathy syndrome 
(RPLS) requires reporting through the AE reporting system. Unexpected, grade 4-5 AEs must be 
reported within 24 hours of knowledge of the event.  Unexpected, grade 3 AEs must be reported 
within three business days of knowledge of the event.  Expected AEs will be reported using 
NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular 
intervals as defined on the Form Submission Schedule. 
 
4.2.3. Patient Evaluations Prior to Enrollment 
 
Table 4.2.3 summarizes patient clinical assessments over the course of the study.  
 
 

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TABLE 4.2.3: CLINICAL STUDIES AND RESEARCH LABS 
Week 
Pre-
Conditioning9 
-1 
-1 
0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
26 
52 
Day2 
-7 
-1 
0 
1 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
100 
180 
365 
PE with performance status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC, chem10, LDH, AST, ALT, GGT, 
AP, bilirubin, INR, PTT, d-dimer, 
fibrinogen, triglycerides 
(See 4.2.4.9 for recommendations to screen for 
reactivation in patients with HLH) 
x 
Bone marrow aspirate5 
x 
GFR  
x 
HLA typing, ABO/Rh typing 
x 
PFT/oxygen saturation 
x 
Chest x-ray or CT scan 
x 
EKG/Echo 
x 
beta-HCG4 
x 
Bone marrow graft - total nucleated cells 
and CD34+ count 
x 
Ferritin 
x 
Hepatitis, HSV, syphilis, HIV, HTLV1, 
VZV tests  
x 
CMV and EBV qPCR 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Infection evaluation 
x 
HLH: LP and/or brain MRI1 
x 
x 
x 
Immune reconstitution 
x 
x 
x 
Immunoglobulin levels 
x 
x 
x 
Chimerism (unfractionated  and CD3+)8 
x 
x3 
x 
x7 
x 
x1 
x 
x 
x 
x 
Optional research blood 
x10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HLH & related disorders: NK function, 
Perforin expression5, SAP expression5 
x 
x 
x 
CGD: DHR assay 
x 
x 
x 
HIGM: CD40L expression6 
x 
x 
x 
IPEX: Treg analysis 
x 
x 
x 
LAD: CD18 expression 
x 
x 
x 
Notes:    1 Recommended but not required 
 
 
 
 
 
6 If available 
2 Please follow the same windows as listed for follow-up visits in Table 4.2.1 
 
 
7 Required if prior chimerism results are equivocal (donor chimerism < 20%) 
3 If neutrophil engraftment achieved before Day +28  
 
 
 
8 Monthly chimerism studies are standard of care 
4 If patient is of childbearing potential 
 
 
 
 
 
9 < 30 days prior to enrollment (unless noted otherwise) 
5 As indicated (perforin study for PRF1 familial HLH; SAP expression for XLP1) 
 
10 Within 14 days prior to onset of conditioning (Day -28 to Day -14) 
 

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The following observations must be performed within 30 days prior to enrollment (unless noted 
otherwise): 
 
1. History, physical examination, height and weight. 
2. Lansky/Karnofsky performance status. 
3. Blood count with differential, chemistries (sodium, potassium, carbon dioxide, chloride, 
magnesium, calcium, phosphorous, BUN, creatinine), lactate dehydrogenase, AST, ALT, 
GGT, alkaline phosphatase, bilirubin (conjugated and unconjugated), INR, PTT, d-dimer, 
fibrinogen, triglycerides, ferritin, soluble IL2R (recommended for HLH patients), 
soluble CD163 (recommended for HLH patients). 
4. Bone marrow aspirate (recommended in patients with cytopenias or other concerns for 
abnormal hematopoiesis). 
5. Disease-specific studies: 
i. 
HLH: NK cell function, diagnostic lumbar puncture and/or brain MRI  
ii. 
HLH: (with PRF1 mutation): Perforin expression by flow cytometry* 
iii. 
XLP: SAP expression by flow cytometry* 
iv. 
CAEBV: EBV qPCR, NK cell function (if available), diagnostic lumbar puncture 
and/or brain MRI  
v. 
HIGM: CD40L expression on activated CD4+ T cells by flow cytometry (if 
available)* 
vi. 
CGD: DHR assay* 
vii. 
IPEX: Quantitative Treg analysis by flow cytometry; Functional Treg assay (if 
available)* 
viii. 
LAD: CD18 expression on granulocytes by flow cytometry* 
*May be performed at any time prior to enrollment 
6. Calculated or radionuclide GFR.  
7. EBV antibody test and PCR, CMV antibody test and PCR, hepatitis panel (HepA Ab, 
HepB sAb, HepB sAg, HepB Core Ab, HepC Ab), herpes simplex, syphilis, HIV and 
HTLV1 I/II antibody, and varicella zoster virus antibody. 
8. HLA typing, ABO and Rh typing, if not already performed. For sibling donors: 6/6 match 
for HLA–A, –B (intermediate or higher resolution) and –DRB1 (at high resolution using 
DNA-based typing); for related donors other than a sibling: 7/8 or 8/8 match for HLA–A, 
–B, –C (at intermediate or higher resolution), and –DRB1 (at high resolution using DNA-
based typing). For unrelated donors: 7/8 or 8/8 match for HLA–A, –B, –C, and –DRB1 
(at high resolution using DNA-based typing).   
9. Baseline peripheral blood samples for chimerism analysis by molecular methods 
(STR/VNTR). 
10. Baseline EKG. 

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11. Baseline echocardiography for left ventricular ejection fraction (LVEF) or left ventricular 
shortening fraction. If tricuspid regurgitation is present, it is recommended to evaluate 
presence of pulmonary hypertension.  It is strongly recommended that these tests be 
performed ≤ 2 weeks prior to enrollment.  However, they can be done up to 6 weeks prior 
to enrollment, provided the patient has been asymptomatic since the time of the tests. 
12. Pulmonary function testing: FEV1 and DLCO if patient is able to undergo PFT testing. If 
not; record oxygen saturation by pulse oxymetry.  It is strongly recommended that these 
tests be performed ≤ 2 weeks prior to enrollment.  However they can be done up to 6 
weeks prior to enrollment, provided the patient has been asymptomatic since the time of 
the tests. 
13. β-HCG serum pregnancy test for females of childbearing potential. 
14. Chest X-ray or CT scan:  It is strongly recommended that the X-ray or scan be performed 
≤ 2 weeks prior to enrollment in symptomatic patients.   
15. Baseline immune profile: Absolute lymphocyte numbers by flow cytometry for 
lymphocyte subpopulations (CD3, CD4, CD8, CD19 and CD16+56 cell subsets), 
immunoglobulin levels (IgG, IgA and IgM). 
16. Optional samples for correlative research studies: Peripheral blood 20 mL in Sodium 
Heparin tubes at three time points: within 14 days prior to start of conditioning (Day -28 
to Day -14); Day -7 and Day -1. For patients that weigh less than 6.7 kg, 3 mL/kg will be 
collected at each time point. 
17. Total nucleated cell count and CD34+ count of the infused product on Day 0. 
 
4.2.4. Patient Evaluations Prior to Conditioning 
 
If an infection occurs or a previously controlled infection worsens between the day of enrollment 
and the day the preparative regimen is scheduled to begin, the infection must be controlled and 
the patient clinically improved prior to initiating the preparative regimen. We recognize that 
patients with CAEBV may have ongoing EBV viremia at the time of initiating pre-transplant 
therapy, but other patients should have no uncontrolled bacterial, viral or fungal infections at the 
time of initiation of the transplant preparative regimen. 
 
4.2.5. Required Post-Transplant Evaluations (Follow evaluation windows listed in Table 4.2.3) 
1. History and physical exam to assess GVHD and other morbidity weekly until Day +100 
post-transplant, then at Day +180 and Day +365.  GVHD evaluation and grading to be in 
keeping with BMT CTN MOP. 
2. Peripheral blood sample for post-transplant chimerism assay (unfractionated and CD3+) 
by molecular methods monthly beginning at Day +28, and at Day +42 if prior chimerism 
results are equivocal (donor chimerism < 20%), then at least monthly (recommended 
every 2 weeks) through Day +100, then at Day +180 and Day +365. An optional 
chimerism study at Day +21 is recommended if neutrophil engraftment occurs before 
Day +28. 

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3. EBV qPCR on plasma or blood cells weekly from Day +1 through Day +100, then at Day 
+180 and Day +365. 
4. CMV qPCR on plasma weekly from Day +1 through Day +100, then at Day +180 and 
Day +365. 
5. Immune reconstitution (absolute lymphocyte numbers) by flow cytometry for 
lymphocyte subpopulations (CD3, CD4, CD8, CD19 and CD16+56 cell subsets), 
immunoglobulin levels (IgG, IgA and IgM) at Day +100 and Day +365. 
6. Disease-specific studies (Pre-therapy, Day +100, Day +365): 
i. 
HLH: NK cell function 
ii. 
HLH (PRF1 mutation): Perforin expression by flow cytometry 
iii. 
XLP: SAP expression by flow cytometry 
iv. 
CAEBV: EBV qPCR, NK cell function (if available), diagnostic lumbar puncture 
and/or brain MRI  
v. 
HIGM: CD40L expression on activated CD4+ T cells by flow cytometry (if 
available) 
vi. 
CGD: DHR assay 
vii. 
IPEX: Quantitative Treg analysis by flow cytometry; Functional Treg assay (if 
available) 
viii. 
LAD: CD18 expression on granulocytes by flow cytometry 
8. Optional samples for correlative research studies: Peripheral blood 20 mL in Sodium 
Heparin tubes collected on Day +1, Day +14, Day +28, Day +42, Day +70, Day +100, 
Day +180, and Day +365. For patients less than 6.7 kg, 3 mL/kg will be collected at each 
time point. 
9.  HLH Reactivation: For patients with HLH or hemophagocytic syndromes, regular surveillance 
labs (blood counts, ferritin, soluble IL2Rα, soluble CD163, d-dimer, fibrinogen, triglyercerides, 
LDH, AST/ALT/GGT and bilirubin) are recommended.  If patients develop persistent fever of 
uncertain etiology, HLH reactivation should be re-evaluated completely according to the 
diagnostic criteria (Table 1.2), along with chimerism studies including CD3+ fraction 
chimerism.  Resources to manage HLH reactivation (systemic or CNS) are outlined in 
Appendix E.

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CHAPTER 5  
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Design 
 
The study is a Phase II, non-randomized, multi-center trial. It is designed to assess overall 
survival 365 days after patients undergo reduced-intensity conditioning (RIC) HCT with 
fludarabine, melphalan, and intermediate timing of alemtuzumab for HLH or related conditions.  
The sample size is a minimum of 35 HLH patients.   
 
5.2. 
Accrual 
 
It is estimated that three years of accrual will be necessary to enroll the targeted sample size.  
Accrual will be reported by race, ethnicity, gender, and age.  
 
5.3. 
Study Duration 
 
Patients will be followed for one year post-transplant.  
 
5.4. 
Randomization 
 
There is no randomization in this trial. 
 
5.5. 
Primary Objective 
 
The primary endpoint is the proportion of patients who survive for one year after transplantation.  
The choice of this endpoint is based on CIBMTR registry data for patients receiving HCT for the 
above diseases between 2008 and 2010.  In these data, the probability of one year survival was 
70% for HLH patients.  Recent single center data with the RIC strategy used in this protocol 
have shown survival probabilities closer to 90%.  The primary analysis will include all patients 
who receive at least one dose of the preparative regimen.  Death from any cause is the event for 
this endpoint.  The study is designed to rule out survival percentages below 70%.  
 
5.6. 
Sample Size and Power Considerations 
 
Sample size calculations were based on an original sample size of 35 patients. After rapid 
accrual, the protocol was amended to include a minimum of 35 HLH patients to improve the 
precision of both the overall estimate and the secondary disease specific subgroup analysis. 
 
Table 5.6.1 provides 90% confidence intervals for a variety of observed proportions.  For 
example if 28 of the 35 patients survive (80% observed survival percentage), the length of the 
confidence interval is 22.2%.  The percentages above and below 80% are intended to represent 
other plausible survival rates.   

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The probability to rule out survival percentages of a certain size is known as “power.”  Table 
5.6.2 provides the probability (or power) that the lower bound of a 90% two-sided confidence 
interval for the overall survival probability will be greater than a threshold of 65%, 70%, 75%, or 
80%.  Based on the table below, there is 87% power at a one-sided  = .05 to reject the null of 
70% survival if the true percentage is 90%.  
 
TABLE 5.6.1:  CONFIDENCE INTERVAL LENGTHS AND POSSIBLE  
CONFIDENCE INTERVALS FOR VARIOUS OBSERVED  
OVERALL SURVIVAL PROBABILITIES 
 
N 
Overall Survival 
(OS) % 
Length of 90% 
Confidence Interval 
Possible 90% Confidence Intervals 
35 
70 
25.4 
(57.3, 82.7) 
35 
75 
24 
(63.0, 87.0) 
35 
80 
22.2 
(68.9, 91.1) 
35 
85 
19.8 
(75.1, 94.9) 
35 
90 
16.6 
(81.7, 98.3) 
 
 
TABLE 5.6.2:  PROBABILITY OF RULING OUT A THRESHOLD OF SIZE  
T FOR VARIOUS TRUE UNDERLYING OVERALL 
SURVIVAL PERCENTAGES 
 
 
 
N 
True 
Overall 
Survival 
% 
 
Probability of Ruling Out Overall Survival Percentages 
of Size T  
 
 
T=80% 
T=75% 
T=70% 
T=65% 
35 
90 
0.31 
0.73 
0.87 
0.98 
35 
85 
0.09 
0.38 
0.57 
0.86 
35 
80 
 
0.14 
0.27 
0.60 
35 
75 
 
 
0.10 
0.32 
35 
70 
 
 
 
0.13 
 
 
5.7. 
Interim Analysis and Stopping Guidelines 
 
Interim analyses for safety will be conducted at times specified in the power and sample size 
calculations. Monitoring of a key safety endpoint (overall mortality) will be conducted monthly, 
and if rate significantly exceeds pre-set thresholds, the NHLBI will be notified in order that the 

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DSMB can be advised.  Policies and composition of the DSMB are described in the BMT CTN's 
Manual of Procedures.  The stopping guidelines serve as a trigger for consultation with the 
DSMB for additional review, and are not formal “stopping rules” that would mandate automatic 
closure of study enrollment. 
The rate of overall mortality will be monitored up to 100 days post-transplant.  Monitoring will 
be performed monthly beginning after the third month of enrollment until enrollment is closed.  
At least three events must be observed in order to trigger review.  Each month, the null 
hypothesis that the 100-day overall mortality rate is less than or equal to 15% is tested.  An 
extension of the sequential probability ratio test (SPRT) will be used to monitor overall 
mortality.  A description of the SPRT is provided below. 
 
The SPRT can be represented graphically.  At each monthly interim analysis, the total time on 
study is plotted against the total number of patient deaths.  The continuation region of the SPRT 
is defined by two parallel lines.  Only the lower boundary will be used for monitoring to protect 
against excessive 100-day overall mortality.  If the graph falls below the lower boundary, the 
SPRT rejects the null hypothesis, and concludes that there are more events than predicted by the 
observed time on study.  Otherwise, the SPRT continues until enrollment reaches the maximum 
sample size. 
 
This procedure assumes an exponential distribution for the time until death during the first 100 
days, but censors follow-up time after 100 days.  Only events that occur on or before the patient 
has been followed for 100 days are counted.  Total time on study is computed as time from 
registration to event, or to 100 days, whichever comes first, summed for all evaluable patients. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The test to be used in this protocol was developed from the following SPRTs:  A SPRT 
contrasting 15% versus 35% 100-day rate of overall mortality results in a common slope of 0.99 
and the intercepts are -2.18 and 1.83. 
 
The actual operating characteristics of the truncated test, shown in Table 5.7.1, were determined 
in a simulation study that assumed uniform accrual of 35 individuals over a 3 year time period 
and exponential time to failure after registration.  Since 100,000 replications were used, the 
estimates have two digits of precision. 
 
 
 

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TABLE 5.7.1:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 100,000 REPLICATIONS  
FOR OVERALL MORTALITY 
 
True 100-Day Rate 
15% 
25% 
30% 
35% 
Probability Reject Null 
0.07 
0.42 
0.65 
0.83 
Mean Month Stopped 
15.8 
17.8 
17.1 
15.7 
Mean # Endpoints in 100 Days 
5.7 
6.2 
6.1 
5.8 
Mean # Patients Enrolled 
16 
18 
17 
16 
 
 
The testing procedure for overall mortality rejects the null hypothesis in favor of the alternative 
7% of the time when the true 100-day overall mortality rate for a treatment is 15%, and 83% of 
the time when the rate is 35%.  This corresponds to a type I error rate of  = 0.07 and a type II 
error rate of  = 0.17.  When the true 100-day overall mortality rate is 35%, on average, the 
DSMB will be consulted 15.7 months after the opening, when approximately 6 events have been 
observed in 16 patients. 
 
5.8. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, HLA match, disease stage, 
serum bilirubin level, serum creatinine level, donor age, donor gender, and donor ethnicity. 
 
5.9. 
Analysis of Primary Endpoint 
 
The primary analysis will consist of estimating the one year overall survival probability based on 
the Kaplan-Meier product limit estimator.  The one year overall survival probability and 
confidence interval will be calculated using Greenwood’s Formula for the variance.  All patients 
who receive at least one dose of the preparative regimen will be considered for this analysis.  
 
5.10. Analysis of Secondary Endpoints 
• Rate of Sustained Engraftment:  The proportion of patients achieving sustained 
engraftment at one year will be estimated along with 95% confidence intervals. 
• Graft Failure: To assess the incidence of primary and secondary graft failure (as 
outlined in Chapter 3), the proportion of subjects experiencing primarily graft failure will 
be estimated and the cumulative incidence of secondary graft failure will be computed 
along with 95% confidence intervals. Death prior to graft failure will be considered as a 
competing risk  
• HLH and CAEBV Reactivation:  To assess the incidence of reactivation, cumulative 
incidence curves will be computed along with 95% confidence intervals. Death prior to 

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reactivation will be considered as a competing risk.  Death due to reactivation will be 
noted. 
• Immune Reconstitution: Summary statistics for absolute number of CD3, CD4, CD8, 
CD16+56, and CD19 cells and immunoglobulin levels IgG, IgA and IgM will be reported 
at baseline, Day +100 and Day +365. Further proportion of subjects experiencing B cell 
reconstitution as defined in Chapter 3 will be estimated along with a 95% confidence 
interval. 
• Correction of Immune Defects: Descriptive statistics for disease-specific immune 
measures will be reported by underlying disease for measurements at baseline, Day +100 
and Day +365. 
• Neutrophil Engraftment: To assess the incidence of neutrophil engraftment from day of 
transplant, a cumulative incidence curve will be computed along with a 95% confidence 
interval. Death prior to neutrophil engraftment will be considered as a competing risk.   
• Platelet Engraftment: To assess the incidence of platelet engraftment (> 20,000) from 
day of transplant, a cumulative incidence curve will be computed along with a 95% 
confidence interval. Death prior to platelet engraftment will be considered as a competing 
risk.   
• Acute GVHD:  To assess the incidence and severity of grades II-IV and grades III-IV 
acute GVHD from day of transplant, the first day of acute GVHD onset at a certain grade 
will be used to calculate a cumulative incidence curve for that acute GVHD grade.  An 
overall cumulative incidence curve will be computed along with a 95% confidence 
interval at one year post-transplant with death considered as a competing risk.   
• First Clinical Onset of Chronic GVHD: To assess the incidence and severity of chronic 
GVHD from day of transplant, a cumulative incidence curve will be computed along with 
a 95% confidence interval at one year post-transplant. Death prior to occurrence of 
chronic GVHD will be considered as a competing risk. 
• Transplant-Related 
Complications: 
 
The 
frequencies 
of 
transplant-related 
complications (veno-occlusive disease (VOD), CNS toxicity, and infection) will be 
described using proportions (95% confidence interval). 
• Disease Group Specific Outcomes: In addition to the overall analysis of the primary and 
secondary endpoints, endpoints will be analyzed within disease subgroups, specifically 
HLH patients versus patients entering with primary immune deficiencies. Note that due 
to the small sample size no formal comparisons between the groups will be made. 
 
5.11. Safety Analysis 
 
The reporting of serious adverse events will be consistent with standard BMT CTN procedures.  
The type and severity of adverse events will be analyzed. 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The Principal Investigator or 
another designated physician will conduct the conference.  Potential risks associated with HCT 
should be discussed as objectively as possible.   
 
The consent document should be reviewed with the patient and family prior to proceeding to 
ablative therapy. 
 
Informed consent from the patient will be obtained using a form approved by the Institutional 
Review Board of the institution enrolling the patient.  
 
2. 
Confidentiality 
 
Confidentiality will be maintained by masking of individual names and assignment of a patient 
identifier code.  The identifier code representing the patient’s identity will be kept separately 
from the research file at the center.  The ID code will be transmitted to the BMT CTN Data and 
Coordinating Center upon enrollment. 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women, ethnic minorities, and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on the incidence of HLH, 
HLH-related disorders and the selected primary immunodeficiencies (CGD, hyper-IgM, IPEX, 
LAD-I).  Centers will be notified if their rates differ significantly from those expected and asked 
to develop appropriate recruitment strategies. 
 

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APPENDIX B 
 
INFORMED CONSENT AND ASSENT 

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Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
Your Name:  
________________________________ 
 
Study Title:  
Reduced-Intensity Conditioning for Children and Adults With 
Hemophagocytic Syndromes or Selected Primary Immune Deficiencies 
(RICHI) 
 
Protocol: 
 
BMT CTN #1204 
 
Principal 
Co-Investigator:  
Carl Allen, MD, PhD 
 
 
 
ceallen@txch.org 
Texas Children’s Hospital 
1102 Bates St., Suite 750 
Houston, TX 77030 
(832) 824-4312 
 
Principal 
Co-Investigator:  
Michael Pulsipher, MD 
 
michael.pulsipher@hsc.utah.edu 
Primary Children’s Medical Center 
100 North Mario Capecchi Dr. 
Salt Lake City, UT 84113 
(801) 662-4732 
 
Transplant Center 
Investigator:  
________________________ 
(Insert contact information for PI at your site) 
 
Sponsor:   
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN).  
 
 
 
 

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1. Introduction 
 
We invite you to join this clinical trial, also 
known as a research study. We are doing 
this study because we want to learn if 
reduced-intensity transplants are safe and 
work well for people with hemophagocytic 
syndromes or immune disorders. A 
reduced-intensity transplant uses lower 
doses of chemotherapy. This type of 
transplant is also called a non-
myeloablative, or ‘mini’ transplant. 
An allogeneic transplant uses cells from a 
family member or an unrelated donor to 
remove and replace your diseased cells. 
An allogeneic transplant generally uses 
higher levels of chemotherapy and 
radiation (also known as high intensity 
treatments or myeloablative conditioning 
regimens) to destroy the diseased cells 
before receiving the donor cells. However, 
high intensity transplants can have more 
side effects during and after transplant. A 
reduced-intensity transplant can have fewer 
side effects, but may have more problems 
with engraftment. Engraftment is the 
ability of the donor cells to replace the 
patient’s cells.  
Your study participation will last for 1 year 
post-transplant. This study will take about 3 
years total and will include 35 HLH 
patients in addition to patients with other 
hemophagocytic syndromes or immune 
disorders from around the United States and 
Canada.  
To be part of the study, you must: 
• Be between the ages of 3 months and 
45 years 
• Have a hemophagocytic syndrome or 
an immune disorder including: 
• Hemophagocytic 
lymphohistiocytosis (HLH) 
• Griscelli syndrome 
• Chediak-Higashi syndrome 
• X-linked lymphoproliferative 
disease 
• Chronic active EBV (CAEBV), 
which is typically associated 
with HLH 
• Chronic granulomatous disease 
(CGD) 
• X-linked hyper IgM syndrome 
(HIGM1) 
• IPEX syndrome 
• Severe leukocyte adhesion 
deficiency (LAD-I)  
• Have a matched related marrow 
donor or unrelated marrow donor 
available. The unrelated donor needs 
to be a close tissue match. 
• Provide a signed consent for 
participation in the study  
This Consent Form tells you about the 
purpose of the study, the possible risks and 
benefits, other treatment options available 
to you, and your rights as a participant in 
the study. Please take your time to make 
your decision.  

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Everyone who takes part in research at 
[insert facility name] should know that: 
• Being in any research study is 
voluntary. 
• You may or may not benefit from 
being in the study.  Knowledge we 
gain from this study may benefit 
others. 
• If you join the study, you can quit 
the study at any time.   
• If you decide to quit the study, it will 
not affect your care at [insert name 
of facility or institution].  
• Please ask the study staff questions 
about anything that you don’t 
understand, or if you would like to 
have more information. 
• You can ask questions now or any 
time during the study. 
• Please take the time you need to talk 
about the study with your doctor, 
study staff, and your family and 
friends.  It is your decision to be in 
the study.  If you decide to join, 
please sign and date the end of the 
Consent Form. 
You and your doctor will discuss other 
treatment options if you don’t want to 
participate in this study. 
 
 
2. Study Background 
The National Institutes of Health (NIH), 
through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), are 
providing staff support and money for this 
research study. The BMT CTN will direct 
the research study. The BMT CTN and the 
NIH will make decisions about how to 
manage the study together.  
Some of the immune system disorders 
included in this study are: Hemophagocytic 
lymphohistiocytosis, Griscelli syndrome, 
Chediak-Higashi syndrome, X-linked 
lymphoproliferative disease, chronic active 
EBV, chronic granulomatous disease, hyper 
IgM syndrome, IPEX syndrome, and severe 
leukocyte adhesion deficiency. These 
disorders prevent the immune system from 
working well. Your immune system fights 
off infections, so people with these disorders 
might develop deadly infections. 
One way to treat these disorders is through a 
blood and bone marrow transplant. A 
transplant replaces your unhealthy blood 
cells with bone marrow cells from a family 
member or an unrelated donor.  It requires a 
close tissue match between you and the 
donor. Your donor could be a sibling (a 
sister or brother) or an unrelated person. In 
the United States, we use the Be The 
Match® Registry to find unrelated donors. 

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A transplant first uses chemotherapy to 
destroy the unhealthy blood cells or stop 
them from growing. Then, we replace the 
destroyed cells with the new cells from your 
donor. In this study, doctors want to use 
lower doses of chemotherapy. This type of 
transplant is called a reduced-intensity 
transplant. 
Your disease can be treated in other ways 
too. You and your doctor will decide on the 
best treatment for you.  
 
 
3. Study Purpose 
We are inviting you to join this study 
because you have an immune system 
disorder, a matched bone marrow donor, and 
a reduced-intensity transplant is a treatment 
option for you. The goal of this study is to 
learn if a reduced-intensity transplant is safe 
and works well to treat your disease. We 
also want to know how well your immune 
system responds to the transplant. 
 
 
4. Right to Ask Questions and/or Withdraw 
You have the right to ask questions about 
the study at any time. If you have questions 
about the study or you want to leave the 
study, please contact: 
[insert contact info for site PI] 
Being in this study is voluntary. You can 
choose not to be in this study or leave this 
study at any time. If you choose not to take 
part or to leave this study, it will not affect 
your regular medical care in any way.    
Your study doctor and study staff will be 
available to answer any questions you may 
have about taking part in or leaving this study.
 
 
5. Study Treatment and Tests 
We will check your health before your 
transplant. We will also check your health 
several times after your transplant for up to 
1 year.   

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______________________________________________________________________________
Before Your Transplant: 
You will be admitted to the hospital 14 days 
before your transplant. Your doctor will put 
an intravenous (IV) catheter (a thin tube) in 
a large vein in your neck or chest. This is 
done to make giving you drugs and blood 
transfusions easier and less painful. This is 
also known as a central venous catheter. 
When you are ready to get your catheter, 
your doctor will explain what will happen in 
more detail. Your anesthesiologist  
 
(the doctor who will give you pain 
medicine) will describe the risks and 
benefits of the pain medicine.     
When the catheter is in your chest, it will 
need to be cleaned and flushed regularly to 
prevent infection and blood clots. Your 
nurse or caregiver will help you clean your 
catheter.
______________________________________________________________________________ 
Reduced-Intensity Transplant: 
To prepare your body for transplant and 
destroy the diseased cells, you will be 
treated with chemotherapy and other 
medicines. Your chemotherapy will start the 
day you are admitted to the hospital (14 days 
before your transplant). 
Study chemotherapy drugs 
The study drugs that will be used for your 
chemotherapy are called alemtuzumab, 
fludarabine, and melphalan.  
We will start giving you alemtuzumab 14 
days before your transplant. It will be given 
as a shot. You will get a dose of 
alemtuzumab once a day for 5 days. The 
first day will be a small test dose. The test 
dose is given to make sure you will not have 
a bad reaction to the full dose. If you have a 
bad reaction, your doctor will talk with you 
about other drug options to prepare for 
transplant.  
The risks of alemtuzumab are listed in 
Section 6: Risks and Discomforts. These 
risks include serious allergic reactions. 
Patients are usually admitted to the hospital 
for their first dose of alemtuzumab. Your 
doctor will decide if you need to stay in the 
hospital for the other doses of alemtuzumab 
or if you can receive them as an outpatient. 
If you stay in the hospital for all of the 
alemtuzumab shots, your doctor might 
discharge you after the shots are done if you 
respond well. If you are discharged, you will 
return to the hospital 8 days before your 
transplant to start receiving the other 
chemotherapy drugs (fludarabine and 
melphalan).  
Fludarabine will be given through your 
central venous catheter, once a day for 5 
days. A central venous catheter is a thin tube 
that is placed in a large vein in your neck or 

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chest. We will give you one dose of 
melphalan 3 days before the transplant. It 
will also be given through your central 
venous catheter.  
You will have 2 days to rest before your 
transplant. We won’t give you any 
chemotherapy drugs on these days. 
Table 1 shows the timeline for the 
chemotherapy drugs and blood tests. This 
timeline does not show the drugs we will 
give you to help prevent Graft Versus Host 
Disease (below).  
Drugs to prevent Graft-Versus-Host Disease 
(GVHD): 
We will give you immune suppressing drugs 
3 days before your transplant. We will 
continue to give you these drugs after your 
transplant. These drugs are important 
because they allow the donor cells to 
perform their new role in your body. They 
can also lower your chances of developing 
GVHD. GVHD happens when the donor 
cells attack your body (GVHD is discussed 
in more detail below).   
You will receive 1 or more standard drugs 
(drugs that are not part of the study) to lower 
your chances of developing GVHD. We will 
give you these drugs for at least 6 months 
after the transplant. They are cyclosporine 
(also called Gengraf® or Neoral®) or 
tacrolimus (also called FK 506 or Prograf®). 
We will give them to you with 
methylprednisolone or prednisone daily 
starting 2 days prior to transplant and 
continuing until 28 days after transplant 
(both of these drugs work the same). 
Donated marrow cells: 
The donated marrow cells will come from a 
related donor or unrelated donor. The donor 
cells will be given through your catheter, 
just like a blood transfusion.
______________________________________________________________________________ 
After Your Transplant:  
The chemotherapy drugs will destroy the 
cells in your bone marrow that produce your 
blood and immune cells. The donor cells 
will produce new blood cells in your body. 
To speed up this process, we may give you a 
drug called Filgrastim (also called G-CSF or 
Neupogen). This drug helps protect against 
infections. It is given as a shot or IV.    
Check-up appointments: 
You will stay in the hospital after your 
transplant until your doctor feels you’re well 
enough to go home. When you’re in the 
hospital, we will watch you carefully for 
signs of infection and other problems. A 
physical exam and blood tests will be done 
every day to know how you’re doing. Your 
doctor may need to give you other drugs, 
tests and treatments if you have problems. 
After you leave the hospital, you will need 
to visit the transplant clinic at least once a 
week for check-ups to make sure you’re still 
doing well. You will also need to visit us 
100 days (3 months), 6 months, and 1 year 
after your transplant so we can check your 
progress and treat any problems. You will 
check in with us less and less over time. 
 

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At these visits, we will take 2 – 6 teaspoons 
of your blood (10 – 30 mL) from your 
catheter or from a vein in your arm if your 
catheter has been removed. We will test 
your blood to see how well your body is 
responding to the chemotherapy drugs and 
the donated cells. 
 
Health Evaluations: 
 
We will test (evaluate) your health during 
the study. These tests and how often they are 
scheduled are standard care for patients 
receiving an allogeneic transplant. They 
would be done even if you were not part of 
this study. 
 
Health evaluations after treatment: 
 
1) Physical exam to assess toxicities, and 
infections weekly until Day +56 and then at 
Days +180 and +365. 
 
2) Physical exam to assess GVHD weekly 
until Day +100 and then at Days +180 and 
+365. 
 
3) Routine blood tests (cell counts and liver 
and kidney function) weekly until Day +56 
and then at Days +180 and +365. 
 
4) Blood or bone marrow tests to find the 
amount of donor cells in your body monthly 
until Day +100 and then at Days +180 and 
+365. This is also called chimerism. 
 
5) Disease-specific tests to see how much 
disease you have before treatment and after 
treatment on Days +100 and +365. 
 
6) Optional blood samples for future 
research (see Section 17: Blood Samples 
for Future Research). 
 
Your doctor may decide that you need other 
tests and treatments that are not part of this 
research study, but are necessary to take care 
of you. 
 
 

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*Legend for Chemotherapy Drugs 
A 
Alemtuzumab test dose 
B 
Alemtuzumab 
C 
Fludarabine 
D 
Melphalan 
Table 1: Timeline for Chemotherapy Drugs and Blood Tests 
Day: 
Before transplant 
Transplant 
Day 
After transplant 
After 
you 
consent 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5 
4 
3 
2 
1 
0 
 
 
1 
 
 
14 
28 
42 
70 
100 
(3 mths) 
180 
(6 mths) 
365 
(1 yr) 
Optional
Blood 
Tests: 
✓ 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Drugs*: 
 
A 
B 
B 
B 
B 
 
C 
C 
C 
C 
C 
D 
 
 
 
 
 
 
 
 
 
 
 

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6. Risks and Discomforts 
You will have side effects while on the 
study. Side effects can range from mild to 
very serious.  
The risks listed in this section might happen 
from transplant. These risks might happen if 
you have a transplant as part of this study or 
standard care. The chances of developing 
GVHD and infections are the same if you 
have a reduced-intensity or standard 
transplant.  
Your doctor will give you drugs to help 
lower the side effects, such as feeling sick to 
your stomach (nausea). In some cases, side 
effects can be long lasting or may never go 
away.  
The chemotherapy drugs can cause leukemia 
years later, but this is rare. These “secondary 
cancers” are often very hard to treat and can 
cause death. 
 
Risks of Study Treatments and Drugs  
 
Possible Side Effects of Study Drugs  
The most common side effects of the 
treatments used in this study are listed 
below. There is also the risk of very 
uncommon or unknown side effects. All 
chemotherapy drugs in this study are 
commonly used in transplant.
 
Likely 
What it means: This type of side effect is expected to occur in more than 
20% of patients. This means that 21 or more patients out of 100 might get 
this side effect. 
Less Likely 
What it means: This type of side effect is expected to occur in 20% of 
patients or fewer. This means that 20 patients or fewer out of 100 might get 
this side effect. 
Rare, but 
Serious 
What it means: This type of side effect does not occur very often – in fewer 
than 2% of patients – but is serious when it occurs. This means that 1 or 2 
patients (or fewer) out of 100 might get this side effect. 

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Alemtuzumab 
Likely 
Less Likely 
 
Rare, but Serious 
 
• Fever 
• Chills 
• Anemia (decreased 
number of red cells) 
• Infection  
• Bleeding  
• Weakened immune system 
• Local irritation (skin) at 
injection site 
• Low number of white 
blood cells 
• Low number of platelets in 
the blood 
 
• Nausea 
• Vomiting 
• Diarrhea 
• Rash 
• Headache 
• Sweating 
• Back pain 
• Severe itching 
• Allergic reaction of skin 
and blood vessels 
• Tiredness 
• Loss of appetite 
• Low blood pressure 
• Irregular heartbeat 
• Shortness of breath 
• Sore throat 
• Pain 
• Cough 
• Abdominal pain 
• Dizziness 
• High blood pressure 
• Blisters 
• Pain in the muscles 
• Herpes simplex infection 
• Swelling of the throat 
• Bacterial infection in the 
bloodstream 

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Fludarabine 
Likely 
 
 
Less Likely 
 
 
 
Rare, but Serious 
 
▪ Infection  
▪ Anemia (low red blood 
cell count) 
▪ Tiredness 
▪ Nausea 
▪ Vomiting 
▪ Pneumonia  
▪ Mouth sores 
▪ Fever 
▪ Swelling of hands and feet 
▪ Weakened immune system 
▪ Pain 
▪ Low number of white 
blood cells 
▪ Low number of platelets in 
the blood 
▪ Electrolyte imbalances 
▪ Diarrhea 
▪ Numbness and tingling in 
hands and/or feet  
▪ Changes in vision 
▪ Skin rash 
▪ Cough  
▪ Changes in heartbeat 
▪ Loss of appetite 
▪ Chills 
▪ Lung inflammation 
 
▪ Changes in vision  
▪ Agitation/nervousness  
▪ Confusion  
▪ Difficulty breathing  
▪ Weakness 
▪ Severe brain injury and death  
▪ Bleeding due to decreased 
numbers of platelets  
▪ Kidney damage that could 
require dialysis 
▪ Coma 
 
 

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B-13 
Melphalan 
 
Likely 
 
 
Less Likely 
 
Rare, but Serious 
▪ Loss of appetite 
▪ Nausea 
▪ Vomiting 
▪ Skin breakdown (if drug 
leaks from vein) 
▪ Anemia (low red blood 
cell count) 
▪ Infection  
▪ Bleeding  
▪ Mouth sores 
▪ Temporary hair loss 
▪ Decreased immunity 
▪ Low number of white 
blood cells 
▪ Low number of platelets in 
the blood 
▪ Diarrhea 
▪ Inflammation of the lung 
▪ Weakness 
▪ Weight loss 
 
 
 
▪ Low blood pressure 
▪ Excessive perspiration 
▪ Allergic reaction 
▪ Damage/scarring of lung 
tissue 
▪ Sterility 
▪ Seizure 
▪ Cancer of bone marrow cells 
▪ Heart stops beating 
▪ Liver damage 
 
Side Effects of Drugs Used To Prevent GVHD 
The side effects of the GVHD drugs (listed below) usually stop when you’re done taking them.  

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Cyclosporine (Gengraf® or Neoral®). 
This drug may be used for all patients 
 
Likely 
 
 
Less Likely 
 
 
Rare, but Serious 
 
▪ Tremors 
▪ High blood pressure 
▪ Kidney problems 
▪ Headaches 
▪ Nausea 
▪ Vomiting 
▪ Stomach pain or 
indigestion 
▪ Swelling of the hands or 
feet  
▪ Increased hair growth 
▪ Electrolyte imbalances 
▪ Confusion 
▪ High levels of 
triglycerides in the blood 
▪ Diarrhea 
▪ Gum enlargement 
▪ Liver dysfunction 
▪ RPLS/PRES1 
 
 
▪ Muscle cramps 
▪ Numbness and tingling of the 
hands or feet 
▪ Seizures 
▪ Dizziness 
▪ Red blood cell destruction 
▪ Temporary blindness 
     1 Reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible                   
encephalopathy syndrome (PRES) – See text below for description   
 

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Tacrolimus (Prograf or FK-506) 
 This drug may be used for all patients. 
 
Likely 
  
 
Less Likely 
 
 
Rare, but Serious 
 
▪ High blood pressure 
▪ High blood sugar 
▪ Anemia (low red blood 
cell count) 
▪ High or low potassium 
levels 
▪ Low magnesium and 
calcium levels 
▪ Loss of appetite 
▪ Diarrhea 
▪ Nausea 
▪ Fever 
▪ Headache 
▪ Hair loss 
▪ Vomiting 
▪ Tingling sensation in the 
extremities 
▪ Itching 
▪ Rash 
▪ Abdominal pain 
▪ RPLS/PRES1 
 
 
 
▪ Confusion 
▪ Painful joints 
▪ Increased sensitivity to light 
▪ Change in vision 
▪ Insomnia (trouble sleeping) 
▪ Infection 
▪ Jaundice (skin yellowing) 
▪ Kidney injury 
▪ Seizures 
1 Reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible 
encephalopathy syndrome (PRES) – See text below for description 
 

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Methylprednisolone and Prednisone 
This drug will be used as part of GVHD prophylaxis for bone marrow recipients. 
 
Likely 
  
 
Less Likely 
 
 
Rare, but Serious 
 
▪ Water retention (storing of 
extra water) 
▪ Overeating 
▪ Weaker immune system 
▪ Temporary personality 
changes 
▪ Abnormal hormone 
production 
▪ High blood sugar 
▪ Slowed growth 
▪ Decreased bone density 
▪ Fat accumulation causing 
a change in facial 
appearance 
▪ Headaches  
▪ Poor wound healing 
▪ Stomach swelling or pain 
▪ Tissue swelling 
▪ High blood pressure 
▪ Stomach ulcer 
▪ Muscle weakness 
▪ Cataracts 
▪ Bone cell death 
▪ RPLS/PRES1 
 
 
▪ Difficulty falling asleep 
▪ Worsening of diabetes 
▪ Inflammation of pancreas 
▪ Personality disturbances 
▪ Bleeding in the stomach and 
intestines 
▪ Increased pressure within the 
eye 
▪ Disturbance of bone calcium 
(might lead to possible 
broken bones or permanent 
bone damage) 
1 Reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible 
encephalopathy syndrome (PRES) – See text below for description   
 
 
 

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Potential Risk of RPLS/PRES 
The Data Safety and Monitoring Board (DSMB) of the Blood and Marrow Transplant Clinical 
Trials Network is a group of transplant, HLH and immune deficiency disease and other experts that 
ensure the safety of patients treated on this and other trials. This group carefully monitors the 
experience of patients to make sure that the side effects that they experience are not unusual or 
more frequent or more severe than would be expected.  
 
The DSMB has noted that patients transplanted on the clinical trial BMT CTN 1204 have a higher 
than expected occurrence of a usually uncommon (<5%) complication called reversible posterior 
leukoencephalopathy syndrome (RPLS) also known as posterior reversible encephalopathy 
syndrome (PRES). Patients with RPLS/PRES have confusion and other changes in their ability to 
think. Sometimes, they experience seizures, sleepiness or, rarely, loss of consciousness.  RPLS is 
diagnosed with an MRI of the brain. In transplant patients, it is usually caused by some of the 
drugs used to prevent or treat graft versus host disease. It can often, but not always, be prevented 
by very careful control of blood pressure. It is treated by changing graft versus host disease drugs, 
controlling blood pressure and/or giving anti-seizure medicines. Three out of thirty-five patients on 
BMT CTN 1204 have developed RPLS/PRES; all were successfully treated for this complication. 
Thus far, no RPLS/PRES has been observed in any patient more than 6 months from their date of 
transplant. We believe that children who are on prednisone or other corticosteroids, or 
immunosuppressive drugs such as cyclosporine or tacrolimus or have high blood pressure are more 
likely to develop RPLS/PRES. 
Filgrastim (G-CSF) 
 
Likely 
  
 
Less Likely 
 
 
Rare, but Serious 
 
▪ Ache or pain inside the 
bones 
▪ Increased levels of liver 
enzymes and uric acid in 
the blood 
▪ Low number of platelets 
in the blood 
▪ Headache 
▪ Tiredness 
▪ Local irritation (skin) at 
injection site 
▪ NauseaBleedingFever 
 
▪ Allergic reaction 
▪ Enlargement or rupture of 
the spleen  
▪ Worsening of pre-existing 
skin rashes 
▪ Temporary hair loss  
▪ Inflammation of a blood 
vessel in the skin 

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If you/your child experience any of these side effects or changes in mental status, you should 
contact your/your child’s transplant physician right away, since early treatment is 
important.  It is also important that any blood pressure medication be taken as prescribed to 
decrease the risk of RPLS/PRES. 
 
Risks of Transplant:  
The following problems might happen from 
your transplant. These problems might 
happen if you have a transplant as part of the 
study or standard care:  
Graft-versus-host disease (GVHD)  
GVHD develops when the white blood cells, 
which are called T cells, in the donor’s cells 
attack your body. You are more likely to get 
GVHD if your donor’s tissue does not 
closely match your tissue.   
 
There are 2 kinds of GVHD: acute and 
chronic. Acute GVHD usually develops in 
the first 3 months after transplant. Chronic 
GVHD usually develops later and lasts 
longer.  
You may experience these side effects with 
acute GVHD:  
▪ Skin rash 
▪ Feel sick to your stomach (nausea) 
▪ Throw up (vomit) 
▪ Diarrhea 
▪ Abdominal (stomach area) pain 
▪ Problems with your liver (your 
doctor will run tests for this) 
▪ Infection 
You may experience these side effects with 
chronic GVHD:  
▪ Skin rashes 
▪ Hair loss 
▪ Thickened skin 
▪ Joint stiffness (knees, elbows, 
fingers) 
▪ Dry eyes 
▪ Dry mouth 
▪ Liver disease (your doctor will run 
tests for this) 
▪ Weight loss 
▪ Diarrhea 
▪ Infection 
We don’t know for sure if you will develop 
acute or chronic GVHD. The chance that 
you will get GVHD is 10-30%. This means 
that 10 to 30 people out of 100 might 
develop it. We will watch you closely for 
GVHD and treat it if it happens.  

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To know for sure if you have acute or 
chronic GVHD, we may do a biopsy of your 
skin. A biopsy is where we take a small 
piece of your skin and look at it under a 
microscope for signs of GVHD. There’s a 
small chance that we might also do a biopsy 
of your intestine and liver. Risks of biopsy 
may include pain, infection, or bleeding. 
In most cases, GVHD can be treated. If 
GVHD does not respond to the drugs, your 
doctor will talk with you about other 
treatment options. If you choose a different 
treatment option, we will give you 
information about the side effects.  
You may need to be treated for GVHD for 
many months or years. GVHD treatments 
can cause your immune system to become 
very weak if it goes on for a long time. This 
means you may develop more infections and 
need to be admitted to the hospital often. 
GVHD can be very serious and hard to treat. 
It might also cause death.   
Damage to your vital organs 
Your vital organs include your heart, lungs, 
liver, intestines, kidneys, bladder and brain. 
The chemotherapy and GVHD drugs may 
hurt these organs. You may develop lung 
problems from chemotherapy or an 
infection.  
Some patients can have veno-occlusive 
disease (VOD) of the liver even from a 
reduced-intensity transplant (lower doses of 
chemotherapy). Patients with VOD become 
jaundiced (yellow skin), have problems with 
their liver, retain too much water (feel 
swollen and uncomfortable), and have 
stomach swelling and pain.  
If there is serious damage to your vital 
organs, you may have to stay in the hospital 
longer or return to the hospital after your 
transplant. Many patients get better, but 
these complications can cause permanent 
damage to your organs or death. 
Serious infections 
It may take many months for your immune 
system to recover from the chemotherapy 
and GVHD drugs. There is an increased risk 
of infection during this time when your body 
is healing.  We will give you drugs to reduce 
the chance of infections, but they may not 
work. If you have an infection, you may 
have to stay in the hospital longer or return 
to the hospital after transplant.  Many 
patients get better, but some infections can 
cause death.  
Graft (donor cells) rejection  
Some patients’ bodies reject the donor cells 
(graft) with a standard (non-reduced-
intensity) transplant. There is an increased 
risk of rejection with a reduced-intensity 
transplant. Also, a certain amount of your 
old blood and marrow cells will remain in 
your body.  
If your body rejects the donor cells, your 
doctor may need to give you a donor 
lymphocyte infusion (DLI). A DLI is an 
extra dose of the donor cells. You may also 
get another transplant, but this is rare. If you 
need a DLI or second transplant, your doctor 
will explain the risks and benefits. 
Central venous catheter  
You may feel pain and bleed a little where 
the catheter is placed in your chest. The 
most common risks of a catheter are blood 

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clots and infections. If you get a clot, we will 
give you a drug to break it up. If the drug 
doesn’t work, the catheter may need to be 
replaced. Infections will also be treated with 
drugs. Sometimes, the catheter has to be 
taken out and a new catheter put in. Also, the 
catheter could puncture (create a hole) in 
your lung and cause serious bleeding, but 
this is very rare.  
We will do an X-ray or CT scan of your 
chest to make sure we know the best place 
to insert the catheter and reduce the risks 
from happening as much as possible.  
Infertility and reduced sexual functioning  
Chemotherapy can cause infertility (inability 
to have children). It may decrease your 
sexual desire and cause female vaginal 
dryness. 
The chemotherapy doses used in this study 
are lower than what is used in standard 
transplants, so the risk of infertility may be 
lower. Some patients who received reduced-
intensity transplants had children. It’s 
difficult to know the exact risk of infertility 
from reduced-intensity transplants. We don’t 
know for sure what your risk of infertility 
will be.  
Risk to the unborn 
The treatments in this study have not been 
proven to be safe at any stage of pregnancy. 
Therefore, if you are pregnant or nursing, you 
are not eligible for this study. Women who 
can become pregnant must use two forms of 
effective birth control while receiving 
chemotherapy and drugs to prevent GVHD. 
Effective birth control is defined as the 
following: 
1. Refraining from all acts of vaginal 
sex (abstinence)  
2. Consistent use of birth control pills 
3. Injectable birth control methods 
(Depo-Provera, Norplant) 
4. Tubal sterilization or male partner 
who has undergone a vasectomy 
5. Placement of an IUD (intrauterine 
device) 
6. Use of a diaphragm with 
contraceptive jelly and/or condoms 
with contraceptive foam every time 
you have sex 
Reproductive Risks  
The drugs used in this research study may 
damage your reproductive organs, affect 
your ability to have children or possibly 
cause birth defects if you take them while 
you are pregnant. It is important that a 
woman is not pregnant or breast-feeding and 
does not become pregnant during the course 
of the study. 
If you are a woman and can become 
pregnant, you will need to take a pregnancy 
test before you start the study. You should 
discuss ways to prevent pregnancy while 
you are in the study. Women who have gone 
through puberty may find that their 
menstrual cycle becomes irregular or stops 
permanently. This does not mean that you 
cannot become pregnant. You must still use 
an effective method of birth control during 

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your transplant and continue until you are 
finished with your GVHD prevention 
treatment. 
If you are a man, your body may not be able 
to produce sperm (become sterile). You 
should talk with your doctor about banking 
your sperm before having a transplant. 
Please check with your doctor to understand 
more about these risks. 
Risk of death   
The side effects of a blood and bone marrow 
transplant might be very serious and cause 
death. Your doctor will do everything to 
make sure your transplant is as safe as 
possible, but there is still a risk of death.  
 
 
 
7. Alternative Treatments 
Participation in this study is optional. If you 
choose not to take part, you may still receive 
a blood or marrow transplant to treat your 
disease. The treatment and evaluations you 
would receive could be very similar to what 
would receive if you join this study.  
Your study doctor will talk with you about 
your options. If you decide not to participate 
in this study, your medical care will not be 
affected in any way. 
Your other choices may include: 
▪ Treatment with other drugs, 
radiation, or a combination of drugs 
and radiation without a transplant  
▪ A blood or marrow transplant that is 
not part of the study, or another type 
of transplant 
▪ Participation in another clinical trial, 
if available (check with your doctor) 
▪ No treatment for your blood disorder 
at this time 
▪ Comfort care: This can occur at any 
stage of a disease. The goal is to 
make you comfortable by treating 
symptoms of the disease and 
improving your quality of life.  You 
may still be receiving treatment for 
your disease. This is different from 
hospice care. 
Every treatment option has benefits and 
risks. Talk with your doctor about your 
treatment choices before you decide if you 
will take part in this study. 
It is important that you talk to your doctor 
about treatment choices before you decide to 
participate in this study. 
 
 

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8. Possible Benefits 
We don’t know if taking part in this study 
will make your health better. If the 
transplant works well, you may not have any 
more symptoms of your disorder. The 
information from this study will help doctors 
learn if reduced-intensity transplants are safe 
and work well for people with 
hemophagocytic syndromes or immune 
disorders. 
 
 
9. New Information Available During the Study 
During this study, the study doctors may learn 
new information about the study drug or the 
risks and benefits of the study. If this happens, 
they will tell you about the new information. 
The new information may mean that you can 
no longer take part in the study, or that you 
may not want to continue in the study.  
If this happens, the study doctor will stop 
your participation and will offer you all 
available care to meet your needs and 
medical conditions. 
 
10. Privacy, Confidentiality and Use of Information 
Your confidentiality is one of our main 
concerns. We will do our best to make sure 
that the personal information in your 
medical record is kept private. However, we 
cannot guarantee total privacy. All your 
medical and demographic (such as race and 
ethnicity, gender and household income) 
information will be kept private and 
confidential. (Name of Transplant Center) 
and the organizations listed below will not 
disclose your participation by any means of 
communication to any person or 
organization, except by your written request 
or permission, or unless required by federal, 
state or local laws, or regulatory agencies.  
Individuals authorized by the organizations 
below will have access to your research and 
medical information. They may use this 
information for inspections or audits to 
study the outcomes of your treatment. In 
agreeing to participate, you consent to such 
inspections and to the copying of parts of 
your 
records, 
if 
required 
by 
these 
organizations. 
We may give out your personal information 
if required by law. If information from this 
study is published or presented at scientific 
meetings, your name and other personal 
information will not be used.  
Information about your transplant from your 
original medical records may be seen or sent 
to national and international transplant 
registries, including: 

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▪ /Institution/ 
▪ The National Institutes of Health (NIH) 
▪ The National Heart, Lung, and Blood 
Institute (NHLBI)  
▪ The National Cancer Institute (NCI) 
▪ Office of Human Research Protection 
(OHRP) 
▪ The Food and Drug Administration (FDA)  
▪ Institutional Review Boards (IRBs) 
responsible for this study 
▪ Data and Safety Monitoring Board 
(DSMB), not part of /Institution/ 
▪ Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), including 
the Center for International Blood and 
Marrow Transplant Research (CIBMTR), 
the National Marrow Donor Program 
(NMDP) and the EMMES Corporation 
who are coordinating the studies of the 
BMT CTN 
▪ Study investigators 
We will not identify you by name in any 
publications or reports that come from these 
organizations or groups. 
Information that does not include personally 
identifiable information about this study has 
been or will be submitted, at the appropriate 
and required time, to the government-
operated clinical trial registry data bank, 
which contains registration, results, and 
other information about registered studies.  
This data bank can be accessed by you and 
the general public at:  
www.ClinicalTrials.gov. Federal law 
requires study information for certain 
studies to be submitted to the data bank. 
For questions about access to your medical 
records, please contact /name/ at /number/. 
11. Ending Your Participation 
The study doctor or the study sponsor may 
stop the study at any time, and we may ask 
you to leave the study. If we ask you to 
leave the study, the reasons will be 
discussed with you. Possible reasons to end 
your participation in this study include: 
▪ You do not meet the study 
requirements.  
▪ You need a medical treatment not 
allowed in this study. 
▪ The study doctor decides that it 
would be harmful to you to stay in 
the study. 
▪ You are having serious side effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or 
take study drugs as directed. 
▪ The study is stopped for any reason. 

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You could have serious health risks if you 
stop treatment during the conditioning 
process before you receive your transplant. 
If you stop taking the immune suppressing 
drugs (see Section 6: Risks and 
Discomforts) too soon after transplant, your 
body could reject the donor stem cells or 
you could develop serious complications 
and possibly die.  
We ask that you talk with the research 
doctor and your regular doctor before you 
leave the study. Your doctors will tell you 
how to stop safely and talk with you about 
other treatment choices.  
If you decide to leave this study after the 
study, or your doctor asks you to leave the 
study for medical reasons, you will need to 
come back to the doctor’s office for tests for 
your safety. Even if you leave the study, the 
information collected from your participation 
will be included in the study results. 
 
 
12. Physical Injury as a Result of Participation 
It is important to tell your study doctor, 
__________________ [investigator's 
name(s)], or study staff if you feel that you 
have been injured from taking part in this 
study. You can tell the doctor in person or 
call him/her at __________________ 
[telephone number]. 
You will get all available medical treatment 
if you are injured from taking part in this 
study. You and/or your health plan will be 
charged for this treatment. The study will 
not pay for medical treatment.  
In case you are injured in this study, you do 
not lose any of your legal rights to receive 
payment by signing this Consent Form. 
 
13. Compensation or Payment
You will not be paid for taking part in this 
study. You will not be compensated or 
reimbursed for any extra costs (for example, 
travel and meals) from taking part in this 
study.  
 
 
14. Costs and Reimbursement

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Most of the tests for this study are standard 
medical care for your transplant and will be 
billed to your insurance company. You and/or 
your health plan/insurance company will need 
to pay for some or all of the costs of standard 
treatment in this study.  
You or your insurance will not be charged for 
tests that are only done for research on this 
study. You will not pay for any extra tests 
that are being done for the study.  
Some health plans will not pay the costs for 
people taking part in studies. Check with 
your health plan or insurance company to 
find out if they will pay.  
For questions about your costs, financial 
responsibilities, and/or medical insurance 
coverage for your transplant and this study, 
please contact /Center/ Financial Counselor 
at /Number/. 
For more information on clinical trials and 
insurance coverage, you can visit the 
National Cancer Institute’s Web site at 
http://cancer.gov/clinicaltrials/understanding
/insurance-coverage. You can print a copy 
of the “Clinical Trials and Insurance 
Coverage” information from this Web site. 
Another way to get the information is to call 
1-800-4-CANCER (1-800-422-6237) and 
ask them to send you a free copy. 
 
 
15. For More Information  
If you need more information about this 
study, or if you have problems while taking 
part in this study, you can contact the study 
doctor or his/her staff. They can be reached at 
the telephone numbers listed here:   
[Insert name and contact detail]
 
16. Contact Someone about Your Rights 
If you wish to speak to someone not directly 
involved in the study, or if you have any 
complaints about the project, or any questions 
about your rights as a research participant, 
then you may contact:  
[Insert appropriate contact details] 
The ethical aspects of this research study have 
been reviewed and approved by [name of 
IRB]. 
For questions about your rights while taking 
part in this study, call the __________[name 
of center] Institutional Review Board (a 
group of people who review the research to 
protect your rights) at __________________ 
telephone number).

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17. Blood Samples for Future Research (Optional) 
This section of the informed consent form is 
about future research studies that will use 
blood samples from people who are taking 
part in the main study. You may choose to 
give blood samples for these future research 
studies if you want to. You can still be a part 
of the main study even if you say 'no' to give 
blood samples for future research studies. 
Researchers are trying to learn more about 
how the human body processes the drugs 
used for transplant and how the body 
recovers after transplant. This research is 
meant to gain knowledge that may help 
people in the future and make transplants 
even more successful.  
If you agree to provide blood samples, 
here is what will happen: 
a) We will collect 11 extra blood samples 
from your catheter or by a vein in your 
arm at the same time you have routine 
blood tests done (Table 1). We will take 
about 4 teaspoons (20 mL) of your blood 
each time. If you weigh less than 6.7 kg, 
the amount of blood will be based on 
your weight (3 mL/kg). 
We will collect your blood on these 11 
days: 
▪ After you consent to giving 
blood samples, but before you 
start the chemotherapy drugs 
▪ 7 days and 1 day before 
transplant 
▪ 1, 14, 28, 42, 70, 100, 180, 365 
days after transplant 
b) The blood samples for future research 
will be sent to the BMT CTN Repository 
for processing and storage. A repository 
is a place that protects, stores and sends 
out samples for approved research 
studies. Only the repository will have the 
link between you and your research 
samples. All research samples will be 
given a bar code that cannot be linked to 
you by future researchers testing your 
samples. 
c) Samples stored in the Repository will be 
used mainly by clinicians and 
researchers in the BMT CTN network. 
In the future, the unused research 
samples and clinical data will be made 
available outside of this network.  
d) Researchers can apply to study the 
materials stored in the Repository. The 
BMT CTN Steering Committee and/or 
the BMT CTN Executive Committee 
must approve each request before they 
will share samples or information with 
researchers. This is to make sure that the 
investigators requesting the samples are 
qualified, and that the research is of high 
quality. 
e) DNA from your stored blood samples 
might be used in genome-wide 
association (GWA) studies for a future 
project either done or supported by the 
National Institutes of Health (NIH). 

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Genome-wide association studies are a 
way for scientists to find genes that have 
a role in human disease or treatment. 
Each study can look at hundreds of 
thousands of genetic changes at the same 
time. 
If your coded samples are used in 
such a study, the researcher is 
required to add your test results and 
sample information into a shared, 
public research database. This public 
database is called the NIH Genotype 
and Phenotype Database and it is 
managed by the National Center for 
Biotechnology Information (NCBI). 
The NCBI will never have any 
information that would identify you, 
or link you to your information or 
research samples although the results 
of genetic studies could theoretically 
include identifying information 
about you.  
Your name and other information that could 
directly identify you (such as address or 
social security number) will not be placed 
into any scientific database. However, 
because your genetic information is unique 
to you, there is a small chance that someone 
could trace it back to you. The risk of this 
happening is small, but may grow in the 
future. Researchers have a duty to protect 
your privacy and to keep your information 
confidential. 
Some general things you should know about 
letting us store your blood for research are: 
▪ We will only store samples from people 
who give us permission. 
▪ Research is meant to gain knowledge that 
may help people in the future. You will 
not get any direct benefit from taking part. 
Additionally, you or your doctor will not 
be given results and they will not be 
added to your medical record. 
▪ A possible risk is the loss of 
confidentiality about your medical 
information. We will use safety measures 
with both your samples and clinical 
information to make sure that your 
personal information will be kept private. 
The chance that this information will be 
given to someone else is extremely small.  
▪ Your blood will be used only for research 
and will not be sold. The research done 
with your blood may help to develop new 
products in the future. You will not get 
paid for any samples or for any products 
that may be developed from current or 
future research. 
You can change your mind at any time 
about allowing us to use your samples and 
health information for research.  
We ask that you contact [Principal 
Investigator] in writing and let him/her 
know you do not want us to use your 
research samples or health information for 
research. His/her mailing address is on the 
first page of this form. However, samples 
and information that have already been 
shared with other researchers cannot be 
taken back or destroyed.  

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Making Your Choice  
Please read each sentence below and think 
about your choice. After reading each 
sentence, please indicate your choice below. 
If you have any questions, please talk to 
your doctor or nurse, or call our research 
review board at ___________________.  
No matter what you decide to do, it will not 
affect your care. 
 
 
Statement of Consent for Future Research Samples 
The purpose of storing blood samples, the 
procedures involved, and the risks and 
benefits have been explained to me. I have 
asked all the questions I have at this time 
and I have been told whom to contact if I 
have more questions. I have been told that I 
will be given a signed copy of this consent 
form to keep. 
I understand that I do not have to allow the 
use of my blood for research. If I decide to 
not let you store research samples now or in 
the future, it will not affect my medical care 
in any way. 
I voluntarily agree that my blood and 
information can be stored indefinitely by the 
BMT CTN and/or NHLBI Repositories for 
research to learn about, prevent, or treat 
health problems. I also understand that my 
DNA and health information may or may 
not be used in genome-wide association 
studies. 
The decision of whether to allow us to use 
the samples for future research and for your 
genetic code to be released onto a public 
database is completely up to you. There will 
be no penalty to you if you decide not to 
allow this, and your decision will in no way 
affect your participation in this research. 
If you agree to allow your samples to be 
used for future research you also agree to 
have your genetic code released to a public 
database and made accessible to other 
researchers.
 
❑ I agree to allow my blood samples to be stored for future research. 
❑ I do not agree to allow my blood samples to be stored for future research. 
__________________________________________  
 
__________________  
 
Signature 
 
 
 
 
 
 
 
Date 

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HIPAA1 authorization to use and disclose 
individual health information for 
research purposes: 
 
a. Purpose:  As a research participant, I 
authorize the Principal Investigator and 
the researcher’s staff to use and disclose 
my individual health information for the 
purpose of conducting the research study 
entitled Reduced Intensity Conditioning 
for Children and Adults with 
Hemophagocytic Syndromes or Selected 
Primary Immune Deficiencies. 
 
b. Individual Health Information to 
be Used or Disclosed: My individual 
health information that may be used or 
disclosed to conduct this research 
includes: demographic information (e.g., 
age, date of birth, sex, weight), medical 
history (e.g., diagnosis, complications 
with prior treatment), physical 
examination findings, and laboratory test 
results obtained at the time of work-up 
and after transplantation (e.g. blood 
tests, biopsy results).  The identities of 
individuals such as names and addresses 
will not be shared or de-identified to 
make sure information cannot be linked 
to you. 
 
 
1 HIPAA is the Health Insurance Portability and 
Accountability Act of 1996, a federal law related to 
privacy of health information 
c. Parties Who May Disclose My 
Individual Health Information: The 
researcher and the researcher’s staff may 
obtain my child’s (my) individual health 
information from: 
(list: hospitals, clinics or providers from 
which health care information can be 
requested) 
 
 
 
 
d. Parties Who May Receive or Use My 
Individual Health Information: The 
individual health information disclosed 
by parties listed in item c and 
information disclosed by my child (me) 
during the course of the research may be 
received and used by the following 
parties: 
• Members of the BMT CTN Data and 
Coordinating Center and BMT CTN 
#1204 Protocol Team 
• National Heart, Lung, and Blood 
Institute (NHLBI) and the National 
Cancer Institute (NCI), both of the 
National Institutes of Health (NIH), 
study sponsors  
• The National Marrow Donor 
Program (NMDP) and the Center for 
International Blood and Marrow 
Transplant Research (CIBMTR) 
• U.S. government agencies that are 
responsible for overseeing research 
such as the Food and Drug 
Administration (FDA) and the Office 
of Human Research Protections 
(OHRP) 
• U.S. government agencies that are 
responsible for overseeing public 
health concerns such as the Centers 
for Disease Control (CDC) and 
federal, state and local health 
departments 
 

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e. Right to Refuse to Sign this 
Authorization: I do not have to sign this 
Authorization.  If I decide not to sign the 
Authorization, I will not be allowed to 
participate in this study or receive any 
research-related treatment that is 
provided through the study.  However, 
my decision not to sign this 
authorization will not affect any other 
treatment, payment, or enrollment in 
health plans or eligibility for benefits.   
 
f. Right to Revoke:  I can change my 
mind and withdraw this authorization at 
any time by sending a written notice to 
the Principal Investigator to inform the 
researcher of the decision.  If I withdraw 
this authorization, the researcher may 
only use and disclose the protected 
health information already collected for 
this research study.  No further health 
information about my child (me) will be 
collected by or disclosed to the 
researcher for this study. 
 
g. Potential for Re-disclosure: My 
individual health information disclosed 
under this authorization may be subject 
to re-disclosure outside the research 
study and no longer protected.  
Examples include potential disclosures 
for law enforcement purposes, mandated 
reporting for abuse or neglect, judicial 
proceedings, health oversight activities 
and public health measures. 
 
h. This authorization does not have an 
expiration date.  However, you can 
elect at any time to withdraw your 
authorization to participate in the 
study. 
 
You will receive a copy of this form. If you 
need more information about this study, ask 
the study doctor. 
 
 

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TITLE: Reduced-Intensity Conditioning for Children and Adults with Hemophagocytic 
Syndromes or Selected Primary Immune Deficiencies (RICHI) 
 
PROTOCOL NUMBER: BMT CTN #1204 
PRINCIPAL INVESTIGATOR(S):  
Name: 
Address: 
Email:  
Phone:  
Fax: 
 
I have read and understood this Consent 
Form. The nature and purpose of the 
research study has been explained to me. 
 
▪ I have had the chance to ask questions, 
and understand the answers I have been 
given. I understand that I may ask 
questions at any time during the study. 
▪ I freely agree to be a participant in the 
study. 
▪ I understand that I may not directly 
benefit from taking part in the study. 
▪ I understand that, while information 
gained during the study may be published, 
I will not be identified and my personal 
results will stay confidential. 
▪ I have had the chance to discuss my 
participation in this research study with a 
family member or friend. 
▪ I understand that I can leave this study at 
any time, and doing so will not affect my 
current care or prevent me from receiving 
future treatment. 
▪ I understand that I will be given a copy of 
this signed consent form. 
 
 
________________________________ 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
Date 
 
________________________________ 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
________________________________ 
 
 
 
 
 
 
 
Name of Counseling Physician 
 
 
 
Date 
 
________________________________ 
 
 
 
 
 
 
 
 
Signature of Counseling Physician 
 
    
 
Date 
 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
 
 
B-32 
Pediatric Assent to Participate in Research 
For Children Ages 7 to 17 years old 
Study Title: Reduced-Intensity Conditioning for Children and Adults with Hemophagocytic 
Syndromes or Selected Primary Immune Deficiencies 
Protocol: 
BMT CTN 1204 
A. Why am I here? 
We are inviting you to join our study because you will receive a bone marrow transplant to 
treat your disease. A transplant uses blood-making cells from another person (donor) to 
replace your cells that are not healthy. A donor is the name for a person who gives some of 
their blood-making cells for a transplant. 
B. Why are you doing this study? 
We want to learn if transplant works to cure your disease.  
C. What will happen to me? 
Before your transplant, you will have check-ups with the study doctors. Then, you will get a 
small tube put in your chest in the operating room (you will be asleep for this).  The small 
tube makes it easier for you to get your medicines. It will also make it easier and less painful 
for drawing blood for tests. 
We will give you medicines that will help make the cells from your donor grow in your body. 
These medicines might make you feel sick. You might throw up, lose your hair, or get sores 
in your mouth.  
After you’re done taking the medicines, you will get cells from your donor. This is your 
transplant. Your donor can be your sister or brother (related) or someone you don’t know 
(unrelated). Your new cells will come from your donor's bone marrow. The cells will make 
new and healthy cells in your body.  
Sometimes the donor cells can cause a problem called graft versus host disease (GVHD). 
GVHD happens when your body attacks the donor cells. It can give you diarrhea, a skin rash, 
make you feel sick and throw up, or make you not feel hungry. Your doctors will give you 
medicines to try to make sure you don’t get GVHD.  

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
 
 
B-33 
You will stay in the hospital for several days before your transplant and for about 4 weeks 
after your transplant. After you go home, you will need to go back to see your doctor often. 
It is possible that your disease will come back. If this happens, your doctor will find another 
way to treat you.  
D. Will it hurt? 
For your transplant, we will put a small tube in your chest. It might hurt a little and you 
might bleed a little. Your doctor and nurses will make sure you feel as little pain as possible.  
E. Will the study help me? 
We don’t know if the study will help you or not. 
F. What if I have questions? 
You can ask any questions that you have about the study.  If you forget to ask a question and 
think of it later, you can call me [insert office number].  You can also ask your question the 
next time you see me. 
You can call the study office at any time to ask questions about the study. 
G. Do I have to be in this study? 
You don't have to be in this study. Your doctor and nurses will not be mad at you if you don't 
want to join. If you decide you don't want to be in this study, you should talk to your doctor, 
nurses and parents about other ways to treat your disease.  
You can say yes now and change your mind later.  
Be sure to talk this over with your parents before you decide if you want be in the study. We 
will also ask your parents to give their permission for you to join this study.  
 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
 
 
B-34 
 
Writing your name on this page means that you agree to be in the study and know what will 
happen to you.  If you decide to quit the study, all you have to do is tell your doctor. 
You and your parent or guardian will get a copy of this form after you sign it. 
 
______________________________________________  ______________________________ 
Signature of Child 
 
 
 
 
 
Date 
 
______________________________________________  ______________________________ 
Print Name of Child 
Age of Child 
 
Certification of Counseling Healthcare Professional: I certify that the nature and purpose, the 
potential benefits, and possible risks associated with participation in this study have been 
explained to the above individual and that any questions about this information have been 
answered. 
 
______________________________________________  ______________________________ 
Counseling Healthcare Professional 
Date 
 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
 
 
C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
Version 4.0 dated June 16, 2015 
 
 
C-2 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
Participants consenting to the optional future research will have samples collected for future 
research supporting the protocol.  All research sample aliquots will be given unique bar code 
designations that generally cannot be linked back to the participant’s name or other identifying 
information, though participants are given the opportunity to consent to research including 
genetic data, in which case the results could theoretically include identifying information. 
Laboratory test results, clinical information, etc., associated with the coded samples may be 
provided to the Investigators to associate biological findings with clinical outcomes.  
Investigators will be able to link results from serial aliquots (for example: Pre-conditioning, Day 
+1, Day +30) plasma samples.  Similarly, investigators will be able to link data from different 
sample types (for example: protein data from plasma and gene expression data from peripheral 
mononuclear cells).  All research samples will be collected and shipped same-day to the BMT 
CTN Repository for processing and sample aliquot storage.  Priority for biological samples will 
be determined according to the BMT CTN# 1204 team, along with the BMT CTN Biomarker 
Committee. 
 
The rationale for this sample collection strategy is to enable independently funded correlative 
biology studies.  The sample collection schedule is designed to allow development of studies to 
test the role of early inflammation and alemtuzumab pharmacokinetics on clinical outcomes 
including immune reconstitution, engraftment and development of mixed chimerism, 
development and clearance of viral infections, and development of GVHD.  Endpoints may be 
determined by clinical reporting, with requirements outlined in the body of the protocol, and/or 
by specific research tests.  For example, chimerism (whole and CD3+ fractions) will be collected 
in clinical labs for all patients, though more refined lineage-specific chimerism may be tested on 
a research basis.  Samples at all time points will also be banked for unspecified future research.   
 
Biomarker 
Approach 
Sample 
Type 
Pre-
Conditioning 
Day 
-7 
Day 
-1 
Day 
+1 
Day 
+14 
Day 
+28 
Day 
+42 
Day 
+70 
Day 
+100 
Day 
+180 
Day 
+365 
Proteonomics 
Plasma 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Gene 
Expression 
PBMC 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Alemtuzumab 
Concentration 
Plasma 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Clinical 
Endpoints 
Sample 
Type 
Pre-
Conditioning 
Day 
-7 
Day 
-1 
Day 
+1 
Day 
+14 
Day 
+28 
Day 
+42 
Day 
+70 
Day 
+100 
Day 
+180 
Day 
+365 
Early 
Inflammation 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Immune 
Reconstitution 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Chimerism 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Viral 
Infections 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
Version 4.0 dated June 16, 2015 
 
 
C-3 
 
Research sample collection and storage plan outlined below: 
 
Subjects 
Research 
Sample Type 
Peripheral Blood 
Collection Volume 
Stored 
Material 
Aliquots Stored 
Patients who 
consent to 
future 
research 
Peripheral 
Blood 
20 mL (Sodium 
Heparin Tubes) 
Maximum blood 
volume collection limit 
at each scheduled time 
point 
 
Pediatric patients (< 
6.7 kg): 3 mL/kg 
Plasma 
Maximum 12 aliquots 
~0.5 to 1.0 mL aliquots; stored at 
-80°C (If ≤ 2 mL plasma: stored 
in 0.25 mL aliquots) 
Viable PBMC 
Maximum 6 aliquots 
1.0 mL aliquots containing ~2.5-
5.0 x 106 PBMC; controlled-rate 
frozen and stored in LN 
(When PBMC recovery is low: 
stored in 1.0 mL aliquots 
containing ~1.0 x 106 PBMC) 
* All blood samples will be collected and shipped same-day for next-day processing and storage at the BMT CTN 
Research Sample Repository. 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
D-1 
APPENDIX D 
 
LANSKY AND KARNOFSKY  
PERFORMANCE STATUS SCALES 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
D-2 
APPENDIX D 
 
LANSKY and KARNOFSKY PERFORMANCE STATUS SCALES 
 
 
LANSKY SCALE (< 16 YEARS) 
Percentage 
 
100 
Fully active 
90 
Minor restriction in physically strenuous play 
80 
Restricted in strenuous play, tires more easily, otherwise active 
70 
Both greater restrictions of, and less time spent in, active play 
60 
Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 
Considerable assistance required for any active play; fully able to engage in quiet 
play 
40 
Able to initiate quiet activities 
30 
Needs considerable assistance for quiet activity 
20 
Limited to very passive activity initiated by others (e.g., TV) 
10 
Completely disabled, not even passive play 
0 
Dead 
 
 
KARNOFSKY SCALE (≥ 16 YEARS) 
Percentage 
 
100 
Normal health 
90 
Minor symptoms 
80 
Normal activity with some effort 
70 
Unable to carry on normal activity but able to care for oneself 
60 
Requires occasional help with personal needs 
50 
Disabled 
40 
Requires considerable assistance and medical care 
30 
Severely disabled, in hospital 
20 
Very sick, active support needed 
10 
Moribund 
0 
Dead 
 
REFERENCE Karnofsky DA: Meaningful clinical classification of therapeutic responses to anti-cancer 
drugs.  Editorial: Clin Pharmacol Ther 2:709-712, 1961. 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
E-1 
APPENDIX E 
 
RECOMMENDATIONS FOR HLH THERAPY PRIOR TO HCT 
AND  
FOR HLH SALVAGE THERAPY 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
E-2 
APPENDIX E 
 
RECOMMENDATIONS FOR HLH THERAPY PRIOR TO HCT AND  
FOR HLH SALVAGE THERAPY  
 
1. Patients with active HLH should be treated according to the Histiocyte Society HLH-94 
Protocol prior to HCT.1 
2. For patients with evidence of refractory HLH despite treatment per HLH-94 (As determined 
by clinician, but may include persistent fever; rising ferritin, rising soluble IL2R, rising 
LDH; clinical and lab evidence of organ damage/failure(Jordan et al., 2011) 
a. Re-escalate dexamethasone and etoposide to maximum of etoposide 150 mg/m2 twice 
weekly and dexamethasone 10 mg/m2/day, then wean etoposide frequency and 
dexamethasone dose as tolerated.   
b. If HLH is refractory despite maximum etoposide and dexamethasone, consider trial of 
alemtuzumab “salvage” therapy:  
- Alemtuzumab: 0.1  mg/kg (IV or subcutaneous) x 1 day, then 0.3 mg/kg (IV or 
subcutaneous) x 3 days 
- Continue dexamethasone at 10 mg/m2/day x 1 week, then wean as tolerated back to 
either “Induction” or “Continuation” per HLH-94 
- Discontinue cyclosporine while patient has symptoms of active/refractory HLH  (Risk 
of PRES may be associated with cyclosporine and active HLH (Thompson et al., 
2009)) 
3. All patients with history of CNS involvement by HLH (pleocytosis, elevated protein, 
abnormal MRI, or hemophagocytosis in CSF) should undergo diagnostic LP and/or at Day 
+30 (+ 1 week), or at any time of unexplained mental status change.  Brain MRI may be 
substituted for LP if patients are not able to tolerate the procedure.  Intrathecal therapy is 
recommended, when clinically safe to administer in patients with pleocytosis or 
hemphagocytosis in CSF, or MRI consistent with HLH-associated inflammation. 
Recommended therapy for CNS inflammation in HLH: Weekly intrathecal therapy is 
generally continued until at least 1 week after resolution of CNS involvement (both clinical 
and CSF indices): age < 1 year: 6 mg  MTX/8 mg hydrocortisone; 1-2 years, 8 mg MTX/10 
mg hydrocortisone; 2-3 years, 10 mg MTX/12 mg hydrocortisone; > 3 years, 12 mg MTX/15 
mg hydrocortisone (Jordan et al., 2011).  

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
F-1 
APPENDIX F 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
F-2 
APPENDIX F 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H

=
:
0
 versus
1
1 :

=
H
 decides in favor of 
1
H  or 
0
H if 

c
Ln 
 
or 

c
Ln 
, respectively, where 

=
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 
c is 
determined to have the size .  When the sample size is not fixed in advance, further 
improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The SPRT 
continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling and 
decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H as soon 
as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities 

and of 
rejecting 
0
H when 
0

=
, and of accepting 
0
H when 
1

=
, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, 
the SPRT with error probabilities 

 and minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
.  If, in addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function 
)
,
(

x
f
, with 
monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1



 has non-
decreasing power function. 
 
For the SPRT with error probabilities 

and , the SPRT boundaries are given approximately by 

/
)
1( −
=
A
 and 
)
1
/(


−
=
B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O
−
−
=
 where 
)
(
h
is the non-trivial solution to the equation 

=1
)
;
(
))
,
(
/
)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E
+
−
=
provides the average sample number 
for an arbitrary .  The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var

.  Thus 
we will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 
 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
F-3 
Derivation of the SPRT for Censored Exponential Survival Times 
 
Suppose that we wish to construct a sequential test for the composite null hypothesis that the rate 
of overall mortality at an early time point t is less than or equal to p0 versus the alternative 
hypothesis that it is greater than or equal to p0.  Let us assume that the survival times, 
nT
T
T
,...,
,
2
1
, 
are i.i.d. with exponential density function 
T
e
T
f



−
=
)
,
(
.  Although an exponential model may 
not fit well for overall mortality, it usually provides a reasonable model over a short time frame 
for modeling toxicity, so in all discussion below we assume that exponential survival times are 
censored at time point t. In the exponential parameterization, a t-day survival rate of p0 translates 
into a mean survival of µ0=-t/ln(1-p0) (rate parameter 
=
0

-ln(1-p0)/t).  . 
 
The SPRT is derived with reference to a simple null and alternative hypothesis for the rate 
parameter, in this case, 
0 :
o
H


=
  versus
1
1 :

=
H
 .  The log-likelihood ratio for the 
exponential 
in 
the 
presence 
of 
censoring 
is 
1
0
1
0
1
0
log
( ;
)
log
( ,
)
(log( )
log(
))
(
)
n
n
n
i
i
i
i
i
i
f x
f x
d
T






−
=
−
−
−



, where d is the number of 
events.   The SPRT can be represented graphically when plotting the number of deaths (d) on the 
y axis against the total time on study 
n
i
iT  on the x axis.  The continuation region in terms of d is 
bounded by two parallel lines given by 
1
0
1
0
1
0
1
0
1
0
1
0
(
)
(
)
log( )
log( )
(log
log
)
(log
log
)
(log
log
)
(log
log
)
n
n
i
i
i
i
B
A
T
d
T




















−
−
+


+








−
−
−
−










 
with 
common 
slope 
1
0
1
0
(
) / (log
log
)




−
−
, 
and 
intercepts 
1
0
log
/ (ln
ln
)
A


−
 
and 
1
0
log
/ (ln
ln
)
B


−
, for the upper and lower bounds, respectively.  For monitoring purposes, at an 
interim analysis calendar time point s, suppose that d(s) events have occurred and that the total 
time on study is 
( )
n
i
i
T s

.The cumulative number of events d(s) is plotted on the y axis against 
the total time on study,
( )
n
i
i
T s

.  When this graph crosses the upper boundary, the null 
hypothesis is rejected. In practice, monitoring will be scheduled monthly after the start of 
enrollment to the study.   
 
A truncated version of the SPRT can be obtained by specifying a maximum sample size.  We 
truncate the SPRT by declaring that if the test has failed to terminate after the maximum sample 
size, that the null hypothesis will be accepted.  Since the probability that the untruncated SPRT 
would reject the null at the maximum sample size is negligible, it makes little difference how the 
final boundary value is selected, and this rule is chosen for simplicity.  The operating 
characteristics of this proposed truncated SPRT for censored exponential data can be estimated 
by simulation. 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
G-1 
APPENDIX G 
 
BLOOD PRESSURE LEVELS BY AGE AND HEIGHT 
PERCENTILE 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
G-2 
APPENDIX G 
 
BLOOD PRESSURE LEVELS BY AGE AND HEIGHT PERCENTILE 
 
 
Blood Pressure Levels for Boys by Age and Height Percentile 
 
BP 
Systolic BP (mmHg)
Diastolic BP (mmHg)
 Percentile of Height  
 Percentile of Height  
Age 
Percentile 
(Year) 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
80 
81 
83 
85 
87 
88 
89 
34 
35 
36 
37 
38 
39 
39 
90th 
94 
95 
97 
99 
100 
102 
103 
49 
50 
51 
52 
53 
53 
54 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
99th 
105 
106 
108 
110 
112 
113 
114 
61 
62 
63 
64 
65 
66 
66 
2 
50th 
84 
85 
87 
88 
90 
92 
92 
39 
40 
41 
42 
43 
44 
44 
90th 
97 
99 
100 
102 
104 
105 
106 
54 
55 
56 
57 
58 
58 
59 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
99th 
109 
110 
111 
113 
115 
117 
117 
66 
67 
68 
69 
70 
71 
71 
3 
50th 
86 
87 
89 
91 
93 
94 
95 
44 
44 
45 
46 
47 
48 
48 
90th 
100 
101 
103 
105 
107 
108 
109 
59 
59 
60 
61 
62 
63 
63 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
99th 
111 
112 
114 
116 
118 
119 
120 
71 
71 
72 
73 
74 
75 
75 
4 
50th 
88 
89 
91 
93 
95 
96 
97 
47 
48 
49 
50 
51 
51 
52 
90th 
102 
103 
105 
107 
109 
110 
111 
62 
63 
64 
65 
66 
66 
67 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
99th 
113 
114 
116 
118 
120 
121 
122 
74 
75 
76 
77 
78 
78 
79 
5 
50th 
90 
91 
93 
95 
96 
98 
98 
50 
51 
52 
53 
54 
55 
55 
90th 
104 
105 
106 
108 
110 
111 
112 
65 
66 
67 
68 
69 
69 
70 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
99th 
115 
116 
118 
120 
121 
123 
123 
77 
78 
79 
80 
81 
81 
82 
6 
50th 
91 
92 
94 
96 
98 
99 
100 
53 
53 
54 
55 
56 
57 
57 
90th 
105 
106 
108 
110 
111 
113 
113 
68 
68 
69 
70 
71 
72 
72 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
99th 
116 
117 
119 
121 
123 
124 
125 
80 
80 
81 
82 
83 
84 
84 
7 
50th 
92 
94 
95 
97 
99 
100 
101 
55 
55 
56 
57 
58 
59 
59 
90th 
106 
107 
109 
111 
113 
114 
115 
70 
70 
71 
72 
73 
74 
74 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
99th 
117 
118 
120 
122 
124 
125 
126 
82 
82 
83 
84 
85 
86 
86 
8 
50th 
94 
95 
97 
99 
100 
102 
102 
56 
57 
58 
59 
60 
60 
61 
90th 
107 
109 
110 
112 
114 
115 
116 
71 
72 
72 
73 
74 
75 
76 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
99th 
119 
120 
122 
123 
125 
127 
127 
83 
84 
85 
86 
87 
87 
88 
9 
50th 
95 
96 
98 
100 
102 
103 
104 
57 
58 
59 
60 
61 
61 
62 
90th 
109 
110 
112 
114 
115 
117 
118 
72 
73 
74 
75 
76 
76 
77 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
99th 
120 
121 
123 
125 
127 
128 
129 
84 
85 
86 
87 
88 
88 
89 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
G-3 
Blood Pressure Levels for Boys by Age and Height Percentile (Continued) 
 
BP 
Systolic BP (mmHg)
Diastolic BP (mmHg)
 Percentile of Height  
 Percentile of Height  
Age 
Percentile 
(Year) 
 
5th 
10th 
25th 
50th 
75th 
90th 95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
10 
50th 
97 
98 
100 
102 
103 
105 
106 
58 
59 
60 
61 
61 
62 
63 
90th 
111 
112 
114 
115 
117 
119 
119 
73 
73 
74 
75 
76 
77 
78 
95th 
115 
116 
117 
119 
121 
122 
123 
77 
78 
79 
80 
81 
81 
82 
99th 
122 
123 
125 
127 
128 
130 
130 
85 
86 
86 
88 
88 
89 
90 
11 
50th 
99 
100 
102 
104 
105 
107 107 
59 
59 
60 
61 
62 
63 
63 
90th 
113 
114 
115 
117 
119 
120 121 
74 
74 
75 
76 
77 
78 
78 
95th 
117 
118 
119 
121 
123 
124 125 
78 
78 
79 
80 
81 
82 
82 
99th 
124 
125 
127 
129 
130 
132 132 
86 
86 
87 
88 
89 
90 
90 
12 
50th 
101 
102 
104 
106 
108 
109 110 
59 
60 
61 
62 
63 
63 
64 
90th 
115 
116 
118 
120 
121 
123 123 
74 
75 
75 
76 
77 
78 
79 
95th 
119 
120 
122 
123 
125 
127 127 
78 
79 
80 
81 
82 
82 
83 
99th 
126 
127 
129 
131 
133 
134 135 
86 
87 
88 
89 
90 
90 
91 
13 
50th 
104 
105 
106 
108 
110 
111 112 
60 
60 
61 
62 
63 
64 
64 
90th 
117 
118 
120 
122 
124 
125 126 
75 
75 
76 
77 
78 
79 
79 
95th 
121 
122 
124 
126 
128 
129 130 
79 
79 
80 
81 
82 
83 
83 
99th 
128 
130 
131 
133 
135 
136 137 
87 
87 
88 
89 
90 
91 
91 
14 
50th 
106 
107 
109 
111 
113 
114 115 
60 
61 
62 
63 
64 
65 
65 
90th 
120 
121 
123 
125 
126 
128 128 
75 
76 
77 
78 
79 
79 
80 
95th 
124 
125 
127 
128 
130 
132 132 
80 
80 
81 
82 
83 
84 
84 
99th 
131 
132 
134 
136 
138 
139 140 
87 
88 
89 
90 
91 
92 
92 
15 
50th 
109 
110 
112 
113 
115 
117 117 
61 
62 
63 
64 
65 
66 
66 
90th 
122 
124 
125 
127 
129 
130 131 
76 
77 
78 
79 
80 
80 
81 
95th 
126 
127 
129 
131 
133 
134 135 
81 
81 
82 
83 
84 
85 
85 
99th 
134 
135 
136 
138 
140 
142 142 
88 
89 
90 
91 
92 
93 
93 
16 
50th 
111 
112 
114 
116 
118 
119 120 
63 
63 
64 
65 
66 
67 
67 
90th 
125 
126 
128 
130 
131 
133 134 
78 
78 
79 
80 
81 
82 
82 
95th 
129 
130 
132 
134 
135 
137 137 
82 
83 
83 
84 
85 
86 
87 
99th 
136 
137 
139 
141 
143 
144 145 
90 
90 
91 
92 
93 
94 
94 
17 
50th 
114 
115 
116 
118 
120 
121 122 
65 
66 
66 
67 
68 
69 
70 
90th 
127 
128 
130 
132 
134 
135 136 
80 
80 
81 
82 
83 
84 
84 
95th 
131 
132 
134 
136 
138 
139 140 
84 
85 
86 
87 
87 
88 
89 
99th 
139 
140 
141 
143 
145 
146 147 
92 
93 
93 
94 
95 
96 
97 
 
BP, blood pressure 
 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
 
For research purposes, the standard deviations in Appendix Table B–1 allow one to compute BP Z-scores and percentiles for 
boys with height percentiles given in Table 3 (i.e., the 5th,10th, 25th, 50th, 75th, 90th, and 95th percentiles). These height 
percentiles must be converted to height Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 
1.28%; 95% = 1.645) and then computed according to the methodology in steps 2–4 described in Appendix B. For children with 
height percentiles other than these, follow steps 1–4 as described in Appendix B. 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
G-4 
Blood Pressure Levels for Girls by Age and Height Percentile 
 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg)
 Percentile of Height  
 Percentile of Height  
Age 
Percentile 
(Year) 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th
25th 
50th 
75th 
90th 
95th 
l 
50th 
83 
84 
85 
86 
88 
89 
90 
38 
39
39 
40 
41 
41 
42 
90th 
97 
97 
98 
100 
101 
102 
103 
52 
53
53 
54 
55 
55 
56 
95th 
100 
101 
102 
104 
105 
106 
107 
56 
57
57 
58 
59 
59 
60 
99th 
108 
108 
109 
111 
112 
113 
114 
64 
64
65 
65 
66 
67 
67 
2 
50th 
85 
85 
87 
88 
89 
91 
91 
43 
44
44 
45 
46 
46 
47 
90th 
98 
99 
100 
101 
103 
104 
105 
57 
58
58 
59 
60 
61 
61 
95th 
102 
103 
104 
105 
107 
108 
109 
61 
62
62 
63 
64 
65 
65 
99th 
109 
110 
111 
112 
114 
115 
116 
69 
69
70 
70 
71 
72 
72 
3 
50th 
86 
87 
88 
89 
91 
92 
93 
47 
48
48 
49 
50 
50 
51 
90th 
100 
100 
102 
103 
104 
106 
106 
61 
62
62 
63 
64 
64 
65 
95th 
104 
104 
105 
107 
108 
109 
110 
65 
66
66 
67 
68 
68 
69 
99th 
111 
111 
113 
114 
115 
116 
117 
73 
73
74 
74 
75 
76 
76 
4 
50th 
88 
88 
90 
91 
92 
94 
94 
50 
50
51 
52 
52 
53 
54 
90th 
101 
102 
103 
104 
106 
107 
108 
64 
64
65 
66 
67 
67 
68 
95th 
105 
106 
107 
108 
110 
111 
112 
68 
68
69 
70 
71 
71 
72 
99th 
112 
113 
114 
115 
117 
118 
119 
76 
76
76 
77 
78 
79 
79 
5 
50th 
89 
90 
91 
93 
94 
95 
96 
52 
53
53 
54 
55 
55 
56 
90th 
103 
103 
105 
106 
107 
109 
109 
66 
67
67 
68 
69 
69 
70 
95th 
107 
107 
108 
110 
111 
112 
113 
70 
71
71 
72 
73 
73 
74 
99th 
114 
114 
116 
117 
118 
120 
120 
78 
78
79 
79 
80 
81 
81 
6 
50th 
91 
92 
93 
94 
96 
97 
98 
54 
54
55 
56 
56 
57 
58 
90th 
104 
105 
106 
108 
109 
110 
111 
68 
68
69 
70 
70 
71 
72 
95th 
108 
109 
110 
111 
113 
114 
115 
72 
72
73 
74 
74 
75 
76 
99th 
115 
116 
117 
119 
120 
121 
122 
80 
80
80 
81 
82 
83 
83 
7 
50th 
93 
93 
95 
96 
97 
99 
99 
55 
56
56 
57 
58 
58 
59 
90th 
106 
107 
108 
109 
111 
112 
113 
69 
70
70 
71 
72 
72 
73 
95th 
110 
111 
112 
113 
115 
116 
116 
73 
74
74 
75 
76 
76 
77 
99th 
117 
118 
119 
120 
122 
123 
124 
81 
81
82 
82 
83 
84 
84 
8 
50th 
95 
95 
96 
98 
99 
100 
101 
57 
57
57 
58 
59 
60 
60 
90th 
108 
109 
110 
111 
113 
114 
114 
71 
71
71 
72 
73 
74 
74 
95th 
112 
112 
114 
115 
116 
118 
118 
75 
75
75 
76 
77 
78 
78 
99th 
119 
120 
121 
122 
123 
125 
125 
82 
82
83 
83 
84 
85 
86 
9 
50th 
96 
97 
98 
100 
101 
102 
103 
58 
58
58 
59 
60 
61 
61 
90th 
110 
110 
112 
113 
114 
116 
116 
72 
72
72 
73 
74 
75 
75 
95th 
114 
114 
115 
117 
118 
119 
120 
76 
76
76 
77 
78 
79 
79 
99th 
121 
121 
123 
124 
125 
127 
127 
83 
83
84 
84 
85 
86 
87 
10 
50th 
98 
99 
100 
102 
103 
104 
105 
59 
59
59 
60 
61 
62 
62 
90th 
112 
112 
114 
115 
116 
118 
118 
73 
73
73 
74 
75 
76 
76 
95th 
116 
116 
117 
119 
120 
121 
122 
77 
77
77 
78 
79 
80 
80 
99th 
123 
123 
125 
126 
127 
129 
129 
84 
84
85 
86 
86 
87 
88 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
G-5 
Blood Pressure Levels for Girls by Age and Height Percentile (Continued) 
 
BP 
Systolic BP (mmHg)
Diastolic BP (mmHg)
 Percentile of Height  
 Percentile of Height  
Age 
Percentile 
(Year) 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
100 
101 
102 
103 
105 
106 
107 
60 
60 
60 
61 
62 
63 
63 
90th 
114 
114 
116 
117 
118 
119 
120 
74 
74 
74 
75 
76 
77 
77 
95th 
118 
118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
99th 
125 
125 
126 
128 
129 
130 
131 
85 
85 
86 
87 
87 
88 
89 
12 
50th 
102 
103 
104 
105 
107 
108 
109 
61 
61 
61 
62 
63 
64 
64 
90th 
116 
116 
117 
119 
120 
121 
122 
75 
75 
75 
76 
77 
78 
78 
95th 
119 
120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
99th 
127 
127 
128 
130 
131 
132 
133 
86 
86 
87 
88 
88 
89 
90 
13 
50th 
104 
105 
106 
107 
109 
110 
110 
62 
62 
62 
63 
64 
65 
65 
90th 
117 
118 
119 
121 
122 
123 
124 
76 
76 
76 
77 
78 
79 
79 
95th 
121 
122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
99th 
128 
129 
130 
132 
133 
134 
135 
87 
87 
88 
89 
89 
90 
91 
14 
50th 
106 
106 
107 
109 
110 
111 
112 
63 
63 
63 
64 
65 
66 
66 
90th 
119 
120 
121 
122 
124 
125 
125 
77 
77 
77 
78 
79 
80 
80 
95th 
123 
123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
99th 
130 
131 
132 
133 
135 
136 
136 
88 
88 
89 
90 
90 
91 
92 
15 
50th 
107 
108 
109 
110 
111 
113 
113 
64 
64 
64 
65 
66 
67 
67 
90th 
120 
121 
122 
123 
125 
126 
127 
78 
78 
78 
79 
80 
81 
81 
95th 
124 
125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
99th 
131 
132 
133 
134 
136 
137 
138 
89 
89 
90 
91 
91 
92 
93 
16 
50th 
108 
108 
110 
111 
112 
114 
114 
64 
64 
65 
66 
66 
67 
68 
90th 
121 
122 
123 
124 
126 
127 
128 
78 
78 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
99th 
132 
133 
134 
135 
137 
138 
139 
90 
90 
90 
91 
92 
93 
93 
17 
50th 
108 
109 
110 
111 
113 
114 
115 
64 
65 
65 
66 
67 
67 
68 
90th 
122 
122 
123 
125 
126 
127 
128 
78 
79 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
99th 
133 
133 
134 
136 
137 
138 
139 
90 
90 
91 
91 
92 
93 
93 
 
BP, blood pressure 
 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
 
For research purposes, the standard deviations in Appendix Table B–1 allow one to compute BP Z-scores and percentiles for 
girls with height percentiles given in Table 4 (i.e., the 5th,10th, 25th, 50th, 75th, 90th, and 95th percentiles). These height 
percentiles must be converted to height Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% 
= 1.28%; 95% = 1.645) and then computed according to the methodology in steps 2–4 described in Appendix B. For children 
with height percentiles other than these, follow steps 1–4 as described in Appendix B. 
 
REFERENCE: http://www.nhlbi.nih.gov/files/docs/guidelines/child_tbl.pdf  
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
H-1 
APPENDIX H 
 
REFERENCES 
 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
H-2 
APPENDIX H 
 
REFERENCE LIST 
 
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transplantation for hemophagocytic lymphohistiocytosis. Bone Marrow Transplant. 42, 175-180. 
Bruck,N., Suttorp,M., Kabus,M., Heubner,G., Gahr,M., and Pessler,F. (2011). Rapid and 
sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation 
syndrome through treatment with anakinra and corticosteroids. J. Clin. Rheumatol. 17, 23-27. 
Burroughs,L.M., Torgerson,T.R., Storb,R., Carpenter,P.A., Rawlings,D.J., Sanders,J., 
Scharenberg,A.M., Skoda-Smith,S., Englund,J., Ochs,H.D., and Woolfrey,A.E. (2010). Stable 
hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients 
with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J. Allergy 
Clin. Immunol. 126, 1000-1005. 
Campbell,D.J. and Ziegler,S.F. (2007). FOXP3 modifies the phenotypic and functional 
properties of regulatory T cells. Nat. Rev. Immunol. 7, 305-310. 
Chatila,T.A., Blaeser,F., Ho,N., Lederman,H.M., Voulgaropoulos,C., Helms,C., and 
Bowcock,A.M. (2000). JM2, encoding a fork head-related protein, is mutated in X-linked 
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Cohen,J.I., Jaffe,E.S., Dale,J.K., Pittaluga,S., Heslop,H.E., Rooney,C.M., Gottschalk,S., 
Bollard,C.M., Rao,V.K., Marques,A., Burbelo,P.D., Turk,S.P., Fulton,R., Wayne,A.S., 
Little,R.F., Cairo,M.S., El-Mallawany,N.K., Fowler,D., Sportes,C., Bishop,M.R., Wilson,W., 
and Straus,S.E. (2011). Characterization and treatment of chronic active Epstein-Barr virus 
disease: a 28-year experience in the United States. Blood 117, 5835-5849. 
Conley,M.E., Notarangelo,L.D., and Etzioni,A. (1999). Diagnostic criteria for primary 
immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and 
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Cooper,N., Rao,K., Gilmour,K., Hadad,L., Adams,S., Cale,C., Davies,G., Webb,D., Veys,P., and 
Amrolia,P. (2006). Stem cell transplantation with reduced-intensity conditioning for 
hemophagocytic lymphohistiocytosis. Blood 107, 1233-1236. 
Cooper,N., Rao,K., Goulden,N., Webb,D., Amrolia,P., and Veys,P. (2008). The use of reduced-
intensity stem cell transplantation in haemophagocytic lymphohistiocytosis and Langerhans cell 
histiocytosis. Bone Marrow Transplant. 42 Suppl 2, S47-S50. 
Davies,E.G. and Thrasher,A.J. (2010). Update on the hyper immunoglobulin M syndromes. Br. 
J. Haematol. 149, 167-180. 

BMT CLINICAL TRIALS NETWORK 
RICHI – Protocol 1204 
 
 
Version 4.0 dated June 16, 2015 
H-3 
Dorsey,M.J., Petrovic,A., Morrow,M.R., Dishaw,L.J., and Sleasman,J.W. (2009). FOXP3 
expression following bone marrow transplantation for IPEX syndrome after reduced-intensity 
conditioning. Immunol. Res. 44, 179-184. 
Etzioni,A. (2010). Defects in the leukocyte adhesion cascade. Clin. Rev. Allergy Immunol. 38, 
54-60. 
Filipovich,A. (2008). Hematopoietic cell transplantation for correction of primary 
immunodeficiencies. Bone Marrow Transplant. 42 Suppl 1, S49-S52. 
Fischer,A., Lisowska-Grospierre,B., Anderson,D.C., and Springer,T.A. (1988). Leukocyte 
adhesion deficiency: molecular basis and functional consequences. Immunodefic. Rev. 1, 39-54. 
Gennery,A.R., Khawaja,K., Veys,P., Bredius,R.G., Notarangelo,L.D., Mazzolari,E., Fischer,A., 
Landais,P., Cavazzana-Calvo,M., Friedrich,W., Fasth,A., Wulffraat,N.M., Matthes-Martin,S., 
Bensoussan,D., Bordigoni,P., Lange,A., Pagliuca,A., Andolina,M., Cant,A.J., and Davies,E.G. 
(2004). Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a 
survey of the European experience, 1993-2002. Blood 103, 1152-1157. 
Gungor,T., Halter,J., Klink,A., Junge,S., Stumpe,K.D., Seger,R., and Schanz,U. (2005). 
Successful low toxicity hematopoietic stem cell transplantation for high-risk adult chronic 
granulomatous disease patients. Transplantation 79, 1596-1606. 
Hannibal,M.C. and Torgerson,T. (1993). IPEX Syndrome. 
Henter,J.I., Elinder,G., Soder,O., and Ost,A. (1991). Incidence in Sweden and clinical features of 
familial hemophagocytic lymphohistiocytosis. Acta Paediatr. Scand. 80, 428-435. 
Henter,J.I., Horne,A., Arico,M., Egeler,R.M., Filipovich,A.H., Imashuku,S., Ladisch,S., 
McClain,K., Webb,D., Winiarski,J., and Janka,G. (2007). HLH-2004: Diagnostic and therapeutic 
guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48, 124-131. 
Henter,J.I., Samuelsson-Horne,A., Arico,M., Egeler,R.M., Elinder,G., Filipovich,A.H., 
Gadner,H., Imashuku,S., Komp,D., Ladisch,S., Webb,D., and Janka,G. (2002). Treatment of 
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