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Bone Marrow Transplantation for Diseases of Childhood

1984; Elsevier BV; Volume: 59; Issue: 3 Linguagem: Inglês

10.1016/s0025-6196(12)60770-8

1942-5546

Richard Kadota, William A. Smithson,

Immunodeficiency and Autoimmune Disorders

Bone marrow transplantation in childhood is an established treatment modality for aplastic anemia, the acute and chronic leukemias, and severe combined immune deficiency. Recently, experience with this treatment has also been favorable with small numbers of children who have Wiskott-Aldrich syndrome, several types of inherited storage diseases, Fanconi's anemia, thalassemia, infantile malignant osteopetrosis, and selected cases of lymphoma and other solid tumors. The psychosocial impact and financial costs of bone marrow transplantation can be substantial. Multi-institutional, prospective, randomized trials that would compare transplantation and conventional therapy are necessary to establish the indications and precise timing for this procedure. Further development of monoclonal antibodies, a better understanding of the histocompatibility antigen systems, and improvement in pretransplantation conditioning regimens should increase the spectrum of effectiveness for bone marrow transplantation in the coming years. Bone marrow transplantation in childhood is an established treatment modality for aplastic anemia, the acute and chronic leukemias, and severe combined immune deficiency. Recently, experience with this treatment has also been favorable with small numbers of children who have Wiskott-Aldrich syndrome, several types of inherited storage diseases, Fanconi's anemia, thalassemia, infantile malignant osteopetrosis, and selected cases of lymphoma and other solid tumors. The psychosocial impact and financial costs of bone marrow transplantation can be substantial. Multi-institutional, prospective, randomized trials that would compare transplantation and conventional therapy are necessary to establish the indications and precise timing for this procedure. Further development of monoclonal antibodies, a better understanding of the histocompatibility antigen systems, and improvement in pretransplantation conditioning regimens should increase the spectrum of effectiveness for bone marrow transplantation in the coming years. Bone marrow transplantation in children has most commonly been used as therapy for aplastic anemia, the leukemias, and immunodeficiency disorders. In recent years, the number of conditions that this procedure has been reported to benefit has expanded to include inherited storage diseases, hereditary anemias, severe infantile osteopetrosis, and selected cases of lymphomas and other solid malignant lesions (Table 1).1Hobbs JR Bone marrow transplantation for inborn errors.Lancet. 1981; 2: 735-739Abstract PubMed Scopus (84) Google Scholar, 2Lenarsky C Feig SA Bone marrow transplantation for children with cancer.Pediatr Ann. 1983; 12: 428-436PubMed Google Scholar Several excellent published reviews have detailed the problems of patients and the methods of management at the transplantation center.3Thomas ED Storb R Clift RA Fefer A Johnson FL Neiman PE Lerner KG Glucksberg H Buckner CD Bone-marrow transplantation.N Engl J Med. 1975; 292 (895-902): 832-843Crossref PubMed Scopus (1422) Google Scholar, 4Gale RP Fox CF Biology of bone marrow transplantation.ICN-UCLA Symp Mol Cell Biol. 1980; 17: 1-566Google Scholar, 5Vossen J Dooren LJ Potential of bone marrow and fetal tissue transplantation in paediatrics.in: Willoughby M Siegel SE Hematology and Oncology. Butterworth Scientific, London1982: 110-161Google Scholar The aim of this article is to summarize the current literature for the practitioner who has the responsibility of caring for children in whom a bone marrow transplant is a consideration.Table 1Spectrum of Diseases for Which Bone Marrow Transplantation Has Been Performed Successfully in Children Aplastic anemiaAcute and chronic leukemiasImmunodeficiency disorders Examples: severe combined immune deficiency and Wiskott-Aldrich syndromeInherited storage diseases Example: mucopolysaccharidosesHereditary anemias Examples: Fanconi's anemia and thalassemia majorInfantile malignant osteopetrosisNonleukemic malignant lesions Examples: selected cases of lymphomas and solid tumors Open table in a new tab At our institution, the bone marrow transplant recipient is admitted to the hospital approximately 1 week before the anticipated day of transplantation. This allows adequate time for insertion of central venous access lines (Hickman or Broviac catheter) and administration of the conditioning regimen. The objectives of conditioning are to ablate the patient's marrow cells, provide immunosuppression to minimize the possibility of graft rejection, and eradicate malignant cells, if present. Depending on the disease being treated, conditioning involves multiple-day chemotherapy, with or without total-body or total-lymphoid irradiation. The bone marrow donor is usually hospitalized 1 day before the transplantation procedure. The amount of bone marrow aspirated depends on the weight of the recipient and the estimated concentration of stem cells in the donor material. Marrow is aspirated from the posterior iliac crests bilaterally with use of general anesthesia. More than 1 liter of marrow may be needed for large adolescent recipients, but much less is sufficient for smaller children. Donor hospitalization time is usually less than 3 days and is proportional to the degree of postoperative discomfort at the sites of donation. Complete hematologic normalization occurs within a few weeks and is aided by iron supplementation and transfusion of a unit of autologous blood. The autologous unit is collected several days before bone marrow donation and is returned to the donor during the marrow aspiration procedure.3Thomas ED Storb R Clift RA Fefer A Johnson FL Neiman PE Lerner KG Glucksberg H Buckner CD Bone-marrow transplantation.N Engl J Med. 1975; 292 (895-902): 832-843Crossref PubMed Scopus (1422) Google Scholar Additional nonautologous blood given to the donor before or during the marrow harvest should be irradiated. No donor fatalities have been reported.2Lenarsky C Feig SA Bone marrow transplantation for children with cancer.Pediatr Ann. 1983; 12: 428-436PubMed Google Scholar The donated bone marrow is administered similar to a simple red blood cell transfusion through an intravenous line. After the infusion procedure, the recipient's hospital course, ideally, should be 6 weeks or less. Parenteral nutrition, broad-spectrum antibiotics, and blood product support are necessary for most children, especially before engraftment. Many centers also maintain patients in special isolation units until the leukocyte count demonstrates moderate regeneration. After hospital dismissal, transplant recipients are reexamined frequently until 100 days after the procedure (the period of greatest risk for complications) or until clinical stability has been established. Usually, immunosuppressive medication is continued throughout this period. Bone marrow transplantation involves a myriad of new stresses, even for the family already accustomed to dealing with the difficulties associated with chronic disease.6Brown HN Kelly MJ Stages of bone marrow transplantation: a psychiatric perspective.Psychosom Med. 1976; 38: 439-446PubMed Google Scholar, 7Patenaude AF Szymanski L Rappeport J Psychological costs of bone marrow transplantation in children.Am J Orthopsychiatry. 1979; 49: 409-422Crossref PubMed Scopus (56) Google Scholar If the sibling donor is a minor, the use of a child advocate or other legal proceedings may be necessary to ensure the rights of the donor because of natural parental ambivalence between potentially saving an ill child and potentially harming a healthy one.7Patenaude AF Szymanski L Rappeport J Psychological costs of bone marrow transplantation in children.Am J Orthopsychiatry. 1979; 49: 409-422Crossref PubMed Scopus (56) Google Scholar, 8Serota FT August CS O'Shea AT Woodward WT Koch PA Role of a child advocate in the selection of donors for pediatric bone marrow transplantation.J Pediatr. 1981; 98: 847-850Abstract Full Text PDF PubMed Scopus (19) Google Scholar Many patients with their families must travel to an unfamiliar, distant metropolitan center for the procedure and remain there for a minimum of 100 days after the transplantation procedure. The patient, parents, donor, and other siblings all require continuous support from the transplantation team as well as support from friends and relatives. In addition to the donation of the bone marrow by one family member, other adult relatives and friends may be requested to donate platelets or granulocytes, a procedure that involves sitting at an apheresis machine for several hours. It has been extremely gratifying to see hometowns of several of our patients voluntarily rally around such families to provide support in terms of money, time, transportation, and blood products. The estimated cost of a typical bone marrow transplantation in the United States is currently in excess of $50,000, and it can be higher if major complications ensue.9Bone marrow transplantation: a lifesaving applied art; an interview with E. Donnall Thomas, M.D..JAMA. 1983; 249: 2528-2536Crossref PubMed Scopus (20) Google Scholar Health insurance will usually cover most of the cost, yet potentially many families must assume the responsibility of paying thousands of dollars themselves. Daily living expenses away from home are not covered by third-party payers and represent a large out-of-pocket expense for most families.10Lansky SB Cairns NU Clark GM Lowman J Miller L True-worthy R Childhood cancer: nonmedical costs of the illness.Cancer. 1979; 43: 403-408Crossref PubMed Scopus (102) Google Scholar Marrow transplantations for experimental indications or use of creative new procedures may not be reimbursed at all. Exhaustion of liquid assets and loss of income while staying with their child compound the strain for parents. Most patients and families have viewed the transplant procedure as a potential means of returning to completely normal health. The stress of the situation may be increased by the impression that bone marrow transplantation offers the only hope for continued survival. The novelty of this form of treatment, its apparent simplicity to the lay observer, the extensive media coverage, and the opportunity to discontinue chemotherapy add to the optimistic state of mind in many situations. Thus, few stresses are more profound than that of death of a marrow recipient at the transplantation center or late failure due to relapse of a malignancy, the latter being especially common in children who undergo marrow transplantation for acute lymphoblastic leukemia in second or greater remission. One of the most important factors that relate to the success of a bone marrow transplantation is the degree of immunologic compatibility between donor and recipient. Currently, such compatibility is assessed by human lymphocyte antigen (HLA) typing at several loci. HLA antigens are thought to be under the genetic control of the major histocompatibility complex on the short arm of chromosome 6. Loci HLA-A, HLA-B, HLA-C, and HLA-DR are defined serologically, whereas HLA-D typing is performed by a oneway mixed lymphocyte culture technique.11Moore SB HLA.Mayo Clin Proc. 1979; 54: 385-393PubMed Google Scholar Other important, poorly characterized, histocompatibility antigens exist, however, as evidenced by the frequent development of graft-versus-host disease despite HLA matching and routine use of immunosuppression after transplantation. Most successful bone marrow transplantation procedures are performed between histocompatible siblings (at least HLA-A, HLA-B, and HLA-D identical), an occurrence with a probability of at least one in four for children having the same biologic parents.12Chan K-W Pollack MS Braun Jr, D O'Reilly RJ Dupont B Distribution of HLA genotypes in families of patients with acute leukemia: implications for transplantation.Transplantation. 1982; 33: 613-615Crossref PubMed Scopus (16) Google Scholar13Spruce W McMillan R Beutler E Bone marrow transplantation for the treatment of severe aplastic anaemia.Clin Haematol. 1983; 12: 285-310PubMed Google Scholar The likelihood of a complete HLA match in other relatives, including parents, is much less. The possibility of finding donor compatibility in an unrelated person is remote. Recently, blood banks at several transplantation centers have begun to collect HLA typings in an attempt to facilitate such a search. Major donor-recipient ABO incompatibility has been managed by several techniques, and the complications have been minimal. Successful methods have included recipient plasma exchange, in vivo antibody adsorption, and in vitro erythrocyte depletion from the donor marrow inoculum.14Bensinger WI Buckner CD Thomas ED Clift RA ABO-incompatible marrow transplants.Transplantation. 1982; 33: 427-429Crossref PubMed Scopus (132) Google Scholar, 15Blacklock HA Prentice HG Evans JPM Knight CBT Gilmore MJML Hazlehurst GRP Ma DDF Hoffbrand AV ABO-incompatible bone-marrow transplantation: removal of red blood cells from donor marrow avoiding recipient antibody depletion.Lancet. 1982; 2: 1061-1064Abstract PubMed Scopus (56) Google Scholar, 16Braine HG Sensenbrenner LL Wright SK Tutschka PJ Saral R Santos GW Bone marrow transplantation with major ABO blood group incompatibility using erythrocyte depletion of marrow prior to infusion.Blood. 1982; 60: 420-425PubMed Google Scholar, 17Curtis JE Messner HA Bone marrow transplantation for leukemia and aplastic anemia: management of ABO incompatibility.Can Med Assoc J. 1982; 126: 649-655PubMed Google Scholar, 18Dinsmore RE Reich LM Kapoor N Gulati S Kirkpatrick D Flomenberg N O'Reilly RJ ABH incompatible bone marrow transplantation: removal of erythrocytes by starch sedimentation.Br J Haematol. 1983; 54: 441-449Crossref PubMed Scopus (62) Google Scholar Differences in other blood antigen systems have not been a problem, with the exception of mismatch in the MNS group being correlated with an increased incidence of graft-versus-host disease in one study.19Sparkes RS Sparkes MC Crist M Yale C Mickey MR Gale RP MNSs antigens and graft versus host disease following bone marrow transplantation.Tissue Antigens. 1980; 15: 212-215Crossref PubMed Scopus (10) Google Scholar Young donor age and the use of male donors have been associated with better results in some series of patients with aplastic anemia,20Bortin MM Gale RP Rimm AA Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia.JAMA. 1981; 245: 1132-1139Crossref PubMed Scopus (93) Google Scholar, 21Gluckman E Barrett AJ Arcese W Devergie A Degoulet P Bone marrow transplantation in severe aplastic anaemia: a survey of the European Group for Bone Marrow Transplantation (E.G.B.M.T.).Br J Haematol. 1981; 49: 165-173Crossref PubMed Scopus (56) Google Scholar, 22Elfenbein GJ Mellits ED Santos GW Engraftment and survival after allogeneic bone marrow transplantation for severe aplastic anemia.Transplant Proc. 1983; 15: 1412-1416Google Scholar but the opposite trend (favoring female donors) was noted in a recent report from Seattle.23Storb R Doney KC Thomas ED Appelbaum F Buckner CD Clift RA Deeg HJ Goodell BW Hackman R Hansen JA Sanders J Sullivan K Weiden PL Witherspoon RP Marrow transplantation with and without donor buffy coat cells for 65 transfused aplastic anemia patients.Blood. 1982; 59: 236-246PubMed Google Scholar None of the variables mentioned in this paragraph should alter decisions about transplantation, unless the circumstance of more than one HLA-identical sibling prevails. An effort should be made to withhold pretransplantation blood transfusions from children with aplastic anemia and other immunocompetent candidates, unless the transfusions are emergently indicated. As reviewed by Storb and Weiden,24Storb R Weiden PL Transfusion problems associated with transplantation.Semin Hematol. 1981; 18: 163-176PubMed Google Scholar patients with aplastic anemia may become sensitized to non-HLA histocompatibility antigens, and attempts at marrow engraftment may result in rejection. While the diagnosis is being confirmed, the child with aplastic anemia and the family should undergo rapid HLA typing, and an early transplantation procedure should be considered. In the event that transfusions become necessary before patient referral can be made, leukocyte-poor red blood cells or platelets (or both) should be used.24Storb R Weiden PL Transfusion problems associated with transplantation.Semin Hematol. 1981; 18: 163-176PubMed Google Scholar If repeated platelet transfusions are needed, then procurement from a single donor may be considered to limit the exposure to antigens. Blood from family members should not be used before transplantation, in order to avoid sensitization to nonshared familial histocompatibility antigens.24Storb R Weiden PL Transfusion problems associated with transplantation.Semin Hematol. 1981; 18: 163-176PubMed Google Scholar When necessary, however, modification of the conditioning regimen can overcome the potential for donor marrow rejection in patients with aplastic anemia who receive pretransplantation blood transfusions (see subsequent material under the heading “Aplastic Anemia”). For the patient with leukemia, marrow rejection has not been a major problem; an incidence of 1% has been reported in two large studies.25Thomas ED Buckner CD Banaji M Clift RA Fefer A Flournoy N Goodell BW Hickman RO Lerner KG Neiman PE Sale GE Sanders JE Singer J Stevens M Storb R Weiden PL One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation.Blood. 1977; 49: 511-533PubMed Google Scholar26Gale RP Kersey JH Bortin MM Dicke KA Good RA Zwaan FE Rimm AA Bone-marrow transplantation for acute lymphoblastic leukaemia.Lancet. 1983; 2: 663-667PubMed Google Scholar Thus, pretransplantation transfusions need not be restricted. A more immediate threat to these children is graft-versus-host disease that is caused by viable lymphocytes in transfused blood products.27Von Fliedner V Higby DJ Kim U Graft-versus-host reaction following blood product transfusion.Am J Med. 1982; 72: 951-961Abstract Full Text PDF PubMed Scopus (133) Google Scholar, 28Wick MR Moore SB Gastineau DA Hoagland HC Immunologic, clinical, and pathologic aspects of human graft-versus-host disease.Mayo Clin Proc. 1983; 58: 603-612PubMed Google Scholar For this reason, many medical centers are irradiating all blood products intended for transfusion into patients with leukemia, whether transplantation is contemplated or not. Similarly, neonates and older pediatric patients with other malignant lesions or severe primary immunodeficiency may benefit from irradiation of blood products.27Von Fliedner V Higby DJ Kim U Graft-versus-host reaction following blood product transfusion.Am J Med. 1982; 72: 951-961Abstract Full Text PDF PubMed Scopus (133) Google Scholar, 28Wick MR Moore SB Gastineau DA Hoagland HC Immunologic, clinical, and pathologic aspects of human graft-versus-host disease.Mayo Clin Proc. 1983; 58: 603-612PubMed Google Scholar Graft-versus-host disease commonly occurs after bone marrow transplantation because a portion of the transplanted organ—that is, immunocompetent lymphocytes—may circulate throughout the body, recognize differences between donor and host cell antigens, and damage target tissues. As reviewed recently by Wick and associates,28Wick MR Moore SB Gastineau DA Hoagland HC Immunologic, clinical, and pathologic aspects of human graft-versus-host disease.Mayo Clin Proc. 1983; 58: 603-612PubMed Google Scholar acute graft-versus-host disease occurs within 100 days after transplantation and primarily involves the skin, bowel, liver, and lymphohematologic system. Chronic graft-versus-host disease, which may follow the acute condition or arise de novo, resembles an overlap of autoimmune collagen and vascular disorders (prominently including features common to scleroderma and Sjögren's syndrome) plus disordered immunity and an increased risk for infections.28Wick MR Moore SB Gastineau DA Hoagland HC Immunologic, clinical, and pathologic aspects of human graft-versus-host disease.Mayo Clin Proc. 1983; 58: 603-612PubMed Google Scholar, 29Atkinson K Storb R Prentice RL Weiden PL Witherspoon RP Sullivan K Noel D Thomas ED Analysis of late infections in 89 long-term survivors of bone marrow transplantation.Blood. 1979; 53: 720-731PubMed Google Scholar, 30Tsoi M-S Immunological mechanisms of graft-versus-host disease in man.Transplantation. 1982; 33: 459-464Crossref PubMed Scopus (52) Google Scholar Incidence estimates in children who undergo bone marrow transplantation are approximately one in two for acute graft-versus-host disease and one in three for the chronic form of the disease.20Bortin MM Gale RP Rimm AA Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia.JAMA. 1981; 245: 1132-1139Crossref PubMed Scopus (93) Google Scholar30Tsoi M-S Immunological mechanisms of graft-versus-host disease in man.Transplantation. 1982; 33: 459-464Crossref PubMed Scopus (52) Google Scholar, 31Bortin MM Gale RP Kay HEM Rimm AA Bone marrow transplantation for acute myelogenous leukemia.JAMA. 1983; 249: 1166-1175Crossref PubMed Scopus (62) Google Scholar, 32Storb R Prentice RL Sullivan KM Shulman HM Deeg HJ Doney KC Buckner CD Clift RA Witherspoon RP Appelbaum FA Sanders JE Stewart PS Thomas ED Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings.Ann Intern Med. 1983; 98: 461-466Crossref PubMed Scopus (246) Google Scholar, 33Zwaan FE Hermans J Report of the E.B.M.T.-Leukaemia Working Party.Exp Hematol 11 Suppl. 1983; 13: 3-6Google Scholar The standard prophylaxis for acute graft-versus-host disease has been methotrexate, but many transplantation centers have had success with other regimens including corticosteroids, antithymocyte globulin, and a new drug, cyclosporin A.9Bone marrow transplantation: a lifesaving applied art; an interview with E. Donnall Thomas, M.D..JAMA. 1983; 249: 2528-2536Crossref PubMed Scopus (20) Google Scholar, 34Barrett AJ Kendra JR Lucas CF Joss DV Joshi R Pendharkar P Hugh-Jones K Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients.Br Med J. 1982; 285: 162-166Crossref PubMed Scopus (77) Google Scholar, 35Hows JM Palmer S Gordon-Smith EC Use of cyclosporin A in allogeneic bone marrow transplantation for severe aplastic anemia.Transplantation. 1982; 33: 382-386Crossref PubMed Scopus (73) Google Scholar, 36Ramsay NKC Kersey JH Robison LL McGlave PB Woods WG Krivit W Kim TH Goldman Al Nesbit Jr, ME A randomized study of the prevention of acute graft-versus-host disease.N Engl J Med. 1982; 306: 392-397Crossref PubMed Scopus (189) Google Scholar, 37Atkinson K Biggs JC Ting A Concannon AJ Dodds AJ Pun A Cyclosporin A is associated with faster engraftment and less mucositis than methotrexate after allogeneic bone marrow transplantation.Br J Haematol. 1983; 53: 265-270Crossref PubMed Scopus (32) Google Scholar, 38Gratwohl A Speck B Wenk M Forster I Müller M Osterwalder B Nissen C Follath F Cyclosporine in human bone marrow transplantation.Transplantation. 1983; 36: 40-44Crossref PubMed Scopus (46) Google Scholar, 39Kahan BD Cyclosporin A: a selective anti-T cell agent.Clin Haematol. 1982; 11: 743-761PubMed Google Scholar, 40Tutschka PJ Beschorner WE Hess AD Santos GW Cyclosporin-A to prevent graft-versus-host disease: a pilot study in 22 patients receiving allogeneic marrow transplants.Blood. 1983; 61: 318-325PubMed Google Scholar For chronic graft-versus-host disease, the combination of azathioprine and prednisone has been reported to be efficacious,41Sullivan KM Shulman HM Storb R Weiden PL Witherspoon RP McDonald GB Schubert MM Atkinson K Thomas ED Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression.Blood. 1981; 57: 267-276PubMed Google Scholar although some children (approximately 10%) will have prolonged, if not permanent, disability from this complication.32Storb R Prentice RL Sullivan KM Shulman HM Deeg HJ Doney KC Buckner CD Clift RA Witherspoon RP Appelbaum FA Sanders JE Stewart PS Thomas ED Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings.Ann Intern Med. 1983; 98: 461-466Crossref PubMed Scopus (246) Google Scholar, 42Thomas ED Allogeneic bone marrow transplantation for blood cell disorders.Birth Defects. 1982; 18: 361-369PubMed Google Scholar One possible benefit of graft-versus-host disease has been noted in marrow recipients who are at high risk for recurrence of leukemia after transplantation. In these patients, moderate to severe acute graft-versus-host disease has been reported to decrease the frequency of relapse of leukemia and to improve overall survival compared with that in marrow recipients who have negligible to mild manifestations of acute graft-versus-host disease.43Weiden PL Flournoy N Thomas ED Prentice R Fefer A Buckner CD Storb R Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts.N Engl J Med. 1979; 300: 1068-1073Crossref PubMed Scopus (1200) Google Scholar, 44Weiden PL Flournoy N Sanders JE Sullivan KM Thomas ED Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation.Transplant Proc. 1981; 13: 248-251PubMed Google Scholar It may be speculated that the new donor cells have the potential to recognize and destroy remaining “foreign” host malignant cells after engraftment. An alternative explanation may be related to the immunosuppressive chemotherapy needed to treat graft-versus-host disease, which is similar to conventional therapy for acute leukemia.45Woods WG Nesbit ME Ramsay NKC Krivit W Kim TH Goldman A McGlave PB Kersey JH Intensive therapy followed by bone marrow transplantation for patients with acute lymphocytic leukemia in second or subsequent remission: determination of prognostic factors (a report from the University of Minne-sota bone marrow transplantation team).Blood. 1983; 61: 1182-1189PubMed Google Scholar What is the lowest mortality rate that can be expected in the usual situation of bone marrow transplantation between histocompatible siblings? The long-term survival rate for pediatric patients who undergo transplantation for aplastic anemia has reached 80% in some series.46Storb R Thomas ED Buckner CD Clift RA Deeg HJ Fefer A Goodell BW Sale GE Sanders JE Singer J Stewart P Weiden PL Marrow transplantation in thirty “untransfused” patients with severe aplastic anemia.Ann Intern Med. 1980; 92: 30-36Crossref PubMed Scopus (172) Google Scholar, 47Feig SA Champlin R Arenson E Yale C Ho W Tesler A Gale RP Improved survival following bone marrow transplantation for aplastic anaemia.Br J Haematol. 1983; 54: 509-517Crossref PubMed Google Scholar In comparison with adults, children generally have had a more favorable result, in part because of fewer problems with graft-versus-host disease.36Ramsay NKC Kersey JH Robison LL McGlave PB Woods WG Krivit W Kim TH Goldman Al Nesbit Jr, ME A randomized study of the prevention of acute graft-versus-host disease.N Engl J Med. 1982; 306: 392-397Crossref PubMed Scopus (189) Google Scholar, 48Storb R Prentice RL Buckner CD Clift RA Appelbaum F Deeg J Doney K Hansen JA Mason M Sanders JE Singer J Sullivan KM Witherspoon RP Thomas ED Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings.N Engl J Med. 1983; 308: 302-307Crossref PubMed Scopus (340) Google Scholar, 49Thomas ED Clift RA Buckner CD Marrow transplantation for patients with acute nonlymphoblastic leukemia who achieve a first remission.Cancer Treat Rep. 1982; 66: 1463-1466PubMed Google Scholar The survival rate for patients with cancer is integrally dependent on the elimination of malignant cells by previous therapy and the sensitivity of any remaining tumor foci to the ablative regimen used immediately before transplantation. Overall, on the basis of experience with aplastic anemia and non-end-stage leukemia, a minimum of one in five to one in three marrow recipients may be expected to succumb within 100 days after marrow infusion, as a result of opportunistic infections, graft-versus-host disease, graft rejection, idiopathic pneumonitis, recurrent malignancy, or a combination of these factors.42Thomas ED Allogeneic bone marrow transplantation for blood cell disorders.Birth Defects. 1982; 18: 361-369PubMed Google Scholar, 50Hoagland HC Letendre L Moore SB Smithson WA Steinmuller D Bone marrow transplantation in clinical hematology (editorial).Mayo Clin Proc. 1982; 57: 668-669PubMed Google Scholar It should be noted that cumulative survival continues to decline after dismissal from the transplantation center, especially in those cases involving transplantation because of a malignant process. Long-term survival statistics associated with individual disease entities will be discussed in later sections of this article. Because most candidates for transplantation do not have an HLA-compatible sibling donor, trials that have used variably HLA-mismatched donor-recipient combinations, including selected parents, have been reported recently. Preliminary results for patients with leukemia do not reveal any statistical difference in morbidity and mortality between selected partially incompatible marrow transplants and those involving HLA-genotypically identical siblings (see subsequent material under the heading “Use of Marrow Donors Other Than HLA-Genotypically Identical Siblings for Acute and Chronic Leukemias”).33Zwaan FE Hermans J Report of the E.B.M.