Dr. Au Wing Yan

January 2008

 

Bone marrow transplantation (BMT) is now more appropriately termed hemopoietic stem cell transplantation (HSCT), as the source of the progenitor cells is no longer confined to the marrow and may be as diverse as peripheral blood and cord blood. However, the term BMT is still popularly used interchangeable with HSCT. There are similarities and differences between marrow transplant and other solid organ or tissue transplant. BMT is used mainly to treat malignant hemic disorders. Less commonly, it is used to replace defective hemopoiesis or immune systems e.g. thalassemia and aplastic anemia. For some diseases, such as myeloma and lymphoma, the patient’s own marrow or stem cells is cryopreserved before high dose chemotherapy and is re-infused for marrow repopulation afterwards (autologous HSCT). Strictly speaking, this is not a form of transplantation, since no “donor” or immunosuppression is used. The following discussion will focus mostly on BMT involving a sibling or unrelated donor (allogeneic HSCT).

The marrow transplantation procedure

 

Unlike solid organ transplantation, all HSCT donors are living donors and the procedure is more akin to special form of blood donation. To avoid rejection of the marrow and to minimize donor marrow attacking host tissue (graft versus host disease GVHD), HLA matching is great importance in donor choice. Usually full matching at all six A, B and DR loci are needed. The chance of each sibling being HLA matched is 25%. For patient without sibling donors, a registered voluntary unrelated donor with the same HLA combination is needed. The current chance of finding one in HK, China, Taiwan and worldwide is about 85%. Unlike blood transfusion or solid organ transplant, ABO blood group matching is not a problem. Both donor and patient will undergo counseling and physical check up for physically and psychological fitness.

 

For the transplant proper, the patient is admitted to a reverse isolation facility and high dose chemotherapy and immunosuppression (+/- radiotherapy) is delivered over several days to ablate the marrow (and the leukemia) and the immune system of the host. Afterwards, stem cells are harvested from the donor, either by direct bone marrow aspiration or by apheresis procedure from the peripheral blood. With systemic immunosuppression (cyclosporine and methotrexate) the cells are infused into the patient similar to a simple blood transfusion. Normally, it would take 14 to 21 days for the infused cells to “engraft” (i.e. for the peripheral neutrophil and platelet count of the patient to rise back from near zero to above 1x109 and 20x109 respectively). During this prolonged period of neutropenia, the patient may suffer from bleeding, mucositis, bacterial, fungal and viral infection, and requires intense nursing care, as well as transfusion, analgesic, intravenous nutrition and antimicrobial support.

 

After engraftment, despite continued immunosuppressants, the donor immune system may attack the host tissues in up to 1/3 of patients (GVHD). This results in hepatitis, diarrhea and skin rash. This unique complication after BMT may be life-threatening, and immunosuppression need to be stepped up. Patients are usually discharged after one month and require regular follow-up and blood and marrow monitoring for a year. Unlike solid organ transplantation, life-long immunosuppressives are not needed. This is because the donor immune system takes over and adapt to the host environment. The host immunity also serves to eradicate residual leukemia. Cyclosporine can usually be taken off by one year after BMT. In the absence of disease relapse, late graft rejections are uncommon.

 

The marrow donor

 

Unlike solid organ donors, the amount of morbidity suffered from the marrow donor is very low. Both marrow aspiration and peripheral blood stem cell (PBSC) apheresis are safe procedures and apart from the risk of general anesthesia for marrow harvest, there are no life-threatening risks. Both procedures are however, more complicated and demanding than a blood donation. For marrow harvest, depending on recipient body weight, 800-1000 ml marrow is harvested from bilateral posterior iliac crests, under general anesthesia. Most donors can leave hospital the next day on oral iron supplements and doloxene analgesics, and do not require blood transfusion. For PBSC donation, the donor requires subcutaneous injection of growth factors at home for 4 days, followed by a morning 3-hour hospital session for plasmapheresis. There are minimal side effects such as low-grade fever and bone pain, which subside rapidly afterwards.

 

The donor exclusion criteria are similar for that of blood transfusion. For matched siblings, even hepatitis B carriage and advanced age are not necessary absolute exclusion criteria. Up to the end of 2007, among 800 related donors for adult patients, the median age of donation was 36 years old (range 8-65, male to female 1:1.07). Among unrelated donors, 128 (60%) are from the HK Marrow Match Foundation. This is currently run by the HK Red Cross and is 55000 strong. Other marrow sources come from Taiwan (48), China (16), USA (14), Japan (5) and other countries (4). Over 40 donor marrows have also been exported from HK to overseas Chinese patients. The HK Red Cross does not charge local patients, but overseas stem cell procurement involves reciprocal costs ranging $106000 to $314000. Among voluntary donors, the median age was 29 (range 18-56), with equal number of male and female donors. In terms of cost and time of procurement, it is obviously much preferable for patients to have local donors.

 

The patient

 

Provided that a donor source is available, the main criteria for HSCT recipient selection are disease control and patient age and fitness. Transplantations performed with uncontrolled disease are associated with unacceptably poor outcome. For some diseases such as acute promyelocytic leukemia and chronic myeloid leukemia, success with arsenic therapy and tyrosine kinase inhibitors means that allogeneic BMT are rarely performed anymore. Since morbidity associated with mismatched or unrelated HSCT are higher, patient selection is more stringent. For elderly patients or those with poor performance status, the use of reduced dose conditioning or “mini-transplants”, which contain more immunosuppressive rather than intense myeloablative conditioning, can reduce the immediate morbidity. The typical age limits for mini-BMT, standard sibling BMT and unrelated BMT are set at 65, 55 and 45 years respectively. The pre-HSCT preparative procedure also included hickman catheter insertion for vascular access, control of hepatitis B activity, surgical and antimicrobial control of fungal and tuberculous infections, dental and dietary assessments, cardiopulmonary assessments, histological review of original diagnosis and social assessment. 

 

The commonest complication after HSCT is disease relapse and this may or may not be salvageable with further HSCT procedures, chemotherapy or novel therapy agents. The common indications for HSCT and the actuarial 3-year survival rate are shown in table 1.

Late complications included bronchiolitis obliterans, zoster and tuberculosis reactivation, infertility and amenorrhea, dry eyes and mouth, cataracts, thyroiditis, avascular necrosis, sepsis and infection, renal impairment and secondary malignancies. A multidisciplinary team for long-term follow-up is needed and close coordination between the referring center and BMT center is needed to optimize patient care. Despite all these, many patients are cured and lead perfectly normal lives.

 

Adult allogeneic stem cell transplantation in Queen Mary Hospital

 

The first allogeneic BMT was performed in QMH in May 1990, and with over 17 years of follow-up in some patients. It remained the only adult allogeneic BMT centre serving the population of Hong Kong and Macau, and is an US NMDP accredited site. Up to 2007, a total of 1340 registered patients had received HSCT procedures in QMH. They included 1104 adult patients and 847 allogeneic procedures. A total of 10 BMT suites with reverse isolation are available for adult patients, with an additional 3 step-down rooms. Patients with discharge difficulties can also apply for accommodation in two “BMT homes” in nearby Wah Kwai estate. As a major Oriental BMT centre, we also strived to share clinical and scientific knowledge in BMT in Chinese patients, with an output of over 200 publications. As in all transplantation fields, activity is limited by budgetary, manpower capacity and timely donor availability.

 

Conclusions

 

With improved microbial, transfusion and growth factor support, DNA based HLA typing accuracy, and astute clinical and nursing experience, survivals in “standard-risk” are ever increasing. On the other hand, with expanded unrelated donor pool, new conditioning techniques and increasing transplantation efficiency, more patients previously considered “high-risk” candidates become salvageable. Indications for HSCT and the source of stem cells are also evolving continuously. Despite the increasing availability of novel agents, allogeneic HSCT is likely to remain the only hope of cure for many patients and disease conditions in the foreseeable future.

 




Table 1: Adult allogeneic stem cell transplantation in Queen Mary Hospital

 

Diagnosis

Number

Actuarial 3-year survival

Acute myeloid leukemia / myelodysplasia

336

55%

Acute lymphoblastic leukemia

129

52%

Chronic myeloid leukemia / MPD

233

69%

Lymphoma (NHL/HL)

68

51%

Myeloma

45

58%

Severe aplastic anemia

22

66%

Others

14

NA

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