Case report Bone marrow transplantation for chronic ... - Nature

Bone Marrow Transplantation, (1999) 24, 567–570  1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt

Case report Bone marrow transplantation for chronic granulomatous disease: long-term follow-up and review of literature TF Leung, KW Chik, CK Li, MMK Shing and PMP Yuen Division of Haematology and Oncology, Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong

Summary: Chronic granulomatous disease (CGD) is a heterogeneous group of disorders with defective respiratory burst activity in phagocytes which results in recurrent pyogenic infections. We report an 8-year-old boy with X-linked CGD who received an HLA-identical BMT from his sister. The nitroblue tetrazolium test returned to normal 3 months post transplant. Neutrophil engraftment has been stable for 7 years post BMT. Our patient was the eighth case of CGD successfully treated by BMT. Conditioning regimens in these patients have consisted mainly of BU and CY. We suggest that BMT is a safe and effective method of cure for patients with CGD. BMT should be considered for patients with HLA-identical siblings. Keywords: bone marrow transplantation; chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare and heterogeneous group of inherited disorders of the immune system associated with defective oxidative metabolism in phagocytes. It is caused by defects in the phagocyte NADPH oxidase that is normally responsible for formation of superoxide, hydrogen peroxide and other toxic oxygen metabolites. These metabolites then kill phagocytosed intracellular organisms. Patients with CGD are prone to develop recurrent pyogenic infections especially with catalase positive microbes.1,2 They are also susceptible to fungal infections such as Aspergillus.2,3 The genetics of X-linked and autosomal forms of CGD have been well-studied.4 A multicentre trial showed that IFN-␥ was useful in preventing serious infections in patients with CGD.5 However, it was less effective for older patients with CGD especially in those not taking concomitant prophylactic antimicrobials. Gene therapy for CGD remains an experimental treatment,6 and BMT is an effective method of cure in these patients.7 Nevertheless, there are only 12 patients who Correspondence: Dr TF Leung, Department of Paediatrics, Lady Pao Children’s Cancer Centre, Prince of Wales Hospital, Shatin, Hong Kong SAR, People’s Republic of China Received 17 November 1998; accepted 5 April 1999

underwent BMT for CGD in the literature because of seemingly high rates of morbidity and mortality. We describe a Chinese boy with X-linked CGD who achieved stable leukocyte engraftment long term after BMT. Details of BMT for the other successful cases are also reviewed. Case report A male child of unrelated parents presented with recurrent sinopulmonary infections and skin abscesses, cervical lymphadenopathy, hepatosplenomegaly, chronic diarrhoea with failure to thrive since 18 months of age. He had also had an episode of Salmonella group E osteomyelitis at 23 months of age. The unstimulated nitroblue tetrazolium (NBT) test and that upon latex stimulation were 0% and 4%, respectively (normal values ⬍12% and 53%). He was thus diagnosed as having CGD. Subsequently, flow cytometry for NBT by dihydrorhodamine and phorbol 12-myristate 13-acetate (PMA) stimulation on mother’s granulocytes revealed two peaks, 0.763 (4.9%) and 237.9 (95.1%), which was compatible with the carrier state for CGD. Our patient developed a severe episode of pneumonia requiring mechanical ventilation 2 years later despite oral cotrimoxazole prophylaxis. Bronchoscopic examination showed a swollen right main bronchus with a whitish nodule that was confirmed to be granulomatous inflammation on biopsy. In view of the recurrent episodes of severe sepsis, he underwent BMT at 8 years of age from his 11-year-old HLA-identical (A11, Aw33, B17, B40, DR3, DRw8) sister who had normal neutrophil functions. Conditioning included BU 3.5 mg/kg p.o. in four divided doses daily from day −9 for 4 days followed by CY 50 mg/kg once daily i.v. for 4 days. GVHD prophylaxis consisted of MTX 15 mg/m2 i.v. on day 1 and 10 mg/m2 i.v. on days 3, 6 and 11 as well as CsA 1.5 mg/kg twice daily i.v. from day −1 to 50 which was then switched to oral when he could tolerate oral feeding. He received BM containing 5.7 × 108 nucleated cells/kg recipient body weight. Subcutaneous GM-CSF at 10 ␮g/kg/day was given from day 0 until neutrophil engraftment. He was also given intravenous ganciclovir for prevention of CMV infection, oral antimicrobials for gut decontamination and cotrimoxazole and intravenous Ig for infection prophylaxis. Neutrophil engraftment (ANC ⭓0.5 × 109/l) occurred on day 24 and

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Table 1

Summary of details of BMT for patients (all males) with CGD

Case No.

Year of BMT

Age ata BMT

Conditioningb regimen

Engraftment

Complications related to BMT

Outcome (Ref.)

1c 2d

1973 1974

2 3.5

12% 100%

Nil Nil

3d

1975

15

100%

Acute and chronic GVHD

Alive with relapse (13) Graft rejection 2 months after BMT; alive 18 months (14) Chronic GVHD (pulmonary insufficiency) and Pseudomonas sepsis; death at 3 months (15)

4c

1975

7

33%

Nil

5d

1982

0.4

23%

Nil

d

6

1985

100%

Nil

Graft rejection 3 months after BMT; died from corpulmonale 7 years later (16) Alive ⬎6 years No infection (17) Alive ⬎4 years (18)

7c

1989

0.7

100%

Nil

Alive ⬎36 months(19)

8d

1989

7

100%

Nil

Alive ⬎21 months (20)

9d

1992

11

DLI at 32 months after BMT; alive ⬎5 years (21)

1993

5

32% (100% post-DLI) 100%

Nil

10d

Nil

Alive ⬎30 months (22)

11d

1994

1.3

100%

VOD and IO

Alive ⬎14 months (23)

12d

1995

8

100%

Acute GVHD

Alive ⬎2 years (24)e

Ourd patient

1992

8

CY (240 mg/kg) CY (150 mg/kg) ALS (210 mg/kg) Procarbazine (37.5 mg/kg) ATS (0.6 ml/kg) TBI (800 rad) CY (240 mg/kg) SPI BU (8 mg/kg) CY (200 mg/kg) BU (13 mg/kg) CY (200 mg/kg) BU (16 mg/kg) CY (300 mg/kg) Buffy coat ×1 BU (16 mg/kg) CY (200 mg/kg) TNI (7.5 Gy) BU (16 mg/kg) CY (200 mg/kg) BU (600 mg/m2) CY (200 mg/kg) BU (8.8 mg/kg) CY (200 mg/kg) VP-16 (900 mg/m2) ATG (36 mg/kg) BU (16 mg/kg) CY (200 mg/kg) BU (14 mg/kg) CY (200 mg/kg)

100%

VOD

11

Alive ⬎85 months

ALS = anti-lymphocyte serum; ATG = anti-thymocyte globulin; ATS = rabbit anti-thymocyte serum; DLI = donor lymphocyte infusion; IO = intestinal obstruction; SPI = selective pelvic irradiation; TNI = total nodal irradiation; VOD = veno-occlusive disease; VP-16 = etoposide. a Age in years. b Numbers in brackets indicate total doses of the drugs used. c Matched unrelated donor. d HLA-identical sibling. e Plus repeated infusions of G-CSF-mobilised, irradiated granulocytes.

the platelet count increased to ⭓20 × 109/l on day 36. He developed features of veno-occlusive disease (VOD) including jaundice and tender hepatomegaly on day 10, with a maximum serum bilirubin of 98 ␮mol/l. The VOD subsided with conservative management. No GVHD was observed throughout the post-BMT period. NBT scores as assessed on flow cytometry by stimulating granulocytes with PMA were 85 and 100 at 3 and 55 months post transplant, respectively (normal 90–100). Peripheral blood leukocytes showed complete donor chimerism by fluorescent in situ hybridisation 6 years after BMT. He was infection free with normal growth parameters at 85 months post transplant. Discussion CGD is an inherited disorder of the immune system caused by defective oxidative metabolism in phagocytes. Patients

have abnormalities in one of the five subunits of NADPH oxidase. The disease transmission is X-linked in 60 to 70% of patients and autosomal recessive in the other cases.1,4 Patients with X-linked CGD have an earlier disease onset and poorer prognosis.8,9 Hence, these children should receive more aggressive treatment. Our patient belonged to the high-risk group as he presented early with serious infections despite antibiotic prophylaxis. Prophylactic antimicrobials including trimethoprimsulfamethoxazole and itraconazole are the mainstay of treatment for patients with CGD.2,10,11 However, serious breakthrough infections are common. Granulocyte transfusion is another feasible treatment option in those who develop invasive fungal infections.3 In addition, a multicentre, double-blinded and placebo-controlled trial demonstrated that IFN-␥ reduced serious infection and duration of hospitalization in patients with CGD.5 However, IFN-␥ failed to improve irreversible tissue damage. Eighteen of 28 (43%) patients developed significant infections on fol-

BMT for chronic granulomatous disease TF Leung et al

low-up for more than 2 years.12 The cost of long-term prophylactic IFN-␥ is tremendous, and side-effects of prolonged administration also remain unclear. Several adults with CGD due to p47 phox deficiency have been successfully treated by gene therapy.6 Nonetheless, this approach is still considered experimental. BMT is currently the only curative treatment for CGD.7 Our patient is one of the 13 reported patients with CGD who underwent BMT (Table 1).13–24 Only one (case 3) of the five patients who were transplanted from 1973 to 1982 had complete haematopoietic reconstitution. However, all patients who underwent BMT after 1985 had long-term stable engraftment although one of them (case 9) required a donor lymphocyte infusion at 32 months post transplant. There was only one child (case 3, 8%) who died from complication of BMT. Eight of 10 patients who underwent BMT from HLA-identical siblings were infection-free on longterm follow-up. Graft rejection occurred in two (67%) children transplanted from matched unrelated donors. These results show that allogeneic BMT from HLA-identical siblings is a reasonably safe and effective method of cure for patients with CGD but the optimal timing of BMT remains undefined. Patients with CGD should be transplanted early before they develop any irreversible organ damage.17 All three patients younger than 18 months at BMT were infectionfree with long-term engraftment.17,19,23 These younger children also suffer from fewer BMT-related complications such as GVHD. Also, IFN-␥ is less effective for older patients with CGD.5 Our 8-year-old patient had long-term stable neutrophil engraftment. One patient (case 6) with severe restrictive lung disease had an improvement in lung function after BMT.18 Another 8-year-old child (case 12) with invasive and multifocal aspergillosis was cured by emergency BMT and G-CSF-mobilised granulocyte transfusion.24 These observations suggest that BMT should also be considered for older patients. Analysis of BMT in successful cases revealed that sustained engraftment has been regularly achieved after 1985 with BU (13–16 mg/kg) and CY (200–300 mg/kg) with or without other cytotoxic conditioning agents. Thus, the use of total body irradiation (case 3) may not be necessary. Four of 13 post-BMT patients (cases 1, 2, 4 and 5) did not have sustained or complete engraftment probably because of inadequate myeloablation achieved by the conditioning regimens.13,14,16,17 Hassan et al25 reported that higher doses of BU were required for BMT in younger children as they had faster BU clearance normalised to body weight. This may be the reason for the incomplete engraftment in the 5month-old patient (case 5).17 All previous reports of BMT for CGD have been anecdotal experiences from single centres. Thus, it is difficult to draw any conclusion on optimal transplant protocols and indications for BMT in these patients. Multicentre collaborative effort is necessary to address these issues. In conclusion, our patient achieved long-term cure for CGD after BMT. This treatment should thus be considered in those who have an HLA-identical donor and who experience serious infections despite prophylactic antibiotics. Intensive conditioning therapy involving BU and CY appears to be essential to achieve adequate myeloablation.

Acknowledgements We would like to acknowledge Dr Eric Chan, Dr BM Jones and Dr JWM Lawton of Clinical Immunology Unit of the University of Hong Kong for performing immunological investigations and to express our sincere thanks to the Hong Kong Paediatric Bone Marrow Transplant Fund for supporting BMT for our patient.

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