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PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Thomas G. Gross, MD, PhD, R. Maarten Egeler, MD, PhD, and Franklin 0. Smith, MD

The first successful allogeneic transplantations of hematopoietic stem cells (HSCT) were performed in the late 1960s in children with congenital immunodefi~iencies.~, l6 The hematopoietic stem cells (HSC) were collected from the bone marrow of siblings who were genotypically identical or matched to the recipient for the human leukocyte antigens (HLAs). The patients achieved engraftment of a functional immune system but not donor hematopoiesis because high-dose chemotherapy or irradiation was not used as a preparative therapy. Since that time, thousands of patients with life-threatening, nonmalignant and malignant diseases have been treated with HSCT. The better understanding of engraftment, immune reconstitution, tolerance, and graft-versus-host disease (GVHD) as well as improved transplant strategies and support- ive care have been major reasons for the success of HSCT as potentially curative therapy for many disorders in children.

INNOVATIVE PREPARATIVE REGIMENS

Until the late 1970s, it was assumed that the antitumor effects associated with HSCT were the result of the preparative chemoradiother-

From the Division of Hematology/Oncology (TGG, FOS); and the Blood and Marrow Transplantation Program (TGG), Children’s Hospital Medical Center, Cincinnati, Ohio; Section of Immunology, Hematology, Oncology, Bone Marrow Transplantation and Autoimmune Diseases, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands (RME)

HEMATOLOGY /ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 15 * NUMBER 5 * OCTOBER 2001 795

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apy, with the HSC source rescuing the individual from long-term aplasia, or absent bone marrow f~nction.~, 52, 53 Based on this assumption, considerable attention was focused on ways to increase the dose of chemotherapeutic agents and external-beam radiation therapy to achieve better tumor kill. This approach had as its goals antitumor cytoreduction and immune suppression to allow for the engraftment of allogeneic HSC. Such high-dose preparative regimens were thought to ablate totally the patient’s marrow (myeloablation), but it is still controversial whether these doses of chemotherapy and radiation therapy are truly myeloabla- t i ~ e . ~ ~ It is more likely that myeloublative regimens result in a period of long-term aplasia that may resolve if life-threatening infectious complications could be avoided. Considerable effort has been devoted to the intensification of myeloablative regimens based on total body irradiation (TBI) and DNA alkylating chemotherapeutic agents (cyclophosphamide, busulfan, nitrosoureas, melphalan, and thiotepa) with or without the addition of other agents, such as DNA repair inhibitors (e.g., etoposide). It has been difficult, however, to show superiority of one regimen over another in terms of overall survival.

Myeloablative doses of chemotherapy and radiation result in severe organ and tissue injury. The increased intensity of these regimens may enhance acute and chronic GVHD, presumably by increasing tissue damage and inflammation.12 These complications are problematic in children, especially those with nonmalignant diseases, who would not benefit from the antitumor features associated with intensive preparative regimens. Children are also susceptible to long-term complications of these regimens, including growth retardation, endocrine abnormalities, developmental disturbances, and secondary malignancies. Despite these significant toxicities, myeloablative preparative regimens frequently fail to eradicate the malignant disease, so relapsed disease continues to be a problem.

In the 1980s and 1990s, at least three major advances in understanding of the role of the HSCT preparative regimen occurred. First, it has become clear that the antitumor effect of allogeneic transplantation is based not only on the cytoreductive effects of high-dose chemoradiother- apy, but also can be attributed to an immune effect mediated by donor lymphocytes (i.e., graft-versus-leukemia [GVL] effe~t).~, 26, 39, 55 This GVL effect is shown best by the ability of donor lymphocyte infusions (DLI) to induce remissions in patients who have had a relapse of their disease after allogeneic transplantation. The GVL effect is particularly effective in patients with chronic myeloid leukemia, is intermediate for acute myeloid leukemia, and is least effective for acute lymphocytic leukemia. Immune antitumor effects have been suggested to be beneficial in other malignancies most often affecting adults, including low-grade lympho- mas, melanoma, and breast car~inoma.~, 9, 11, 56, 57

Second, animal models and preliminary human clinical trials suggest that although the engraftment of allogeneic HSC requires immune suppression, engraftment is not necessarily dependent on myeloablative doses of chemotherapy and radiation (see Box). Immunosuppressive but

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nonmyeloablative preparative regimens (variably called nonmyeloablative, miniaZlografts, transplant-Zite, or reduced-intensity transplants) are currently an active area of investigation at many institutions worldwide.

Third, it has been shown that high-dose radiation can be delivered selectively to hematopoietic cells and tissues, allowing for dose intensification to malignant cells and sparing nonhematopoietic tissues from the toxicities associated with further dose intensifi~ation.~~, 32-35 The ability of radiolabeled monoclonal antibodies (mAbs) to deliver high doses of radiation selectively to malignant cells is being explored at a few research institutions.

Nonmyeloablative Preparative Regimens

Nonmyeloablative preparative regimens are based on the use of intensive immune suppression followed by the infusion of allogeneic HSC from bone marrow, peripheral blood, or cord blood, resulting in a state of mixed chimerism.46 Later, DLI is used to augment the GVL effect and to convert the mixed chimeric state to full donor hematopoiesis. For patients with malignant diseases, the use of nonmyeloablative transplants is based on the concept of immune modulation, attempting to harness the GVL effect. It is possible that mixed chimerism may cause a state of tolerance, resulting in less GVHD, by virtue of having host immune effector cells present with donor immune cells. For patients with nonmalignant diseases in which the GVL effect is of no benefit to the patient, mixed chimeric hematopoiesis may be sufficient for the correction of many genetic diseases. Additionally, as a result of potentially reduced short-term and long-term, transplant-related toxicities associated with these lower intensity preparative regimens, this approach may make allogeneic transplantation available to pediatric patients with significant organ dysfunction.'

Although there are an increasing number of preclinical animal studies exploring the potential for nonmyeloablative therapy, to date, there are few published human clinical tria1s.l. 14, 25, 36, 45, 50 7% e preliminary clinical trials have been limited by small numbers of patients, great heterogeneity in patient age and diseases, and a wide diversity of nonmyeloablative preparative regimens and GVHD prophylaxis regimens (see Box). Despite these limitations, several consistent observations have been made. First, nonmyeloablative preparative regimens appear to be tolerable. Second, allogeneic engraftment with mixed chimerism of lymphoid and other hematopoietic lineages has been achieved in some patients. Third, the overall incidence and severity of acute and chronic GVHD appears to be similar to that observed with conventional myeloablative transplantation. Fourth, in patients who did not develop significant GVHD, DLI have been possible post transplant. Finally, antitumor responses were noted in some patients. The preliminary human experience with this novel approach is encouraging, but the results are

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still insufficient to determine the overall safety and efficacy of this approach, particularly in children.

A report by Amrolia et all suggested the potential use of this innovative approach for children with congenital immunodeficiencies. Eight children with various severe immunodeficiencies and significant organ dysfunction received marrow not depleted of T cells from related (n = 2) or unrelated donors (n = 6) after a nonmyeloablative preparative regimen. All patients achieved partial or full donor immune and hematopoietic engraftment. Clinically significant acute GVHD was not seen, but one patient developed limited chronic GVHD. One patient died of recurrent disease. All of the surviving patients were reported to have had good recovery of T-cell numbers with normal mitogen responses. This preliminary report is important to the pediatric community. It suggests the feasibility and tolerability of nonmyeloablative transplantation across histocompatibility barriers, even in patients with pretrans- plant organ dysfunction.

Nonmyeloablative Preparative Regimens

Melphalan/fl~darabine~~ Melphalan/cladri bineI4 FIudarabine/rnelphalan/antilyrnphocyte Fludarabine/cyclophospharnide8, 25

Fludarabine/cisplatin/cytarabinez5 Cyclophosphamide/antithyrnocyte globulin/thyrnic radiation50 FIudarabine/busuIfan/antithyrnocyte TBI (200 cGy)/mycophenylate rnofetiI/cycl~sporine~~~ 59

Radiolabeled Monoclonal Antibodies

One of the major failures of HSCT for malignant disease is relapse of disease after transplantation. One approach is the use of nonmyeloablative allogeneic transplantation, as previously discussed, and using the immune-mediated antitumor effects of DLI. An alternate approach is to use radiolabeled mAb therapy to deliver higher doses of radiation selectively to malignant cells with less toxicity to normal, nonhemato- logic organs and tissues. To this end, investigators have used mAbs directed toward different cell surface molecules (targets) present on normal and malignant hematopoietic cells (e.g., CD33 and CD45) and different radioisotopes with variable degrees of success.3o, 32-35 The most encouraging results have been reported by Matthews et al.32, 33 Investigators used an iodine-131-labeled anti-CD45 mAb to irradiate hematopoietic tissues selectively followed by a standard preparative regimen of cyclophosphamide and TBI (12 G Y ) . ~ ~ The CD45 cell surface antigen is an


attractive target for radiolabeled mAbs because it is expressed by all nucleated normal and malignant hematopoietic cells. Although normal recipient marrow also is killed, the patient is rescued with donor HSC. Twenty adult patients with acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndrome were treated with iodine-131 estimated to deliver 3.5 to 7 Gy to the liver. These doses delivered an additional 4 to 30 Gy of radiation to the bone marrow with 7 to 60 Gy to the spleen. Toxicities were not measurably different from that seen in patients who received the cyclophosphamide and TBI without the addition of the radiolabeled mAb. Of these high-risk patients, 9 of 13 with acute myeloid leukemia or myelodysplastic syndrome and 2 of 7 with acute lymphocytic leukemia remained disease-free at a median follow- up of 17 months.

This innovative approach to deliver additional radiation selectively to malignant cells with a relative sparing of normal organs and tissues is encouraging. Building on these results and the benefit offered by nonmyeloablative preparative regimens, investigators are exploring the combined use of radiolabeled mAbs followed by nonmyeloablative transplantation. If successful, these approaches may modify the long- standing paradigms of allogeneic transplantation, while providing greater cure rates with less toxicity.

GRAFT-VERSUS-HOST DISEASE AND IMMUNE TOLERANCE

Graft-versus-host disease (GVHD) remains a major barrier in pediatric HSCT. GVHD is the donor immune system rejecting the recipient’s body. This reaction involves cellular components, primarily donor T cells, but natural killer (NK) cells and monocytes/macrophages also may play a role as well as inflammatory cytokines (e.g., interleukin-1 [IL-11, IL-2, y-interferon, and tumor necrosis factor [TNF]).I2 As opposed to solid-organ transplantation, in which patients require lifelong immunosuppression to control the host-versus-graft reaction, or graft rejection, in HSCT the donor immune system usually becomes tolerant of the recipient’s body, and lifelong immunosuppressive medication is not needed. However, GVHD and complications of its treatment (i.e., intensive immunosuppression) are a major cause of morbidity and mortality in HSCT. GVHD is two distinct syndromes, acute and chronic GVHD, which differ in pathophysiology and clinical manifestations.l2! 49

The pathophysiology of acute GVHD is based on an inflammatory reaction with donor cells rejecting host tissues, and type 1 T-helper (Thl) cells have been implicated as important in mediating acute GVHD. Traditionally, GVHD has been defined as occurring within 100 days of HSCT. HLA mismatching is the most predictive factor for developing GVHD. Younger age in either the donor or the recipient is associated with less GVHD; in general, children have a lower incidence of severe

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GVHD compared with adults. Acute GVHD affects the skin, gastrointestinal tract, and liver. Skin manifestations may range from a limited rash to diffuse involvement with desquamation and formation of bullae. Acute hepatic GVHD is manifested as cholestatic jaundice, and gastrointestinal involvement usually manifests as cramping watery diarrhea that may progress to bloody diarrhea or adynamic ileus. A variant of gastrointestinal acute GVHD is limited to the upper gastrointestinal tract and usually presents as anorexia and dyspepsia. Although biopsies are helpful in making the diagnosis, the severity of disease and prognosis are based on clinical staging, with more severe and multiple organ involvement having a worse prognosis.

The pathophysiology of chronic GVHD is less inflammatory reaction and often more fibrotic changes in affected tissues. Manifestations of chronic GVHD resemble autoimmune disease and can affect the skin, liver, eyes and oral mucosa, gastrointestinal tract, musculoskeletal system, and hematopoietic system. It is believed that type 2 T-helper (Th2) cells are important in mediating chronic GVHD. Chronic GVHD gener- ally does not occur before 100 days post-HSCT. Chronic GVHD that progresses directly from acute GVHD has a poor prognosis. As with acute GVHD, tissue biopsies are essential in diagnosing chronic GVHD, but severity and prognosis are based on extent of clinical symptoms, with limited chronic GVHD (localized skin or hepatic involvement) having a good prognosis and extensive chronic GVHD (generalized skin or hepatic involvement with any other organ involvement) having a poor prognosis.

Treatment of acute GVHD focuses on eliminating activated alloreac- tive T-cell clones.49 Numerous approaches have been studied, including the use of high-dose corticosteroids, antithymocyte antibodies (ATG, OKT3, ricin-linked anti-T-cell antibodies), and anti-TNF and IL-2 recep- tor antibodies and psoralen plus ultraviolet A irradiation (PUVA) for cutaneous disease. Immunosuppressive therapy to keep remaining allo- reactive cells from being activated usually is required with agents such as cyclosporine, FK506, or mycophenolate mofetil. Of all these agents, high-dose corticosteroids remain the most effective in treating GVHD. GVHD that is resistant to corticosteroid therapy is often fatal, with death resulting from refractory disease as well as infections from the required intensive immunosuppression. Treatment of chronic GVHD should begin with the earliest development of symptoms and requires continued therapy for a minimum for 6 to 9 months, even if symptoms resolve. Therapy for chronic GVHD includes corticosteroids usually in combina- tion with another agent, often cycl~sporine.~~ As with acute GVHD, disease that does not respond to corticosteroids has a poor prognosis, with infections as the major cause of morbidity and mortality. Patients with GVHD require prophylactic antibiotics, antifungals, antivirals, and often intravenous immunoglobulin supplementation with close observa- tion and early intervention for all suspected infections.

The best therapy for GVHD is pre~ent ion .~~ GVHD prophylaxis


usually includes cyclosporine for at least 3 to 6 months, with or without the addition of a short post-HSCT course of methotrexate or corticosteroids (or both). Depletion of donor T cells, either in vitro of the HSC graft or in vivo using anti-T-cell antibodies, has been used to decrease the incidence and severity of GVHD. A report by Beelen et a14 suggests that the practice of using antimicrobial agents to decontaminate the gut may help in the prophylaxis for GVHD. In all approaches, the goal is to prevent T-cell alloreactivity until the HSC graft can become tolerant of the patient.

Immunologic recovery is a double-edged sword in allogeneic HSCT. Donor cellular immunity is requisite for the transplant to be successful and is beneficial in establishing donor engraftment, prevention of relapse, and life-threatening infections, but GVHD can be fatal. A major emphasis of research is to understand immune tolerance to retain the benefits of donor immunity without developing GVHD. A novel approach is the induction of tolerance in vitro before infusing the HSC graft into the patient.’* In this study, 12 patients underwent haploidentical HSCT for high-risk hematologic malignancies. Before HSCT, donor marrow was cultured with recipient peripheral blood in the presence of CTLA-4-Ig, a molecule known to block T-cell activation and to enhance T-cell tolerance. No T-cell depletion was performed on the marrow, and patients received a standard preparative regimen and GVHD prophylaxis. One patient (9%) failed to engraft, three patients developed GVHD (25%) but none died of GVHD, four (33%) patients died of infections, but only one patient relapsed. These results suggest that tolerance can be achieved in vitro without affecting the GVL reaction, but more investigation is required to decrease graft failure and to enhance immunity against infections.

SOURCES OF HEMATOPOIETIC STEM CELLS

Another major barrier to the success of pediatric HSCT is donor availability. In the bone marrow, stem cells can self-renew, proliferate, and differentiate into many different cell lineages, including mature red cells, platelets, monocytes/macrophages, and neutrophils. HSC can differentiate into lymphoid lineage cells, including NK cells, B cells, and T cells. A transplant of HSC contains all the required cellular elements necessary for complete reconstitution of the hematopoietic and immune system in the recipient. Monocytes produced by the marrow migrate to tissues and reside permanently as macrophages-Langerhans’ cells (skin), Kupffer cells (liver), microglial cells (brain), osteoclasts (bone), and pulmonary macrophages. HSCT for certain genetic metabolic diseases is based on donor stem cells generating macrophages to deliver deficient enzyme or protein to affected tissues. In addition to bone marrow, other sources of HSC suitable for transplantation include cyto-

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kine-mobilized peripheral blood progenitor cells (PBPC) and umbilical cord blood (UCB).

The choice of HSC source is predicated on the disease for which the HSCT is performed, availability of donors, and the research interest of the institution performing the transplant. Autologous HSCT is used most commonly for children with neuroblastoma, lymphoma, Wilms’ tumor, some sarcomas, and brain tumors. Hematopoietic diseases and genetic disorders are treated most often with allogeneic transplantation. For allogeneic transplantation, the preferred donor source is an HLA-identical relative, which is most often a sibling. In children, HLA-identical transplants usually result in rapid engraftment, a relatively low risk of severe acute and chronic GVHD, and the successful development of immune tolerance and immune reconstitution. Be- cause no more than 25% to 30% of children have an HLA-matched related donor, alternative donor sources have been explored. These include bone marrow, PBPC, or UCB from unrelated donors or mismatched related donors. Although nonrelapse mortality, largely secondary to GVHD and infections, is higher with alternative donor HSC sources, these sources are being used increasingly to treat children who may benefit from HSCT.*

Cytokine-Mobilized Peripheral Blood Progenitor Cells

Following the discovery that hematopoietic growth factors cause a transient release of HSC into the peripheral blood circulation, it was shown that a sufficient number of HSC can be collected by leukapheresis and that rapid, sustained engraftment could be achieved after transplantation with these PBPC.24, 27 Most studies, primarily in adult patients, comparing PBPC with bone marrow have shown more rapid hematopoietic recovery using PBPC.6, 42, 44 At present, most autologous HSCTs are performed using PBPCS.~~ Because of the rapid engraftment, PBPC have been used in allogeneic HSCT.6, 29, 48 Despite the infusion of 10-fold more T cells with PBPC compared with bone marrow, the risk and severity of acute GVHD does not appear to be increased, but significantly more chronic GVHD has been observed. It has been suggested this increased chronic GVHD may result in more of the GVL effect and reduce relapse; however, longer follow-up is required to determine if the use of PBPC portends an advantage in disease-free survival compared with bone marrow.

Most experience with allogeneic PBPC has been in the adult setting. Although PBPC has virtually replaced the use of bone marrow for autologous transplantation in children, the use of allogeneic PBPC in children raises several important questions. First, a proposed advantage of PBPC is that patients avoid the risk of general anesthesia required for marrow harvest. Collection of PBPC in small children requires the

*References 1, 2, 10, 15, 19-21, 29, 31, 38, 40, 54, 58.


placement of an apheresis catheter in the central venous system, at least temporarily, which often requires general anesthesia. This procedure is justifiable for children undergoing autologous HSCT, but it may be difficult to justify for a normal sibling donor. There are concerns about the use of hematopoietic growth factors and PBPC collections in normal pediatric sibling donors. Until these complex issues are addressed ade- quately, allogeneic PBPC transplantation from donors not of age to give informed consent should be performed only in the context of rigorous research trials.

Levine et alZ9 published results using granulocyte colony-stimulating factor-mobilized PBPC from 24 HLA identical or 5/6 matched related donors. Eighteen patients were transplanted for leukemia and 6 for a nonmalignant disorder. The median donor age was 15 years (range, 8 to 38 years), and only 2 donors required placement of a central venous catheter. Only one leukapheresis collection was needed in 20 cases. The CD34 cell dose was twofold more than would be expected using bone marrow. All patients engrafted neutrophils rapidly at a median of 13 days, and 19 that were evaluable for platelet engraftment were platelet transfusion independent at a median of 12 days. One patient with thalassemia died of graft failure on day 63 post transplant. Of the 23 patients evaluable, 43% developed severe acute GVHD, and 2 died of acute GVHD. Of the 19 patients evaluable, 2 developed extensive and 10 limited chronic GVHD, and 1 patient died of chronic GVHD. The actuarial risk of relapse was 19% at 2 years with a 2-year disease-free survival of 65%. This study shows the feasibility of collecting granulocyte colony-stimulating factor-mobilized PBPC from relatively large children. It also shows the potential risk of increased GVHD with allogeneic PBPC. Larger prospective studies are needed to define the safety and efficacy of allogeneic PBPC in children.

Umbilical Cord Blood

Since 1988, UCB has been used increasingly as an alternate source of HSC for children and adults undergoing HSCT for various malignant and nonmalignant disorders. Although accurate numbers are not available, it is estimated that UCB has been used as the HSC source in more than 2000 transplant recipients worldwide.

Preliminary studies suggest UCB may have advantages and disad- vantages over other sources of HSC.l5, 28, 31, 38, 40, 54* 58 Potential advantages include rapid donor selection and HSC acquisition and possibly less acute and chronic GVHD, without increases in relapse. Potential disad- vantages include a higher rate of graft failure, particularly in older and larger recipients. Despite increases in understanding of UCB, many issues relevant to UCB biology, collection, storage, and transplantation are not fully defined.

Since the first allogeneic transplant using UCB, only a limited number of reports have been published. Although preliminary reports pro-

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vide important information, few controlled clinical trials show the true safety and efficacy of UCB as a source of HSC for transplantation. The engraftment rate and the incidence and severity of acute and chronic GVHD has not been defined in prospective, controlled clinical trials. Rocha et a138 provide valuable information regarding the use of related donor UCB in pediatric recipients, however. These investigators performed a retrospective, age-controlled study of 113 HLA-matched related donor UCB transplants compared with 2052 recipients of HLA-matched related donor bone marrow transplant recipients. Multivariate analysis showed a lower risk of acute and chronic GVHD among recipients of UCB. Mortality and survival were similar between the two HSC sources, despite a higher probability of nonengraftment (11Y0) among UCB recipients. Because a randomized study of related donor UCB and bone marrow is unlikely to occur, this case-controlled study may provide the best data comparing UCB with bone marrow in the HLA-matched, related donor HSCT setting. Similar studies for unrelated UCB and bone marrow are awaited.

Mismatched Related Donor

For patients lacking an HLA-matched sibling, transplantation from an HLA-mismatched family member is a possible option. The major advantage of mismatched related donor is donor availability. Using haploidentical HSCT, a donor is available greater than 90% of the time, and delays to HSCT may be reduced. With an increasing degree of HLA mismatching, the risk and severity of acute and chronic GVHD increases, but T-cell depletion of the bone marrow or PBPC graft can decrease this risk.2, 2o Reduction of GVHD by T-cell depletion must be balanced, however, against a higher risk of nonengraftment, increased relapse rate, prolonged immune reconstitution, and increased risk of Epstein-Barr virus-associated lymphoproliferative 2o

Aversa et aI2 published results using haploidentical HSCT in 15 children with high-risk acute leukemia. All donors were 3/6 HLA- mismatched. Patients received granulocyte colony-stimulating factor- mobilized PBPC at high doses, with a median CD3Ppositive cell dose of 12 X 106/kg recipient weight. The PBPC graft was severely depleted of T cells, resulting in a median CD3-positive cell dose of 3 x lo4/ kg recipient weight. The recipients received no posttransplant GVHD prophylaxis. Thirteen patients (87%) achieved donor neutrophil recovery at a median of 11 days and platelet recovery at a median of 13 days. The two patients who failed to engraft received a second T-cell-depleted PBPC after an intensive immunosuppressive reconditioning and engrafted with full donor chimerism. None of the patients developed acute or chronic GVHD. The relapse rate was 50% at 1 year post transplant, and there were two deaths secondary to infections, with one secondary to Epstein-Barr virus-associated lymphoproliferative disorders. The 2- year disease-free survival was 33%. This study shows that graft failure


may be overcome by increasing the CD34+ cell dose, despite significant HLA disparity. Additionally, acute and chronic GVHD may be overcome without posttransplant prophylaxis even in a haploidentical setting, presumably as a result of extensive T-cell depletion. Although these results are promising, this study shows that relapse continues to be a significant problem as well as immune reconstitution and prevention of lethal infectious complications.

SUMMARY

The successful use of allogeneic HSCT for children with malignant and nonmalignant diseases continues to be limited by the development of acute and chronic GVHD, infectious complications, delayed recovery of the immune system, acute and long-term toxicity, and relapse of disease. Significant advances have been made, particularly in the ability to identify suitable sources of HSC. Future advances will depend on a better understanding of the biology of HSC sources, GVHD, immune reconstitution, and common complications. Improved therapies are dependent on participation of children in well-designed, translational and clinical transplant studies.

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Address reprint requests to Thomas G. Gross, MD, PhD

Division of Hematology/Oncology Children’s Hospital Medical Center

3333 Burnet Avenue Cincinnati, OH 45229

E-mail: [email protected]