Bone marrow transplantation in Canada.

Bone marrow transplantation is an established form of therapy for aplastic anemia and severe combined immunodeficiency. It is also a therapeutic option for acute leukemia in remission. Unfortunately, compatible donors are not available for most patients who could benefit from it. Further refinement of the techniques involved may make it suitable for more patients. Graft rejection, recurrent leukemia, graft-versus-host disease and interstitial pneumonia continue to be the main unsolved complications of bone marrow transplantation, but recent advances have decreased their frequency and severity. Most of the complications of allogeneic bone marrow transplantation may be eliminated with the use of autologous stem cells. For further refinement bone marrow transplantation should continue to be performed in large centres that combine treatment with research.     

Bone marrow transplantation. Part II--autologous.

Autologous bone marrow transplantation provides an effective form of "rescue" following high-dose therapy used for treating certain malignant diseases. The high doses of radiotherapy or chemotherapy, or both, should allow for greater tumor cell kill if dose-response to therapy exists for that tumor. The use of autologous bone marrow obviates the need for an HLA-identical donor, and the need for pretransplant immunosuppression; no graft-versus-host disease would ensue. We review in part II the history and background, methods of obtaining autologous stem cells, and details of the results achievable with this type of therapy. We discuss potential difficulties with autologous transplantation, as well as possible future areas of research.     

Bone marrow transplantation. Part I--Allogeneic.

Major progress in experimental and clinical research has made allogeneic bone marrow transplantation a highly effective therapy for a variety of malignant and nonmalignant diseases. Allogeneic bone marrow transplantation from histocompatible donors is now the therapy of choice for some of these disorders. We review in part I the history, technical approach, complications, and the results achievable with this therapeutic approach. Further experimentation and future goals are also discussed.     

Bone marrow transplantation for Niemann-Pick mice

The Niemann-Pick mice which received bone marrow transplants showed a decreased accumulation of sphingomyelin and cholesterol quantitatively in their spleen. The sphingomyelin deposit in the bone marrow was also reduced histochemically. However, the neurological manifestations were not improved by the bone marrow graft.     

Bone marrow transplantation beyond treatment of aplasia and neoplasia.

Marrow transplantation has proved to be an important modality in the treatment of aplastic anemia, acute leukemia, and some other malignant diseases of hemopoietic cells. Much less attention has been paid to the role of marrow transplantation in the treatment of stem cell disorders such as sickle cell disease, chronic granulomatous disease, or Gaucher''s disease. Allogeneic transplantation is successful in these disorders, but carries a considerable risk to the recipient. Autologous transplantation becomes a reality when efficient gene transfer with sustained expression is developed. As methods are developed to harvest hemopoietic stem cells from the peripheral blood and to amplify these cells without causing them to differentiate, transplantation will become increasingly valuable in the treatment of stem cell disorders.     

Bone marrow transplantation for leukaemia in Europe

The European Bone Marrow Transplant Leukaemia Registry has collected data from 52 European centers between 1979 and 1986. More than 2,000 transplants performed for a haematological malignancy were reported. The present analysis shows that the most important factor influencing leukaemia free survival, transplant related mortality and relapse incidence is the stage of the disease at the time of the transplant. Outcome is highly better when the transplant is performed for acute myeloid and acute lymphocytic leukaemia in first complete remission and for chronic myelocytic leukaemia in first chronic phase. Additional prognostic factors are age, the method for graft-versus-host disease prevention and the donor recipient sex combination. Results are better for younger patients, for patients given cyclosporine for prevention of graft-versus-host disease and are worse for male patients receiving a female donor bone marrow. The results are not influenced by the year of the transplant per se and by the center size.     

Bone marrow transplantation in children with neuroblastoma

Neuroblastoma is the third most frequent malignant tumor in childhood. One-third of the patients over one year of age at the time of diagnosis suffer from the disseminated form (stage IV). Despite highly aggressive chemotherapy survival rates are poor. One hundred and eighty-seven patients with neuroblastoma stage IV have been treated according to the German protocol NB 85. The probability of disease free survival is only 15% after 70 months. Treatment strategy in our protocol includes autologous and allogeneic bone marrow transplantation (BMT) for patients with stage IV (and greater than 1 year old). Twenty-two patients were grafted (7 allogeneic and 15 autologous). The conditioning regimen consisted mainly of high-dose melphalan (180 mg/m2) and total body irradiation (TBI) (3.4 Gy). Survival rates are discussed in the context of the chemotherapy protocol. Our own experience with autologous BMT is poor, despite of different purging methods. For this reason we decided to focus on allogeneic BMT. We have grafted five patients within the last 3 years. Three of them are alive and well, on died from veno-occlusive disease 70 days after BMT, and the remaining patient, grafted from a syngeneic donor, died from relapsing tumor. The main problem in neuroblastoma stage IV is resistance to chemotherapy. Intensification of the conditioning regimen or double autografting leads to a rate of toxic deaths close to 20% (Zucker, EBMT 1987) which is not tolerable. New improvements in the conditioning regimen have to be found to increase the effect of BMT.     

Bone marrow cryopreservation and clinical implications in autologous bone marrow transplantation

A simple, rapid and effective technique using the IBM (Cobe)-2991 cell processor for the concentration of buffy coat cells from large volume marrow has been well adopted (n = 16). Only about one-eighth of the original volume was obtained while retaining more than 90% of the total nucleated cells to be cryopreserved in polyolefine bags with TC-199 culture medium and final 10% dimethylsulfoxide (DMSO) (n = 9), processed by a computerized Nicool ST-20 (France) programmed freezer and stored in a vapor phase of liquid nitrogen at -196 degrees C. Stem cell assay by CFU-GM after thawing yielded a mean of 50.39 +/- 19.54% which has been satisfactory for clinical implementation. So far, three cases with hematological malignancies had been rescued by autologous cryopreserved marrow after supralethal doses of chemoradiotherapy. Two patients with acute nonlymphocytic leukemia transplanted in 1st remission as of Oct. 31 had been disease free for 178+ and 157+ days, respectively, after transplant which was taken at the corresponding age of 53 and 42 years. The other patient who was a victim of Hodgkin's disease, stage IV, and was transplanted in 3rd remission, expired on the 59th day because of the complication of idiopathic interstitial pneumonitis despite excellent granulocytopoietic reconstitution. The preliminary results are encouraging for further exploitation, especially for those who would otherwise be candidates for allogeneic bone marrow transplantation but are limited by age or lack of an HLA-identical sibling to serve as marrow donors.