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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Rationale for HCT
Blood and marrow transplantation (BMT) or HCT is a procedure that involves infusion of cells (hematopoietic stem cells; also called hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen given to the patient consisting of agents designed to do the following:
HCT is currently used in the following three clinical scenarios:
Autologous Versus Allogeneic HCT
The two major transplant approaches currently in use are autologous (using the patient's own hematopoietic stem cells) and allogeneic (using related or unrelated donor hematopoietic stem cells). Autologous transplant treats cancer by exposing patients to mega-dose (myeloablative) therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient's previously stored hematopoietic stem cells. It has also been used to attempt to reset the immune system in severe autoimmune disorders. In order for autologous transplant to work, the following must apply:
Allogeneic transplant approaches to cancer treatment also may involve high-dose therapy, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to mega-dose therapy alone and/or involve the bone marrow, thus requiring allogeneic approaches for optimal outcome. Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, and brain tumors.
Determining When HCT is Indicated: Comparison of HCT and Chemotherapy Outcomes
Because the outcomes using chemotherapy and HCT treatments have been changing with time, regular comparisons between these approaches should be performed to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat using a human leukocyte antigen (HLA)-matched sibling donor have established the benefit of HCT by direct comparison.[1,2] However, for very high-risk patients such as those with early relapse of ALL, randomized trials have not been feasible because of investigator bias.[3,4] In general, HCT approaches offer benefit only to children at high risk for relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HCT if reasonably HLA-matched donors are available have come to be the preferred approach for many diseases. Less well-established, higher-risk approaches to HCT (HLA haploidentical or significantly mismatched donors) are generally reserved for only the very highest-risk patients.
When comparisons of similar patients treated with HCT or chemotherapy are made and when randomized or intent-to-treat studies are not feasible, the following issues should be considered:
One source of bias difficult to control for or detect is physician bias for or against HCT. The effect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.
Collection and Storage of Autologous Hematopoietic Stem Cells
Autologous procedures require collection of peripheral blood stem cells (PBSCs) from patients by the process of apheresis. Bone marrow can be used for the transplant, but PBSCs have been shown to lead to quicker recovery and less toxicity. Patients under consideration for autologous HCT are generally given chemotherapy to demonstrate tumor responsiveness and minimize risk of tumor contamination in their bone marrow. After a number of rounds of chemotherapy, they undergo the apheresis procedure, either as their blood counts recover from chemotherapy or during a break between chemotherapy treatments. Growth factors such as granulocyte colony-stimulating factor (G-CSF) are used to increase the number of circulating stem and progenitor cells (CD34+ cells). Collection centers monitor the CD34+ number in the patient and product each day to determine the best time to begin collection and when collection is complete. The collected PBSCs are cryopreserved for later use; after completion of an intensive preparative regimen using high-dose chemotherapy that varies according to tumor, the PBSCs are administered back to the patient at the time of transplant.
General Indications for Autologous Procedures/Preparative Regimens/Tumor Purging
In pediatrics, the most common autologous transplant indications are high-risk neuroblastoma, relapsed Hodgkin and non-Hodgkin lymphoma, high-risk and relapsed brain tumors, and relapsed or resistant germ cell tumors. Regimens specific to given tumors are described in disease-specific PDQ treatment summaries.
Preparative regimens for allogeneic transplant are mainly needed to ensure engraftment of the donor marrow or cord blood. Use of high-dose tumor-specific agents, however, has not shown benefit, especially if such agents add toxicity to the approach. Unlike allogeneic procedures, the tumor-specific activity and intensity of agents used for autologous regimens have been shown to be important in improving survival. One concern with autologous approaches to these and other tumor types has been the contamination of the collected stem cell product by persistent tumor cells. Although a wide variety of techniques have been developed to remove or "purge" tumor cells from products, most studies looking into these approaches have shown no benefit to tumor purging.
HLA Matching and Hematopoietic Stem Cell Sources
Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic HCT (see Table 1).
Figure 1. HLA Complex. Human chromosome 6 with amplification of the human leukocyte antigen (HLA) region. The locations of specific HLA loci for the class I B, C, and A alleles and the class II DP, DQ, and DR alleles are shown.
HLA class I (A, B, C, etc.) and class II (DRB1, DQB1, DPB1, etc.) alleles are highly polymorphic, therefore finding appropriately matched unrelated donors is a challenge for some patients, especially those of certain racial groups (e.g., African Americans and Hispanics). Because full siblings of cancer patients have a 25% chance of being HLA matched, they have been the preferred source of allogeneic hematopoietic stem cells. Early serologic techniques of HLA assessment defined a number of HLA antigens, but more precise DNA methodologies have shown HLA allele-level mismatches in up to 40% of serologic HLA antigen matches. These differences are clinically relevant, as use of donors with allele-level mismatches affect survival and rates of graft-versus-host disease (GVHD) to a degree similar to patients with antigen-level mismatches. Because of this, DNA-based allele-level HLA typing is standard when choosing unrelated donors.
HLA matching considerations for sibling and related donors
The most commonly used related donor is a sibling from the same parents who is HLA matched for HLA A, HLA B, and HLA DRB1 at a minimum, at the antigen level. Given the distance on chromosome 6 between HLA A and HLA DRB1, there is approximately a 1% possibility of a crossover event occurring in a possible sibling match. Because a crossover event could involve the HLA C antigen and because parents may share HLA antigens that actually differ at the allele level, many centers perform allele-level typing of possible sibling donors at all of the key HLA antigens (HLA A, B, C, and DRB1). Any related donor that is a nonfull sibling should have full HLA typing because similar haplotypes from different parents could differ at the allele level. Although single-antigen mismatched related donors (5/6 antigen matched) have been used interchangeably with matched sibling donors in some studies in the past, a large Center for International Blood and Marrow Transplant Research (CIBMTR) study in pediatric HCT recipients showed that use of 5/6 antigen matched related donors who are not siblings results in rates of GVHD and overall survival equivalent to 8/8 allele level matched unrelated donors and slightly inferior survival compared to fully matched siblings.
HLA matching considerations for unrelated donors
Optimal outcomes are achieved in unrelated allogeneic marrow transplantation when the pairs of antigens at HLA A, B, C, and DRB1 are matched between the donor and the recipient at the allele level (termed an 8/8 match). A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% to 10% with a similar increase in the amount of significant (grades III–IV) acute GVHD. Of these four antigen pairs, different reports have shown HLA A, C, and DRB1 mismatches to potentially be more highly associated with mortality than the other antigens,[2,4,5] but the differences in outcome are small and inconsistent, making it very difficult to conclude presently that one can pick a more favorable mismatch by choosing one type of antigen mismatch above another. Many groups are attempting to define specific antigens or pairs of antigens that are associated with poor outcome, but such studies require very large numbers of patients and exclusion of specific antigens or antigen pairs for donor choice is not widely practiced.
Although it is well understood that class II antigen DRB1 mismatches increase GVHD and worsen survival, the need to match for two other important class II antigens, DQB1 and DPB1, is controversial. DQB1 mismatches have been associated with significant increases in acute GVHD, but subsequent studies have not shown a difference in overall survival. Many centers have adopted a policy to attempt to match patients at DQB1 in addition to the other four pairs of antigens; full matches using this approach are thus termed 10/10 HLA matches. Such matching is possible for a high percentage of patients because of strong linkage disequilibrium between DRB1 and DQB1, resulting in many 8/8 matched donors also being 10/10 matches. DPB1 mismatches have similarly been shown to lead to increased GVHD without a change in survival.[7,8] Although some centers attempt to match for DPB1 (12/12 match), it is challenging, because due to less linkage disequilibrium, only about 15% of 10/10 matches will also be 12/12 matches; studies showing whether it is better to mismatch at DQB1 compared with DPB1 have not been performed. A study grouping DPB1 antigens into permissive groups allowed up to 50% of patients with 10/10 matches to choose a favorable DPB1 match, but this classification system is not yet generally accepted.
Figure 2. HLA allele duplication in a donor or recipient results in a "half" match and a mismatch that will either occur in a direction that promotes GVHD (GVH-O) or a direction that promotes rejection (R-O).
If a donor or recipient has a duplication of one of their HLA alleles, they will have a "half" match and a mismatch only in one direction. Figure 2 illustrates that these mismatches will either occur in a direction that promotes GVHD (GVH-O) or a direction that promotes rejection (R-O). When comparing 8/8 matched unrelated donors with 7/8 donors mismatched in the GVH-O direction, 7/8 mismatched in the R-O direction, or 7/8 mismatched in both directions, the mismatch in the R-O direction leads to rates of grades III and IV acute GVHD similar to the 8/8 and better than the other two combinations. The 7/8 mismatched in only the R-O direction is preferred over GVH-O and bidirectional mismatches. It is important to note that this observation in unrelated donors differs from observations in cord blood recipients outlined below.
HLA matching and cell dose considerations for unrelated cord blood HCT
Another commonly used hematopoietic stem cell source is that of unrelated umbilical cord blood, which is harvested from donor placentas moments after birth and cryopreserved, HLA typed, and banked. Unrelated cord blood transplantation has been successful with less stringent HLA matching requirements compared with standard related or unrelated donors, probably due to limited antigen exposure experienced in utero and different immunological composition. Cord blood matching is generally performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. This means that matching of only six antigens is necessary to choose units for transplantation. Although better outcomes occur when 6/6 or 5/6 HLA matched units are used, successful HCT has occurred even with 4/6 or less matched units in many patients. In a large CIBMTR/Eurocord study, better matching at the allele level using eight antigens (matching for HLA C, A, B, and DRB1) resulted in less transplant-related mortality and improved survival. Best outcome was noted with 8/8 allele matching versus 4/8 to 7/8 matches, with poor survival in patients with five or more allele mismatches. Patients receiving 8/8 matched cord blood did not require higher cell doses for better outcome, but those with one to three allele mismatches had less transplant-related mortality with total nucleated cell counts greater than 3 × 107 /kg and those with four allele mismatches required a total nucleated cell count greater than 5 × 107 /kg to decrease transplant-related mortality. Many centers will type up to ten alleles and use the best match possible, but the impact of DQB1 mismatched has not been shown to affect outcome. Higher cell doses in cord blood units have been shown to improve outcomes when allele level typing is not done as well, especially when the units have higher levels of HLA mismatch. One study showed that survival of recipients of 4/6 matched cords with cell doses greater than 5 × 107 total nucleate cells/kg recipient weight is similar to 5/6 matched cord recipients receiving a cell dose of 2.5 to 5 × 107 total nucleate cells/kg. Although no clear improvement in survival occurred for cell doses above 5 × 107 total nucleate cells/kg, higher doses of cells improved outcomes for all levels of HLA mismatch.
As with unrelated donors, occasionally, individuals can have duplicate HLA antigens (e.g., the HLA A antigen is 01 on both chromosomes). When this occurs in a donor product and the antigen is matched to one of the recipient antigens, the recipient immune response will see the donor antigens as matched (matched, in the rejection direction), but the donor immune response will see a mismatch in the recipient (mismatch in the GVHD direction). This unique type of partial mismatching has been shown to be important in cord blood transplant outcomes. Mismatches that are only in the GVHD direction (GVH-O) lead to lower transplant-related mortality and overall mortality compared with those with recipient direction only (R-O) mismatches. R-O mismatches have outcomes similar to those caused by bidirectional mismatches. Current recommendations are for transplant centers to choose GVH-O mismatches above R-O or bidirectional mismatches.
Two aspects of umbilical cord blood HCT have made it more widely applicable. First, because a successful procedure can occur with multiple HLA mismatches, over 90% of patients from a wide variety of ethnicities are able to find a at least a 4/6 matched cord blood unit, allowing a method of performing HCT for populations that traditionally have not had HCT options because of having rare HLA haplotypes.[1,16] Second, as mentioned above, adequate cell dose (minimum 2–3 × 107 total nucleate cells/kg and 1.7 × 105 CD34+ cells/kg) has been shown to be associated with improved survival.[17,18] Total nucleate cells is generally used to judge units because techniques to measure CD34+ doses have not been standardized. Because even large single umbilical cord blood units are only able to supply these minimum doses to recipients weighing up to 40 kg to 50 kg, early umbilical cord blood HCT focused mainly on smaller children. Later studies showed that this size barrier could be overcome by using two umbilical cord blood units as long as each of the units is at least a 4/6 HLA match with the recipient; because two cords result in much higher cell doses, umbilical cord blood transplantation is now used widely for larger children and adults. Single-center studies have suggested that the use of two umbilical cord blood units may decrease relapse in patients with malignancies; however, this has not been validated in multicenter studies. It has been shown that grades II to IV acute GVHD is higher when two versus one umbilical cord blood unit is used; but transplant-related mortality has not been noted to be increased. One study comparing adult and older pediatric patients transplanted with either double 4/6 to 6/6 matched umbilical cord blood or unrelated bone marrow/PBSCs showed survival to be equivalent.
Comparison of stem cell products
Currently, the three stem cell products used from both related and unrelated donors are bone marrow, peripheral blood stem cells (PBSCs), and cord blood. In addition, bone marrow or PBSCs can be T-cell depleted by several methods and the resultant stem cell product has very different properties. Finally, partially HLA-matched (half or more antigens [haploidentical]) related bone marrow or PBSCs can be used after in vitro or in vivo T-cell depletion and this product also behaves differently compared with other stem cell products. A comparison of stem cell products is presented in Table 3.
The main differences between the products are associated with the numbers of T-cells and CD34+ progenitor cells present; very high levels of T-cells are present in PBSCs, intermediate numbers in bone marrow, and low numbers in cord blood and T-cell depleted products. Patients receiving T-cell depleted products or cord blood generally have slower hematopoietic recovery, increased risk of infection, late immune reconstitution, higher risks of nonengraftment, and increased risk of Epstein-Barr virus (EBV)–associated lymphoproliferative disorder. This is countered by lower rates of GVHD and an ability to offer transplantation to patients where full HLA matching is not available. Higher doses of T and other cells in PBSCs result in rapid neutrophil recovery and immune reconstitution, but also increased rates of chronic GVHD.
There are only a few studies directly comparing outcomes of different stem cell sources/products in pediatric patients. A retrospective registry study of pediatric patients undergoing HCT for acute leukemia compared those receiving related donor bone marrow with related donor PBSCs. Although the bone marrow and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and transplant-related mortality associated with PBSC led to poorer survival in the PBSC group. A retrospective study of Japanese children with acute leukemia compared 90 children who received PBSCs with 571 children who received bone marrow; the study confirmed higher transplant-related mortality due to GVHD and inferior survival among the children who received PBSCs. These reports, combined with lack of prospective studies comparing bone marrow and PBSCs, has led most pediatric transplant protocols to prefer bone marrow to PBSCs from related donors. For those requiring unrelated donors, a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial randomizing bone marrow and PBSCs that included pediatric patients demonstrated that overall survival was identical using either source, but rates of chronic GVHD were significantly higher in the PBSC arm. In an attempt to determine whether unrelated bone marrow or cord blood is better, a retrospective CIBMTR study of pediatric acute lymphoblastic leukemia patients undergoing HCT who received 8/8 HLA allele-matched unrelated donor bone marrow was compared with those receiving unrelated cord blood. The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched cord blood; survival after 8/8 HLA-matched unrelated bone marrow was slightly less and was statistically identical to patients receiving 5/6 and 4/6 HLA-matched cord blood units. Based upon these studies, most transplant centers consider matched sibling bone marrow to be the preferred stem cell source/product. If a sibling donor is not available, fully matched unrelated donor bone marrow or PBSCs or HLA matched (4/6 to 6/6) cord blood lead to similar survival. Although adult studies of T-cell depleted unrelated bone marrow or PBSC have shown outcomes similar to non-T-cell depleted approaches, large pediatric trials or retrospective studies comparing T-cell depleted matched or haploidentical bone marrow or PBSCs have not occurred.
Early HCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival as the number of donor/recipient HLA mismatches increased. Studies have further demonstrated that even with very high numbers of donors in unrelated donor registries, patients with rare HLA haplotypes and patients with certain ethnic backgrounds (e.g., Hispanic, African American, Asian-Pacific Islander, etc.) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).
In order to allow access to HCT for patients without HLA matched donor options, investigators developed techniques allowing use of siblings, parents, or other relatives who share only a single haplotype of the HLA complex with the patient and are thus "half" matches. The majority of approaches developed to date rely on intense T-cell depletion of the product prior to infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery. This can result in lethal infections, increased risk of EBV-lymphoproliferative disorder, and high rates of relapse. This has generally lead to inferior survival compared with matched HCT and has resulted in the procedure being generally practiced only at larger academic centers with a specific research focus aimed at studying and developing this approach.
Current approaches are rapidly evolving, resulting in improved outcome, with some pediatric groups reporting survival similar to standard approaches.[29,30] Newer techniques of T-cell depletion and add-back of specific cell populations (i.e., CD3/19 negative selection) may decrease transplant-related mortality. Reduced toxicity regimens have led to improved survival, better supportive care has decreased the chance of morbidity from infection or EBV-lymphoproliferative disorder, and some patient/donor combinations that have specific killer immunoglobulin-like receptor mismatches have shown decreased likelihood of relapse (refer to the Role of killer immunoglobulin-like receptor mismatching in HCT section of this summary for more information). Finally, techniques such as using combinations of granulocyte-colony stimulating factor (G-CSF) primed bone marrow and PBSCs with posttransplant antibody based T-cell depletion  or post-HCT cyclophosphamide (chemotherapeutic T-cell depletion)  have made these procedures more accessible to centers because expensive and complicated processing necessary for traditional T-cell depletion are not used. Reported survival using many different types of haploidentical approaches varies between 25% to 80% depending upon the technique used and the risk of the patient undergoing the procedure.[28,29,33,34] Whether haploidentical approaches are superior to cord blood or other stem cell sources for a given patient group has not been determined because comparative studies have yet to be performed.
Immunotherapeutic Effects of Allogeneic HCT
Graft-versus-leukemia (GVL) effect
Early studies in hematopoietic cell transplantation (HCT) focused on delivery of intense myeloablative preparative regimens followed by "rescue" of the hematopoietic system with either an autologous or allogeneic bone marrow. Investigators quickly showed that allogeneic approaches led to a decreased risk of relapse caused by an immunotherapeutic reaction of the new bone marrow graft against tumor antigens. This phenomenon came to be termed the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect, and has been shown to be associated with mismatches to both major and minor HLA antigens. The GVL effect is challenging to use therapeutically because of a strong association between GVL and clinical graft-versus-host disease (GVHD). For standard approaches to HCT, the highest survival rates have been associated with mild or moderate GVHD (overall grade I or II) compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.
Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study is comparing rates of relapse and survival between patients undergoing myeloablative HCT with autologous versus allogeneic donors for a given disease. In this setting, a clear advantage has been noted when allogeneic approaches are used for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). For ALL and AML specifically, autologous HCT approaches to most high-risk patient groups have shown results similar to chemotherapy, while allogeneic approaches have been superior.[35,36] Patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HCT.
Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens (refer to the Principles of HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL, as the intensity of the preparative regimen is not sufficient for cure in most cases. Although studies have shown benefit for patients pursuing this approach if they are ineligible for standard transplantation, because pediatric cancer patients can generally undergo myeloablative approaches safely, this approach has not been used for the majority of children with cancer who require HCT.
Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL
One can deliver GVL therapeutically through infusion of cells after transplant that either specifically or nonspecifically target tumor. The most common approach is the use of DLI. This approach relies on the persistence of donor T-cell engraftment after transplant to prevent rejection of donor lymphocytes infused to induce the GVL. Therapeutic DLI results in potent responses in patients with CML who relapse after transplant (60%–80% enter into long-term remission), but responses in other diseases (AML and ALL) have been less potent, with only 20% to 30% long-term survival. DLI works poorly in patients with acute leukemia who relapse early and who have high levels of active disease. Late relapse (>6 months after transplant) and treatment of patients into complete remission with chemotherapy prior to DLI have been associated with improved outcomes. Infusions of DLI modified to enhance GVL or other donor cells (natural killer [NK] cells, etc.) have also been studied, but have yet to be generally adopted.
Another method of delivering GVL therapeutically is the rapid withdrawal of immune suppression after HCT. Some studies have scheduled more rapid immune suppression tapers based upon donor type (related donors more quickly than unrelated donors due to GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient "chimerism") or minimal residual disease in order to assess risk of relapse and trigger rapid taper of immune suppression. A combination of early withdrawal of immune suppression after HCT with addition of DLI to prevent relapse in patients at high risk of relapse due to persistent/progressive recipient chimerism has been tested in patients transplanted for both ALL and AML. For patients with ALL, one study found increasing recipient chimerism in 46 of 101 patients. Thirty one of those patients had withdrawal of immune suppression and a portion went on to receive DLI if GVHD did not occur. This group had a 37% survival compared with 0% in the 15 patients who did not undergo this approach (P <.001). For patients with AML after HCT, about 20% experienced mixed chimerism after HCT and were identified as high risk. Of these, 54% survived if they underwent withdrawal of immune suppression with or without DLI; there were no survivors among those who did not receive this therapy.
Other approaches under evaluation
The role of killer immunoglobulin-like receptor mismatching in HCT
Donor-derived NK cells in the post-HCT setting have been shown to promote engraftment, decrease GVHD, lessen relapse of hematological malignancies, and improve survival.[44,45,46] NK cell function is modulated by interactions with a number of receptor families, including activating and inhibiting killer immunoglobulin-like receptors. The killer immunoglobulin-like receptor effect in the allogeneic HCT setting hinges upon expression of specific inhibitory killer immunoglobulin-like receptors on donor-derived NK cells and either the presence or absence of their matching HLA class I molecules (killer immunoglobulin-like receptor ligands) on recipient leukemic and normal cells. Normally the presence of specific killer immunoglobulin-like receptor ligands interacting with paired inhibitory killer immunoglobulin-like receptor molecules prevents NK cell attack of healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells and they may not have the appropriate inhibitory killer immunoglobulin-like receptor ligand. This mismatch of ligand and receptor allows NK cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.
The original observation of decreased relapse with certain killer immunoglobulin-like receptor-ligand combinations was made in the setting of T-cell depleted haploidentical transplantation and was strongest after HCT for AML.[45,47] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate killer immunoglobulin-like receptor-ligand combinations. Many subsequent studies did not detect survival effects for killer immunoglobulin-like receptor-incompatible HCT using standard transplantation methods,[48,49] which has led to the conclusion that T-cell depletion may be necessary to remove other forms of inhibitory cellular interactions. Decreased relapse and better survival have been noted with donor/recipient killer immunoglobulin-like receptor-ligand incompatibility after cord blood HCT, a relatively T-cell–depleted procedure.[50,51] In contrast to this notion, one study demonstrated that some killer immunoglobulin-like receptor mismatching combinations (activating receptor KIR2DS1 with the HLA C1 ligand) can lead to decreased relapse after AML HCT without T-cell depletion. The role of killer immunoglobulin-like receptor incompatibility in sibling donor HCT and in diseases other than AML is controversial.[29,53]
A current challenge associated with the killer immunoglobulin-like receptor field is that several different approaches have been used to determine what is killer immunoglobulin-like receptor compatible and incompatible.[47,54] Standardization of classification and prospective studies should help clarify the utility and importance of this approach. Currently, because a limited number of centers perform haploidentical HCT and the data in cord blood HCT are early, most transplant programs do not use killer immunoglobulin-like receptor mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of killer immunoglobulin-like receptor incompatibility remaining secondary.
NK cell transplantation
With low risk of GVHD and demonstrated efficacy in decreasing relapse in post-haploidentical HCT settings, NK cell infusions have been studied as a method of treating high-risk patients and consolidating patients in remission. The University of Minnesota group initially failed to demonstrate efficacy with autologous NK cells, but found that intense immunoablative therapy followed by purified haploidentical NK cells and IL-2 maintenance led to remission in 5 of 19 high-risk AML patients. Researchers at St. Jude Children's Research Hospital treated ten intermediate-risk AML patients who had completed chemotherapy and were in remission with lower-dose immunosuppression followed by haploidentical NK cell infusions and IL-2 for consolidation. Expansion of NK cells was noted in all nine of the killer immunoglobulin-like receptor-incompatible donor/recipient pairs. All ten children remained in remission at 2 years. A follow-up phase II study is underway, as are many investigations into NK cell therapy for a number of cancer types.
Principles of Allogeneic HCT Preparative Regimens
In the days just prior to infusion of the stem cell product (bone marrow, peripheral blood stem cell, or cord blood), hematopoietic cell transplantation (HCT) recipients receive chemotherapy/immunotherapy sometimes combined with radiation therapy. This is called a preparative regimen and the original intent of this treatment was to:
With the recognition that donor T-cells can facilitate engraftment and kill tumors through graft-versus-leukemia effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HCT approaches focusing on immune suppression rather than myeloablation have been developed. The resultant lower toxicity associated with these regimens has led to lower rates of transplant-related mortality and an expansion eligibility for allogeneic HCT to older individuals and younger patients with pre-HCT comorbidities that put them at risk for severe toxicity after standard HCT approaches. The many preparative regimens available now vary tremendously in the amount of immunosuppression and myelosuppression that they cause, with the lowest intensity regimens relying heavily on a strong graft-versus-tumor effect.
Figure 3. Selected preparative regimens frequently used in pediatric HCT categorized by current definitions as non-myeloablative, reduced-intensity, or myeloablative. Although FLU plus Treosulfan and FLU plus Busulfan (full-dose) are considered myeloablative approaches, some refer to them as reduced toxicity regimens.
Although these regimens represent a spectrum of varying degrees of myelosuppression and immune suppression, they have been categorized clinically in the following three major categories:
Figure 4. Classification of conditioning regimens in 3 categories, based on duration of pancytopenia and requirement for stem cell support. Myeloablative regimens (MA) produce irreversible pancytopenia and require stem cell support. Nonmyeloablative regimens (NMA) produce minimal cytopenia and would not require stem cell support. Reduced-intensity regimens (RIC) are regimens which cannot be classified as MA nor NMA. Reprinted from Biology of Blood and Marrow Transplantation, Volume 15 (Issue 12), Andrea Bacigalupo, Karen Ballen, Doug Rizzo, Sergio Giralt, Hillard Lazarus, Vincent Ho, Jane Apperley, Shimon Slavin, Marcelo Pasquini, Brenda M. Sandmaier, John Barrett, Didier Blaise, Robert Lowski, Mary Horowitz, Defining the Intensity of Conditioning Regimens: Working Definitions, Pages 1628-1633, Copyright 2009, with permission from Elsevier.
The use of reduced-intensity conditioning and nonmyeloablative regimens is well-established in older adults who cannot tolerate more intense myeloablative approaches,[59,60,61] but only a handful of younger patients with malignancies have been studied using these approaches.[62,63,64,65,66] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk for transplant-related mortality with myeloablative regimens (e.g., history of previous myeloablative transplant, severe organ system dysfunction, or active invasive fungal infection) and successfully treated them with a reduced-intensity regimen. Transplant-related mortality was low in this high-risk group, and long-term survival occurred in most patients with minimal or no detectable disease present at the time of transplantation. Because the risks of relapse are higher with these approaches, their use in pediatric cancer is currently limited to patients ineligible for myeloablative regimens.
Establishing donor chimerism
Intense myeloablative approaches almost invariably result in rapid establishment of hematopoiesis derived completely from donor cells upon count recovery within weeks of the transplant. The introduction of reduced-intensity conditioning and nonmyeloablative approaches into HCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that is sometimes only partial. DNA-based techniques have been established to differentiate donor and recipient hematopoiesis, applying the word chimerism (from the Greek chimera, a mythical animal with parts taken from various animals) to describe whether all or part of hematopoiesis after HCT is from the donor or recipient.
There are several implications to the pace and extent of donor-chimerism eventually achieved by an HCT recipient. For patients receiving reduced-intensity conditioning or nonmyeloablative regimens, rapid progression to full donor chimerism is associated with less relapse, but more graft-versus-host disease (GVHD). The delayed pace of obtaining full-donor chimerism after these regimens has led to late-onset acute GVHD, occurring as much as 6 months to 7 months after HCT (generally within 100 days after myeloablative approaches). A portion of patients achieve stable mixed chimerism of both donor and recipient. Mixed chimerism is associated with more relapse after HCT for malignancies and less GVHD; however, this condition is often advantageous for nonmalignant HCT, where usually only a percentage of normal hematopoiesis is needed to correct the underlying disorder and GVHD is not beneficial. Finally, serially measured decreasing donor chimerism, especially T-cell specific chimerism, has been associated with increased risk of rejection.
Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). These approaches are frequently used to address this issue, and have been shown in some cases to decrease relapse risk and stop rejection.[42,71] Timing of tapers of immune suppression and doses and approaches to the administration of DLI to increase or stabilize donor chimerism vary tremendously between transplant regimens and institutions.
Pre-HCT Comorbidities that Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Charlson Comorbidity Index
Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, functional status, etc.) is associated with risk of transplant-related mortality. The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index. Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the Charlson Comorbidity Index elements were correlated with transplant-related mortality in adult and pediatric patients. They also determined several additional comorbidities that have predictive power specific to transplant patients. Successful validation defined what is now termed the HCT-Charlson Comorbidity Index. Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (see Table 4).
The predictive power of this index for both transplant-related mortality and overall survival (OS) is strong, with a hazard ratio of 3.54 (95% confidence interval [CI], 2.0–6.3) for nonrelapse mortality (NRM) and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or more compared with those who have a score of 0. Although the original studies were performed with patients receiving intense, myeloablative approaches, the HCT-Charlson Comorbidity Index has been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens as well. It has also been combined with disease status  and Karnofsky score, leading to even better prediction of survival outcomes.
The large majority of patients assessed in the HCT-Charlson Comorbidity Index studies have been adults, and the comorbidities listed are skewed toward adult diseases. The relevance of this scale for pediatric and young adult recipients of HCT has been explored in two studies. A retrospective cohort study was conducted at four large centers of pediatric patients with a median age of 6 years and a wide variety of both malignant and nonmalignant disorders. The HCT-Charlson Comorbidity Index was predictive of both NRM and survival, with 1-year NRM of 10%, 14%, and 28% and 1-year OS of 88%, 67%, and 62% for patients with scores of 0, 1–2, and 3+, respectively. A second study included young adults (aged 16–39 years) and demonstrated similar increases in mortality with higher HCT-Charlson Comorbidity Index scores (NRM 24% and 38% and OS 46% and 28% for patients with scores of 0–2 and 3+, respectively). In both studies, more than three-quarters of the reported comorbidities were associated with respiratory or hepatic conditions and infection.[5,6] Patients with pre-HCT pulmonary dysfunction were at particularly high risk for comorbidity, with a 2-year OS of 29% compared with 61% in those with normal lung function before HCT.
Selected HCT-Related Acute Complications
Sinusoidal obstruction syndrome/veno-occlusive disease
Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is defined clinically by right upper quadrant pain with hepatomegaly, fluid retention (weight gain and ascites), and hyperbilirubinemia. Pathologically, the disease is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of myeloablative transplantations in children, and risk factors include the use of busulfan (especially before therapeutic pharmacokinetic monitoring), total-body irradiation, serious infection, graft-versus-host disease (GVHD), and pre-existing liver dysfunction due to hepatitis or iron overload.[7,8] Life-threatening SOS/VOD generally occurs early after transplantation and is characterized by multiorgan system failure. Milder, reversible forms can occur with full recovery expected.
Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied with mixed results, but recent studies have suggested prophylactic ursodiol may have an effect on SOS/VOD. One small, retrospective, single-center study showed a benefit from corticosteroid therapy; this requires further validation. Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has been shown to decrease mortality in the treatment of severe VOD [12,13,14] and seems to show efficacy in decreasing VOD incidence when used prophylactically.[Level of evidence: 1iiA] Defibrotide is not FDA approved but is routinely used by U.S. centers through a pre-approval protocol.
Although transplant-associated microangiopathy clinically mirrors hemolytic uremic syndrome, its causes and clinical course are different from other hemolytic uremic syndrome–like syndromes. Studies have linked this syndrome with disruption of alternative complement pathways. Transplant-associated microangiopathy has most frequently been associated with the use of the calcineurin inhibitors, tacrolimus and cyclosporine, and has been noted to occur more frequently when either of these two medications are used in combination with sirolimus. Diagnostic criteria for this syndrome have been standardized and include the presence of schistocytes on a peripheral smear and increased lactic dehydrogenase, decreased haptoglobin, and thrombocytopenia with or without anemia. Suggestive symptoms consistent but not necessary for the diagnosis include a sudden worsening of renal function and neurologic symptoms. Treatment for transplant-associated microangiopathy includes cessation of the calcineurin inhibitor and substitution with other immune suppressants if necessary. In addition, careful management of hypertension and renal damage by dialysis, if necessary, is vital. Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most transplant-associated microangiopathy associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after stopping sirolimus, and in some cases, both medications.
Idiopathic pneumonia syndrome
Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs within the first few months after transplantation. Diagnostic criteria include signs and symptoms of pneumonia, evidence of nonlobar radiographic infiltrates, and abnormal pulmonary function, all in the absence of documented infectious organisms. With this in mind, early assessment by bronchioalveolar lavage to rule out infection is important. Time of onset ranges from 14 days to 90 days after the infusion of donor cells. Mortality rates of 50% to 70% have been reported, although these estimates are from the mid-1990s and outcomes may have improved. Possible etiologies include direct toxic effects of the conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli. Traditional therapy has been high-dose methylprednisolone and pulmonary support. The addition of etanercept, a soluble interleukin-2 receptor, to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies, but multicenter studies showing improved long-term survival are lacking. In recent years, the incidence of this complication appears to be decreasing, possibly due to less-intensive preparative regimens, better HLA matching, and better definition of occult infections through polymerase chain reaction (PCR) testing of blood and bronchioalveolar specimens.
Epstein-Barr virus–lymphoproliferative disorder
Epstein-Barr virus (EBV) infection increases through childhood from approximately 40% in 4-year olds to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk for reactivation of EBV when undergoing HCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin or alemtuzumab, and to a lesser degree, use of cord blood).[22,23,24] Patients experiencing EBV reactivation can vary from isolated increase in EBV titers in the bloodstream as measured by PCR to an aggressive monoclonal disease with marked lymphadenopathy presenting as lymphoma (lymphoproliferative disorder). Isolated bloodstream reactivation can improve in some cases without therapy as immune function improves; however, lymphoproliferative disorder may require more aggressive therapy. Treatment of EBV-lymphoproliferative disorder in the past has relied on decreasing immune suppression and treatment with chemotherapy such as cyclophosphamide. Recently, CD20-positive EBV-lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy, rituximab.[25,26] In addition, some centers have found efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells. Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.
Acute graft-versus-host disease (GVHD)
GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities present in the tissues of a recipient. Acute GVHD usually occurs within the first 3 months of transplantation, although delayed acute GVHD has been noted in reduced-intensity conditioning and nonmyeloablative approaches, where achieving a high level of full donor chimerism is sometimes delayed. Typically, acute GVHD presents with at least one of three manifestations: skin rash, hyperbilirubinemia, and secretory diarrhea. Acute GVHD is classified by grading the severity of skin, gastrointestinal, and liver involvement and further combining the individual grading of these three areas into an overall stage that is prognostically significant (see Tables 5 and 6). Patients with grade III or IV acute GVHD are at higher risk for mortality, generally due to organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.
Prevention and treatment of acute GVHD
Morbidity and mortality from acute GVHD can be reduced through immune suppressive medications given prophylactically or T-cell depletion of grafts, either ex vivo by actual removal of cells from a graft or in vivo with anti-lymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]). Approaches to GVHD prevention in non-T-cell–depleted grafts have included intermittent methotrexate, a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics), or various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil. When significant acute GVHD occurs, first-line therapy is generally methylprednisolone. Patients with acute GVHD resistant to this therapy have a poor prognosis but a good percentage of cases respond to second-line agents (e.g., mycophenolate mofetil, infliximab, pentostatin, sirolimus, or extracorporeal photopheresis). Complete elimination of acute GVHD with intense T-cell depletion approaches has generally resulted in increased relapse, more infectious morbidity, and increased EBV-lymphoproliferative disorder. Because of this, most HCT GVHD prophylaxis is given in an attempt to balance risk by giving sufficient immune suppression to prevent most severe acute GVHD but not completely removing GVHD risk.
Chronic Graft-versus-Host Disease
Chronic GVHD is a syndrome that may involve a single or several organ systems, with clinical features resembling autoimmune diseases.[32,33] Chronic GVHD is usually first noted 2 to 12 months after HCT. Traditionally, symptoms occurring more than 100 days after HCT were considered to be chronic GVHD, and symptoms occurring earlier than 100 days post-HCT were considered to be acute GVHD. Because some approaches to HCT can lead to late-onset acute GVHD, and manifestations that are diagnostic for chronic GVHD can occur earlier than 100 days, the following three distinct types of chronic GVHD have been described:
Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT  and in 20% to 45% of children after unrelated donor HCT, with higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk with cord blood.[35,36] The tissues that are commonly involved include skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may be involved.
Risk factors for the development of chronic GVHD include the following:[34,37,38]
The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive Schirmer test). Tables 7 to 11 list organ manifestations of chronic GVHD with a specific listing of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsy of affected sites may be needed to confirm the diagnosis.
Common skin manifestations include alterations in pigmentation, texture, elasticity, and thickness, with papules, plaques, or follicular changes. Patient-reported symptoms include dry skin, itching, limited mobility, rash, sores, or changes in coloring or texture. Generalized scleroderma may lead to severe joint contractures and debility. Associated hair loss and nail changes are common. Other important symptoms that should be assessed include dry eyes and oral changes such as atrophy, ulcers, and lichen planus. In addition, joint stiffness along with restricted range of motion, weight loss, nausea, difficulty swallowing, and diarrhea should be noted.
Several factors have been associated with increased risk of nonrelapse mortality (NRM) in children who develop significant chronic GVHD. Children who received HLA mismatched grafts, PBSCs, who were older than 10 years, or who had platelet counts of less than 100,000/µL at diagnosis of chronic GVHD have an increased risk of NRM. NRM was 17%, 22%, and 24% at 1, 3, and 5 years after diagnosis with chronic GVHD. Many of these children require long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died either of relapse or NRM, a third were off immune suppression, and a third still required some form of immune suppressive therapy.
Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 proposed broadening the description of chronic GVHD to three categories in order to better predict long-term outcomes. The three current NIH grading categories are as follows:
Thus, high-risk patients include those with severe disease of any site or extensive involvement of multiple sites, especially those with symptomatic lung involvement, greater than 50% skin involvement, platelet count of less than 100,000/µl, poor performance score (<60%), weight loss greater than 15%, chronic diarrhea, progressive onset chronic GVHD, or a history of steroid treatment with greater than 0.5 mg/kg/day of prednisone for acute GVHD.
Treatment of chronic GVHD
Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including use of calcineurin inhibitors. Topical therapy to affected areas is preferred for patients with limited disease. A number of agents such as mycophenolate mofetil, pentostatin, sirolimus, and rituximab, have been tested with some success. Other approaches including extracorporeal photopheresis have been evaluated and show some efficacy in a percentage of patients.
Besides significantly affecting organ function, quality of life, and functional status, infection is the major cause of chronic GVHD-related death. Therefore, all patients with chronic GVHD should receive prophylaxis against Pneumocystis jirovecii pneumonia, common encapsulated organisms, and varicella by using agents such as trimethoprim/sulfamethoxazole, penicillin, and acyclovir. While disease progression is the primary cause of death in long-term follow-up of hematopoietic stem cell transplantation patients with no chronic GVHD, transplant-related complications account for 70% of the deaths in patients with chronic GVHD. Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.
Data from studies of child and adult survivors of HCT have shown a significant impact from treatment-related exposures on survival and quality of life. Of those alive at 2 years after HCT, a 9.9-fold increased risk of premature death has been noted.
Methodological Challenges Specific to HCT
Although the main cause of death in this cohort is from relapse of the primary disease, a sizeable number of these patients die from graft-versus-host disease (GVHD)-related infections, second malignancies, or cardiac or pulmonary issues.[2,3,4,5] In addition, other studies have revealed that up to 40% of HCT survivors experience either severe, disabling, and/or life-threatening events or die because of an adverse event associated with cancer treatment.[6,7]
Before initiating studies aimed at decreasing the incidence or severity of these effects, it is important to understand what leads to the development of these complications:
Individuals differ in their susceptibility to specific organ damage from chemotherapy or in their risk of GVHD based upon genetic differences in both the donor and recipient, which modifies the effect of these exposures.[8,9,10]
Cardiovascular System Late Effects
Although cardiac dysfunction has been studied extensively in non-HCT settings, less is known about the incidence and predictors of congestive heart failure following HCT in childhood. Potentially cardiotoxic exposures unique to HCT include the following:
HCT survivors are at increased risk of developing cardiovascular risk factors such as hypertension and diabetes, likely due in part to exposure to TBI and prolonged immunosuppressive therapy following allogeneic HCT, or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[7,11]
Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) treated in Seattle from 1985 to 2006. The survivors and a population-based comparison group were matched by age, year, and sex. Survivors experienced increased rates of cardiovascular death (adjusted incidence rate difference, 3.6 per 1,000 person-years [95% confidence interval, 1.7–5.5]) and had an increased cumulative incidence of ischemic heart disease, cardiomyopathy/heart failure, stroke, vascular diseases, and rhythm disorders. Survivors also had an increased cumulative incidence of related conditions that predispose towards more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).
In addition, cardiac function and pre-HCT exposures to chemotherapy and irradiation have been shown to have significant impact on post-HCT cardiac function. In evaluating post-HCT patients for long-term issues, it is important to consider levels of pre-HCT anthracycline and chest irradiation. Although more specific work needs to be done to verify this, current evidence suggests that the risk of late-occurring cardiovascular complications following HCT may be largely due to pre-HCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[14,15]
Central Nervous System Late Effects
A preponderance of studies report normal neurodevelopment after HCT, with no evidence of decline.[16,17,18,19,20,21,22,23]
Researchers from St. Jude Children's Research Hospital have reported on the largest longitudinal cohort to date, describing remarkable stability in global cognitive function and academic achievement during 5 years of posttransplant follow-up.[19,20,21] This group reported poorer outcome in patients undergoing unrelated donor transplant in those who received TBI, and in those who experienced GVHD, but these effects were small compared with the much larger effects seen based on differences in socioeconomic status. The majority of published studies report similar outcomes. Normal cognitive function and academic achievement was reported in a cohort of 47 patients followed prospectively through 2 years post-HCT. Stable cognitive function was also noted in a large cohort followed from pretransplant to 2 years post-HCT. A smaller study reported similar normal functioning and absence of declines over time in HCT survivors. HCT survivors did not differ from their siblings in cognitive and academic function, with the exception that survivors performed better than siblings on measures of perceptual organization. Based on the findings to date, it appears that HCT poses low to minimal risk for late cognitive and academic deficits in survivors.
A small number of studies, however, report some decline in cognitive function after HCT.[24,25,26,27,28,29] These studies tended to include samples with a high percentage of very young children. One study reported a significant decline in IQ in their cohort at 1 year post-HCT, and these deficits were maintained at 3 years post-HCT.[25,26] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who were transplanted with TBI.[28,29]
Digestive System Late Effects
Gastrointestinal, biliary, and pancreatic dysfunction
Most gastrointestinal late effects are related to protracted acute GVHD and chronic GVHD (refer to Table 12).
As GVHD is controlled and tolerance is developed, most symptoms resolve. Major hepatobiliary concerns include the consequences of viral hepatitis acquired before or during the transplant, biliary stone disease, and focal liver lesions. Viral serology and polymerase chain reaction should be performed to differentiate this from GVHD presenting with hepatocellular injury.
Iron overload occurs in almost all patients who undergo HCT, especially if the procedure is for a condition associated with transfusion dependence before HCT (e.g., thalassemia, bone marrow failure syndromes) or pre-HCT treatments requiring transfusions after myelotoxic chemotherapy (e.g., acute leukemias). Inflammatory conditions such as GVHD also increase gastrointestinal iron absorption. The effects of iron overload on morbidity post-HCT have not been well studied; however, reducing iron levels after HCT for thalassemia has been shown to improve cardiac function. Non-HCT conditions leading to iron overload can lead to cardiac dysfunction, endocrine disorders (e.g., pituitary insufficiency, hypothyroidism), diabetes, neurocognitive effects, and second malignancies.
Although data supporting iron reduction therapies such as phlebotomy or chelation after HCT have not identified specific levels at which iron reduction should be performed, higher levels of ferritin and/or evidence of significant iron overload by liver biopsy or T2-weighted magnetic resonance imaging (MRI)  should be addressed by iron reduction therapy.
Endocrine System Late Effects
Studies show that rates of thyroid dysfunction in children after myeloablative HCT vary, but larger series report an average incidence of about 30%.[62,63,64,65,66,67,68,69,70,71] A lower incidence in adults (on average, 15%) and a notable increase in incidence in children younger than 10 years undergoing HCT, suggest that a developing thyroid gland may be more susceptible to damage.[62,64,68] Pretransplant local thyroid radiation contributes to high rates of thyroid dysfunction in patients with Hodgkin lymphoma. Early studies showed very high rates of thyroid dysfunction after high single-dose fractions of TBI, but traditional fractionated TBI/cyclophosphamide compared with busulfan/cyclophosphamide shows similar rates of thyroid dysfunction, suggesting a role for high-dose chemotherapy in thyroid damage.[65,66,67] Rates of thyroid dysfunction associated with newer combinations of busulfan/fludarabine or reduced-intensity regimens have yet to be reported.
Of note, higher rates of thyroid dysfunction occur with single-drug versus three-drug GVHD prophylaxis, along with increased rates of thyroid dysfunction after unrelated versus related donor HCT (36% vs. 9%), suggesting a role for allo-immune damage in causing thyroid dysfunction.[67,74]
Growth impairment is generally multifactorial. Factors that play a role in failure to achieve expected adult height in young children who have undergone HCT include the following:
The incidence of growth impairment varies from 20% to 80% depending on age, risk factors, and the definition of growth impairment used by reporting groups.[69,70,75,76,77,78] Risk factors include the following:[65,66,76,79]
Patients younger than 10 years at the time of HCT are at highest risk of growth impairment, but also respond best to growth hormone replacement therapy. Early screening and referral of patients with signs of growth impairment to endocrinology specialists can result in significant restoration of height in younger children.
Abnormal body composition/metabolic syndrome
Adult survivors after allogeneic HCT have a risk of premature cardiovascular-related death that is increased 2.3-fold compared with the general population.[81,82] The exact etiology of cardiovascular risk and subsequent death is largely unknown, although development of metabolic syndrome (a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), especially insulin resistance, as a consequence of HCT has been suggested.[83,84,85] In studies of conventionally treated leukemia survivors compared with those who underwent HCT, transplant survivors are significantly more likely to manifest metabolic syndrome or multiple adverse cardiac risk factors including central adiposity, hypertension, insulin resistance, and dyslipidemia.[30,86,87] The concern over time is that survivors who develop metabolic syndrome after HCT will be at higher risk for developing significant cardiovascular-related events and/or premature death from cardiovascular-related causes.
The association of obesity with diabetes and cardiovascular disease risk in the general population is well established, but obesity as determined by body mass index (BMI) is uncommon in long-term survivors after HCT. However, despite having a normal BMI, HCT survivors develop significantly altered body composition that results in both an increase in total percent fat mass and a reduction in lean body mass. This finding is termed sarcopenic obesity and results in a loss of myocyte insulin receptors and an increase in adipocyte insulin receptors; the latter are less efficient in binding insulin and clearing glucose, ultimately contributing to insulin resistance.[88,89,90] Preliminary data from 119 children and young adults and 81 healthy sibling controls found that HCT survivors had significantly lower weight but no differences in BMI or waist circumference when compared with siblings. HCT survivors had a significantly higher percent fat mass and lower lean body mass than the controls. HCT survivors were significantly more insulin resistant than controls, and they also had a higher incidence of other cardiovascular risk factors such as total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Of note, these differences were found only in patients who had received TBI as part of their transplant conditioning regimen.
Musculoskeletal System Late Effects
Low bone mineral density
A limited number of studies have addressed low bone mineral density after HCT in children.[92,93,94,95,96,97,98] A significant portion of children experienced reduction in total-body bone mineral density or lumbar Z-scores showing osteopenia (18%–33%) or osteoporosis (6%–21%). Although general risk factors have been described (female gender, inactivity, poor nutritional status, white or Asian ethnicity, family history, TBI, craniospinal irradiation, corticosteroid therapy, GVHD, cyclosporine, and endocrine deficiencies [e.g., growth hormone deficiency, hypogonadism]), reported populations have been too small to perform multivariate analysis to test the relative importance of each of these factors.[99,100,101,102,103,104,105,106,107,108,109]
Some studies in adults have shown improvement over time in low bone mineral density after HCT;[97,110,111] however, this has yet to be shown in children.
Treatment for children has generally included a multifactor approach, with vitamin D and calcium supplementation, minimization of corticosteroid therapy, weight-bearing exercise, and resolution of other endocrine problems. The role of bisphosphonate therapy in children with this condition is unclear.
Reported incidence of osteonecrosis in children after HCT was 1% to 14%; however, these studies were retrospective and underestimate actual incidence, as patients may be asymptomatic early in the course. Two prospective studies have shown an incidence of 30% to 44% with routine MRI screening of possible target joints.[96,112] Osteonecrosis generally occurs within 3 years after HCT, with a median onset of about 1 year. The most common locations include knees (30%–40%), hips (19%–24%), and shoulders (9%). Most patients experience osteonecrosis in two or more joints.[72,113,114,115]
In one prospective report, risk factors by multivariate analysis included age (markedly increased in children older than 10 years; odds ratio, 7.4) and presence of osteonecrosis at the time of transplant. It is important to note that pre-HCT factors such as corticosteroid exposure are very important in determining patient risk. In this study, 14 of 44 children who developed osteonecrosis had the disease before HCT.
Treatment has generally consisted of minimization of corticosteroid therapy and surgical joint replacement. Most patients are not diagnosed until they present with symptoms. Of note, in one study of 44 patients with osteonecrosis lesions in whom routine yearly MRI was performed, four resolved completely, and two had resolution of one of multiply involved joints. The observation that some lesions can heal over time suggests caution in the surgical management of asymptomatic lesions.
Reproductive System Late Effects
Delayed, absent, or incomplete pubertal development occurs commonly after HCT. Two studies showed pubertal delay or failure in 16% of female children who received cyclophosphamide alone, 72% of those who received busulfan/cyclophosphamide, and 57% of those who underwent fractionated TBI. In males, incomplete pubertal development or failure was noted in 14% of those who received cyclophosphamide alone, 48% of those who received busulfan/cyclophosphamide, and 58% of those who underwent TBI.[71,116] Boys receiving more than 2,400 cGy of radiation to the testicles develop azoospermia and also experience failure of testosterone production, requiring supplementation to develop secondary sexual characteristics.
Pretransplant and transplant cyclophosphamide exposure is the best studied agent affecting fertility. Postpubertal women younger than 30 years can tolerate up to 20 g/m2 of cyclophosphamide and have preserved ovarian function; prepubertal females can tolerate as much as 25g/m2 to 30 g/m2. Although the additional effect added by pretransplant exposures to cyclophosphamide and other agents has not been specifically quantitated in studies, these exposures plus transplant-related chemotherapy and radiation therapy lead to ovarian failure in 65% to 84% of females undergoing myeloablative HCT.[118,119,120,121] The use of cyclophosphamide, busulfan, and TBI as part of the preparative regimen are associated with worse ovarian function. Younger age at the time of HCT is associated with a higher chance of menarche and ovulation.[122,123]
Studies of pregnancy are challenging because data are seldom collected that indicate whether individuals are trying to conceive. Nonetheless, a large study of pregnancy in pediatric and adult survivors of myeloablative transplantation demonstrated conception in 32 of 708 patients (4.5%). Of those trying to conceive, patients exposed to cyclophosphamide alone (total dose 6.7 g/m2 with no pretransplant exposure) had the best chance of conception (56 of 103, 54%), while those receiving myeloablative busulfan/cyclophosphamide (0 of 73, 0%) or TBI (7 of 532, 1.3%) had much lower rates of conception.
The ability of men to produce functional sperm decreases with exposure to higher doses and specific types of chemotherapy. Most men will become azoospermic at a cyclophosphamide dose of 300 mg/kg. After HCT, 48% to 85% will experience gonadal failure.[118,124,125] One study showed that men who received cyclophosphamide conceived only 24% of the time compared with 6.5% of men who received busulfan/cyclophosphamide and 1.3% of those who underwent TBI.
Effect of reduced toxicity/reduced intensity/nonmyeloablative regimens
Based on clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, use of reduced intensity/toxicity and nonmyeloablative regimens will likely lead to a higher chance of preserved fertility after HCT. Because the use of these regimens is relatively new and mostly confined to older or sicker patients, most reports have consisted of single cases. Registry reports are beginning to describe pregnancies after these procedures, but large case-control studies have yet to show in detail the effect of less-toxic regimens on this complication.
Respiratory System Late Effects
Chronic pulmonary dysfunction
Two forms of chronic pulmonary dysfunction are observed after HCT:[126,127,128,129,130]
The incidence of both forms of lung toxicity can range from 10% to 40% depending on donor source, the time interval after HCT, definition applied, and presence of chronic GVHD. In both conditions, collagen deposition and the development of fibrosis either in the interstitial space (restrictive lung disease) or peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.
The most common form of obstructive lung disease following allogeneic HCT is bronchiolitis obliterans.[128,132,133] This condition is an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive obstructive lung disease. Historically, the term bronchiolitis obliterans has been used to describe chronic GVHD of the lung and begins 6 to 20 months after HCT. Pulmonary function tests show obstructive lung disease with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in one second (FEV1), and associated decreases in the FEV1/FVC ratio with or without significant declines in the diffusion capacity of the lung for carbon monoxide (DLCO). Risk factors for bronchiolitis obliterans include the following:[126,132]
The clinical course of bronchiolitis obliterans is variable, but patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression.
Restrictive lung disease is defined by reductions in FVC, total lung capacity (TLC), and DLCO. In contrast to obstructive lung disease, the FEV1/FVC ratio is maintained near 100%. Restrictive lung disease is common after HCT and has been reported in 25% to 45% of patients by day 100. Importantly, declines in TLC or FVC occurring at 100 days and 1 year after HCT are associated with an increase in nonrelapse mortality. Early reports suggested that the incidence of restrictive lung disease increases with advancing recipient age, but more recent studies have revealed significant restrictive lung disease in children receiving HCT. The most recognizable form of restrictive lung disease is bronchiolitis obliterans organizing pneumonia. Clinical features include dry cough, shortness of breath, and fever. Radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in less than 10% of HCT recipients, the development of bronchiolitis obliterans organizing pneumonia is strongly associated with prior acute and chronic GVHD.
Standard treatment for obstructive lung disease combines enhanced immunosuppression with supportive care including antimicrobial prophylaxis, bronchodilator therapy, and supplemental oxygen when indicated. Unfortunately, the response in patients with restrictive lung disease to multiple agents including corticosteroids, cyclosporine, tacrolimus, and azathioprine is limited. The potential role for tumor necrosis factor-alpha in the pathogenesis of both obstructive and restrictive lung disease suggests that neutralizing agents such as etanercept may have promise.
Urinary System Late Effects
Chronic kidney disease is frequently diagnosed after transplant. There are many clinical forms of chronic kidney disease, but the most commonly described ones include thrombotic microangiopathy, nephrotic syndrome, calcineurin inhibitor toxicity, acute kidney injury, and GVHD-related chronic kidney disease. Various risk factors associated with the development of chronic kidney disease have been described; however, recent studies suggest that acute and chronic GVHD may be a proximal cause of renal injury.
In a systematic review of 9,317 adults and children from 28 cohorts who underwent HCT, approximately 16.6% (range, 3.6% to 89%) of patients developed chronic kidney disease, defined as a decrease in estimated glomerular filtration rate of at least 24.5 mL/min/1.73 m2 within the first year after transplant. The cumulative incidence of chronic kidney disease developing approximately 5 years after transplant ranges from 4.4% to 44.3%, depending on the type of transplant and stage of chronic kidney disease.[138,139] Mortality rates among patients with chronic kidney disease in this setting are higher than in transplant recipients who retain normal renal function, even when controlled for comorbidities.
It is important to aggressively treat hypertension in patients post-HCT, especially in those treated with prolonged courses of calcineurin inhibitors. Whether post-HCT patients with albuminuria and hypertension benefit from treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers requires further study, but careful control of hypertension with captopril, an ACE inhibitor, did show a benefit in a small study.
Quality of Life
Health-related quality of life (HRQL)
HRQL is a multidimensional construct, incorporating a subjective appraisal of one's functioning/well-being, with reference to the impact of the health issues on overall quality of life.[142,143]. Many studies have shown that HRQL varies according to the following:
Pre-HCT factors, such as family cohesion and the child's adaptive functioning, have been shown to affect HRQL. Several groups have also identified the importance of pre-HCT parenting stress on parental ratings of children's HRQL post-HCT.[145,146,147,148,149] A report of the trajectories of HRQL over the 12 months following HCT noted that the poorest HRQL was seen at 3 months post-HCT, with steady improvement thereafter. Recipients of unrelated donor transplants had the steepest declines in HRQL from baseline to 3 months. Another study reported that compromised emotional functioning, high levels of worry, and reduced communication during the acute recovery period had a negative impact on HRQL at 1-year post-HCT. Longitudinal studies identified an association of additional baseline risk factors with the trajectory of HRQL following HCT that includes the following:
A report on the impact of specific HCT complications on children's HRQL indicated that HRQL was worse among children with severe end-organ toxicity, systemic infection, or GVHD. Cross-sectional studies report that the HRQL among pediatric HCT survivors of 5 years or more is reasonably good, although psychological, cognitive, or physical problems appear to negatively influence HRQL. Female gender, causal diagnosis for HCT (acute myelogenous leukemia, worse HRQL), and intensity of pre-HCT therapy were all identified as affecting HRQL post-HCT.[156,157] Finally, another cross-sectional study of children 5 to 10 years post-HCT cautioned that parental concerns about the child's vulnerability may induce overprotective parenting.
Physician reported physical performance
Clinician reports of long-term disability among childhood HCT survivors suggest that the prevalence and severity of functional loss is low. A study from the European Group for Blood and Marrow Transplantation used the Karnofsky performance scale to report outcomes among 647 HCT survivors (surviving ≥5 years). In this cohort, 40% of survivors were younger than 18 years when transplanted; only 19% had Karnofsky scores of less than 100. Seven percent had scores less than 80, defined as the inability to work. Similar low rates of clinician-graded poor functional outcome were reported by two other groups.[156,159] Among 50 survivors of childhood allogeneic HCT treated at the City of Hope National Medical Center and Stanford University Hospital, all had Karnofsky scores of 90 or 100. Among 73 young adults (mean age, 26 years) treated at the Karolinska University Hospital, the median Karnofsky score at 10 years post-HCT was 90.
Self-reported physical performance
Self-reported and proxy data among survivors of childhood HCT indicate similar low rates of functional loss. One study evaluated 22 survivors of childhood allogeneic HCT (mean age at HCT, 11 years; mean age at questionnaire, 25 years) and reported no differences between survivors' scores and population-expected values on standardized physical performance scales. Another study compared a group of survivors transplanted for childhood leukemia (n = 142) with a group of childhood leukemia survivors treated with chemotherapy alone (n = 288). There were no differences between the groups on the physical function and leisure scales using multiple standardized measures
Conversely, in the Bone Marrow Transplant Survivors Study (BMTSS), among 235 survivors of childhood HCT, 17% reported long-term physical performance limitations compared with 8.7% of a sibling comparison group. Additionally, a Seattle study evaluated physical function in 214 young adults (median age at questionnaire, 28.7 years; 118 males) who were transplanted at a median age of 11.9 years. When compared with age- and sex-matched controls, the HCT survivors in this cohort scored one-half standard deviation lower on the physical function, role physical, and physical component summary subscales of the SF-36, a quality-of-life measure. Finally, a Swedish study also identified lower self-reported physical health among 73 young adult (median age, 26 years) HCT survivors who were a median of 10 years from transplant. HCT survivors scored significantly below population normative values on physical functioning (90.2 for HCT survivors vs. 95.3 for population), satisfaction with physical health (66.0 for HCT survivors vs. 78.7 for population), and role limitation due to physical health (72.7 for HCT survivors vs. 84.9 for population).
Measured physical performance
Objective measurements of function in the pediatric HCT patient and survivor population hints that loss of physical capacity may be a bigger problem than revealed in studies that rely on either clinician or self-report data. Most of these data are from objective measures of cardiopulmonary fitness. One study used exercise capacity with cycle ergometry in a group of 20 children and young adults before HCT, 31 patients 1-year post-HCT, and 70 healthy controls. Average peak oxygen consumption was 21 ml/kg/min in the pre-HCT group, 24 ml/kg/min in the post-HCT group, and 34 ml/kg/min in the healthy controls. Among the HCT survivors, 62% of those with cancer diagnoses scored in the lowest fifth percentile for peak oxygen consumption compared with healthy controls. Another study examined exercise capacity with a Bruce treadmill protocol in 31 survivors of pediatric HCT. In this cohort, 25.8% of HCT survivors had exercise capacities in the 70% to 79% of predicted category, and 41.9% had exercise capacities in the less than 70% of predicted category. In a third study of exercise capacity among 33 HCT survivors transplanted at a mean age of 11.3 years, at the 5-year post-HCT time point, only 4 of 33 survivors scored above the 75th percentile on a serial cycle ergometry test.
Predictors of poor physical performance
In the BMTSS, associations were found between chronic GVHD, cardiac conditions, immune suppression, or treatment for a second malignant neoplasm and poor physical performance outcomes. In the a study from the Fred Hutchison Cancer Research Center, poor performance was associated with myeloid disease.
Published Guidelines for Long-Term Follow-Up
A number of organizations have put forward consensus guidelines for follow up for late effects after HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR) along with the American Society of Blood and Marrow Transplant (ASBMT) in cooperation with five other international transplant groups published consensus recommendations for screening and preventive practices for long-term survivors of HCT. Although some pediatric-specific challenges are addressed in these guidelines, many important pediatric issues are not. Some of these issues have been partially covered by general guidelines published by the Children's Oncology Group (COG) and other children's cancer groups (UK, Scotland, and Netherlands). To address the lack of detailed pediatric-specific late effects data and guidelines for long-term follow-up after HCT, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) published six detailed papers outlining existing data and summarizing recommendations from key groups (CIBMTR/ASBMT, COG, and the UK), along with expert recommendations for pediatric specific issues.[8,30,61,168,169,170] Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are underway, the PBMTC summary and guideline recommendations provide the most current outline for following children for late effects after HCT.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with hematopoietic stem cell transplantation. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Allogeneic Hematopoietic Cell Transplantation (HCT)
Added a Figure about human leukocyte antigen (HLA) allele duplications and types of mismatches.
Added text about how HLA allele duplication in a donor or recipient results in a "half" match and a mismatch that will either occur in a direction that promotes graft-versus-host disease (GVHD) (GVH-O) or a direction that promotes rejection (R-O). The 7/8 mismatched in only the R-O direction is preferred over GVH-O and bidirectional mismatches (cited Hurley et al. as reference 10).
Added text about the results of a large Center for International Bone Marrow Transplant Research/Eurocord study; best outcome was noted with 8/8 allele matching. Cord blood transplant patients with one to four allele mismatches required a higher cell dose to decrease transplant-related mortality (cited Eapen et al. as reference 12).
Added Kanda et al. as reference 14.
Added text about a retrospective study of Japanese children with acute leukemia that compared 90 children who received peripheral blood stem cells (PBSCs) with 571 children who received bone marrow; the study confirmed higher transplant-related mortality due to GVHD and inferior survival among the children who received PBSCs (cited Shinzato et al. as reference 24).
Revised text to state that donor-derived natural killer cells in the post-HCT setting have been shown to promote engraftment, decrease GVHD, lessen relapse of hematological malignancies, and improve survival (cited Bari et al. as reference 46).
Complications After HCT
Added text to state that one small, retrospective, single-center study showed a benefit from corticosteroid therapy; this requires further validation (cited Myers et al. as reference 11).
Added Richardson et al. as reference 14.
Added text to state that studies have linked transplant-associated microangiopathy with disruption of alternative complement pathways (cited Jodele et al. as reference 16).
Late Effects After HCT in Children
Added Sun et al. as reference 1.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hematopoietic cell transplantation in treating childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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National Cancer Institute: PDQ® Childhood Hematopoietic Cell Transplantation. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childHCT/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-04-08
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