Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:48-52

Original Article

Bone Marrow Transplant for Non-Malignant Diseases

CK Li, MP Yuen, MK Shing, KW Chik, DH Lai, SH Cheng, KS Tsang


Abstract

Twenty patients received bone marrow transplant for treatment of non-malignant diseases over a four-year period. Sixteen patients were suffering from transfusion dependent thalassaemia, three patients from severe aplastic anaemia and one from chronic granulomatous disease. The donors were all HLA identical siblings of the patients. All the patients engrafted successfully after bone marrow transplant and there was no early mortality within the first three months after transplant. One thalassaemia patient rejected the bone marrow at five months after transplant and subsequently died from infection. The other nineteen patients were now all free from the primary diseases at a median follow up of 27 months (range 2 to 49 months). There were no long term complications in the survivors. In conclusion, bone marrow transplant provided a high chance of cure for non-malignant diseases.

Keyword : Bone marrow transplant; Chronic granulomatous disease; Severe aplastic anaemia; Thalassaemia


Abstract in Chinese

Introduction

Bone marrow transplantation (BMT) has been practiced for more than three decades. Initially BMT was applied to treatment of haematological malignancies such as acute leukaemia. It was later extended to other malignancies including lymphoma and more recently breast cancers. Severe aplastic anaemia was the first non-malignant disease treated by BMT. From 1980s, other non-malignant diseases were also successfully treated by BMT. Thalassaemia, immunodeficiency syndromes and hereditary metabolic diseases are the more commonly transplanted nonmalignant diseases. This is a report of the experience of a single institution on treatment of non-malignant diseases and also other non-malignant diseases which are potentially treated by BMT are discussed.

Patients and Methods

Patients with non-malignant diseases receiving BMT at Department of Paediatrics in Prince of Wales Hospital, Hong Kong were retrospectively reviewed. The pre-transplant patient characteristics, BMT preparative regimens, post-transplant complications and survivals were analyzed. The bone marrow was not T-cell depleted and infused directly to recipients immediately after harvest. The patients were treated with methrotrexate for four doses and cyclosporin for six months as graft versus host disease prophylaxis. Grading of graft versus host disease was according to established criteria. Engraftment was defined as the achievement of neutrophil count more than 0.5 x 109/L for two consecutive days after BMT. Diseases were considered as cured if the patients were asymptomatic of the primary diseases and did not require the pre-transplant treatment any more. Thalassaemia patients were considered as cured if transfusion was no longer required after BMT. Severe aplastic anaemia patients becoming transfusion independent and without neutropenia after BMT would be regarded as cured. Immunodeficiency syndrome patients free from severe infection and with normalization of immune function after BMT would be considered cured.

The donor or recipient source of the bone marrow after BMT was determined by sex chromosomes in donor-recipient sex mismatched setting. In more recent years, DNA probes to X and Y chromosomes were tested by fluorescent in-situ hybridization (FISH). In sex matched settings, polymerase chain reaction (PCR) amplification of multiallelic variable number of tandem repeat regions of the genome had been used to distinguish donor or recipient source. Red cell genotype study was not possible in most of the cases because most patients had received transfusion before BMT. If all the bone marrow derived cells were of donor origin, this would be assigned as complete chimerism'. If both donor and recipient cells were present in the bone marrow derived cells, this would be regarded as "mixed chimerism".

Result

From November 1991 to September 1995, a total of 20 patients with non-malignant diseases received allogeneic bone marrow transplant in Prince of Wales Hospital. The outcome of these patients was analyzed at 1st December 1995 (Table). All the donors were HLA identical siblings of the patients. There were 16 transfusion dependent thalassaemia, three severe aplastic anaemia and one chronic granulomatous disease. The thalassaemia patients were diagnosed before one year of age and then received regular monthly transfusion. Except for two very young patients, the other patients were all treated with desferrioxamine therapy. Two of the three severe aplastic anaemia patients were transplanted within one month of the diagnosis and did not receive any immunosuppressive treatment before BMT. One patient had been treated with two courses of immunosuppressive treatment before BMT. The immunosuppressive treatment included antithymocyte globulin, cyclosporin and steroid. The patient failed to respond to immunosuppressive treatment and was transplanted eight months after diagnosis. The chronic granulomatous disease patient was diagnosed at age of two years. He suffered from repeated episodes of life-threatening infections and was transplanted at age of eight years.

Table BMT of Non-malignant Disease: Patient Characteristics and Outcome
No. Sex Age of BMT (yr) Diagnosis Conditioning Alive Disease status Donor or Recipient Cell Origin (Time of test)* Follow Up Duration (month)
1. M 1.2 SAA CY-ATG Y Cured 28% Donor+ (44 m) 49
2. M 8.5 CGD Bu-CY Y Cured All Donor+ (34 m) 46
3. M 16.4 BTM Bu-CY-ATG Y Cured 73% Donor+ (34 m) 39
4. F 2.7 BTM Bu-CY Y Cured N.E. 34
5. M 5.5 BTM Bu-CY Y Cured All Donor+ (24 m) 33
6. M 14.8 BTM Bu-CY-ATG Y Cured 86% Donor+ (24 m) 30
7. M 8.5 BTM Bu-CY-ATG Y Cured N.E. 29
8. M 5.2 BTM Bu-CY-ATG Y Cured 93% Donor+ (24 m) 29
9. M 3.2 BTM Bu-CY-ATG Y Cured N.E. 28
10. M 13.4 BTM Bu-CY-ATG Y Cured All Donoro (24 m) 27
11. F 12 HbH Bu-CY-ATG N Rejection at 5 month Mixed Donor and Recipiento (3 m) 10
12. F 9.2 BTM Bu-CY-ATG Y Cured All Donoro (19 m) 20
13. F 10.7 SAA CY-ATG Y Cured 97.4%+ (10 m) 13
14. F 19 BTM Bu-CY-ATG Y Cured All Donor+ (10 m) 13
15. M 9 BTM Bu-CY-ATG Y Cured All Donoro (9 m) 11
16. F 14 BTM Bu-CY-ATG Y Cured All Donor+ (8 m) 10
17. M 12.8 BTM Bu-CY-ATG Y Cured N.E. 5
18. F 21.1 BTM Bu-CY-ATG Y Cured All Donor?(3 m) 3
19. M 10 BTM Bu-CY-ATG Y Cured 95.2% Donor+ (1 m) 3
20. F 4 SAA Cy-ATG Y Cured All Donoro (1 m) 2
+ : By Fluorescent In-situ Hybridisation test for chromosome X and Y proles. o : By DNA study. N.E.: Not evaluable. *: Months after BMT. CY-ATG: Cyclophosphamide 150 mg/kg, Antithymocyte globulin 90 mg/kg. Bu-CY: Busulphan 14-16 mg/kg, Cyclophosphamide 200 mg/kg. Bu-CY-ATG: Busulphan 16 mg/kg, Cyclophosphamide 150-200 mg/kg, Antithymocyte globulin 110 mg/kg. SAA: Severe aplastic anaemia, BTM: β-Thalassaemia major, CGD: Chronic granulomatous disease.

All the patients received non-radiation preparative regimen before transplant. Thalassaemias were treated with busulphan and cyclophosphamide. Antithymocyte globulin was also given as part of the preparative regimen to prevent graft rejection except in two patients. Severe aplastic anaemias were prepared with cyclophosphamide and antithymocyte globulin. Chronic granulomatous disease was prepared with busulphan and cyclophosphamide. All the patients engrafted successfully after BMT. The patients engrafted at a mean of 15.8 days (range 12 to 24 days). Grade I acute graft versus host disease developed in three patients, and six patients developed grade II graft versus host disease. All the patients showed good response to short term steroid treatment. No patient developed chronic graft versus host disease at the time of analysis. Septicaemia and fungaemia developed in four patients and one patient respectively. They were all treated successfully by antimicrobials. There were no treatment related mortality within the first three months of transplant. One thalassaemia patient rejected the bone marrow graft at five months after BMT and became severe aplastic anaemia after transplant. She received a second transplant and had rejection again after transient engraftment. She died of infection 10 months after the first transplant. The other 15 thalassaemia patients were all transfusion independent. The haemoglobin levels were all above 10 g/dl. They were treated with desferrioxamine or phlebotomy until iron overload subsided. Ten of the 15 survivors were now more than one year of follow up after BMT.

The three severe aplastic anaemia patients were all transfusion independent and free from infection after BMT. The haemoglobin was above 10g/dl, neutrophils more than 10 x 109/L and platelet more, than 100 x 109/L. The chronic granulomatous disease patient was free from severe infection and his immune function tests repeated after BMT returned to normal. All these patients did not have any long term complications after BMT during the follow up period. For patients who were more than nine months after BMT, they all returned back to normal school. Chimerism study by FISH or DNA study showed that seven of sixteen evaluable patients had variable degree of mixed chimerism. One patient showed mixed chimerism state at three months after BMT and then developed graft rejection two months later. Five of these seven patients were now more than one year after transplant and did not show any sign of rejection. Two patients still remained in stable clinical condition more than three years post-transplant.

Discussion

Bone marrow transplant was introduced in early 1970s for treatment of malignant diseases. Severe aplastic anaemia was successfully treated by BMT since early 1970s.1 More than 1000 cases of aplastic anaemia were transplanted since then. The first case of thalassaemia successfully treated by BMT was reported from Seattle.2 However the vast experience of BMT on thalassaemia was gained in Italy.3 In recent years, other non-malignant diseases had also been treated by BMT. The rationale of using BMT to treat non-malignant diseases is to replace the abnormal bone marrow, or the abnormal bone marrow derived systems such as immune system or macrophage-phagocytic system by a normal bone marrow.

The BMT unit of Department of Paediatrics in Prince of Wales Hospital had performed 20 BMT for non-malignant diseases in the past 4 years. Eighty percent of the cases were transfusion dependent thalassaemias. The survival of severe thalassaemia patients treated by regular transfusion and chelation therapy are much longer than before, however there are still potentially fatal complications relating to treatment. Theoretically the thalassaemia patients receiving hypertransfusion regimen and adequate chelation therapy should have survival approaching that of normal people. However the transfusion complications cannot be completely prevented. Transfusion transmitted hepatitis and other infections still occur despite of improvement in screening techniques. Cirrhosis of liver is a major threat to the long term survival of these patients.4 Poor compliance with daily subcutaneous injection of desferrioxamine is not uncommon especially in adolescents. There are still patients dying from complications of iron-overload despite of free supply of desferrioxamine. BMT provides a chance of cure for this disease and patients will then not require any further transfusion.

Busulphan and cyclophosphamide had been shown to be an effective preparative regimen for ablation of bone marrow in non-malignant diseases. Cyclophosphamide also provides immunosuppression of the recipients so stable engraftment of the foreign bone marrow can occur. However, thalassaemia patients usually had received many transfusion before BMT and they were exposed to multiple foreign HLA antigens. Therefore there is a higher chance of rejection of bone marrow graft especially in those who had received large number of transfusions. Antithymocyte globulin is a potent immunosuppressive agent and had been used for treatment of severe immune mediated diseases such as severe aplastic anaemia. It was included as part of our preparative regimen for thalassaemia patients except the first two patients. The preparative treatment was quite well tolerated and there was no treatment related death in our series. All the patients had reconstitution of new bone marrow after transplant. Except one patient rejected the bone marrow graft at five months post-transplant, all the other 15 patients were now still transfusion independent. The haemoglobin levels were maintained above 10 g/dl and free from symptoms of anaemia. Ten of the 15 survivors were now more than one year of follow up after BMT. Our survival figure is comparable to that of the Italian centres.3 There was no chronic complications detected so far in this group of patients. We had included some older age group patients, one of them was 21 years old, and they all had sustained engraftment. The low rejection rate and better disease free survival as compared with other series in the region5 might be related to the routine use of antithymocyte globulin in our patients. BMT will save the patients from life long transfusion and painful chelation therapy. The savings from the expensive long-term chelation therapy is also more than the expense of a BMT. We believed that BMT is the preferred treatment of transfusion dependent thalassaemia if HLA identical siblings are available. At the moment, use of mismatched family donors or unrelated donors for BMT is still not justified because of the poor results.6

Severe aplastic anaemia has a high mortality in patients receiving supportive treatment. In recent years, the use of combination immunosuppressive treatment had achieved a response rate of up to 65%.7 The non-responders had a high chance of mortality as result of life threatening bleeding or infection. There was also report of late haematological complications, paroxysmal nocturnal haemoglobiuria and myelodysplastic syndrome, in survivors after previous immunosuppressive treatment.8 BMT had been shown to have a high success rate especially in young patients. 85-90% survival was reported in patients less than 18 years of age.9 Untransfused patients before transplant had the best chance of cure by BMT. Two of our three aplastic anaemia patients were transplanted within one month of diagnosis. They had only received minimal number of transfusions before transplant. One patient failed two courses of immunosuppressive treatment before transplant and received many red cell and platelet transfusions before BMT. She also engrafted rapidly after BMT and remained in remission for more than one year. With the excellent result of early transplants for severe aplastic anaemia, HLA typing of the family members should be pursued as quickly as possible after diagnosis. If HLA identical sibling is available, BMT is the preferred option of treatment. BMT also has the advantage of eliminating abnormal clone in the bone marrow and thus avoid the long term haematological complications. However, due to limited number of BMT beds in Hong Kong, some patients may not be transplanted soon after diagnosis. These patients should be treated with a course of immunosuppressive treatment.

Immunodeficiency syndromes is another group of patients who benefits most with BMT. Various immunodeficiency syndromes have been successfully cured by BMT, including severe combined immunodeficiency syndromes and Wiskott-Aldrich syndrome.10,11 Chronic granulomatous disease had been less commonly reported to be treated with BMT.12 Patients who were successfully treated by BMT acquiring not only a new haemopoietic system, but most importantly a normal bone marrow derived immunological system. The immune function returns to normal after sustained engraftment and the patients are then free from the severe infections. Severe immunodeficiency syndromes should be transplanted early so as to avoid severe infections which may put the patients at higher risk of treatment related mortality in the early post-transplant period.

BMT had been applied to other non-malignant disease in recent years. Other haematological diseases were also successfully cured by BMT including Fanconi's anaemia, Diamond Blackfan syndrome and sickle cell anaemia.13,14 Lysosomal storage diseases are hereditary metabolic diseases with enzyme defects which lead to accumulation of abnormal metabolites. The new bone marrow after BMT provides a normal macrophage system which produce normal amount of the deficient enzyme.15 The mechanism of enzyme transfer from the newly developed macrophages to the pre-existing abnormal system is still not fully understood. However, it was demonstrated to have normal enzyme levels and disappearance of abnormal metabolites after BMT. Patients with mucopolysaccharidosis did show clinical improvement after BMT.16 Early transplants should be performed so that the irreversible damages could be prevented.

One important difference between non-malignant and malignant diseases is the absence of abnormal clone in non-malignant diseases. Residual recipient bone marrow cells after BMT, known as mixed chimerism, usually preceed the recurrence of malignancies. However, the mixed chimerism state in non-malignant diseases may last for many years without any clinical problem. The recipient and donor cells remain in a harmonious state without rejecting each other. The donor cells provide adequate deficient materials to the patients such as beta globin chains in thalassaemia and enzymes in metabolic diseases. This non-harmful mixed chimerism state was also demonstrated in six of our seven patients with mixed chimerism. This phenomenon has important implication that very intensive myeloablative preparative regimen to eradicate every single recipient cell may not be necessary in non-malignant diseases. The more intensive the preparative regimen, the higher the chance of life threatening complications after BMT may occur. Non-radiation regimens were used in many centres for non-malignant diseases and they are usually associated with less treatment related mortality.

Bone marrow transplant has been demonstrated to cure some of the hereditary non-malignant diseases including both haematological and metabolic diseases. Acquired disease is still limited to severe aplastic anaemia. The non-malignant diseases may not be so rapidly fatal as the malignant diseases, but the supportive treatment currently used in most of these diseases only delay the inevitable death and the patients may suffer for long duration before they succumb. Early transplant will prevent the occurrence of irreversible damages and also save the resources of the community in the long run. Recently there has also been proposal of treating autoimmune diseases with BMT.17 The rationale of doing BMT for these patients is to provide a new healthy immune system. In conclusion, BMT can achieve cure in a high proportion of patients suffering from non-malignant diseases. There is still ground for improvement so as to make transplant more safe and to avoid mortality.


References

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