We describe the successful hematopoietic stem cell transplant of a 22-year-old patient with chronic granulomatous disease at our center. Our case was a relatively old male patient compared with other patients having the diagnosis of chronic granulomatous disease who underwent hematopoietic stem cell transplant. The patient was diagnosed as chronic granulomatous disease at the age of 1 year when he developed repeated bacterial infections since 2 months of age and laboratory test revealed 0% of normal control value on nitroblue tetrazolium test. In December 2011, at 22 years of age, he underwent an allogeneic hematopoietic stem cell transplant from human leukocyte antigen fully matched sibling. Conditioning regimen was busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. He received methotrexate and cyclosporine as prophylaxis for graft-versus-host disease. Engraftment was achieved at day 13. At the time of this writing, the patient is alive and well with no serious complication and without any evidence of graft-versus-host disease or rejection 12 months after stem cell transplant.
Key words : CGD, Stem cell, Transplantation
Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency disease occurring in 1 out of 250 000 populations.1 Chronic granulomatous disease is an X-linked or autosomal-recessive disorder caused by impairment of oxidative antimicrobial activity of phagocytes, and characterized by recurrent and life-threatening bacterial and fungal infections and granuloma formation in vital organs.2 Chronic granulomatous disease still causes significant morbidity and death. Patients who have recurrent infections, particularly with catalase-positive organism, including Staphylococcus and Aspergillus. Patients also manifest noninfectious chronic inflammation or granuloma, leading to constrictive lung disease, chronic colitis/enteritis, or obstruction of the digestive/urinary tract. Such complications are the main cause of death by the end of the third decade of life, even when prophylactic antibiotics and antifungal agents or ýnterferon-gamma are administered.3 Currently, the only known cure for CGD is allogeneic hematopoietic stem cell transplant.4 However, organ toxicity and severe complications remain serious problems, particularly in high-risk CGD patients with active inflammatory disease or severe infection.3 Reduced intensity conditioning regimen is an alternative for such patients.5
From 1973, when the first CGD bone marrow transplant was performed until now, the result of 99 transplants, not including cord blood, have been published as single-case reports. Allogeneic stem cell transplant for CGD is becoming more common and reflects increased overall transplant success within the last 10 years. We report one adult high-risk patient with CGD complicated by severe infection and noninfectious chronic inflammation who underwent an allogeneic stem cell transplant from an HLA-matched sibling donor. We used a combination of busulfan and cyclophosphamide as myeloablative conditioning regimen. This is the first case of CGD who underwent an allogeneic stem cell transplant in our center in southern Iran. We have long-term experience in transplant of inherited nonmalignant hematologic disorders with more than 200 transplants for thalassemia, Fanconi anemia, and other rare congenital diseases during the past 20 years, but this is the first experience of a CGD stem cell transplant at our center.6-8 Our patient is relatively old compared with other patients with a diagnosis of CGD who underwent HSCT.
A 22-year-old man, a known case of x-linked CGD for many years, was referred to our transplant center for evaluation of allogeneic stem cell transplant. The patient was diagnosed as having CGD at the age of 1 year, when he developed repeated bacterial infections since 2 months of age, and laboratory test revealed 0% of normal control value on nitroblue tetrazolium test. The patient had recurrent infections for 20 years. He had been recurrently admitted for treatment of pneumonia resulting in bilateral lobectomy of the lung. Aspergillosis has never been documented in his previous admissions. To relieve symptoms and infection-susceptible state, the patient underwent an allogenic HSCT. Before transplant the diagnosis reconfirmed with nitroblue tetrazolium test and flow cytometry. In our pretransplant evaluation, the result of a computer tomography test paranasal sinus was normal, chest computed tomography scan finding showed diffuse ground-glass opacity and mosaic pattern in both lungs parenchyma in favor of fibrosis and multiple pleural base nodules were seen, pulmonary function tests showed restrictive pattern, and the results of an echocardiography were normal.
The conditioning regimen was busulfan-based myeloablative conditioning included 16 mg/kg busulfan in 4 days and 120 mg/kg cyclophosphamide in 3 days. Prophylaxis of graft-versus-host disease consisted of cyclosporine and short-term methotrexate. For seizure prophylaxis, phenytoin was administered at a dosage of 300 mg/d in 3 divided doses, starting from 1 day before initiation, to 48 hours after completion of busulfan administration. Stem cell source was peripheral blood stem cell of his human leukocyte antigen fully matched sister with matched blood type. The donor was a healthy 25-year-old woman with a normal nitroblue tetrazolium test without any history of medical disease. Her body weight of 5.7 × 108/ kg, composed of unmanipulated peripheral blood mononuclear cells (6.8 × 106 CD 34+ cells) were infused to recipient. The patient was treated in a HEPA (high-efficiency particulate air)-filtered room and remained in an isolated room until engraftment. Prophylactic antibiotics, antifungal (itraconazole), and antiviral (acyclovir) were administered during the neutropenic period. After the transplant, the patient received G-CSF 5 μ/kg/d until her absolute neutrophil count was > 0.5 × 109/L for 3 consecutive days. All the blood products, including packed cells and platelets, were irradiated with gamma rays to prevent posttransfusion graft-versus-host disease.
Granulocyte engraftment (absolute neutrophil count > 500/mm3 for 3 consecutive days) was achieved by postoperative day No. 13, and platelet engraftment (> 20 000/mL) was achieved on postoperative day No. 19. On postoperative day No. 30, the patient had symptoms of intractable itching without any skin lesions. A skin biopsy showed evidence of graft-versus-host disease, which after treatment with a short course of prednisolone, improved. Chimerism analysis revealed full-donor chimerism, with more than 95% of nucleated cells derived from donor on postoperative day No. 28. Normal value of nitroblue tetrazolium test observed on postoperative days No. 45, No. 90, No. 180, and No. 360. His pulmonary restriction became better gradually until 6 months after the hematopoietic stem cell transplant. Cyclosporine dosage was gradually reduced in 6 months posttransplant and discontinued. At 12 months’ follow-up, discontinuation of all antibiotics and antifungal, the patient was well, with no evidence of new bacterial or fungal infection or inflammatory process, and laboratory data (i.e., nitroblue tetrazolium test) proved good neutrophil function. Also, the patient did not show any sign of chronic graft-versus-host disease.
Allogeneic hematopoietic stem cell transplant is the only known curative treatment option at present time, although gene therapy, as new method of therapy, is under investigation.9 Hematopoietic stem cell transplant has a significantly high risk of morbidity and death, especially when recipients also have inflammatory diseases or infections.4
Before the introduction of fludarabine, a myeloablative conditioning regimen of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg was used to avoid several late effects of total body irridiation.5,10 Introduction of fludarabine changed this strategy of myeloablative, and a reduced intensity conditioning regimen became an alternative choice.11 With this method, graft rejection is more likely, but the risk of graft-versus-host disease, particularly acute graft-versus-host disease and regimen related toxicity, appears to be reduced.12-14 This type of conditioning also allows transplant during ongoing infection, with fewer infection-related deaths.
For patients with chronic granulomatous disease, the time of transplant is crucial. In most cases of chronic granulomatous disease, hematopoietic stem cell transplant is postponed until the patient is chronically ill. However, if the transplant is delayed, the chances of severe infections, the risk of graft-versus-host disease, and other serious transplant complications significantly increase.4
The diagnosis of chronic granulomatous disease is usually established early in life (median age of diagnosis is 5.4 years). There is limited experience in transplants in adult chronic granulomatous disease. A summary of 13 reports of bone marrow transplant for chronic granulomatous disease shows the median age at transplant to be 7 years (ranging from 0.4 to15 years of age).15
In this report, we presented a 22-year-old male adult who had a high-risk chronic granulomatous disease. The reported hematopoietic stem cell transplant-associated mortality of adult chronic granulomatous disease patients are 50% (2 of 4) and 60% (3 of 5) in 2 studies4,5; and this is higher than the reported 34% of adult thalassemia patients.16 Adult chronic granulomatous disease patients who frequently experience organ dysfunction, overt infection, inflammatory and postinflammatory are at high risk for transplant. Because of the age of our patient, previous lobectomy, and history of repeated and chronic infection, made him a poor risk at transplant. In our case, delay in sending him to the transplant center resulted in severe morbidity before transplant.
The EBMT group recommended myeloablative regimen, with cyclophosphamide and busulfan for allogeneic HLA-matched related donors for a transplant with excellent results in low-risk chronic granulomatous disease patients.17,18 Other researchers believe that the myeloablative conditioning is associated with higher rate of severe acute graft-versus-host disease and pulmonary infection with a transplant related mortality of about 30%, especially in advanced chronic granulomatous disease patients.4,19 Horwitz and associates who used an immunosuppressive conditioning without myeloablation reported in increase in the risk for rejection,5 so, despite the high risk status of our case, we used a myeloablative regimen. Although in our center and in Iran, there is good and prolonged experiences for transplant of other nonmalignant hematologic disorders, such as thalassemia, with disease-free survival up to 70% to 80%,6-8 as the first case of chronic granulomatous disease successful transplant, which showed hematopoietic stem cell transplant has evolved from an experimental procedures to standard of care for many diseases categories.
In conclusion, our experience as first case of hematopoietic stem cell transplant for chronic granulomatous disease in our center showed adult chronic granulomatous disease patients with therapy refractory infection and organ dysfunction may still be eligible for hematopoietic stem cell transplant. Although high-risk adult chronic granulomatous disease patients can undergo transplant with acceptable outcomes, we think it is safer and more effective to perform hematopoietic stem cell transplant in younger patients with proven diagnosis of chronic granulomatous disease before the beginning of life-threatening inflammatory complication and organ damage; so, hematopoietic stem cell transplant should be considered as an early treatment option.
Volume : 12
Issue : 5
Pages : 490 - 493
DOI : 10.6002/ect.2013.0078
From the Department of Hematology, Medical Oncology and Stem Cell
Transplantation, Hematology Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran
Acknowledgements: The authors declare that they have no conflicts of interest, and that there was no funding for this study.
Corresponding author: Mani Ramzi, Zand Blvd. Nemazi Hospital, Department of Hematology, Medical Oncology and Stem Cell Transplantation, Shiraz University of Medical Sciences, Shiraz, Iran
Phone: +98 711 647 4301
Fax: +98 711 6474301