CGD analysis since January 1, 1995

Principal Investigator: Karin Chen
Keywords: Chronic Granulomatous Disease , CGD , Primary Children's Hospital , University of Utah Department: Pediatric Administration
IRB Number: 00074398 Co Investigator:  
Specialty: Pediatric Hematology and Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Diana Hernandez
diana.hernandez@hsc.utah.edu
801-662-5352

Brief Summary

Primary Objective

The primary objective of this protocol is to estimate the 1-year, 2-year and 3-year

(and longer if possible) overall survival probabilities post-HCT of CGD subjects

born on or after 1988 who receive HCT on or after 1995.

Secondary Objectives

1. To compare overall survival from birth between patients born on or after 1988 who receive HCT on or

after 1995 vs. those born on or after 1988 who receive conventional therapy, after adjusting for

differences in year of birth and oxidase activity.

2. To compare the prevalence of recent infections or inflammatory complications (within one year of last

contact), between transplanted patients who are at least 3 years post-transplant and non-transplanted

controls who are at least 3 years post diagnosis. This analysis will adjust for birth year and oxidase

activity. We will also conduct separate analysis of the rates of recent infections as well as the prevalence

of inflammatory complications alone, in addition to the combined prevalence estimate.

3. To compare the prevalence of recent infections or inflammatory complications (within one year of last contact), between transplanted patients who are at least 3 years post-transplant vs. their prevalence of recent infections or inflammatory complications in the one year period prior to transplant. We will also conduct separate analysis of the rates of recent infections as well as the prevalence of inflammatory complications alone, in addition to the combined prevalence estimate.

4. To compare the prevalence of recent infections or inflammatory complications (within one year of most recent myeloid chimerism assessment) between transplanted patients who are at least 3 years posttransplant and who have achieved partial reconstitution (> 5 and < 15% myeloid engraftment) vs. those who have achieved > 15% myeloid chimerism. The question to be answered by this objective is whether stable long term restoration of oxidase normal granulocytes to 15% of cells or higher in HCT transplanted CGD subjects results in reduction or cessation of incidence of infections and prevalence of autoimmune/inflammation complications. We will also conduct separate analyses of the rates of recent infections as well as the prevalence of inflammatory complications alone, in addition to the combined prevalence estimate.

5. To conduct a similar analysis comparing the prevalence of new infections and inflammatory disease of CGD subjects enrolled in a cross-sectional analysis.

6. To estimate the proportion of patients who will resolve pre-existing inflammatory complications after HCT. 7. To describe chimerism in leukocyte lineages (myeloid, T and B cell) resulting from HCT for CGD at Day 100, Month 6, and annually for three years post-transplant.

8. If sufficient patient numbers are available, we will explore the association of clinical outcomes (survival, infection, autoimmune disease, chimerism, GVHD) with the use of regimen type (myeloablative vs.nonmyeloablative), and degree of HLA matching, as well as age, presence of infection and/or inflammatory disease at the time of transplant, and evidence of portal hypertension or thrombocytopenia.

9. We will assess outcomes when the sibling donor is an oxidase normal or is a CGD phenotype mosaic female carrier of X-linked CGD (for patients with X-linked CGD).

10. To determine the level of engraftment in transplanted patients more than two years post-transplant.

11. To compare the quality of life in transplanted patients alive at least two years post-transplant to nontransplanted patients as stratified by oxidase positive or oxidase null residual oxidase activity (and if possible, other pre-transplant conditions impacting on quality of life). For HCT subjects, will evaluate if there is an association between degree of myeloid chimerism post-HCT and quality of life.

Tertiary Objectives

Our study will examine clinical elements and biomarkers for their potential to affect or predict outcomes of HCT for CGD. The tertiary objectives of this study are:

1. To examine whether there is an association between degree of myeloid chimerism at one year after transplant and subsequent infection rates or development of inflammatory/autoimmune disease.

2. To explore pre-transplant clinical elements and biomarkers that can potentially predict survival after HCT in CGD subjects.

3. To evaluate the microbiome in patients with CGD and CGD colitis as well as assess the effect of transplantation on the microbiome.

Inclusion Criteria

Non-Transplanted CGD Patients with Birth Year In or After 1988

A non-transplant comparison group will be sought to compare to the transplanted

patient group enrolled in either the retrospective or prospective cohort of the

longitudinal study. Limiting the birth year to 1988 for both the transplanted group

and the non-transplant comparison group serves to more closely achieve a similar

median and range of age of patients in the transplanted and non-transplanted

group. However, it is acknowledged that advances in conventional management

Retrospective, Longitudinal Cohort may be responsible for the observation that mortality that previously occurred in childhood may be delayed to the 3rd and 4th decade of life (Kuhns 2010)1.

Non-Transplant CGD Patients Who Are Currently Surviving Will be Invited to Participate in the Prospective Cohort of the Longitudinal Study

- Provision of written informed consent will be required for inclusion in the Prospective Cohort of the Longitudinal Analysis.

- Non-transplant patients meeting all of the criteria in Section 4.2.2.4 AND currently surviving will be contacted as tointerest in participation in the Prospective Cohort of the Longitudinal Analysis.

-  Following provision of written informed consent for the Prospective Cohort of the Longitudinal Analysis, the eligibility form will be completed for submission to the PID-CGD Review Panel.

-  It is recognized that the potential pool of patients available for the prospective non-transplant cohort of the Longitudinal Analysis (Part 1) will be relatively limited. Therefore, such patients will be enrolled as subjects in this study IF FEASIBLE.

 

Transplanted Retrospective, Longitudinal Cohort

 

  1. CGD Patients Undergoing Transplant 1995 to Present with Birth Year In or After 1988.  CGD Patients will be Defined by Defective Neutrophil NADPH Oxidase Function and by Clinical History Consistent with CGD:

 

A. Function: Assays of NADPH Oxidase Function

I. Dihydrorhodamine (DHR) Assay (Quantitative; Preferred):

o Blood sample was obtained at a time when patient was clinically stable and not critically ill, with control samples performed simultaneously indicating a qualified assay;

 

and

o Assay unequivocally demonstrates CGD with an SI < 35 or equivalent. (See Section 3.1.1 and Table 3.1 for definitions, how definitions will be applied to confirmdiagnosis of CGD, and for grouping of CGD into oxidase positive vs oxidase-null cohorts). Assay report, including mean fluorescence intensity (MFI) from unstimulated and stimulated samples and gating strategy, must be de- identified and provided. (Report must be from a CLIA- certified laboratory or equivalent).

OR

 

 

II. Nitroblue Tetrazolium (NBT) Oxidation Test (Non- Quantitative):

o Diagnostic of CGD (reported as reduced granulocyte oxidative response). Report must be de-identified and provided. (Report must be from a CLIA-certified laboratory or equivalent).

 

AND

 

Clinical History: One or More of the Following

  • Severe and/or recurrent infection (liver, perirectal or lung abscess; pneumonia; adenitis; or osteomyelitis) due to, for example, Staphylococcus aureus, Burkholderia sp, Serratia marcescens, non-albicans Candida sp, Aspergillus sp or other mold; or Nocardia sp or other deep tissue infection characteristic of CGD
  • Sterile granulomatous disease in respiratory, gastrointestinal or urogenital tracts; or Crohn’s disease-like colitis
  • A family history consistent with either X-linked or autosomal recessive CGD

 

Transplanted Prospective, Longitudinal Cohort

Patients who are to undergo transplantation during the study period must be further characterized as oxidase-null or oxidase positive by level of oxidase production by either:

O DHR assay stimulation Index: where SI ≤ 2.5 will be

classified as oxidase-null CGD. Those with SI > 2.5 will

be classified as oxidase positive CGD. A single validated

test that is accepted by the PID-CGD Review Panel is

adequate, but testing on two occasions for validation is

desirable. (See discussion in Section 3.1.1 and Table 3.1

for definitions and how definitions will be applied for

grouping into oxidase-null cohort)

OR

O Ferricytochrome C reduction assay of granulocytes with

O 2 < 2.3 nmoles /106 cells/h classifed as oxidase-null

CGD. A single validated test that is accepted by the

PID-CGD Review Panel is adequate, but testing on two

occasions for validation is desirable.

OR

O Genetic sequencing reporting a mutation that is

unequivocally associated to absent oxidase production.

(e.g. null mutations) will be classified as oxidase-null

CGD. (See discussion in Appendix I for how family

history, genotype and CGD mutation information will be

applied to assigning patients lacking any quantitative

oxidase activity measurements to residual oxidase-null

or residual oxidase-positive groups).

 

 

Transplanted Cross-sectional Cohort

To participate in the Cross-Sectional Analysis, patients must have previously been enrolled into the Longitudinal Analysis of Protocol 6903. The only modification of this standard procedure is that a transplant subject currently in process of a follow-up visit with their PIDTC physician may sign the written informed consent for the Cross- Sectional Analysis and data and patient samples may be collected, while investigation as to previous enrollment in the Longitudinal Analysis is underway. However, patient data collected for the cross-sectional visit will not become a part of the data set for Protocol 6903 until previous enrollment in the Longitudinal Analysis is verified, or the patient is successfully enrolled via procedures for the Longitudinal Analysis (see Section 7 for further details).

 

Eligibility for the Cross-Sectional Analysis is the same as for the Longitudinal Analysis except for the following:

 

All transplanted subjects in the Cross-Sectional Analysis are surviving and shall have at least 2 years of follow-up post-transplant to be included.

 If currently surviving, the non-transplant subject will be contacted as to interest in participation in the Cross-Sectional Analysis.

 Provision of written informed consent will be required for inclusion in the Cross-Sectional Analysis

 

Non-transplanted Cross-sectional Cohort

All non-transplanted subjects enrolled in the Retrospective Cohort of the Longitudinal Analysis who are currently surviving shall be considered for potential participation in the Cross-Sectional Analysis.

 If currently surviving, the non-transplant subject will be contacted as to interest in participation in the Cross-Sectional Analysis.

 Provision of written informed consent will be required for inclusion in the Cross-Sectional Analysis.

 

Exclusion Criteria

 Presence of other primary immunodeficiency syndromes that do not meet the clinical and laboratory criteria for CGD.

 Rac2 Deficiency

 MPO Deficiency

 Glutathione deficiency

 Leukocyte adhesion deficiency syndrome

Non-transplant subjects:

 The above exclusions pertain.

 In addition, non-transplant subjects will be excluded if the only assessment of oxidase function available is the nitroblue tetrazolium (NBT) test (a non-quantitative test).