Table of Contents

HK J Paediatr (New Series)
Vol 3. No. 1, 1998

HK J Paediatr (New Series) 1998;3:45-48

Original Article

Immunosuppressive Therapy for Severe Aplastic Anaemia in Children

YL Lau, SY Ha, GCF Chan, DCK Chiu, ACW Lee


Aplastic anaemia is characterised by pancytopenia and bone marrow failure. The treatment of choice for children is matched related bone marrow transplantation. If that is not available, immunosuppressive therapy has resulted in substantial improvement in blood counts. We review our experience in using immunosuppressive therapy for aplastic anaemia in children seen in Queen Mary Hospital from 1990 to 1997. Seven children (4 boys and 3 girls) with median age at diagnosis of 5.8 years (range 1.1 to 8.9 years) received immunosuppressive therapy for their severe aplastic anaemia during this 8-years period. Five were classified as idiopathic, one had evidence of Epstein-Barr virus-associated hepatitis and one Fanconi anaemia. The median level (range) for haemoglobin was 6.8 gm/dl (3.2 to 10.0), absolute neutrophil count (ANC) 0.2 x 109/L (0.04 to 0.69) and platelet count 9 x 109/L (3 to 18). The median follow-up was 3 years (range 1 to 7.8 years). They all received different combinations of immunosuppressive agents including anti-lymphocyte globulin, cyclosporine and steroid. Two patients also received granulocyte colony-stimulating factor. The patient with Fanconi anaemia only had transient response. Of the remaining 6 patients, 4 achieved transfusion-independent status, with 2 of normal or near normal blood counts and 2 of low platelet counts; the other 2 patients with ANC over 1 x 109/L were still platelet dependent. The time to recovery of blood counts was prolonged. The response to immunosuppressive therapy of our patients may not be as prompt and as good as that reported overseas.

Keyword : Anti-lymphocyte globulin; Aplastic anaemia; Bone marrow transplantation; Cyclosporine; Immunosuppressive therapy

Abstract in Chinese


Aplastic anaemia is a heterogeneous group of diseases characterised by pancytopenia and bone marrow failure.1 The yearly incidence in children has been estimated to be about 2 per million in Nordic countries.2 It may be inherited as part of a constitutional syndrome or acquired.1

Acquired aplastic anaemia can occur after drug ingestion, chemical or radiation exposure, or hepatitis. Prognosis for children with aplastic anaemia has improved over the years with bone marrow transplantation (BMT) from HLA-matched related donors as the treatment of choice.3-6 For those without related HLA-matched donors, immunosuppressive therapy has been shown to result in substantial improvement in blood counts.7-10 This observation suggests, despite many initial inciting factors, aplastic anaemia might have a common immunopathological mechanism.11 We review our experience in using immunosuppressive therapy for aplastic anaemia in children seen in Queen Mary Hospital from 1990 to 1997.


The records of all children diagnosed with aplastic anaemia who were seen in the Department of Paediatrics, Queen Mary Hospital from January 1990 to December 1997 were reviewed. Children who had severe cytopenia of at least two cell lines (platelets <20x109/L, neutrophils <0.5x109/L, reticulocyte < 1%) and a hypoplastic bone marrow were classified as having severe aplastic anaemia. A standard approach was used for the treatment of severe aplastic anaemia. Children who had a fully HLA-matched related donor underwent bone marrow transplantation. Those who had no donor were treated with immunosuppressive therapy. We identified seven children with severe aplastic anaemia who received immunosuppressive therapy during this eight-years period and they formed the subjects of this retrospective review.


Four boys and three girls with severe aplastic anaemia who received immunosuppressive therapy were identified (Table I). Their median age at diagnosis was 5.8 years (range 1.1 to 8.9 years). Initial investigations included Ham's test, serologic tests for hepatitis A, B ± C, cytomegalovirus and Epstein-Barr virus (EBV), liver and renal function tests and cytogenetic study. Five patients had no identifiable cause for their aplastic anaemia and were classified as idiopathic. One patient had evidence of EBV-associated hepatitis and her clinical course was reported before.12 One patient was diagnosed to have Fanconi anaemia by increased chromosome breakage. The blood counts at diagnosis are shown in Table I. The median level (range) for haemoglobin was 6.8 gm/dL (3.2 to 10.0), absolute neutrophil count (ANC) 0.2x109/L (0.04 to 0.69) and platelet count 9x109/L (3 to 18). The patients had a median follow-up of 3 years (range 1 to 7.8 years) (Table II).

Table I Presenting Features of Children with Severe Aplastic Anaemia
  Initial Haematologic Evaluation
Patient Sex Age
Etiology Hb
1 M 5.8 Fanconi 4.6 2.9 0.69 3 0.7
2 F 8.9 Hepatitis 10.0 0.6 0.45 4


3 F 1.8 Idiopathic 6.2 1.46 0.14 6 0.1
4 F 6.8 Idiopathic 3.2 5.2 0.09 9 < 0.1
5 M 7.4 Idiopathic 6.8 4.85 0.39 13 1.6
6 M 1.1 Idiopathic 8.5 2.61 0.04 10 < 0.1
7 M 1.8 Idiopathic 8.4 6.46 0.20 18 < 0.1
Bone marrow examination showed hypocellular marrow in all patients with patient 3 at 20% and patient 7 less than 20%


Table II Responses to immunosuppressive therapy
  Time (months) from diagnosis to Most recent haematological evaluation  
Patient Treatment ANC
Follow up
1 ALG, PRED, OXM NA NA NA NA 6.2 0.2 4 7.8
2 MP, ALG 6 8 6 10 13.4 3.5 179 6.6
3 MP, ALG, OXM, CSA 3 3 13 23 13.3 2.2 136 4.3
4 MP, ALG(2), OXM, CSA 20 29 37 NA 12.9 2.4 93 3
5 CSA 3 12 20 NA 11.8 1.8 65 2.8
6 MP, ALG(2), OXM, CSA, G-CSF 20 29 NA NA 10.1 2.5 5 2.7
7 MP, ALG(2), CSA, G-CSF 2 11 NA NA 8.2 1.1 5 1
ALG, anti-lymphocyte globulin; ALG(2), two courses of anti-lymphocyte globulin given at an interval of 6 months; PRED, prednisolone; OXM, oxymethalone; MP, methylprednisolone; CSA, cyclosporine A; G-CSF, granulocyte colony-stimulating factor; ANC, absolute neutrophil count; NA, not achieved.

Treatment and Current Status

The treatment these patients received and their responses are summarised in Table II. Apart from patient 1 who has Fanconi anaemia, all other 6 patients had different degrees of responses to the immunosuppressive therapy with or without haematopoeitic growth factors. The treatment protocol has changed with time and included components reported in various protocols in the 1990's as shown in Table III.7-10 For example, patient 2, 3 and 4 had used protocol as reported in reference 9 while patient 7 as in reference 10. Because of poor response, they might have received additional treatment, such as cyclosporine in patient 3 and 4 while patient 6 received both protocols reported in reference 9 and 10 in succession. Apart from methylprednisolone and horse anti-lymphocyte globulin, patient 2 also received acyclovir for two weeks after the initial protocol as her response was poor and her aplastic anaemia was considered to be associated with EBV-induced hepatitis. Patient 5 only received cyclosporine as the sole immunosuppressive agent. They all tolerated the immunosuppressive therapy with no significant toxicity apart from patient 1 who had severe acne while on oxymethalone. All patients are alive and home at the time of reporting.


The probability of survival for patients with severe aplastic anaemia before the availability of BMT and immunosuppressive therapy was about 20% only.13 Now with matched related donors, the survival could be as high as 89% at 8 years in some centres.4 However most patients lack HLA-identical family members and would need alternative treatments, usually immunosuppressive therapy.7-10

Despite the fact that acquired aplastic anaemia is a heterogeneous group of diseases, the common underlying pathological mechanism might be immune-mediated.11 For example gamma-interferon gene expression in the bone marrow has been shown to be prevalent in patients with acquired aplastic anaemia.11 Gamma-interferon is usually regarded as an inhibitor of haematopoeisis and may play a pathophysiologic role in acquired aplastic anaemia, in which a cellular immune response harmful to haematopoiesis is induced by various antigenic stimuli, such as viruses, drugs and chemicals. This is compatible with clinical reports that immunosuppressive therapy, usually consisting of anti-lymphocyte globulin alone or in combination with other agents such as cyclosporine and steroids, could result in substantial improvement in blood counts in patients with acquired aplastic anaemia.7-10

However due to the low incidence of acquired aplastic anaemia and lack of a commonly used multi-centre protocol, children have been treated with varying types of drugs dosages and schedules, making treatment comparisons almost impossible.14-16 In studies combining children and adults reported in 1990's using different protocols, the overall response rate to immunosuppressive therapy has varied from 30% to 82%.7-10 (Table III) For our 6 children with acquired aplastic anaemia only 2 had good response with normal or near-normal blood counts (patient 2 and 3) while 4 only had partial response, out of which 2 are still platelet-dependent (patient 6 and 7). Patient 4 and 5 are transfusion-independent. (Table II) Out of the three cell lineages, platelet recovery was the slowest as well as most resistant to treatment. The future use of combination therapy of immunosuppressive agents together with thrombopoeitin and G/GM-CSF will be of interest. Despite the limited number of patients reported here, it is our impression through exchanges with local colleagues that the response to immunosuppressive therapy among local patients is also not as prompt and as good as that reported overseas. As could be seen in table II, the time from diagnosis to normal or near-normal blood counts is rather prolonged although the overall response rate is still comparable to those in the literature (Table III). The contribution of better supportive care in the improved survival of these patients still remains undefined. More definitive answer would need a systematic review of all local data as well as a unified protocol for all children with aplastic anaemia locally.

Table III Response rates to immunosuppressive therapy in studies reported in 1990's
Reference (year) Number of patients Therapy Responses^ No response Dead
#7 (1991) 43 ALG, MP, CSA 30 (70%)* 8 (19%) 5 (11%)
  41 ALG, MP 19 (46%) 13 (32%) 9 (22%)
#8 (1992) 46 CSA 15 (32%)+ 17 (37%) 14 (31%)
  48 ALG, PRED 17 (30%) 14 (29%) 17 (36%)
#9 (1993) 69 ALG, MP, OXM 39 (56%)** 18 (26%) 12 (17%)
  65 ALG, MP 26 (40%) 28 (43%) 11 (17%)
#10 (1995) 40 ALG, MP, CSA, G-CSF 33 (82%)** 4 (10%) 3 (8%)
ALG, anti-lymphocyte globulin; CSA, cyclosporin A; PRED, prednisone; MP, methylprednisolone; OXM, oxymethalone; G-CSF, granulocyte colony-stimulating factor.
^ responses include complete and partial response; * response at 6 months; + response at 12 months; ** response at 120 days

For those treated with and responded to the immunosuppressive therapy, there is still an increased incidence of myelodysplastic syndrome, leukaemia and paroxysmal nocturnal haemoglobinuria.17 Therefore even with a comparable short to medium-term survival rate and response rate, immunosuppressive therapy should still be a second-line treatment option after matched related BMT for children with severe aplastic anaemia. For those who failed the immunosuppressive therapy, BMT using matched unrelated donors (MUD) may be an option but the treatment procedure was associated with an early mortality rate of 50% or more as well as significant long-term morbidity.18,19

It is interesting to note that the conditioning regimen and graft-versus-host prophylaxis commonly used in matched related BMT for patients with aplastic anaemia also include agents used in immunosuppressive therapy, i.e. anti-lymphocyte globulin, cyclosporine and cyclophosphamide. High dose cyclophosphamide has been used to induce complete remission in patients with severe aplastic anaemia without BMT.20 A large phase III study, co-ordinated by the National Institute of Health, Bethesda, involving comparing the efficacy of immunosuppression with cyclophosphamide/cyclosporine versus anti-lymphocyte globulin/cyclosporine is currently in progress.

In conclusion, the prospect of short to medium-term survival for children with severe aplastic anaemia has improved tremendously over the years but for those without matched related donors, treatment with immunosuppressive agents has yet to be standardised and improved.


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