Pediatric Annals

Marrow Transplantation in Pediatric Hamatologic Disorders

Naynesh Kamani, MD

Abstract

After several years of pioneering work in animals, clinical application of bone marrow transplantation began in the 1950s. However, it is only over the last IS years that this lifesaving procedure has become a part of the clinician's armamentarium for the therapy of a number of hématologie and immunodeficiency diseases. It is new considered the therapy of choice in the treatment of aplastic anemia and severe combined immune deficiency and in selected cases of leukemia.'·3 Bone marrow transplantation offers the only curative therapy presently available for a number of other lethal non-malignant hematopoietic disorders (Table I).3,4 In this article, the role of bone marrow transplantation in the management of pediatrie non-malignant hématologie disorders will be reviewed.

INTRODUCTION

Approximately 5,000 bone marrow transplants have now been done and increasing numbers of centers are starting to perform them. Despite important recent advances in the management of patients undergoing transplants, this procedure is still associated with significant morbidity and mortality. It remains an intensive and costly form of therapy requiring long-term hospitalization and places major demands on physicians, nurses, auxiliary supportive staff and on the patients and their families.5,6

Bone marrow transplants between genetically identical members of the same species, eg, identical twins, are referred to as syngeneic; those between genetically dissimilar members of the same species, eg, siblings, are called aUogeneic transplants. In autologous bone marrow transplants, a patient's own cryopreserved marrow is re-infused after appropriate chemoradiotherapy. Allogeneic transplants, usually from histo- identical sibling donors, constitute the majority of transplants being performed today.

CLINICAL BONE MARROW TRANSPLANTATION

In man, histocompatibility is evaluated by performing human leukocyte antigen (HLA) typing at the A, B, C and DR loci using serologie techniques and demonstrating HLAD identity by mutual nonreactivity in mixed leukocyte culture (MLC). These HLA determinants are under the genetic control of the major histocompatibility complex which resides on the short arm of chromosome 6-7 With most organ transplants, eg, liver, heart and cadaveric pancreas transplants, histocompatibility between the donor and recipient does not seem to affect outcome. With bone marrow transplantation, however, donor-recipient histoidentity is critical in determining the success of the procedure and HLA mismatched transplants are frequently associated with graft rejection or severe and often fatal graft-vs. -host disease (GVHD). GVHD presumably occurs when immunocompetent donor T lymphocytes recognize host tissues as foreign and react against them. Clinically, GVHD is seen in varying severity in over half of all allogeneic transplants from histoidentical sibling donors suggesting the existence of so-called "minor" histocompatibility differences between the donor and recipient which are undetectable by presently available techniques.8

ABO blood group incompatibility is no longer a contraindication to performing bone marrow transplants and severe hemolytic reactions can be readily avoided by employing various techniques aimed at removing either red celts or plasma from the donor marrow prior to infusion into the recipient. Such manipulation of donor marrow does not affect engraftment, graft- vs. -host disease or overall success of the procedure.9

Table

OSTEOPETROSIS

Infantile malignant osteopetrosis is an autosomal recessive disease characterized by impaired bone résorption due to defective osteoclastic activity. Bony encroachment on marrow spaces and cranial foramina leads to decreased hematopoiesis and cranial nerve deficits. Despite extramedullary hematopoiesis, patients become pancytopenic and succumb within the first few years of life to infection or bleeding. As osteoclasts are derived from pluripotent stem cells, marrow transplantation can cure this disease. Tb date, close to a dozen patients have received transplants usually following conditioning with busulfan and cyclophosphamide. The majority have become long-term survivors, with either mixed or full chimerism, normalization of peripheral counts, résorption of osteosclerosis and stabilization of their neurological deficits.3,4 The…

After several years of pioneering work in animals, clinical application of bone marrow transplantation began in the 1950s. However, it is only over the last IS years that this lifesaving procedure has become a part of the clinician's armamentarium for the therapy of a number of hématologie and immunodeficiency diseases. It is new considered the therapy of choice in the treatment of aplastic anemia and severe combined immune deficiency and in selected cases of leukemia.'·3 Bone marrow transplantation offers the only curative therapy presently available for a number of other lethal non-malignant hematopoietic disorders (Table I).3,4 In this article, the role of bone marrow transplantation in the management of pediatrie non-malignant hématologie disorders will be reviewed.

INTRODUCTION

Approximately 5,000 bone marrow transplants have now been done and increasing numbers of centers are starting to perform them. Despite important recent advances in the management of patients undergoing transplants, this procedure is still associated with significant morbidity and mortality. It remains an intensive and costly form of therapy requiring long-term hospitalization and places major demands on physicians, nurses, auxiliary supportive staff and on the patients and their families.5,6

Bone marrow transplants between genetically identical members of the same species, eg, identical twins, are referred to as syngeneic; those between genetically dissimilar members of the same species, eg, siblings, are called aUogeneic transplants. In autologous bone marrow transplants, a patient's own cryopreserved marrow is re-infused after appropriate chemoradiotherapy. Allogeneic transplants, usually from histo- identical sibling donors, constitute the majority of transplants being performed today.

CLINICAL BONE MARROW TRANSPLANTATION

In man, histocompatibility is evaluated by performing human leukocyte antigen (HLA) typing at the A, B, C and DR loci using serologie techniques and demonstrating HLAD identity by mutual nonreactivity in mixed leukocyte culture (MLC). These HLA determinants are under the genetic control of the major histocompatibility complex which resides on the short arm of chromosome 6-7 With most organ transplants, eg, liver, heart and cadaveric pancreas transplants, histocompatibility between the donor and recipient does not seem to affect outcome. With bone marrow transplantation, however, donor-recipient histoidentity is critical in determining the success of the procedure and HLA mismatched transplants are frequently associated with graft rejection or severe and often fatal graft-vs. -host disease (GVHD). GVHD presumably occurs when immunocompetent donor T lymphocytes recognize host tissues as foreign and react against them. Clinically, GVHD is seen in varying severity in over half of all allogeneic transplants from histoidentical sibling donors suggesting the existence of so-called "minor" histocompatibility differences between the donor and recipient which are undetectable by presently available techniques.8

ABO blood group incompatibility is no longer a contraindication to performing bone marrow transplants and severe hemolytic reactions can be readily avoided by employing various techniques aimed at removing either red celts or plasma from the donor marrow prior to infusion into the recipient. Such manipulation of donor marrow does not affect engraftment, graft- vs. -host disease or overall success of the procedure.9

Table

TABLEI"SEVERE" APLASTIC ANEMIA*

TABLEI

"SEVERE" APLASTIC ANEMIA*

Table

TABLE 2INDICATIONS FOR (HARROW TRANSPLANTATION IN NONMALIGNANT HEMATOLOGIC DISORDERS

TABLE 2

INDICATIONS FOR (HARROW TRANSPLANTATION IN NONMALIGNANT HEMATOLOGIC DISORDERS

Donor Selection

Once a potential BMT candidate has been identified, search for a donor should be carried out by HLA typing of all siblings and parents. There is about a one-in-three chance of finding a histoidentical sibling. The likelihood of finding an HL A- matched related nonsibling donor is very small. Because of the extreme polymorphism of the HLA system, the chance of identifying a nonrelated histocompatible donor is even more remote.

Pre-Transplant Care

Prior to transplantation, the recipient undergoes a thorough evaluation to determine his overall clinical status. A 2week course of high-dose trimethopritn-sulfamethoxazole is usually given as chemoprophylaxis against Pneumocysus connu pneumonia. A unit of blood is collected a few weeks prior to marrow donation from older donors to be re- infused during or after their marrow harvest.

The recipient is usually admitted to the hospital about a week prior to the anticipated day of marrow infusion. Central venous catheters are inserted under anesthesia and the conditioning regimen appropriate for the individual patient's disease is administered. This usually involves giving very high doses of chemotherapy with or without total body irradiation. The resultant myeloablation and immunosuppression enables the donor marrow to engraft, helps to prevent graft rejection, and eradicates any existing malignant cells.

Intra-Transplant Care

The donor is admitted the day before the marrow harvest and is usually discharged within a couple of days. Marrow harvest is accomplished in the operating room under general or local anesthesia by repeated, multiple bone marrow aspirations from the posterior iliac crests bilaterally. The procedure is associated with little morbidity and no donor deaths have occurred as yet. 10 The amount of marrow aspirated depends on the size of the recipient. The harvested marrow is processed, placed in transfusion bags and intravenously administered to the recipient in a manner akin to a blood transfusion. The dose of nucleated marrow cells (NMC) usually administered is about 1 to 5 x 10p 8 NMC per kg of recipient's body weight.11

The recipient is managed in strict reverse isolation, either in a single room or in a laminar air-flow unit, during the 4 to 6 weeks it usually takes for engraftment and hématologie reconstitution. Most patients are placed on a low-bacteria diet and oral non-absorbable antibiotics and strict skin hygiene is maintained to reduce the risk of infection from the patient's own flora. The side effects of the preconditioning regimen usually become most evident during the week preceding early marrow engraftment. These include mucositis, fever, nausea, diarrhea, parotitis and dermal erythema. During the pancytopenic phase, the recipient is at high risk for infectious and hemorrhagic complications. The average patient will require about three platelet transfusions and one to two packed red cell transfusions weekly for the first 2 to 4 weeks. All blood products need to be irradiated in order to avoid GVHD. All patients receive parenteral hyperalimentation and most will require parenteral antibiotics for variable periods of time. With engraftment, which usually starts in the second week post-transplant, acute GVHD can occur and can be fatal in severe cases.

Brat-Transplant Care

Although hématologie reconstitution with donor marrow is usually complete by 3 months, full immunologie recovery takes between 6 to 12 months and the patient needs to be closely followed up for the first few months.12 During longterm follow-up, the recipient is monitored for infections, late effects of chemoradiotherapy, recurrence of his underlying disease and chronic graft vs. host disease. Interstitial pneumonitis is a frequent complication during the first 6 months following transplantation. It occurs in over a third of all allogeneic transplant recipients and is associated with a mortality rate approaching 70%.13

ACQUIRED APLASTIC ANEMIA

Severe aplastic anemia (SAA) is a rare disease characterized by pancytopenia and hypocellular bone marrow (Table 2). Its estimated incidence in the US is about 13 per 1 million population. It may be primary (idiopathic) or secondary to environmental factors including viruses, drugs and chemical agents. It may occasionally be preceded by other diseases such as paroxysmal nocturnal hemoglobinuria and systemic lupus erythematosus. Although a small percentage of patients will recover spontaneously, the disease in the majority is associated with high morbidity and mortality. Bone marrow transplantation from a hisrocompatible donor is now considered the treatment of choice in young patients with severe aplastic anemia.14

As soon as a diagnosis of SAA is made, histocompatibility studies should be initiated to locate a potential donor. If available, a syngeneic donor is preferred but most transplants have been performed using histoidentical sibling donors. In the rare instance where both parents share one HLA haplotype, one of the parents may be phenotypically identical with the child and can serve as the donor but chances for a successful outcome are reduced. Since many patients with SAA lack donors, alternative donors or methods of therapy should be considered. Several transplant centers are conducting pilot studies using unrelated HLA-identical donors procured through large computer files containing names of HLA-typed volunteers.

If a suitable bone marrow donor is available, the patient with SAA should be referred to a transplant facility promptly. Pretransplant transfusions of blood products should be avoided if possible since these increase the risks of sensitization and subsequent graft rejection. Blood products from the donor or other family members should not be used and repeated platelet transfusions should be obtained from a single donor to limit exposure to a small number of antigens. If available, leukocyte-poor red cells and platelets are preferred.

The conditioning regimen for SAA consists of near-lethal doses of cyclophosphamide (200 mg/kg given over 4 days). This regimen allows prompt engraftment in almost all aplastics who have not been transfused prior to transplantation. In transplant recipients who have been multiply transfused, graft rejection can occur in up to 60% of patients.15,16 This high rate of rejection has now been reduced to less than 10% by intensifying the immunosuppressive regimen with either low dose total body irradiation, additional chemotherapy, anti-thymocyte globulin, cyclosporin A, lymphoid irradiation or peripheral blood buffy coat transfusions from the donor.15'19 Graft rejection is manifested by failure of sustained engraftment and a return to an aplastic state. Efforts at retransplantation are usually unsuccessful.

Success rates for bone marrow transplantation in patients with SAA using presently available techniques for immunosuppression and histoidentical donors have improved steadily over the past decade. Most centers report long-term survival rates between 60% and 80%. GVHD frequently occurs but its incidence is significantly lower in younger recipients. Most long-term survivors lead an excellent quality of life and have full hématologie reconstitution. About 10% continue to have chronic GVHD that is refractory to treatment. 20

Several centers have compared antithymocyte globulin (ATG) therapy with bone marrow transplantation in patients with SAA. Although respectable survival rates can be achieved with ATG therapy and complications of ATG therapy are milder, many of the survivors have incomplete hématologie recovery and continue to require transfusion support. Until one can predict which patient with SAA will respond to ATG therapy, bone marrow transplantation is preferred therapy for the pediatrie patient with SAA who has a histoidentical donor. 21,22

FANCONTS ANEMIA

Fanconi's anemia (FA) is an autosomal recessive inherited disorder in which marrow aplasia is associated with multiple congenital malformations and abnormalities in peripheral blood chromosomes. Severe aplastic anemia may not be evident until the second or third decade of life. The majority of patients die as a result of severe aplasia or in some cases, by development of acute leukemia.

Some patients with FA will respond to androgens and corticosteroids but BMT is the only therapeutic modality that can potentially cure the stem cell defect. The probability of identifying histoidentical sibling donors is higher in FA possibly because of consanguinity in the family. All donors, however, should undergo cytogeneric analyses to evaluate chromosomal stability.

In FA, a generalized defect in DNA repair results in increased chromosomal instability and extreme sensitivity to alkylating agents and radiation. The early experience with BMT in this disease was dismal due to the high morbidity and mortality resulting from the toxicity of the conditioning regimen. Using lower doses of cyclophosphamide and thoracoabdominal irradiation in a series of seven patients, Gluckman et al have reported marked improvement in longterm survival rates. 23 Other centers have achieved long-term survival rates approaching 50% using modified immunosuppressive regimens.24

CONGENITAL HYPOPLASTIC ANEMIA

Congenital hypoplastic anemia (Blackfan- Diamond syndrome) is a pediatrie disorder characterized by pure red cell hypoplasia without involvement of other cell lines. A few patients undergo spontaneous remission; the majority will respond to corticosteroide but a small percentage of patients are refractory to treatment and eventually succumb to transfusional hemosiderosis. Bone marrow transplantation has restored normal erythropoiesis in two patients. One patient died on day 55 from interstitial pneumonia25 while the other was alive at day 650 with normal hemopoiesis at the time of the report.26 Although the exact timing for transplantation and the ideal pretransplant regimen remain undefined, bone marrow transplantation should be considered for patients with congenital hypoplastic anemia who are unresponsive to steroid therapy.

THALASSEMIA

Thalassemia major is a genetic disorder characterized by defective hemoglobin chain synthesis resulting in shortened erythrocyte survival and severe anemia. Chronic anemia leads to extramedullary erythropoiesis with marked hyperplasia of red cell precursors and progressive hemosiderosis. In the absence of treatment, most patients die in the first decade of life from cardiac or liver failure. Standard therapy at present consists of repeated blood transfusions and regular chelation therapy. Results from hypertransfusion-deferoxamine programs in the management of thalassemia have been encouraging but the effects of long-term chelation therapy need to be studied in order to fully evaluate this mode of treatment.

The use of bone marrow transplants in the therapy of thalassemia is now being explored. The myeloablative/ immunosuppressive regimen (for younger minimally transfused recipients) has consisted of high-dose cyclophosphamide and either busulfan or dimethylmyleran.27'28 Results for these patients have been generally favorable with lasting engraftment and full chimerism. Most of the patients who have received multiple transfusions prior to transplant have experienced graft rejection and recovery of autologous marrow function despite the use of fairly intensive conditioning regimens that included total body irradiation.27 Whether or not the pathologic changes of hemosiderosis can be reversed with bone marrow transplantation is not known but results of transplantation studies in dogs suggest that resolution of these changes may occur.

More widespread use of bone marrow transplantation in thalassemia cannot be advocated until the incidence of the immunologie and infectious complications of allogeneic transplants is reduced. More effective preconditioning regimens need to be developed, especially for the heavily transfused patient, whose already damaged heart and liver must be able to withstand these regimens. The optimum age at which transplants can be performed is undefined but transplants are likely to be more successful in younger recipients who are less likely to develop GVHD or graft rejection. Over the next few years, the role of marrow transplants in thalassemia will come under greater scrutiny as more data are gathered and transplanted patients are followed for longer periods of time.

SICKLE CELL DISEASE

A recent report by Johnson et al has shown that bone marrow transplantation can reverse the hemoglobinopathy of sickle-cell anemia. 29 Their patient, an 8-year-old black girl with sickle cell anemia, was successfully transplanted for acute myelogenous leukemia in first remission with marrow from her brother who had sickle-cell trait. At the time of the report, she was doing well at 16 months post-transplant with hemoglobin A,, S and A2 levels similar to those of the donor.

With conservative supportive therapy, the long-term prognosis for most patients with sickle-cell disease is quite good. Therefore, although bone marrow transplants constitute the only definitive therapy presently available for this disease, this modality should only be contemplated as an option in certain selected patients with sickle-cell anemia, perhaps in younger patients who develop serious complications very early. Considerations described above for thalassemia also pertain to the applicability of marrow transplants in sickle cell disease.

Table

TABLESANTICIPATED ADVANCES IN BMT FOR HEMATOLOGIC DISORDERS

TABLES

ANTICIPATED ADVANCES IN BMT FOR HEMATOLOGIC DISORDERS

OSTEOPETROSIS

Infantile malignant osteopetrosis is an autosomal recessive disease characterized by impaired bone résorption due to defective osteoclastic activity. Bony encroachment on marrow spaces and cranial foramina leads to decreased hematopoiesis and cranial nerve deficits. Despite extramedullary hematopoiesis, patients become pancytopenic and succumb within the first few years of life to infection or bleeding. As osteoclasts are derived from pluripotent stem cells, marrow transplantation can cure this disease. Tb date, close to a dozen patients have received transplants usually following conditioning with busulfan and cyclophosphamide. The majority have become long-term survivors, with either mixed or full chimerism, normalization of peripheral counts, résorption of osteosclerosis and stabilization of their neurological deficits.3,4 The experience gathered thus far suggests that if a donor exists, marrow transplants should be performed early in the disease, preferably before neurologic complications set in. Earlier transplants may also help prevent the development of post -transplant hypercalcémie which has been fatal in two transplant recipients.

GRANULOCYTE DISORDERS

Many disorders of granulocyte differentiation or function exist that can be potentially cured by bone marrow transplantation. Transplants have been performed in a handful of patients with chronic grami lomatous disease, infantile agranulocytosis (Kostmann's syndrome), Chediak-Higashi syndrome, neutrophil actin deficiency and neutrophil membrane GP-18Û deficiency. These procedures have met with limited success partly because of the frequent post- transplant septic complications.4 It has been difficult to achieve full chimerism in most patients but many of them may benefit significantly from stable, partial chimerism.30

PEDlATRIC MALIGNANCIES

Bone marrow transplantation is the therapy of choice for acute lymphoblastic leukemia in second remission in children with histoidentical donors. It appears to be the preferred form of therapy for acute myelogenous leukemia in first remission. Marrow transplants are now being performed in increasing numbers of patients with chronic myelogenous leukemia, neuroblastoma, non-Hodgkin's lymphoma and other solid tumors. The application of transplants in the therapy of pediatrie malignancies has been discussed in several recent reviews.3,6,31,32

SUMMARY AND FUTURE DIRECTION

The modem era of human bone marrow transplantation began less than two decades ago but it has already evolved into a widely used therapeutic procedure for a number of lifethreatening hématologie and immunologie diseases. It is the therapy of choice for young patients with bone marrow aplasia, for severe combined immunodeficiency and for selected cases of acute leukemia. It offers the only potentially curative treatment modality for a number of inherited disorders. The limited availability of histocompatible donors continues to be a major drawback. Graft-vs. -host-disease, interstitial pneumonia and graft rejection continue to take their toll on transplant recipients.

The incidence of graft rejection in severe aplastic anemia has been markedly reduced in recent years. It is hoped that with the development of effective and feasible techniques to remove mature T cells from donor marrow, GVHD will become less frequent or prevented. Along with advances in the therapy of GVHD, this will reduce transplant-associated morbidity and mortality and open the door to the more frequent use of partially matched or mismatched donors thereby greatly increasing the donor pool. Better understanding of the pathogenesis of idiopathic interstitial pneumonia and the development of new antimicrobials can be expected to better address the problem of post-transplant interstitial pneumonitis (Table 3).

Recent progress in genetic engineering has enabled scientists to carry out nucleic acid hybridization and gene cloning and transfer. These important advances, along with those mentioned above, should contribute to making bone marrow transplantation a safer and less complicated procedure and widen its applicability to many more genetic and acquired hématologie and immunodeficiency disorders as well as inborn errors of metabolism.

REFERENCES

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2. Thomas ED, Storb R, Glifi RA, et al: Bone marrow transplantation. N EngU Mtd 1975; 292:832-843. 895-902.

3. O'Rtilly RJ: Allogene ic bone marrou/ transplantation: Current status and future directions. Blood 19T3; 62:941.

4. O'Reillv RJ. Brochstein ], Dinsmore R, et al: Marrow transplantation lor congenital disorders. Wn Hemotol 1984; 21:188.

5. KamaniN, August CS: Bone marrow transplantation. Problems and prospects. Md OmNAm 1984:68:657.

6. Lenarsky C. Feig SA: Bone marrow transplantation for children with canecí. ftdiorr Am 1983; 11:428.

7. Yuris Ey, Awdeh 2, Raum D, et al: The MHC in bone marrow transplantation. Clim Hemoiol 1983; 12:641.

8. Sullivan KM, Pafkman Ri The pathophysiology and treatment of erafr- versus- host disease. Ctn Hemotol 19T3; 12:775.

9. Buckner CD, Clift RA, Sanders JE: A BO- incompatible marrow transplant!. Tramplantation 1978-, 26:233.

10. Bortin MM. Buckner CD: Major complications of marro* harvesting (bi transplantation. ExpHcmatol 1983; 11:916.

11. Thomas ED, Siorb R: Technique for human marrow grafting. Blood 1970; Î6:507.

12. Witherspoon RP, Luro LG. Srorb R: Immunologie reconstituí ion after human marrow grafting. Semm Htmatol 1984; 21:2.

13. Meyers JD, Fluomoy N, Thomas ED: Non-bacterial pneumonia after allogene«: bone marrow transplantation: A review of ten years' experience. Rev Injea Dis 1982; 4:1119.

14. Camina BM, Stoib R, Thomas ED: Aplastic anemia. Rathogenesis, diagnosis, treatment, and prognosis. N Entf ) Med 1982; 306:645-652, 712-718.

15. Storb R, 1AtIdCn PL: Transfusion problems associated with transplantation. Sanm HemowI1981; 18:163.

16. StOfb R, Prentice RL, Thomas ED: Marrow transplantai ion for treatment of aplastic anemia: An analysis of fetors associated with graft re/cccion. N EnglJ M(d 1977; 296:61.

17. Elfenbein FJ, Mellits ED, Santos GW, et al: Engraftment and survival after allogeneic bone marrow transplantation for s«vere aplastic anemia. Transplani Prof 1983; 15:1412.

18. Ramsay NKC, Kim TH1 McO la ve P, et al: Total lymphoid irradiation and cyetophosphamide conditioning prior to bone marrow transplantation ibr patient: with severe aplastic anemia. Blood 1983; 62:622.

19. UCLA Bone Marrow Transplant Team: Prevention of graft rejection following bone marrow transplantation. Blood 19Sh 57:9.

20. Sullivan KM, DecgHJ, Sanders JE, et al: Late complications after marrow transplantation. SenunHemotol 1984; Zt:S3.

21. Cluckinan E, Barrett A], Árcese W, et al: Bone marrow transplantation in severe aplastic anemia: A survey of the European group for bone marrow transplantation (EGBMT). BrJ Haemaiol 1981; 49:165.

22. Bayever E, Champlin R, Ho W, et al: Comparison between bone marrow transplantation and antilhymocyte globulin in treatment of young patients with severe aplastic anemia. } Potion 1984; 105:920.

23. Gluckman E, Berger R1 Dutrei J: Bone marrow transplantation Ibr Panconi anemia. Smtm Hematol 1984; 21:20.

24. Deeg Hf1 Storb R1 Thomas ED, et at: Fanconis anemia treated by allogene ic bone marrow transplantation. Blood 1983; 61:954.

25. August CS, King E, GithensJH. et al; Establishment of erythropoiesis following bone marrow transplantation ina patient with congenital hypoplastic anemia. Blood 1976; 48:491.

26. Inondo A, Gari)o J, Baro ], et al: Complete recovery of hemopoiesis following bone marrow transplant in a patient with unresponsive congenital hypoplastic anemia. Blood 1984; 64:348.

27. Lutarti Izzi G, Izzi T, Eblchi P, et al· Bone marrow transplantation in thalassemia. Exf> Hcmaioi 1983; ll(Suppl):101.

28. Thomas ED, Sanders JE, Borgna-Pignatti C. et al: Marrow transplantation for thalassemia. Lancet 1982; 2:2 27.

29. Johnson FL, Look AT, Gockerman J, et al: Bone marrow transplantation in a patient with sickic-cell anemia. N EngíJ Med 1984; 311:760.

30. Kamani N, August CS. Douglas SD, et al: Bone marrow transplantation in chronic granulomatous disease. J fWiorr 1984; 105:42.

31. Thomas ED: Marrow transplantit ion for malignant disease. J Clm Oniol 1983; 1:517.

32. Gale RP, Kersey JH, Bortin MM, n al: Bone marrow transplantation for acute lytnphoblastic leukemia. Lancri 1983; 2:663.

TABLEI

"SEVERE" APLASTIC ANEMIA*

TABLE 2

INDICATIONS FOR (HARROW TRANSPLANTATION IN NONMALIGNANT HEMATOLOGIC DISORDERS

TABLES

ANTICIPATED ADVANCES IN BMT FOR HEMATOLOGIC DISORDERS

10.3928/0090-4481-19850901-09

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