Consensus Conference on Unrelated Donor Bone Marrow Transplantation: Royal College of Physicians of Edinburgh, October 29th and 30th, 1996

BMTs from unrelated donors for leukemias are increasing greatly in number and also in proportion to matched sibling donor transplants. The panel has considered unrelated donor transplant (UD-BMT) on the basis of efficacy, toxicity, and indications in leukemias. The conclusions and statements are based largely but not exclusively on information provided at the Consensus Conference.

(1) Unrelated BMTs for some types of leukemia can produce prolonged quiescence and, in some cases, eradication of disease.

(2) Data based on serologically matched donors at HLA A,B and DR suggest that matched unrelated transplants may have similar survival to sibling transplants in comparable disease states. This is accepted as a reasonable statement but begs the question of what is implied by matched in unrelated transplants. Much of the data concerning the survival and toxicity in unrelated transplants have come from studies using serologic typing. The effect of molecular typing on outcome may alter indications.

(3) Information on the place of sibling transplants compared with chemotherapy and autologous transplants in the management of some leukemias has been provided by randomized studies organized by the EORTC and the MRC. These studies define the place of sibling BMT in the management of acute leukemias. Conclusions drawn from these studies on the presence or absence of benefit of sibling transplants may apply to unrelated transplants.

(4) In a few situations, the evidence for efficacy is based on the level 1 documentation of zero survival after conventional therapy but with some survivors after transplant (eg, childhood acute lymphoblastic leukemia [ALL] with early bone marrow relapse). However, in situations in which alternative therapies occasionally succeed, level 1 evidence from randomized trials is rarely available to help in decision making.

(5) There is variation in outcome reported from different sources for particular conditions. In part, this may be because subdivisions of different types of leukemia are not always accurately defined. Attempts to identify subgroups and to compare like with like are essential, even though they may make data collection and comparisons more arduous.

(6) It is important that rigorous economic evaluations and quality of life studies are performed alongside like with like comparisons.

(1) Increasing age and degree of mismatch each increase the probability of transplant-related mortality and morbidity and need to be taken into account when assessing the use of UD-BMT in any situation. In young (<20 years) good-risk patients, the mortality of the procedure is of the order of 15%, which increases in older patients (at 45 years to 30% or more).

(2) Transplants with an HLA-mismatched (A,B or DR) marrow have a high toxicity compared with matched marrow and cannot be equated with sibling transplants.

(3) There are, to date, few published studies concerning quality of life in recipients of UD-BMT. To inform decision making, such information must be collected using well-validated standardized tests.

(1) Information that allows the classification of various diseases into good, standard, and high risk is essential in allowing comparative assessment of treatments including UD-BMT.

(2) Evidence suggests that the results of UD-BMT are better when performed early in some diseases. However, the timing of UD-BMT depends on the consideration of other treatment options.

(3) For patients with chronic myelogenous leukemia (CML) in chronic phase or accelerated phase, UD-BMT should be considered as the best available treatment at present for patients without a matched sibling donor, providing that the unrelated donor provides a close match (level 1c evidence).

(4) For patients with acute myelogenous leukemia (AML) in first remission, UD-BMT has little place at the present time. In second complete remission, it may be considered, although its role in relation to other therapies requires further evaluation. UD-BMT has a clear place in a subgroup of patients with initial refractory disease, secondary AML, and high risk myelodysplastic syndromes (level 1c evidence).

(5) For a small group of children with very high-risk ALL in first remission and for children in second remission who have sustained an early bone marrow relapse, data suggest that survival may be improved by UD-BMT (level 1c evidence). Similar criteria may apply to adult ALL, but present data are even more limited.

(6) The results of UD-BMT for desperate disease (such as CML in blast crisis or acute leukemia in overt relapse) are discouraging (10% or less survival) and are associated with marked and often unquantitated toxicity. It may be considered that toxicity inflicted on the unsuccessful recipients negates the slim chance of benefit to those where the treatment is successful in terms of survival.

(1) UD-BMT should only be performed where there are facilities for full characterization of the recipient's disease, molecular HLA typing, and guaranteed reporting to national or international registries.

(2) For conditions in which there is no level 1 evidence and there is doubt about the benefits of UD-BMT versus other therapies, the procedure is only justified as part of a randomized trial (or formal pilot for such a trial).

(3) With respect to more general planning of services, it is important to research the issue of whether UD-BMT should take place in a limited number of specialized units.

(1) PBSC collection has potential advantages compared with collection of bone marrow under general anesthetic. However, there are uncertainties concerning short-term and long-term toxicity of using granulocyte colony-stimulating factor with PBSC. This is inevitable because of the small numbers that have been performed in healthy donors. It would seem reasonable to offer to volunteer donors the alternative of PBSC collection, emphasizing the uncertainties, but only where properly informed consent is possible and agreed standardized protocols are followed that include systematic long-term follow-up of the donors.

(2) Policies on anonymity differ widely throughout the world. There are good reasons to maintain strict anonymity between donor and recipient despite theoretical problems in donor recruitment. The potential problems of breaking this anonymity seem to outweigh the benefits of disclosure. Systematic investigation of these matters should be performed.

(3) Further research addressing the complex ethical and psychosocial issues surrounding related and unrelated donors should be undertaken.

Dr Corinne Camilleri-Ferrante (Consultant in Public Health Medicine, Director Anglia Clinical Audit and Effectiveness Team); Prof Cam Donaldson (Professor of Health Economics, University of Aberdeen); Prof Ted Gordon-Smith, Chairman (Professor of Haematology, St George's Hospital Medical School, London); Dr Lesley Fallowfield (Reader in Psycho-Oncology, Department of Oncology, University College London Medical School); Prof Alois Gratwohl (Division of Haematology, Department of Internal Medicine, Kantonsspital Basel, Switzerland); Prof Roy Meadow, Vice-Chairman (President, College of Paediatrics and Child Health and Professor of Paediatrics and Child Health, St James's University Hospital, Leeds); Becky Miles (Regional Cancer Adviser, NHS Executive and Chair National Cancer Alliance); Dr Donald J. Moir (Consultant in Haematology, Milton Keynes General Hospital, Milton Keynes); Prof David Sackett (Director, NHS R&D Centre for Evidence-Based Medicine, Oxford); and Geoffrey Watts (Presenter of Medicine Now, BBC Radio 4).

Dr Claudio Anasetti (Director, Unrelated Donor Marrow Transplants, Fred Hutchinson Cancer Research Center, Seattle); Prof Alan K. Burnett (Department of Haematology, University of Wales College of Medicine); John Cairns (Health Economics Research Unit, Aberdeen); Dr Geoffrey Carroll (Director of Public Health and Clinical Policy, North Essex Health Authority); Prof Judith M. Chessells (Leukaemia Research Fund Professor of Haematology and Oncology, University of London); Dr Jacqueline M. Cornish (Associate Specialist, Bone Marrow Transplant Unit, Bristol Royal Hospital for Sick Children); Prof Eliane Gluckman (Bone Marrow Transplant Unit, Hôpital Saint-Louis, Paris); Prof John M. Goldman (Professor of Leukaemia Biology and Director of LRF Centre for Adult Leukaemia); Prof Norbet C. Gorin (Department of Haematology, Hôpital Saint-Antoine, Paris); Dr Helen E. Heslop (Associate Professor, St Jude Children's Research Hospital, Memphis); Dr Mary M. Horowitz (Professor of Medicine, Scientific Director, International Bone Marrow Transplant Registry, Milwaukee); Prof Jill M. Hows (Professor of Clinical Haematology, Division of Transplantation Sciences, University of Bristol); Prof Dieter F. Hoelzer (Haematology Department, University of Frankfurt); Prof T. Andrew Lister (Professor of Medical Oncology, St. Bartholomew's Hospital, London); Prof Guido Lucarelli (Department of Haematology, Hospital of Pesaro); Prof Shelia A.M. McLean (International Bar Association Professor of Law and Ethics in Medicine at Glasgow University); Dr Anthony Oakhill (Professor of Childhood Leukaemia and Transplantation, Bristol Royal Hospital for Sick Children); Dr Alistair C. Parker (Senior Lecturer in Medicine, Royal Infirmary of Edinburgh); Dr John Porter (Senior Lecturer, Department of Haematology, University College London); Dr Michael N. Potter (Senior Lecturer Honorary Consultant in Haematology/Bone Marrow Transplant, United Bristol Healthcare Trust and Bristol University); Dr Raymond L. Powles (Head and Physician in Charge, Leukaemia and Myeloma Units, The Royal Marsden NHS Trust, London); Dr Nigel H. Russell (Senior Lecturer and Consultant in Haematology, University of Nottingham); Dr Paul A. Veys (Consultant in Charge, Bone Marrow Transplantation, Great Ormond Street Hospital for Children NHS Trust); and Dr Ruth M. Warwick (London and South East Zone of the National Blood Service).

Scientific: Prof Ian M. Franklin (Professor of Transfusion Medicine, Department of Medicine, Glasgow University); Prof Martin J. Pippard (Professor of Haematology, Ninewells Hospital and Medical School, University of Dundee); Prof Rod K. Griffiths (Regional Director of Public Health and Deputy Regional Director, NHS Executive [West Midlands Regional Office]); Prof David C. Linch (Professor of Haematology, University College London); and Prof Gordon D.O. Lowe (College Deputy Assessor, Royal College of Physicians of Edinburgh; Department of Medicine, Royal Infirmary, Glasgow).