Pediatric Annals

Bone Marrow Transplantation for Pediatric Leukemia

Jean E Sanders, MD

Abstract

Studies during the 1950s using rodent models led to the recognition that living bone marrow cells could be transplanted from one animal to another.1 After another decade of research, the principles of transplantation biology, human tissue typing, and supportive care of the patient without marrow function were sufficiently developed for marrow grafting to become a realistic therapeutic modality. The modern era of clinical bone marrow transplantation began in the late 1960s when a few patients with advanced leukemia, severe combined immunodeficiency disease, and Wiskott-Aldrich syndrome successfully received marrow grafts from HL A- identical siblings. Marrow transplantation has now become an established treatment modality for a number of pediatrie immunologic, hematologic, and oncologie diseases (Table 1). This article reviews the current status of bone marrow transplantation for children with hematologic malignancies who receive marrow from HLA-identical sibling donors or who receive autologous marrow.

DONOR SELECTION

In order to receive a bone marrow transplant, a source of the marrow to restore normal hematopoiesis following the preparative regimen must be deter' mined before the transplant procedure can occur. The marrow donor may be the patient (autologous transplant), an identical twin (syngenic transplant) or a histocompatible donoi; most frequently a sibling (allogeneic transplant). To determine if a matched sibling donor is available, human lymphocyte antigen (HLA) typing of the patient, all siblings, and parents must be performed. The HLA complex is composed of a series of genetic loci on the short arm of chromosome 6. This set of genes is usually inherited as one group or haplotype. Every individual inherits one haplotype from each parent. Siblings who inherit the same haplotype from each parent are matched for the HLA region and constitute the usual donor-recipient pair for an allogeneic graft. An identical twin represents a special situation where donor and recipient are matched for all genetic loci. Within a family, there is a 25% likelihood for each sibling to be HLA-identical to the patient.

Table

Dental Abnormalities. Irradiation given to growing bones results in injuries that influence subsequent bone growth. Children given 10 Gy/TBI in the transplant-preparative regimen have developed disturbances in tooth development and facial growth. All children under the age of 6 at the time of TBI had arrested root development, premature apical closure, enamel hypoplasia, and microdontia. Those over the age of 7 usually had only arrested root development.

Central Nervous System Abnormalities. Children surviving long-term after treatment for acute leukemia have been observed to have neuropsychological deficits, especially if cranial irradiation was used in therapy. Children under the age of 8 at the time of irradiation had lower IQ scores and performed less well with visual motor; fine motor, abstract thinking, and spatial processing tasks than patients who had not received irradiation. Preliminary results from a prospective study performed at the Fred Hutchinson Cancer Research Center suggest that with increasing time after irradiation, there is a decrease in overall IQ score with performance IQ being the most significantly affected.

Secondary Malignancies. Trie development of secondary malignancies after cure of a primary malignancy has been observed in both nontransplant and marrow transplant patients. A recent analysis of more than 2000 marrow transplant recipients has demonstrated that 35 developed secondary malignancies between 6 months and 10 years after transplant. Major risk factors identified were GVHD immunosuppressive therapy and TBI.27

SUMMARY

The ability to deliver high-dose chemotherapy with or without radiotherapy followed by marrow rescue has made marrow transplantation die treatment of choice for children with AML in first remission, juvenile CML, and adult-type CML in chronic phase. For patients with ALL or NHL who relapse, transplantation in second remission represents a reasonable…

Studies during the 1950s using rodent models led to the recognition that living bone marrow cells could be transplanted from one animal to another.1 After another decade of research, the principles of transplantation biology, human tissue typing, and supportive care of the patient without marrow function were sufficiently developed for marrow grafting to become a realistic therapeutic modality. The modern era of clinical bone marrow transplantation began in the late 1960s when a few patients with advanced leukemia, severe combined immunodeficiency disease, and Wiskott-Aldrich syndrome successfully received marrow grafts from HL A- identical siblings. Marrow transplantation has now become an established treatment modality for a number of pediatrie immunologic, hematologic, and oncologie diseases (Table 1). This article reviews the current status of bone marrow transplantation for children with hematologic malignancies who receive marrow from HLA-identical sibling donors or who receive autologous marrow.

DONOR SELECTION

In order to receive a bone marrow transplant, a source of the marrow to restore normal hematopoiesis following the preparative regimen must be deter' mined before the transplant procedure can occur. The marrow donor may be the patient (autologous transplant), an identical twin (syngenic transplant) or a histocompatible donoi; most frequently a sibling (allogeneic transplant). To determine if a matched sibling donor is available, human lymphocyte antigen (HLA) typing of the patient, all siblings, and parents must be performed. The HLA complex is composed of a series of genetic loci on the short arm of chromosome 6. This set of genes is usually inherited as one group or haplotype. Every individual inherits one haplotype from each parent. Siblings who inherit the same haplotype from each parent are matched for the HLA region and constitute the usual donor-recipient pair for an allogeneic graft. An identical twin represents a special situation where donor and recipient are matched for all genetic loci. Within a family, there is a 25% likelihood for each sibling to be HLA-identical to the patient.

Table

TABLE 1Diseases Treated With Marrow Transplantation

TABLE 1

Diseases Treated With Marrow Transplantation

To collect the marrow, the donor is taken to the operating room where, under sterile conditions and anesthesia, multiple bone marrow aspirations from the iliac crests are performed. As the marrow is obtained, it is mixed with heparin and tissue culture medium, filtered, and transferred to a transfusion bag. The volume of marrow aspirated is between 10 mL/kg to 20 mL/kg of donor or recipient weight depending on who is smaller. Children as young as 4 months of age have successfully and safely donated marrow for either themselves or older siblings.2 Every effort is made not to administer a red cell transfusion to donors too young to have an autologous unit of blood collected before the procedure. The marrow cell dose usually ranges from 2 to 5 × 108 nucleated cells/kg of recipient weight. ABO incompatibility (major or minor) between donor and recipient is not a contraindication for transplant since this may be overcome by the removal of RBC or plasma from the donor marrow or the removal of recipient antibodies through plasma exchange. The collected marrow is either administered intravenously to the patient immediately or cryopreserved for future use.

PREPARATIVE REGIMEN

Patients who are to receive a marrow transplant for malignancy must be prepared or conditioned for the transplant with high-dose chemotherapy or chemoradiotherapy. The basic regimen includes cyclophosphamide combined with either busulfan or total body irradiation (TBI). The purpose of this treatment is to eliminate residual malignant cells and to provide adequate immunosuppression to permit acceptance of the new marrow graft by the patient. The doses of chemotherapy or chemoradiotherapy administered are intentionally marrow ablative or lethal to future production of normal hematopoietic cells. Thus, these high doses may not be administered without the ability to restore the patient's normal hematopoietic function with the transplant. Following completion of the 7- to 10-day preparative regimen, the donor bone marrow is infused intravenously.

During the next 2 to 4 weeks, until the infused marrow produces sufficient hematopoietic cells, these patients must receive intensive supportive care with frequent erythrocyte and platelet transfusions as well as broad-spectrum antibiotics for infection prophylaxis and treatment. Because of their profound immunosuppression, patients are also at risk for developing opportunistic viral infections. Studies have demonstrated that acyclovir presents reactivation of herpes simplex virus and may be helpful in preventing reactivation of cytomegalovirus (CMV).3

GRAFT-VERSUS-HOST DISEASE

Patients given allogeneic marrow are at risk for developing graft-versus-host disease (GVHD), which is mediated by immunocompetent T-lymphocytes from the marrow graft. These lymphocytes are capable of inducing injury to skin, liver, and gastrointestinal tissue in the host.1 Because injury to these target organs may be substantial or even fatal, major efforts have been directed at preventing GVHD. Graft-versushost disease prophylaxis has been either ex vivo, involving the removal of T-lymphocytes from donor marrow, or in vivo with administration of agents such as methotrexate, cyclosporine, and steroids early posttransplant.4 Treatment of acute GVHD involves further immunosuppression with steroids, antithymocyte globulin (ATG), anti-CD 5, and other anti-Pan-T lymphocyte monoclonal antibodies.5

The occurrence of GVHD in patients with malignancy, however, may have a beneficial graft-versustumor effect. Some studies report that patients who develop GVHD posttransplant have a lower relapse rate than those who do not.6

TRANSPLANT RESULTS

Acute Myelogenous Leukemia (AML)

Even though remission induction rates for children with AML have improved, the long-term disease-free survival remains approximately 50% at 3 years in most studies.7 Once the disease recurs, long-term leukemiafree survival is rare with conventional therapy. Marrow ablative chemoradiotherapy followed by matched sibling donor marrow infusion was first used by investigators at the Fred Hutchinson Cancer Research Center for patients with end-stage disease.8 Among the initial 54 patients with AML, six became longterm survivors and were cured of their disease. Having demonstrated that patients could be cured of their leukemia with this approach, the next step was to transplant patients earlier in the course of their disease.

Thus, in Seattle, patients in first remission received a transplant after a similar preparative regimen and matched sibling marrow. Among these initial 19 patients, 10 became long-term disease-free survivors who are now more than 10 years posttransplant.9 In a series of 38 children transplanted in first remission, the disease-free survival rate was 64% with a relapse rate of less than 20%. I0 Other centers have reported similar transplant results for patients in first remission.

Comparing current transplant results with conventional chemotherapy results for patients in first remission is needed because studies suggest that similar disease-free survival rates may be achieved. In one pediatrie trial involving 347 children, all received identical induction therapy. Those with matched sibling donors were transplanted with identical preparative regimens and those without donors received one of two chemotherapy regimens. At 3 years, the disease-free survival rate is significantly better in the transplanted patients (49%) than in the chemotherapy treated patients (36%). Thus, transplantation remains the treatment of choice for children with AML in first remission.

Because only one third of children are likely to have a matched sibling donor, use of autologous transplant in first remission is being evaluated. Preliminary results suggest that similar disease-free survival rates may be achieved. However, a prospective study with appropriate chemotherapy and allogeneic transplant comparison groups is needed.

Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia is the most common leukemia among children and also the most successfully treated with conventional chemotherapy. Approximately 60% to 70% of these patients are now cured with intensive induction regimens and 2 to 3 years of maintenance therapy.1 ' Thus, for the majority of children with ALL, marrow transplantation is not considered until after an on-therapy relapse. Although second remissions are usually achieved, the ultimate long-term disease-free survival rate has usually been poor. Recent reports suggest that some patients in second remission may achieve prolonged disease-free survival with intensive chemotherapy. However, follow-up has not been sufficient to determine the number that may be cured by this approach.12

Marrow transplantation has been used in combination with high-dose chemoradiotherapy for children who have matched sibling donors and are in second or subsequent remission. A 35% to 40% long-term disease-free survival rate for patients transplanted in second remission 2 to 10 years after transplant has been reported, with relapse rates after transplant approximating 40% to 50%. l3 One study that used hyperfractionated TBI (three times per day to a total dose of 13.20 Gray [Gy] radiation units) instead of single exposure (9.5 to 10 Gy) or single daily exposures (total 12 to 15.75 Gy) used by other centers reported an actuarial disease-free survival rate of 63% at 2 years and a relapse rate of 15% for patients in second remission.14 All studies have reported a 20% to 35% disease-free survival rate for patients in third or subsequent remission at time of transplant, with relapse rates of 60% to 75%. Children in resistant relapse at the time of transplant have survival rates ranging from 10% to 15%, with relapse rates of 75% to 80%.15

All of these transplant results were from single-arm studies. Two reports have compared transplantation in second or subsequent remission at their institution with a group of similar patients receiving conventional chemotherapy at that institution during the same time period. Both reports showed that children who received a marrow transplant had superior diseasefree survival compared with those treated with conventional chemotherapy.16,17 For ALL patients who receive a marrow transplant, the preferred time to perform the transplant is while the patient is in second remission.

Recurrent leukemia is the major problem after transplant for children with ALL, especially those beyond second remission. Novel approaches of improving the disease-free survival rate by decreasing the posttransplant relapse rate are needed. Studies that address new transplant preparative regimens or that use immune biologic response modifiers are being conducted to address this problem.

As with AML, only about one third of patients will have a matched sibling donor. Alternative sources of marrow are being explored. One of these is autologous marrow that has been collected and cryopreserved while the patient is in remission. The major problem, however, is the high relapse rate (70% to 75%) with a resultant disease-free survival rate of 20%.18 This may be a result of residual leukemia cells present in the autologous marrow or the lack of a graft -versusleukemia effect. Methods of therapy that address the relapse problem after autologous transplant are currently being investigated.

Chronic Myelogenous Leukemia (CML)

Although CML, a myeloproliferative stem-cell disorder, accounts for <5% of pediatrie leukemia cases, it should be addressed when considering marrow transplantation for children with leukemia. Two types of CML are seen in children, and these two types differ markedly in their characteristics and natural history Juvenile CML, which occurs in very young children (<5 years of age) and frequently presents more like an acute leukemia, is ineffectively treated with conventional chemotherapy. Allogeneic marrow transplantation is the treatment of choice for these patients and results in 30% to 50% becoming longterm disease-free survivors.19

The adult form of CML is the more common type of CML in children and is characterized by the presence of high white blood cell counts and the Philadelphia chromosome. While CML usually has a chronic phase requiring minimal therapy for a number of years, all patients ultimately enter an acute phase that is fatal. Conventional therapy does not alter the course of CML. Bone marrow transplantation following high-dose' chemoradiotherapy, initially performed in patients in the acute phase, demonstrated that some patients could be cured of their disease. The next studies used transplantation earlier in the disease course, ie, during the chronic phase. Transplant results for patients in the chronic phase patients have shown that 50% to 85% may be cured.20 The best results have been achieved if the marrow transplant from the matched sibling donor is performed within a year following diagnosis. Recurrent CML after transplant for chronic phase patients ranges from 15% to 30%. Although patients in the acute phase (blast crisis) of their disease continue to receive marrow transplantation in an effort to cure them, recurrent leukemia is a major problem for this group. Clearly, for patients with CML, marrow transplantation from a matched sibling donor should be performed shortly after the diagnosis is made while patients are in the chronic phase of their disease.

For patients without a matched sibling donor, autologous transplants have been attempted. Results to date have been dismal. Alternative sources of marrow, such as a partially matched family member or a matched unrelated donor, should be used.21

Non-Hodgkin's Lymphoma

Current conventional therapeutic protocols provide excellent disease-free survival for children with non-Hodgkin's lymphoma.22 However, patients who relapse or have refractory disease may benefit from high-dose chemotherapy or TBI followed by an infusion of bone marrow (allogeneic, syngeneic, or autologous). Patients beyond initial remission but with nonresistant disease have disease-free survival rates approximating 30% to 45% after transplant, whereas those with more advanced and refractory disease have survival rates of 15% to 20%.23 Both allogeneic and autologous transplants have been performed for these children, but no clear superior choice of marrow source has been determined.

LONG-TERM COMPLICATIONS

The major late effects, which may occur months to years after the marrow transplant, are outlined in Table 2.

Effects Related to the Original Leukemia

As noted throughout the section on transplant results, despite the intensive chemoradiotherapy preparative regimens, relapse of the original disease often occurs. The most common type of relapse is in the bone marrow. Although some patients achieve another remission with chemotherapy, almost none are able to be cured with this approach alone. Second marrow transplants have been performed for some patients. A variety of intensive chemotherapy-only preparative regimens have been used. Approximately 20% of these patients survive disease free for 1 to 7 years after the second transplant.24 While these results are encouraging, the ultimate goal is to prevent posttransplant relapse from occurring.

Effects Related to the Transplant Procedure

Engraftment. The majority of long-term survivors have stable engraftment with all hematopoietic cell lines of donor origin present. Reappearance of lymphocytes of host origin is usually followed by graft rejection, and reappearance of myeloid cells of host origin is usually followed by leukemic relapse.

Chronic Graft- Versus-Host Disease. Chronic GVHD occurs in 30% of children surviving more than 100 days after a matched sibling transplant. Its clinical, pathologic, and laboratory features resemble several of the naturally occurring autoimmune diseases. Major organ systems that may be involved include the skin, liver, mouth, eye, and mucous membranes. Early diagnosis and therapy with immunosuppressive agents such as prednisone, azathioprine, and cyclosporine are necessary to promote resolution of the abnormalities and development of immunologie tolerance. Once all evidence of chronic GVHD is undetectable either clinically or pathologically, immunosuppressive therapy is tapered and discontinued. Patients who do not receive early treatment have a 20% survival without disability, whereas with early administration of appropriate therapy, more than 70% survive without disability.25

Immunologic Recovery. All marrow transplant recipients have profound impairment of most immune functions during the first 6 months after transplant. Nonchronic GVHD patients develop normal immune function in approximately 1 year; however; those with chronic GVHD have immune reconstitution that is even further delayed. Related to this delay in immune function recovery, patients with chronic GVHD are at risk for developing serious and potentially fatal infections. Prophylaxis with intravenous gamma globulin and antibiotics has been useful to decrease the infection incidence.

Immunity transfers from donor to recipient. Immune memory to diphtheria and tetanus antigens may be protective for some time, but testing patients for antibody levels 1 or more years after transplant is important to determine whether primary or booster immunizations are needed.

Effects Related to the Preparative Regimen

Neuroendocrine Function. Thyroid function after preparative regimens with high-dose chemotherapy only is normal, but after TBI, approximately 25% to 56% develop compensated or overt hypothyroidism between 1 and 10 years after transplant. Children who have received fractionated rather than single-dose TBl have substantially less thyroid function abnormalities.26

Growth velocity rates in young patients who receive TBI are usually decreased, especially around the time of puberty. Subnormal growth hormone levels have been noted in 87% of children who received both previous cranial irradiation and TBI, whereas approximately 50% have growth hormone deficiency if only TBI has been administered. Treatment with growth hormone supplementation has resulted in some improvement in height, but the amount of height velocity gained per year is usually less than that observed in nonirradiated growth hormone deficient children.

Puberty as measured by the appearance of secondary sexual characteristics is usually delayed for children who have received transplant preparative regimens that contain TBI. Gonadotropi levels indicate that this is a result of primary gonadal failure. Preliminary data suggest that children who receive high-dose busulfan in the chemotherapy-only preparative regimen also may have gonadal failure. These patients require the use of appropriate sex hormone supplementation to promote development of secondary sex characteristics.

Table

TABLE 2Late Effects Following Transplantation

TABLE 2

Late Effects Following Transplantation

Dental Abnormalities. Irradiation given to growing bones results in injuries that influence subsequent bone growth. Children given 10 Gy/TBI in the transplant-preparative regimen have developed disturbances in tooth development and facial growth. All children under the age of 6 at the time of TBI had arrested root development, premature apical closure, enamel hypoplasia, and microdontia. Those over the age of 7 usually had only arrested root development.

Central Nervous System Abnormalities. Children surviving long-term after treatment for acute leukemia have been observed to have neuropsychological deficits, especially if cranial irradiation was used in therapy. Children under the age of 8 at the time of irradiation had lower IQ scores and performed less well with visual motor; fine motor, abstract thinking, and spatial processing tasks than patients who had not received irradiation. Preliminary results from a prospective study performed at the Fred Hutchinson Cancer Research Center suggest that with increasing time after irradiation, there is a decrease in overall IQ score with performance IQ being the most significantly affected.

Secondary Malignancies. Trie development of secondary malignancies after cure of a primary malignancy has been observed in both nontransplant and marrow transplant patients. A recent analysis of more than 2000 marrow transplant recipients has demonstrated that 35 developed secondary malignancies between 6 months and 10 years after transplant. Major risk factors identified were GVHD immunosuppressive therapy and TBI.27

SUMMARY

The ability to deliver high-dose chemotherapy with or without radiotherapy followed by marrow rescue has made marrow transplantation die treatment of choice for children with AML in first remission, juvenile CML, and adult-type CML in chronic phase. For patients with ALL or NHL who relapse, transplantation in second remission represents a reasonable therapeutic option. The role of marrow transplantation for patients in the advanced stages of their disease will continue to be explored to develop promising new therapies, which may improve results of transplantation earlier in the disease course. Development of transplant preparative regimens that have the same or improved therapeutic efficacy with less late effects is especially important for growing and developing children.

In the meantime, all children who have received a marrow transplant must be followed for development of delayed effects, which may not appear until years after the transplant procedure. Children who are cured of their leukemia continue to occasionally visit the pediatrie hematologist/oncologist, but they do so less often with increasing time after curative therapy. Thus, it is necessary for the primary care pediatrician to be familiar with the details regarding the child's previous therapy in order to anticipate and to be prepared to treat the delayed effects. Attention to school performance is of particular importance for early identification of those children who may need special educational attention.

Advances in the treatment of children with leukemia continue to be made both with chemotherapy and with marrow transplantation that should result in greater numbers of children being cured. Until a method is developed to prevent childhood leukemia from occurring, marrow transplantation is likely to continue to be performed.

REFERENCES

1. Thomas ED, Scorb R, Gift RA, et al. Bone-marrow transplantation. N Engl J Med. 1975;292:832-843, 895-902.

2. Sanders J, Buckner CD, Bensinger WI, Levy W, Chard R, Thomas ED. Experience with marrow harvesting from donors less than 2 years of age. Bone Marrow Transplant. 1987;2:45-50.

3. Meyers JD, Reed EC, Shepp DH, et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med. 1988;318:70-75.

4. Storb R, Deeg HJ, Pepe M, et al. Methotrexate and cyclosporlne venus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood, 1989;73:1729-1734.

5. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76:1464-1472.

6. Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic grait-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989;73:1720-1728.

7. Weinstein HJ, Mayer RJ. Rosenthal DS, Coral FS, Caitta BM, Gelber RD. Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood. 1983;62:315-319.

8. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia created by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49:511-533.

9. Clift RA, Buckner CD, Thomas ED, et al. The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone marrow Transplant. 1987;2:243-258.

10. Sanders JE, Thomas ED Buckner CD. et al. Marrow transplantation for children in first remission of acute nonlymphoblascic leukemia: an update. Blood. 1985;66:460-462.

11. Niemeyer CM, Hitchcock-Bryan S, Sallan SE. Comparative analysis of treatment programs for childhood acute lymphoblastic leukemia. Semin Oncol. 1985;12:122-130.

12. Rivera GK, Buchanan G, Boyett JM, et al. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse. A pediatric oncology group study. N Engl J Med. 1986;315:273-278.

13. Sanders JE, Thomas ED, Buckner CD, Duney K. Marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood. 1987;70:324-326.

14. Bruchstein JA, Kernan NA, Groshen S, et al. Allogeneic bone marrow transplantation after hyperftacrionaied total-body irradiation and cyclophosphamide in children with acute leukemia, N Engi; Mid. 1987;317:1618-1624.

15. Sanders JE, Floumof N, Thomas ED, et al. Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse and graft-versus-host disease. Med Pediatr Oncol. 1985;13:165-172.

16. Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981;305:846-851.

17. Woods WG, Nesbit ME, Ramsay NKC, et al. 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 Minnesota Bone Marrow Transplantation Team). Blood. 1983;61:1182-1189.

18. Ramsay N, Le Bien T, Nesbit M, et al. Autologous bone marrow transplantation fut patients with acute lymphoblastic leukemia in second or subsequent remission: results of bone manow neared with monoclonal antibodies BA-1, BA-2, and BA-3 plus complement. Blood. 1985;66:508-513.

19. Sanders JE, Buckner CD Thomas ED, et al. Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia. Blood. 1988;71:1144-1146.

20. Clift RA, Buckner CD Appelbaum FA, et al. Allogeneic marrow transplantation in patients with chronic myelokl leukemia in the chronic phase. A randomized trial of two irradiation regimens. Blood. 1991;77:1660-1665.

21. Beatty FG, Ash R, Hows JM, McGlave PB. The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: experience of four marrow transplant centers. Bone Morrow Transplant. 1989;4:287-290.

22. Anderson JR, Wilson JF, Jenkin DT, et al. Childhood non-Hodgkins lymphoma. The results of a randombed therapeutic trial comparing a four-drug regimen (COMP) with a 10-drug regimen (LSA^sub 2^-L^sub 2^). N Engl J Med. 1983;308:559-565.

23. Appelbaum FR. Marrow transplantation for malignant lymphoma. Bone Marrow Transplant. 1987;2:227-231.

24. Sanders JE, Buckner CD, Clift RA, et al. Second marrow transplants in patients with leukemia who relapse after allogeneic marrow transplantation. Bone Marrow Transplant. 1988;3:11-19.

25. Sullivan KM. Chronic graft-versus-host disease. In: Champlin R, ed. Bone Morrow Transplant. Boston, Mass: Kluwer Academic; 1990:79-98.

26. Sanders JE, Pritchard S, Mahoney P, et al. Growth and development following marrow transplantation for leukemia. Blood. 1986;68:1129-1135.

27. Witherspoon RP, Raher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplattic anemia. N Engt J Med 1989-32 1:784- 789.

TABLE 1

Diseases Treated With Marrow Transplantation

TABLE 2

Late Effects Following Transplantation

10.3928/0090-4481-19911201-06

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