Abstract

Background

Hematopoietic stem cell transplantation (HSCT) is the only available cure for chronic granulomatous disease (CGD). Preexisting infections tend to put CGD patients at high risk for myeloablative HSCT related complications, making reduced intensity conditioning (RIC) an attractive option for these patients. However, published studies using RIC HSCT in CGD have shown a high rate of graft rejection.

Objectives

To characterize the clinical features and outcomes of high-risk children with chronic granulomatous disease transplanted at Children's Hospital of Los Angeles with a RIC regimen.

Methods

Patients with CGD with pre-existing co-morbidities that precluded the use of myeloablative HSCT and who received RIC HSCT were selected for review. Conditioning regimen consisted of targeted dose Campath (with level monitoring), Fludarabine 30 mg/m2/dose x 3 doses and Total Body Irradiation 200 cGy x 2 doses. Tacrolimus (or cyclosporine) and Mycophenolate Mofetil (MMF) were used for graft-versus-host disease (GVHD) prophylaxis.

Results

Four children (median age 102 months, range 24-180 months) with severe CGD (serious bacterial/fungal infections pretransplantation) and significant comorbidities (Table 1) received RIC matched unrelated donor HSCT. Two patients received a 9/10 HLA allele matched graft, and the other two received a 10/10 HLA allele matched graft. Three patients received peripheral blood stem cells (PBSCs), and the one other patient received a bone marrow (BM) graft. For the PBSC grafts, the mean total nucleated cell (TNC) dose was 24.3 x 10e8/kg (range 11.9-24.5 x 10e8/kg), the mean CD34+ cell dose was 9.4x10e6/kg (range 3.7-11.8 x 10e6/kg), and the mean CD3+ cell dose was 60.3x10e7/kg (range 33.8-77.1 x 10e7/kg). The patient who received a bone marrow graft developed primary graft failure and autologous recovery 4 months after HSCT. Only one patient who was non-compliant with immune-suppressive medications developed grade 4 acute graft-versus-host disease (GVHD) with subsequent extensive chronic GVHD. None of the other patients have any evidence of active GVHD at the most recent follow up. Median follow up of all patients is 23.5 months (range 13-28 months) and three of the four patients are alive with a high donor chimerism (100%).

Table 1

Patient Characteristics

Pt #Age (months) at HSCTComorbidities at HSCTAllele matchSourceCell dose/kgFollow up (months)Last donor chimerismHighest acute GVHDHighest chronic GVHD
TNCCD34CD3
24 Autoimmune colitis 10/10 BM 8.9x10e8 6.4x10e6 9.2x10e7 28 3% 2 (skin) none 
72 TB meningitis, osteomyelitis, gastrostomy tube, hydrocephalus, VP shunt 10/10 PBSC 24.3x10e8 3.7x10e6 77.1x10e7 13 100% none none 
66 Persistent Acidomonas methanolica lung & lymph node infection 9/10 PBSC 11.9x10e8 9.4x10e6 33.8x10e7 28 100% 4 (skin, gut) extensive 
90 IBD, diverting ileostomy 9/10 PBSC 24.5x10e8 11.8x10e6 60.3x10e7 19 100% 2 (skin) none 
Pt #Age (months) at HSCTComorbidities at HSCTAllele matchSourceCell dose/kgFollow up (months)Last donor chimerismHighest acute GVHDHighest chronic GVHD
TNCCD34CD3
24 Autoimmune colitis 10/10 BM 8.9x10e8 6.4x10e6 9.2x10e7 28 3% 2 (skin) none 
72 TB meningitis, osteomyelitis, gastrostomy tube, hydrocephalus, VP shunt 10/10 PBSC 24.3x10e8 3.7x10e6 77.1x10e7 13 100% none none 
66 Persistent Acidomonas methanolica lung & lymph node infection 9/10 PBSC 11.9x10e8 9.4x10e6 33.8x10e7 28 100% 4 (skin, gut) extensive 
90 IBD, diverting ileostomy 9/10 PBSC 24.5x10e8 11.8x10e6 60.3x10e7 19 100% 2 (skin) none 

HSCT- Hematopoietic Stem Cell Transplant; TB- tuberculous; VP- ventriculo-peritoneal; IBD- Inflammatory Bowel Disease; BM- Bone Marrow; PBSC- Peripheral Blood Stem Cells; TNC- Total Nucleated Cells; GVHD- Graft-versus-host disease.

Discussion

Patients with CGD often have multiple co-morbid conditions that lead to an increased risk of transplantation related mortality with myeloablative conditioning regimens. RIC regimens are increasing being used to decrease the short and long term toxicity of transplantation. Previous studies have suggested a high rate of graft rejection with RIC in CGD. Most of the published data on RIC HSCT in CGD patients pertains to the use of bone marrow grafts from HLA-matched siblings. In our series, we demonstrate that RIC (campath, fludarabine, and TBI) matched unrelated donor PBSC transplantation in CGD patients with life threatening infections leads to excellent engraftment, durable donor chimerism, and correction of neutrophil dysfunction, excellent survival and a low incidence of severe graft-vs-host disease. Thus, RIC HSCT represents a possible curative strategy for CGD patients with co-morbidities who are not eligible for myeloablative HSCT.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.