Bone Marrow Transplantation for Diseases of Childhood

Subject Review Bone Marrow Transplantation for Diseases of Childhood RICHARD P. KADOTA, M . D . , Resident in Pediatric Hematology and Oncology*; WILLIAM A. SMITHSON, M . D . , Department of Pediatrics

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 transplanta­ tion 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 com­ monly 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 inher­ ited storage diseases, hereditary anemias, severe infantile osteopetrosis, and selected cases of lymphomas and other solid malignant lesions (Table 1). 1 , 2 Several excel­ lent published reviews have detailed the problems of patients and the methods of management at the trans­ plantation center. 3 " 5 The aim of this article is to summa­ rize the current literature for the practitioner who has the responsibility of caring for children in whom a bone marrow transplant is a consideration. PATIENT A N D FAMILY ASPECTS Preparation of the Transplant Recipient.—At our institu­ tion, 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 che­ motherapy, with or without total-body or total-lymphoid irradiation. *Mayo Graduate School of Medicine, Rochester, Minnesota. Address reprint requests to Dr. W. A. Smithson. Mayo Clin Proc 59:171-184, 1984

Marrow Donor Considerations.—The bone marrow donor is usually hospitalized 1 day before the transplan­ tation 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. Mar­ row 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 normaliza­ tion 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. 3 Addi­ tional nonautologous blood given to the donor before or during the marrow harvest should be irradiated. No donor fatalities have been reported. 2 Course of Care at the Transplantation Center.—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 be­ fore engraftment. Many centers also maintain patients in special isolation units until the leukocyte count demon­ strates moderate regeneration. After hospital dismissal, transplant recipients are reexamined frequently until 100 days after the procedure (the period of greatest risk for 171

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BONE MARROW TRANSPLANTATION IN CHILDREN

Table 1.—Spectrum of Diseases for Which Bone Marrow Transplantation Has Been Performed Successfully in Children

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experimental indications or use of creative new proce­ dures may not be reimbursed at all. Exhaustion of liquid assets and loss of income while staying with their child Aplastic anemia compound the strain for parents. Acute and chronic leukemias Most patients and families have viewed the transplant Immunodeficiency disorders Examples: severe combined immune deficiency and Wiskott-Aldrich procedure as a potential means of returning to com­ pletely normal health. The stress of the situation may be syndrome Inherited storage diseases increased by the impression that bone marrow transplan­ Example: mucopolysaccharidoses tation offers the only hope for continued survival. The Hereditary anemias novelty of this form of treatment, its apparent simplicity to Examples: Fanconi's anemia and thalassemia major the lay observer, the extensive media coverage, and the Infantile malignant osteopetrosis opportunity to discontinue chemotherapy add to the Nonleukemic malignant lesions Examples: selected cases of lymphomas and solid tumors 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 transplan­ complications) or until clinical stability has been estab­ tation for acute lymphoblastic leukemia in second or lished. Usually, immunosuppressive medication is con­ greater remission. tinued throughout this period. Psychosocial Issues.—Bone marrow transplantation GENERAL INFORMATION FOR THE PHYSICIAN involves a myriad of new stresses, even for the family Donor-Recipient Compatibility.—One of the most im­ already accustomed to dealing with the difficulties asso­ portant factors that relate to the success of a bone marrow ciated with chronic disease. 6,7 If the sibling donor is a transplantation is the degree of immunologic compati­ minor, the use of a child advocate or other legal pro­ bility between donor and recipient. Currently, such ceedings may be necessary to ensure the rights of the compatibility is assessed by human lymphocyte antigen donor because of natural parental ambivalence between (HLA) typing at several loci. HLA antigens are thought to potentially saving an ill child and potentially harming a be under the genetic control of the major histocompatihealthy one. 7 , 8 Many patients with their families must bility complex on the short arm of chromosome 6. Loci travel to an unfamiliar, distant metropolitan center for the HLA-A, HLA-B, HLA-C, and HLA-DR are defined seroprocedure and remain there for a minimum of 100 days logically, whereas HLA-D typing is performed by a one­ 11 after the transplantation procedure. The patient, parents, way mixed lymphocyte culture technique. Other im­ donor, and other siblings all require continuous support portant, poorly characterized, histocompatibility anti­ from the transplantation team as well as support from gens exist, however, as evidenced by the frequent friends and relatives. In addition to the donation of the development of graft-versus-host disease despite HLA bone marrow by one family member, other adult rela­ matching and routine use of immunosuppression after tives and friends may be requested to donate platelets or transplantation. Most successful bone marrow transplantation proce­ granulocytes, a procedure that involves sitting at an apheresis machine for several hours. It has been ex­ dures are performed between histocompatible siblings (at tremely gratifying to see hometowns of several of our least HLA-A, HLA-B, and HLA-D identical), an occur­ patients voluntarily rally around such families to provide rence with a probability of at least one in four for children 12,13 The likelihood of a support in terms of money, time, transportation, and having the same biologic parents. complete HLA match in other relatives, including par­ blood products. ents, is much less. The possibility of finding donor com­ The estimated cost of a typical bone marrow transplan­ patibility in an unrelated person is remote. Recently, tation in the United States is currently in excess of blood banks at several transplantation centers have be­ $50,000, and it can be higher if major complications 9 gun to collect HLA typings in an attempt to facilitate such ensue. Health insurance will usually cover most of the a search. cost, yet potentially many families must assume the Major donor-recipient ABO incompatibility has been responsibility of paying thousands of dollars themselves. Daily living expenses away from home are not covered managed by several techniques, and the complications by third-party payers and represent a large out-of-pocket have been minimal. Successful methods have included expense for most families. 10 Marrow transplantations for recipient plasma exchange, in vivo antibody adsorption,

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and in vitro erythrocyte depletion from the donor marrow inoculum. 1 4 " 1 8 Differences in other blood antigen sys­ tems 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. 19 Young donor age and the use of male donors have been associated with better results in some series of patients with aplastic anemia, 20 " 22 but the opposite trend (favoring female donors) was noted in a recent report from Seattle.23 None of the variables mentioned in this paragraph should alter decisions about transplantation, unless the circumstance of more than one HLA-identical sibling prevails. Pretransplantation Blood Transfusions.—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, 2 4 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. 24 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. 24 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").

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ease commonly occurs after bone marrow transplanta­ tion because a portion of the transplanted organ—that is, immunocompetent lymphocytes—may circulate throughout the body, recognize differences between do­ nor and host cell antigens, and damage target tissues. As reviewed recently by Wick and associates,28 acute graftversus-host disease occurs within 100 days after trans­ plantation and primarily involves the skin, bowel, liver, and lymphohematologic system. Chronic graft-versushost 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 syn­ drome) plus disordered immunity and an increased risk for infections. 28 " 30 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. 20,30 " 33 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. 9 , 3 4 " 4 0 For chronic graft-versus-host disease, the combination of azathioprine and prednisone has been reported to be efficacious, 41 although some children (approximately 10%) will have prolonged, if not perma­ nent, disability from this complication. 3 2 , 4 2

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 dis­ ease has been reported to decrease the frequency of relapse of leukemia and to improve overall survival com­ pared with that in marrow recipients who have negligible to mild manifestations of acute graft-versus-host dis­ ease. 43,44 It may be speculated that the new donor cells have the potential to recognize and destroy remaining "foreign" host malignant cells after engraftment. An al­ ternative explanation may be related to the immunosupFor the patient with leukemia, marrow rejection has not been a major problem; an incidence of 1 % has been pressive chemotherapy needed to treat graft-versus-host r e p o r t e d in t w o large s t u d i e s . 2 5 , 2 6 T h u s , p r e ­ disease, which is similar to conventional therapy for 45 transplantation transfusions need not be restricted. A acute leukemia. more immediate threat to these children is graft-versusFactors Influencing Survival.—What is the lowest host disease that is caused by viable lymphocytes in mortality rate that can be expected in the usual situation transfused blood products. 2 7 , 2 8 For this reason, many of bone marrow transplantation between histocompatmedical centers are irradiating all blood products in­ ible siblings? The long-term survival rate for pediatric tended for transfusion into patients w i t h leukemia, patients who undergo transplantation for aplastic anemia whether transplantation is contemplated or not. Simi­ has reached 80% in some series. 46,47 In comparison with larly, neonates and older pediatric patients with other adults, children generally have had a more favorable malignant lesions or severe primary immunodeficiency result, in part because of fewer problems with graftmay benefit from irradiation of blood products. 27,28 versus-host disease. 36,48,49 The survival rate for patients Craft-Versus-Host Disease.—Graft-versus-host dis­ with cancer is integrally dependent on the elimination of

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BONE MARROW TRANSPLANTATION IN CHILDREN

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 opportunis­ tic infections, graft-versus-host disease, graft rejection, idiopathic pneumonitis, recurrent malignancy, or a combination of these factors. 4 2 , 5 0 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 pro­ cess. Long-term survival statistics associated with indi­ vidual disease entities will be discussed in later sections of this article. Lack of a Compatible Marrow Donor.—Because most candidates for transplantation do not have an HLA-compatible sibling donor, trials that have used variably HLAmismatched donor-recipient combinations, including se­ lected 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 Sib­ lings for Acute and Chronic Leukemias"). 33,51,52 Addi­ tionally, some transplantation centers have attempted to minimize the potential for graft-versus-host disease in partially mismatched situations by removing donor Tlymphocytes with monoclonal antibodies or by using agglutination and adsorption techniques before marrow infusion. 53,54 Another approach to bone marrow transplantation in a child without a histocompatible sibling has been to use an unrelated person who is, by chance, HLA-phenotypically identical. Recently, such transplants have been performed successfully in several patients with aplastic anemia. 5 5 , 5 6 Programs based on computer files of HLAtyped blood donors are currently being piloted. With refinement of the production of monoclonal anti­ bodies, removal of some types of leukemic lymphoblasts in vitro from marrow samples has become possible. This capability has been used successfully in a few cases for processing autologous marrow; thus, autotransplantation has been possible, and the need for a donor and the risk of graft-versus-host disease have been e l i m i ­ nated. 5 7 , 5 8 These exciting new methods of marrow ma­ nipulation hold considerable promise for the future but currently are experimental and not universally applicable (Table 2).

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Table 2.—Potential Approaches to Bone Marrow Transplantation When an HLA-Genotypically Identical Sibling Is Not Available Perform transplantation with use of a partially mismatched related marrow donor, with or without selective removal of donor Tlymphocytes Perform transplantation with use of HLA-phenotypically identical mar­ row from an unrelated volunteer blood bank donor Purge autologous marrow of malignant cells with monoclonal anti­ bodies and thus eliminate the need for a donor and the risk of graft-versus-host disease

RESULTS OF BONE MARROW TRANSPLANTATION Severe Combined Immune Deficiency.—Bone marrow transplantation for immune deficiency disorders has been performed since the late 1960s, when the first successful trials were reported. 5 9 , 6 0 The most experience has been accumulated with severe combined immune deficiency, a lethal condition that is characterized by impaired cellular and humoral immunity. Patients di­ agnosed as having severe combined immune deficiency are actually a heterogeneous group, as evidenced by differences in inheritance patterns and residual Immu­ nologie function. 5 As reviewed previously (Table 3), marrow transplanta­ tion with use of an HLA-compatible sibling has produced sustained engraftment in most children with various types of severe combined immune deficiency. 1 , 5 , 6 ' Pretransplantation conditioning has not been necessary to attain only lymphoid reconstitution. 1 , 5 , 6 2 When necessary, multiple transplantation attempts have been performed in individual patients. In the subgroup of patients who have severe combined immune deficiency with deficient adenosine deaminase activity and no histocompatible marrow donor, results of transplantation should be com­ pared with those of intermittent transfusions of irradiated red blood cells, which have improved immune function in some children. 6 3 Another interesting subtype of severe combined im­ mune deficiency, reticulardysgenesis, is associated with agranulocytosis. This disorder is thought to be produced by an abnormality that affects a population of pluripotential stem cells that give rise to lymphocyte precursors and other blood cells, including granulocytes. Successful hematopoietic and lymphoid reconstitution after allogeneic bone marrow transplantation has been reported. 64 Infection has been a major complication of marrow transplantation in patients with severe combined im­ mune deficiency. 61 Most children have acquired signifi­ cant pathogens early in life which are present at the time of transplantation. Usually such infections play a promi­ nent role in posttransplantation mortality. 61 Thus, mar-

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BONE MARROW TRANSPLANTATION IN CHILDREN

Table 3.—Results of Transplantation of Fetal Tissue or Bone Marrow for Severe Combined Immune Deficiency Success rate Tissue Bone marrow from a sibling Bone marrow from a relative Bone marrow from a relative Bone marrow from an unrelated donor Fetal liver with or without fetal thymus Fetal thymus or cultured thymic fragments

Donor-recipient · Bortin and 61 HLA compatibilities Rimm* A, B, and D

Vossen and Doorent5

10 of 16

32 of 44

D with or without A, B, or both A, B, or both

4 of 12

9 of 15

1 of 18

Oof 3

A and B or D or A, B, and D

Oof 2

1 of 5

2 of 10

3 of 52

4 of 11

1 of 28

•Still alive after 6 months with some immune reconstitution. f'Sustained reconstitution." Note: Some degree of patient overlap exists between these two reviews.

row transplantation should be performed as soon as possible, preferably early in the first year of life. In the patient without a histocompatible donor, other tissues have been transplanted in an effort to restore immunity. Use of fetal liver, thymus, and cultured thymic fragments has been attempted; the success rates have been variable and generally less favorable than the suc­ cess of HLA-matched marrow transplantations (Table 3). 5 , 6 1 Likewise, marrow grafting between HLA-mismatched donor-recipient combinations has produced suboptimal results. 5,61 One possible exception has been reported recently in which five of six haploidentical marrow transplantations were successfully performed for severe combined immune deficiency after T-lymphocyte depletion by selective agglutination and adsorption. 54 Of interest, antibody formation was apparently induced from host B cells in cooperation with donor T cells. Similar T-and B-cell chimerism has been noted previous­ ly in bone marrow and other tissue transplants for severe combined immune deficiency. 5,65 Wiskott-Aldrich Syndrome and Other Immunodeficiencies.—The classic Wiskott-Aldrich syndrome is an X-linked recessive condition that is characterized by thrombocytopenia, eczema, and variable cellular and humoral immune deficits. 66 Conventionally treated chil­ dren have usually succumbed during childhood or young adulthood as a result of infection, hemorrhage, or a lymphoreticular malignant lesion, although an occa­ sional forme fruste variant has been noted. 6 7 In a few cases, treatment with transfer factor or thymic hormones

175

has been associated with clinical improvement. 68,69 Cur­ rent survival projections with optimal supportive care must be tempered by reports of development of malig­ nant lesions in 12 to 30% of patients. 70,71 At three centers, bone marrow transplantation from an HLA-matched sibling donor has been successfully per­ formed in six c h i l d r e n w i t h W i s k o t t - A l d r i c h syn­ drome. 72 " 74 Substantial improvement in immune compe­ tency, eczema, and thrombocytopenia was noted after the procedure. Other immunodeficiencies for which a successful marrow transplantation has been performed include cases of Chediak-Higashi syndrome, infantile agranulocytosis (Kostmann's syndrome), and the recently described phagocytic cell disorder associated with ab­ sence of a neutrophil membrane glycoprotein. 75 " 77 Two attempts at marrow transplantation for chronic granulomatous disease have not resulted in long-term success, because of displacement of a suboptimal graft in one patient and severe graft-versus-host disease in the other. 78,79 Additionally, antibodies against "leukocyte oxidase" may be present in patients with chronic granulomatous disease who have received previous transfu­ sions; thus, the effectiveness of transplanted normal white blood cells can potentially be decreased. 1 In con­ trast to severe combined immune deficiency, all of the conditions mentioned in this section have been treated with a pretransplantation regimen to immunosuppress and ablate the host bone marrow. Inherited Storage Diseases.—Inherited storage dis­ eases progressively involve multiple tissues and result in early mortality for severely affected children. For the mucopolysaccharidoses, enzyme replacement by means of plasma infusions, leukocyte transfusions, and skin or cultured fibroblast transplants has been variably success­ ful. 8 0 Optimal intracellular delivery of these missing macromolecules may necessitate association with targetspecific recognition markers to promote efficient uptake by means of exacting receptor mediation. 81 Bone marrow transplantation can provide a continu­ ous supply of circulating granulocytes and tissue-pene­ trating monocytes that may spill their intracellular con­ tents, including a missing enzyme. 1 Successful proce­ dures have been reported for Hurler's syndrome, 82,83 Sanfilippo type B syndrome, 8 4 Maroteaux-Lamy syn­ drome, 85 Morquio's syndrome, 86 and type 3 neuronopathic subacute Gaucher's disease. 87 Within 1 to 6 months, favorable biochemical and clinical changes have been noted, including resolution of hepatosplenomegaly, increased joint mobility, improved pulmonary function, corneal clearing, and a reduction of marrow storage cells (for example, Gaucher's cells). Stabilization of intellectual status has been claimed after transplanta-

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engraftment. Four of seven children 6 years of age or younger had functioning grafts. The decision to perform a marrow transplantation for thalassemia must be con­ sidered carefully for each case and weighed against the morbidity and mortality that may be expected from re­ cent supertransfusion-deferoxamine programs. 99,100 Infantile Malignant Osteopetrosis.—Infantile malig­ nant osteopetrosis is a lethal autosomal-recessive dis­ order that is characterized by impaired osteoclastic bone resorption in conjunction with a normal rate of osteoblastic bone formation. This imbalance leads to excessive accumulation of osteoid that encroaches on the normal hematopoietic marrow spaces, the foramina of cranial nerves, and the cranial cavity itself. 101 The result is a leukoerythroblastic anemia and progressive hepatosplenomegaly plus hydrocephalus and cranial nerve def­ icits, including loss of vision and hearing. Bone marrow transplantation is the only available therapeutic modality that has halted the progressive morbidity and prevented early mortality in patients with severe infantile osteope­ trosis. Current opinion suggests that osteoclasts are de­ Involved investigators have reported that there has rived from pluripotential hematopoietic stem cells that been no difficulty with engraftment despite multiple pre-' first become circulating monocytes, then become tissue to bone to fuse and form vious transfusions but that the posttransplantation course macrophages, and finally return 102 multinucleated osteoclasts. has been more complicated than usual because of a high frequency of hemorrhagic cystitis and mucositis. 92 These The five most recently described children from three complications have been attributed to increased tissue transplantation centers have been successfully engrafted sensitivity of affected patients to cyclophosphamide and with HLA-matched sibling marrow in four cases and an irradiation due to a defect in DNA repair capability. HLA-B locus mismatch in one case. 103 " 105 Osteopetrosis Recently, the conditioning regimen has been modified by recurred 13 months later in one patient in whom en­ using an in vivo radiosensitivity test before transplan­ graftment of donor hematopoietic elements was not tation. Four consecutively examined children have sub­ achieved. The other four children have demonstrated sequently undergone successful transplantation proce­ pronounced clinical and radiologic improvement after 4, dures and have had less morbidity. 9 6 One note of caution 8,16, and 28 months of follow-up. Hematologic normal­ in selecting a sibling donor for marrow transplantation is ization and regression of hepatosplenomegaly have been that Fanconi's anemia may not be fully manifested until noted within the first 6 months and have been followed late childhood. Therefore, potential donors must be care­ by internal and external bone remodeling in ensuing fully screened by a thorough physical examination and months. Early engraftment may occur, in part, in extralaboratory evaluation, including an assessment of chro­ medullary tissues because the hematopoietic marrow mosomal stability. 91 space remains limited for an extended period after trans­ Thalassemia.—The first report of a successful bone plantation. Neurologic stabilization or improvement (in­ marrow transplantation for thalassemia major was pub­ cluding vision and hearing), which has been noted, probably depends on the degree of injury before trans­ lished in 1982. 9 7 A 16-month-old boy who previously had received 250 ml of packed red blood cells had plantation. This result highlights the problem that some infants may be born blind or have other deficits even at reconstitution of a normal marrow after transplantation birth. Perhaps when an affected fetus can be recognized from an HLA-identical sibling. Further trials have been in utero by radiologic examination, induction of delivery reported on a preliminary basis from Italy, where 14 at 36 to 38 weeks of gestation could be followed rapidly children have undergone marrow transplantation with 98 by parental or sibling marrow transplantation to mini­ use of several different conditioning regimens. After mize irreversible morbidity. 1 The results of bone marrow short follow-up periods ranging from 20 to 175 days, none of the seven patients older than 6 years of age transplantation for hereditary disorders are summarized in Table 4. (presumably with advanced disease) has had a successful tion, but no definite improvement has been observed. The potential to reverse brain damage has been suggested by murine studies in which some microglial and a few pluripotential stem cells seemed to be of hematopoietic origin. 8 8 " 9 0 Crossing an intact blood-brain barrier, how­ ever, may not be possible by the time marrow transplan­ tation is performed. Fanconi's Anemia.—Fanconi's anemia is an autosomal-recessive disorder that is associated with a defect in DNA repair and multiple congenital anomalies. A l ­ though modern supportive care may improve survival, the prognosis for affected children is poor. 91 As recently reviewed by Deeg and colleagues, 92 the results of mar­ row transplantation have been moderately successful. In their experience, four of eight HLA-matched sibling transplant patients became long-term survivors (followup of 647 to 3,435 days), a finding not statistically different from the results of marrow transplantations for other types of aplastic anemia. Earlier experience from other transplantation centers revealed 3 additional longterm successes in 12 attempts. 93 " 95

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Table 4.—Results of Bone Marrow Transplantation for Hereditary Disorders in Which There Is Successful But Limited Experience

Disease

No. of successful procedures

Wiskott-Aldrich syndrome72"74

6

Immunodeficiencies in­ volving granulocytes75-77

3

Storage diseases82"87

7

Fanconi's anemia92'96

11

Thalassemia major97·98

5

Infantile malignant osteopetrosis'03-'05

4

Comments Substantial improvement in immune com­ petency, eczema, and thrombocytopenia Includes Chediak-Higashi syndrome, infantile agranulocytosis, and immunodeficiency as­ sociated with lack of a neutrophil membrane protein Includes Hurler's syn­ drome, Sanfilippo type B syndrome, Maroteaux-Lamy syndrome, Morquio's syndrome, and Gaucher's disease Also, 13 reported deaths after transplantation92 All successful transplan­ tations in children <7 years old; brief followup period Substantial hematologic and radiologic im­ provement as well as stabilization of neuro­ logic status

Acute Lymphoblastic Leukemia.—Acute lymphoblastic leukemia is the most common malignant process in children. It is currently treated with multiagent chemo­ therapy, usually in association with irradiation, and the result is an overall long-term survival rate of 50 to 60%. 1 0 6 ' 1 0 7 Numerous favorable and unfavorable prog­ nostic factors have been delineated which allow catego­ rization of patients and tailoring of their therapy. 1 0 6 , 1 0 7 Recently, a West German collaborative group reported a better than 70% long-term survival, including high-risk patients, with use of a new, intensive chemotherapeutic regimen. 108 This program and other modifications of treatment are currently being evaluated in a multi-institu­ tional, prospective, randomized manner. Because of the potential curability of childhood acute lymphoblastic leukemia by conventional modalities, bone marrow transplantation is currently not recom­ mended unless primary therapy fails. Experience with transplantation performed during a relapse of acute lym­ phoblastic leukemia has shown less than 20% long-term survival, primarily due to recurrence of leukemia. 2 6 , 1 0 9

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Attempts to intensify the pretransplantation conditioning regimen (that is, to eradicate the remaining malignant cells with higher dose irradiation or additional chemo­ therapeutic agents) have not improved long-term results. 26,109 " 111 Yet, it is notable that this cure rate has been achieved in a group of patients who, otherwise, would not be expected to survive. The child who has a relapse of leukemia shortly after the discontinuation of, or while still receiving, chemo­ therapy has an extremely poor prognosis. Almost all such children will not sustain a second remission. 112 " 114 If reinduction of remission is successful, then marrow transplantation is appropriate for those children with an HLA-compatible sibling donor. A second course of cra­ nial irradiation should be avoided during reinduction if total-body irradiation is intended as part of the pre­ transplantation conditioning regimen. 115 The results of bone marrow transplantation for acute lymphoblastic leukemia in second or greater remission from several institutions are summarized in Table 5 45,116-Π8 Overall, approximately one in three pediatric patients who receive a marrow transplant for acute lym­ phoblastic leukemia in second or greater remission will become a long-term survivor. Relapse of leukemia has been a major problem, including a few unusual cases of recurrence of disease in donor cells after allogeneic engraftment. 119 ' 121 Why do children who undergo transplantation for acute lymphoblastic leukemia fare so poorly? What im­ provements can be made? Apparently, many of the re­ maining malignant cells must not be sensitive to current pretransplantation conditioning regimens. Unfortunate­ ly, the optimal combination of drugs and irradiation has remained elusive. Manipulation of the antileukemic ef­ fects of graft-versus-host disease and prolonged posttransplantation maintenance chemotherapy are being evaluated for additive beneficial effects. 45,111 If the new, intensive, multi-institutional chemotherapy trials fail to achieve anticipated high success rates, then marrow transplantation during a first remission may become reaTable 5.—Rate of Continuous Complete Remission (CCR) After Bone Marrow Transplantation for Acute Lymphoblastic Leukemia in Second or Greater Remission Reference

Patient ages (yr)

Johnson et a l " 6 Barrett et a l " 7 Woods et al 45 Dinsmore et a l * " 8

1-17 1-17 3-26 <20

No. in CCR 9 5 5 9

of of of of

24 11 15 14

Follow-up (mo) 17-55 7-16 24-48 12-34

These patients underwent transplantation during a second remission only. The first three reports included patients in second or greater remission at the time of transplantation.

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BONE MARROW TRANSPLANTATION IN CHILDREN

sonable for selected children with unfavorable prognos­ tic risk factors. A recent survey of 20 adult and pediatric patients who underwent transplantation during a first remission of poor-prognosis acute lymphoblastic leuke­ mia demonstrated a favorable trend but not a statistically significant advantage in survival over transplantation performed during a second remission. 26 Nonetheless, future prospective, randomized trials are necessary be­ fore the efficacy of these procedures can be critically assessed. As mentioned previously, development of monoclonal antibodies to remove leukemic cells also has begun to make autotransplantation a reality. 5 7 , 5 8 Acute Nonlymphoblastic Leukemia.—In comparison with childhood acute lymphoblastic leukemia, acute nonlymphoblastic leukemia has been more difficult to eradicate with conventional treatment programs. As re­ viewed recently, approximately 25% of children have had a continuous remission for at least 2 years, although some studies report rates as high as 5 6 % . 1 2 2 , 1 2 3 The International Bone Marrow Transplant Registry tabulated a 34% 2-year unadjusted actuarial survival in a study of 26 adults and children who underwent transplantation during a second to fourth remission after a relapse of leukemia. 31 Transplantation done during relapse has been used as a salvage procedure in additional patients (0 to 29%), including some patients in whom transplanta­ tion was not accompanied by attempts at reinduction of remission. 3 1 ' 1 0 9 ' 1 2 4 Proper therapy for acute nonlymphoblastic leukemia after achievement of a first remission is the most impor­ tant and controversial issue surrounding this diag­ nosis. 125 As summarized in Table 6, bone marrow trans­ plantation in children has produced impressive rates of continuous complete remission (more than half of the patients may become long-term survivors), in contrast to standard chemotherapeutic programs. 126 " 129 Firm con­ clusions, however, about the role of bone marrow trans­ plantation versus chemotherapy must await completion of ongoing prospective, controlled trials of the Children's Cancer Study Group and other institutional trials.

Table 6.—Rate of Continuous Complete Remission (CCR) After Bone Marrow Transplantation for Acute Nonlymphoblastic Leukemia in First Remission Reference

Patient ages (yr)

Powleset al 126 Sanders et al' 2 7 Kersey et al' 2 8 Forman et al 129

8-17 2-17 6-28 <20

No. in CCR 5 of 10 of 11 of 8 of

7 13 17 10

Follow-up (mo) 10-24 20-53 14-38 6-64

Mayo Clin Proc, March 1984, Vol 59

Chronic Granulocytic Leukemia.—Chronic granulo­ cytic leukemia occurs in two different forms in children. Children at any age (mostly older than 2 years) may manifest the "adult" form of the disease, in which the Philadelphia chromosome is usually present and the terminal event is a blast crisis 2 to 5 years after the initial manifestation, despite suppressive chemotherapy. 130,131 The "juvenile" form of chronic granulocytic leukemia is distinguished by its occurrence in infants and toddlers, prominent lymphadenopathy and skin lesions, increased fetal hemoglobin and other fetal red blood cell character­ istics, monocytosis in the blood and marrow, absence of the Philadelphia chromosome, and poor response to busulfan and other antileukemic agents. 130 The median survival is less than 9 months; thus, the impression is that this disease may be more aptly described as a subacute myelomonocytic leukemia. Many centers have performed marrow transplantation for the "adult" type of chronic granulocytic leukemia because of its eventual lethality. 33,132 " 136 As summarized in Table 7, transplantations done while the patient was still in the chronic phase of leukemia have resulted in continuous complete remission rates of more than 50% after variable durations of follow-up. 1 3 3 " 1 3 5 One institu­ tion has reported a similar survival rate for patients who have undergone transplantation during the accelerated phase of chronic granulocytic leukemia, 136 but this suc­ cess rate has not been universally experienced. 33,137 A recent survey of 13 transplantation centers revealed an actuarial disease-free survival of 35% at 2 years for 50 marrow recipients who had chronic granulocytic leuke­ mia in the accelerated phase. 137 Transplantation during the blast phase of chronic granulocytic leukemia has salvaged less than 20% of patients. 3 3 , 1 3 2 , 1 3 7 In a few patients who have undergone transplantation during a second chronic phase, the survival rate has been better than that for transplantations during the blast phase, but results are preliminary. 137 Further studies are necessary to standardize definitions of disease progression, deter­ mine reliable prognostic indicators, and thereby assess optimal timing for marrow transplantation. Inasmuch as "juvenile" chronic granulocytic leukemia is refractory to currently available chemotherapy, mar­ row transplantation has become the treatment of choice, especially if an HLA-compatible sibling donor is avail­ able. Because of the rarity of this condition, only three successful procedures have been reported thus far. 9,138 After 1 to 5 years of follow-up, all three children are doing well. In contrast to patients with the "adult" form of chronic granulocytic leukemia, those with the "juvenile" form should undergo transplantation with less delay be­ cause of its characteristically short median survival.

Mayo Clin Proc, March 1984, Vol 59

BONE MARROW TRANSPLANTATION IN CHILDREN

179

Table 7.—Rate of Continuous Complete Remission (CCR) After Bone Marrow Transplantation for Chronic Cranulocytic Leukemia (CGL) in Adults and Children

Reference

Phase of CGL at time of transplantation

No. in CCR

Follow-up (mo)

Clift et al' 3 3 Feferetal' 34 Goldman et al 135

Chronic Chronic Chronic

6 of 10 8 of 12 12 of 14

12-36 21-65 3-37

Use of Marrow Donors Other Than HLA-Genotypically Identical Siblings for Acute and Chronic Leukemias.—As mentioned earlier in this review, several cen­ ters have performed marrow transplantations with use of donors other than HLA-genotypically identical siblings. Preliminary analyses involving patients with acute and chronic leukemia (adults and children) have not revealed statistical differences in morbidity and mortality between the matched and partially mismatched groups (136 pa­ tients in three series). 33,51,52 In these reports, methotrexate or cyclosporin was administered after transplanta­ tion, and no attempt was made to remove donor T cells. At one institution, patients younger than 20 years of age fared more favorably (8 of 15 were alive and well at 6 months to 3 years after transplantation) than older pa­ tients. 52 Although there is considerable heterogeneity among patients described in the literature with regard to stage of disease and degree of donor-recipient incompat­ ibility, results are encouraging and further trials seem warranted. Lymphomas and Other Solid Tumors of Children.— Experience with bone marrow transplantation as therapy for lymphomas and other solid tumors in children is limited. Thus, the procedure must be considered experi­ mental. One report has described 10 patients (4 to 29 years of age) who underwent allogeneic marrow trans­ plantation for disseminated Burkitt's or poor-prognosis T-cell lymphoblastic lymphoma. 1 3 9 Five had survived with unmaintained remissions after 18 to 73 months of follow-up (Table 8). Autologous marrow rescue (that is, autologous bone marrow transplantation) has been used for patients with

solid tumors when myelosuppression has been the limit­ ing toxic side effect of antineoplastic therapy. The theo­ retical and practical considerations of such a maneuver have been reviewed. 1 4 5 , 1 4 6 The maximal tolerated dose of some drugs may be increased up to 10 times the usual levels by this procedure. It has been postulated that the best time for autotransplantation is after completion of therapy for induction of remission. Multiple autologous marrow transplantation procedures are possible if the cumulative toxicity of the therapeutic regimens is not limiting. Bone marrow transplantation has been used success­ fully in small numbers of patients with advanced neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, and retinoblastoma (Table 8). 1 4 0 " 1 4 4 , 1 4 7 Of note is the use of high-dose melphalan plus marrow infusion (either autol­ ogous or allogeneic) for disseminated neuroblastoma, which almost always has been resistant to conventional treatment. 1 4 1 , 1 4 2 , 1 4 7 Further pilot studies are under way. Aplastic Anemia.—Bone marrow transplantation in­ volving HLA-identical siblings has been used success­ fully as treatment of aplastic anemia, of either primary (idiopathic) or secondary origin. Patients who have not received transfusions have had the most favorable re­ sults, 46 although recently, children who had received pretransplantation transfusions did well with modifica­ tions of the conditioning regimen (for example, addition of donor buffy coat cells, total-lymphoid irradiation, or low-dose total-body irradiation). 2 3 , 4 7 , 1 4 8 As noted in Table 9, survival, usually with full hematologic reconstitution after transplantation, has ranged from 44 to ß4
20,23,46,47,148

Table 8.—Results of Bone Marrow Transplantation for the Treatment of Malignant Processes Other Than Leukemia Type of malignant process Non-Hodgkin's lymphoraa' Neuroblastoma' 40 ' 43 Ewing's sarcoma144 Rhabdomyosarcoma140 Retinoblastoma'40

39

•Continuous complete remission.

Patient ages (yr)

No. in CCR*

Follow-up (mo)

4-29 2-22 15-20 3-14 3, 4

5 of 10 15 of 38 2 of 3 2 of 4 1 of 2

18-73 1-41 12 and 13 3 and 6 2

180

BONE MARROW TRANSPLANTATION IN CHILDREN

Table 9.—Results of Bone Marrow Transplantation for Aplastic Anemia Reference

Patient ages (yr)

Survival (no. of patients)

Follow-up (mo)

Starb et al 46 Bortin et al* 20 Starb et al 23 Feig et al 47 Ramsay et al' 4 8

1-17 <20 1-17 <25 1-40

16 of 19 44 of 100 11 of 16 27 of 34 29 of 40

9-84 >12 26-62 14-58 1-59

*A survey of 22 different transplantation centers. For children without an HLA-identical sibling donor, treatment has consisted of androgens, corticosteroids, an anti lymphocyte globulin, or some combination of these agents. Antilymphocyte globulins or antithymocyte glob­ ulins have shown promise; survival rates have been equivalent to those for marrow transplantation in some studies. 149 " 154 In many patients, however, the hematologic indices do not return to normal with use of globulin preparations, and supportive care is necessary for months to years. 1 5 3 · 1 5 5 ' 1 5 6 Bone marrow transplantation performed in situations in which an HLA-genotypically identical sibling has not been available has resulted in a very high failure rate (more than 80%) for patients with aplastic anemia. 1 3 , 5 6 Recently, several favorable exceptions have been re­ ported w i t h use of h i s t o c o m p a t i b l e unrelated d o ­ nors. 5 5 , 5 6 One 3-year-old child received marrow that was phenotypically identical at the HLA-A, B, C, D, and DR loci, plus compatible at several other new determi­ nants—MB, MT, and SB. 56 Before definitive recommen­ dations can be made, further experience is necessary with this situation and comparisons must be made with long-term results achieved in children treated w i t h antilymphocyte globulins or antithymocyte globulins.

Mayo Clin Proc, March 1984, Vol 59

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