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Home > Living Well > Health Library > Childhood Hematopoietic Cell Transplantation (PDQ®): Treatment - Health Professional Information [NCI]
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 HSCT
Blood and marrow transplantation, or HSCT, is a procedure that involves infusion of hematopoietic stem cells (along with hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen consisting of agents designed to do the following:
HSCT is currently used in the following three clinical scenarios:
Autologous Versus Allogeneic HSCT
The two major HSCT approaches currently in use are the following:
An autologous transplant treats cancer by exposing patients to high-dose therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient's previously stored hematopoietic stem cells. The transplant can be performed in a single procedure or tandem sequential procedures. For autologous transplants to result in cure of malignancies, the following must apply:
Autologous transplants have also been used to reset the immune system in patients with severe autoimmune disorders.
Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, and brain tumors. Autologous transplant techniques are also being used to enable engraftment of genetically modified autologous hematopoietic stem cell progenitors to correct or ameliorate inherited disorders (e.g., immunodeficiencies, metabolic disorders, and hemoglobinopathies).
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 or graft-versus-leukemia treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to even high doses of chemotherapy and/or involve the bone marrow, thus requiring allogeneic approaches for optimal outcome.
Determining When HSCT Is Indicated: Comparison of HSCT and Chemotherapy Outcomes
Because the outcomes using chemotherapy and HSCT treatments have been changing over time, these approaches should be compared regularly to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat trials using an HLA-matched sibling donor have established the benefit of HSCT by direct comparison.[1,2] However, for very high-risk patients, such as those with early relapse of acute lymphoblastic leukemia, randomized trials have not been feasible because of investigator bias.[3,4]
In general, HSCT typically benefits only children at high risk of relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HSCT if appropriate allogeneic donors are available are the preferred approach for many diseases. Less well-established, higher-risk approaches to HSCT are generally reserved for only the very highest-risk patients. However, higher-risk approaches, such as haploidentical transplantation, are becoming safer and more efficacious and are increasingly used interchangeably with fully matched allogeneic approaches.[6,7,8,9] (Refer to the Haploidentical HSCT section of this summary for more information.)
When comparisons of similar patients treated with HSCT or chemotherapy are made in the setting where randomized or intent-to-treat studies are not feasible, the following issues should be considered:
To account for time-to-transplant bias, the chemotherapy comparator arm should include only patients who maintained remission until the median time to HSCT. The HSCT comparator arm should also include only patients who achieved the initial remission mentioned above and maintained that remission until the time of HSCT.
High-risk and intermediate-risk patient groups should not be combined because a benefit of HSCT in the high-risk group can be masked when outcomes are similar to those achieved in the intermediate-risk group.
Physician bias, for or against HSCT, is difficult to control for or detect. The effects of access to HSCT and therapeutic bias on outcomes of pediatric malignancies for which HSCT may be indicated have been poorly studied.
Collection and Storage of Autologous Hematopoietic Stem Cells
Autologous procedures require collection of growth-factor–mobilized peripheral blood stem cells (PBSCs) from patients by the process of leukapheresis. Bone marrow can be used for autologous transplants, but PBSCs lead to quicker blood count recovery, resulting in less transplant-related toxicity.
Patients being considered for autologous hematopoietic stem cell transplantation (HSCT) are generally given chemotherapy to determine tumor responsiveness and minimize the risk of tumor contamination in their bone marrow. After a number of rounds of chemotherapy, patients undergo the leukapheresis procedure, either as their blood counts recover from chemotherapy or during a break between chemotherapy treatments. Growth factors such as granulocyte colony-stimulating factor are used to increase the number of circulating stem and progenitor cells (CD34+ cells). Collection centers monitor the CD34-positive number in the patient and product each day to determine the best time to begin collection and when collection is complete. Patients with low numbers of CD34-positive cells before collection can often have their cells successfully collected using alternative mobilization approaches (e.g., addition of plerixafor). The collected PBSCs are cryopreserved for later use. After completion of an intensive preparative regimen using high-dose chemotherapy, which varies according to the tumor type, the PBSCs are administered back into 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 the following:
Tumor-specific regimens are described in disease-specific PDQ treatment summaries.
The tumor-specific activity and intensity of agents used for autologous regimens have been shown to be important in improving survival.
The contamination of the collected stem cell product by persistent tumor cells is one concern with autologous approaches for these and other tumor types. Although many techniques have been developed to remove or purge tumor cells from products, studies have shown no benefit to tumor purging.
Improved Outcomes After Allogeneic Transplantation
Over the past one to two decades, significant advances have led to improved outcomes after allogeneic hematopoietic stem cell transplantation (HSCT).[1,2,3] The most significant improvements in survival occurred in unrelated and alternative donor procedures.[4,5,6] Possible explanations for these improvements in survival include improved patient selection, better supportive care, refined treatment regimens, improved approaches specific to stem cell sources, and better HLA typing. All of these factors may have contributed to better outcomes; however, the section below focuses on modifiable aspects of HSCT (i.e., optimization of HLA typing and selection of stem cell sources).
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 HSCT (refer to Figure 1 and Tables 1 and 2).
Figure 1. HLA Complex. Human chromosome 6 with amplification of the 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, DRB3, DRB4, DRB5, 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 American patients, Hispanic patients, and Asian-Pacific Islander patients).[7,8] Full siblings of cancer patients have a 25% chance of being HLA matched.
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 because the use of donors with allele-level mismatches affects survival and rates of graft-versus-host disease (GVHD) to a degree similar to that in patients with antigen-level mismatches. Because of this, DNA-based allele-level HLA typing is standard when unrelated donors are being chosen.
HLA matching considerations for sibling and related donors
The most commonly used related donor is a sibling from the same parents who, at a minimum, is HLA matched for HLA A, HLA B, and HLA DRB1 at the antigen level. Given the distance between HLA A and HLA DRB1 on chromosome 6, 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 not a full 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) were used interchangeably with matched sibling donors in some studies, a large Center for International Blood and Marrow Transplant Research (CIBMTR) study in pediatric HSCT recipients showed that the use of 5/6 antigen-matched related donors resulted in rates of GVHD and overall survival (OS) equivalent to rates in 8/8-allele-level-matched unrelated donors and slightly inferior survival than in fully matched siblings. Any siblings with single mismatches should have extended typing to ensure that if the mismatch is caused by a crossover, it only occurs with one antigen. If clinicians choose siblings with multiple antigen mismatches as donors, haploidentical approaches may be warranted.
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) (refer to Table 2). A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% and 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,[9,12,13] but the differences in outcome are small and inconsistent, making it very difficult to conclude that one can pick a more favorable mismatch by choosing one type of antigen mismatch over another. Many study groups are attempting to define specific antigens or pairs of antigens that are associated with either good or poor outcomes. For example, a specific HLA C mismatch (HLA-C*03:03/03:04) has outcomes similar to a match; therefore, selection of this mismatch is desirable in an otherwise matched donor/pair combination.
It is well understood that class II antigen DRB1 mismatches increase GVHD incidence and worsen survival. Subsequent data have also shown that multiple mismatches of DQB1, DPB1, and DRB3,4,5 lead to worse outcomes in the setting of less than 8/8 matches. DPB1 mismatches have been extensively studied and classified as permissive or nonpermissive on the basis of T-cell epitope matching. Patients with 10/10 matches and nonpermissive DPB1 mismatches have more transplant-related mortality but have survival rates similar to those with DPB1 matches or permissive matches. Those with 9/10 matches who have nonpermissive DPB1 mismatches had worse survival than did those with permissive mismatches or DPB1 matches.[16,17,18]
With these findings in mind, although a 7/8- or 8/8-matched unrelated donor can be used routinely, outcomes may be further improved with the following:
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 occur in either a direction that promotes GVHD (GVH-O) or a direction that promotes rejection (R-O). When 8/8-matched unrelated donors are compared 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 rates in the 8/8 matched and better than in 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. The National Marrow Donor Program has published guidelines for HLA matching. The term for allele-level matching used in their guidelines is antigen recognition domain, which refers to the fact that the allele-level similarities used to define the specific HLA type are associated with areas directly used for antigen recognition. Polymorphisms of the HLA proteins outside of these areas are not involved in the function of these molecules; therefore, they are often not assessed as part of HLA testing and unlikely to contribute to HLA mismatch.
HLA matching and cell dose considerations for unrelated cord blood HSCT
Another commonly used hematopoietic stem cell source is unrelated umbilical cord blood, which is harvested from donor placentas moments after birth. The cord blood is processed, HLA typed, cryopreserved, and banked.
Unrelated cord blood transplantation has been successful with less-stringent HLA matching requirements compared with standard related or unrelated donors, probably because of limited antigen exposure experienced in utero and different immunological composition. Cord blood matching has traditionally been performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. This means that until just recently, attempted matching of only six antigens has been necessary to choose units for transplantation.
Although better outcomes occur when 6/6 or 5/6 HLA-matched units are used, successful HSCT has occurred even with 4/6 or less HLA-matched units in many patients. In a large CIBMTR/Eurocord study, better matching at the allele level using eight antigens (matching for HLA A, B, C, 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 outcomes; however, those with one to three allele mismatches had less transplant-related mortality with total nucleated cell counts higher than 3 × 107 /kg, and those with four allele mismatches required a total nucleated cell count higher than 5 × 107 /kg to decrease transplant-related mortality. This observation was noted to be especially important in cord blood transplantation for nonmalignant disorders, where any mismatching below 7/8 alleles led to inferior survival. Many centers will type additional alleles and use the best match possible, but the impact of DQB1, DPB1, and DRB3,4,5 mismatches has not been studied in detail.
As in unrelated peripheral blood stem cells (PBSCs) or bone marrow donors, extended HLA testing can support the selection of appropriate cord blood units in HLA-sensitized patients to avoid the potential risk of graft failure.[27,28] Evidence also suggests that selecting a mismatched cord blood unit, where the mismatch involves a noninherited maternal antigen, may improve survival.[29,30]
As with unrelated donors, individuals can occasionally 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 (mismatched in the GVHD direction). This variation of partial mismatching has been shown to be important in cord blood transplant outcomes. Mismatches that are only in the GVHD direction (i.e., GVH-O) lead to lower transplant-related mortality and overall mortality than those with rejection direction only (i.e., R-O) mismatches. R-O mismatches have outcomes similar to those of bidirectional mismatches. Although these studies suggest that using unidirectional mismatching as a criteria for cord blood selection may be beneficial, a Eurocord–European Society for Blood and Marrow Transplantation analysis disputes the value of this type of mismatching.
Two aspects of umbilical cord blood HSCT have made the practice more widely applicable. First, because a successful procedure can occur with multiple HLA mismatches, more than 95% of patients from a wide variety of ethnicities are able to find at least a 4/6-matched cord blood unit.[7,34] Second, as mentioned above, adequate cell dose (minimum 2–3 × 107 total nucleated cells/kg and 1.7 × 105 CD34+ cells/kg) has been shown to be associated with improved survival.[35,36] Total nucleated cells are generally used to judge units because techniques to measure CD34-positive 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 HSCT focused mainly on smaller children. Later studies showed that barriers of this size 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 cord blood units provide higher cell doses, umbilical cord blood transplantation is now used widely for larger children and adults.
If a single unit provides an adequate cell dose, there may be disadvantages to adding a second unit.[Level of evidence: 1iiA] Two randomized trials showed that in children who had adequately sized single units, the addition of a second unit did not alter relapse, transplant-related mortality, or survival rates, but was associated with higher rates of extensive chronic GVHD.[38,39]
Investigators have shown that by using combinations of cytokines and other compounds to expand cord blood for a period of time before infusion, engraftment of cord blood cells can occur more rapidly than after standard approaches.[40,41,42,43] Although some studies that used multiple units or split units showed that expanded units will engraft early and then give way to nonexpanded units for long-term reconstitution, other studies are showing persistence of expanded cells, implying preservation of stem cells through the expansion process.[42,43] A number of these approaches are under investigation. Their effect on efficacy and survival of children using cord blood as a stem cell source has yet to be established, and none are approved by the U.S. Food and Drug Administration (FDA).
Comparison of stem cell products
Currently, the following three stem cell products are used from both related and unrelated donors:
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 from other stem cell products. A comparison of stem cell products is presented in Table 3.
The main differences between the products are the numbers of T cells and CD34-positive 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 for whom full HLA matching is not available. Higher doses of T cells and other cells in PBSCs result in rapid neutrophil recovery and immune reconstitution but also increase rates of chronic GVHD.
Only a few studies have directly compared outcomes of different stem cell sources/products in pediatric patients.
Evidence (comparison of outcomes of stem cell sources/products in children):
These reports, combined with a lack of prospective studies comparing bone marrow and PBSCs, have led most pediatric transplant protocols to prefer bone marrow over PBSCs from related donors. This approach is further supported by a meta-analysis that included additional retrospective trials.
A large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial for patients requiring unrelated donors included a number of pediatric patients. Patients were randomly assigned to receive either bone marrow or PBSCs. This trial demonstrated that OS was identical using either source, but rates of chronic GVHD were significantly higher in the PBSC arm, with a small increase in rejection in the bone marrow arm. Rejections were rare in pediatric patients. There was an insufficient number of patients to draw specific conclusions about rejection risk in children who received bone marrow.
Published studies comparing unrelated cord blood and bone marrow have been retrospective, with weaknesses inherent in such analyses.
Evidence (comparison of unrelated cord blood versus bone marrow outcomes):
On the basis of 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, HLA-matched (4/6 to 6/6 or 6/8 to 8/8) cord blood from a single unit with an adequate cell dose, or a haploidentical HSCT lead to similar survival rates.[Level of evidence: 3iiiDii] Although adult studies of T-cell–depleted unrelated bone marrow or PBSCs 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 been conducted.
Early HSCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival rates as the number of donor/recipient HLA mismatches increased. Other studies showed 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, and Asian-Pacific Islander patients) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).
To allow access to HSCT for patients without fully HLA-matched donor options, investigators have developed techniques allowing the 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. Most approaches developed to date rely on intense T-cell depletion of the product before infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery, which can result in lethal infections, increased risk of EBV-associated lymphoproliferative disorder, and high rates of relapse. This led to inferior survival compared with matched-donor HSCTs in the past and resulted in the procedure being used mainly at larger academic centers with a specific research focus on studying and developing this approach.
Current approaches, however, are rapidly evolving, resulting in improved outcomes, with some pediatric groups reporting survival similar to that of standard approaches.[62,63] These approaches include the following:
Reported rates of survival using many different types of haploidentical approaches range from 25% to 80%, depending on the technique and the risk of the patient undergoing the procedure.[61,62,67,68]; [Level of evidence: 3iiiA] Retrospective trials in adults have shown similar outcomes after haploidentical-donor transplants compared with matched-unrelated donor or cord blood transplants.[70,71] One prospective randomized trial in adults with hematologic malignancies that used reduced-intensity regimens showed similar progression-free survival, but lower relapse rates and better OS using haploidentical donors. Pediatric trials using haploidentical donors have shown better outcomes with myeloablative preparative regimens, and survival is comparable to nonhaploidentical approaches.[58,73] Whether haploidentical approaches are superior to cord blood or other unrelated donor stem cell sources for children has not been determined because prospective comparative studies have yet to be performed.
Even more than with other stem cell sources, patients undergoing haploidentical procedures can develop anti-HLA antibodies that, if directed against nonshared haploidentical antigens, can greatly increase the risk of rejection. Clinicians should choose donors with HLA types against whom the recipient does not have an antibody present, if possible. Guidelines on how to best approach this issue have been published.
Other donor characteristics associated with outcome
HLA matching has consistently been the most important factor associated with improved survival in nonhaploidentical allogeneic HSCT, but a number of other donor characteristics have been shown to affect key outcomes. Higher cell dose from the donor (refer to the HLA matching and cell dose considerations for unrelated cord blood HSCT section of this summary for more information) has also been shown to be important when related, unrelated, or haploidentical bone marrow or PBSC donors are used.[75,76] The effects of donor age, blood type, CMV status, sex, and parity of female donors have also been studied.
Ideally, after HLA matching, transplant centers should select donors based on the following characteristics:
It is rare for a donor/recipient pair to fit perfectly into this algorithm, and determining which of these characteristics should be chosen over others has been controversial. A CIBMTR study examined 6,349 patients who underwent transplant for hematological malignancies from 1988 to 2006 and a confirmation cohort of 4,690 patients who underwent transplant between 2007 and 2011. The study tested the effect of donor characteristics while adjusting for disease risk and other key transplant characteristics.[78,84]
Thus, after HLA matching, donor age is likely the most important factor to optimize. Of note, if the recipient is CMV negative, finding a CMV-negative donor is also a high priority.
A number of studies have attempted to identify characteristics of the best donors for haploidentical procedures. As with conventional bone marrow transplantation, use of younger donors appears to be beneficial, but data regarding donor sex are inconclusive. Studies involving intense T-cell depletion have noted better outcomes using maternal donors, but studies using posttransplant cyclophosphamide or intense immune suppression seem to favor male donors.[87,88] Further study is needed to clarify this important issue. One large comparison of haploidentical donors showed an effect of ABO incompatibility on engraftment (risk of rejection doubling from 6% to 12%, ABO match vs. ABO major mismatch), and patients receiving bidirectionally mismatched donors had a 2.4-fold increase in grades II to IV acute GVHD. As with nonhaploidentical donors, significant improvement of outcomes has been noted when younger donors are used for haploidentical procedures compared with older donors, with a hazard ratio of 1.13 for each decade of life that the donor is older.
Immunotherapeutic Effects of Allogeneic HSCT
Graft-versus-leukemia (GVL) effect
Early studies in HSCT focused on the 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 GVL or graft-versus-tumor (GVT) effect and has been 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 GVHD. For standard approaches to HSCT, the highest survival rates have been associated with mild or moderate GVHD (grades I to II in AML and grades I to III in ALL), compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.[91,92,93]; [Level of evidence: 3iDi]
Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study compares rates of relapse and survival between patients undergoing myeloablative HSCT with either autologous or allogeneic donors for a given disease.
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 Allogeneic HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL because, in most cases, the intensity of the preparative regimen is not sufficient for cure. Although studies have shown benefit for patients pursuing this approach when they are ineligible for standard transplantation, this approach has not been used for most children with cancer who require HSCT because pediatric cancer patients can generally undergo myeloablative approaches safely.
Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL
GVL can be achieved therapeutically through the infusion of cells after transplant that either specifically or nonspecifically target the 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 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 patients with other diseases (such as AML and ALL) have been less potent, with long-term survival rates of only 20% to 30%. 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 the treatment of patients into complete remission with chemotherapy before DLI have been associated with improved outcomes. Infusions of donor lymphocytes 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 HSCT. Some studies have scheduled more rapid immune suppression tapers based on donor type (related donors are tapered more quickly than are unrelated donors because of less GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient chimerism, from the Greek chimera, a mythical animal with parts from various animals) or MRD to assess the risk of relapse and trigger rapid taper of immune suppression.
A combination of early withdrawal of immune suppression after HSCT with DLI to prevent relapse in patients at high risk of relapse because of persistent/progressive recipient chimerism has been tested in patients who underwent transplant for both ALL and AML.[Level of evidence: 2A]; [Level of evidence: 3iiDii]
Other immunological and cell therapy approaches under evaluation
Role of killer immunoglobulin-like receptor (KIR) mismatching in HSCT
Donor-derived NK cells in the post-HSCT setting have been shown to promote the following:[106,107,108]
NK-cell function is modulated by interactions with a number of receptor families, including activating and inhibiting KIR. The KIR effect in the allogeneic HSCT setting hinges on the expression of specific inhibitory KIR on donor-derived NK cells and either the presence or absence of their matching HLA class I molecules (KIR ligands) on recipient leukemic and normal cells. Normally, the presence of specific KIR ligands interacting with paired inhibitory KIR molecules prevents NK cell attack on healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells, and they may not have the appropriate inhibitory KIR ligand. 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 KIR-ligand combinations was made in the setting of T-cell–depleted haploidentical transplantation and was strongest after HSCT for AML.[107,109] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate KIR-ligand combinations. Many subsequent studies did not detect survival effects for KIR-incompatible HSCT using standard transplantation methods,[110,111,112] 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 KIR-ligand incompatibility after cord blood HSCT, a relatively T-cell–depleted procedure.[113,114] In contrast to this notion, one study demonstrated that some KIR mismatching combinations (activating receptor KIR2DS1 with the HLA C1 ligand) can lead to decreased relapse after AML HSCT without T-cell depletion. The role of KIR incompatibility in sibling donor HSCT and in diseases other than AML is controversial, but in pediatrics, at least two groups have found better outcomes with specific types of KIR mismatching in ALL.[62,116,117]
A current challenge associated with studies of KIR is that several different approaches have been used to determine what is KIR incompatible and what are the most favorable combinations of KIR molecules in donor-recipient pairs.[109,118] Activating KIR molecules have also been shown to contribute to the effect. The standardization of classification and prospective studies should help clarify the utility and importance of this approach. Because a limited number of centers perform haploidentical HSCT and the results of other approaches to HSCT are preliminary, most transplant programs do not use KIR mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of KIR mismatching or choosing donors with favorable KIR activation profiles remaining secondary.
With a low risk of GVHD and demonstrated efficacy in decreasing relapse in posthaploidentical HSCT settings, NK-cell infusions as a method of treating high-risk patients and consolidating patients in remission have been studied:
Evidence (NK-cell transplantation outcomes):
Other investigators have used expanded/activated NK cells before and after HSCT. One approach that included the culturing of haploidentical NK cells with membrane-bound IL-21 showed marked expansion and high activity. These cells were then infused just before haploidentical HSCT, followed by additional infusions on day +7 and +28 after HSCT.
Although early survival rates in this high-risk AML cohort are high, multicenter confirmatory studies will be necessary to establish the efficacy of these types of NK-cell approaches.
Chimeric antigen receptor (CAR) T-cell therapy
For T cells to attack cellular targets (viruses or cancer cells), they must bind to class I major histocompatibility complex (MHC) molecules on the surface of the target cells and avoid suppressor signals sent by regulatory T cells and other surface molecule interactions. Gene transfer technologies can modify T cells to express MHC-independent antibody-binding domains (CAR molecules) aimed at specific target proteins on the surface of tumors. To minimize the chance of suppressor mechanisms affecting CAR T-cell function and to create a cytokine milieu conducive to CAR T-cell expansion, lymphodepleting chemotherapy is generally given before CAR T-cell infusions. CAR T-cell–mediated responses are further enhanced by adding intracellular costimulatory domains (e.g., CD28, 4-1BB), which cause significant CAR T-cell expansion and may increase the lifespan of these cells in the recipient.
Investigators using this technology have targeted a variety of tumors/surface molecules, but the best-studied example in pediatric patients is CAR T cells aimed at CD19, a surface receptor on B cells. Several groups have reported significant rates of remission (70%–90%) in children and adults with refractory B-cell ALL,[124,125,126,127] and several groups have reported persistence of CAR T cells and remission beyond 6 months in most patients studied.[127,128] Early loss of the CAR T cells is associated with relapse, and the best use of this therapy (bridge to transplant vs. definitive therapy) is under study.
Responses have been associated with a significant increase in inflammatory cytokines, termed cytokine release syndrome (CRS), which presents as a sepsis-like situation that can be successfully treated with anti–interleukin-6 receptor (IL-6R) therapies (tocilizumab), often in combination with steroids.[129,130] CRS presents as fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. Whether patients with CRS require therapy depends on severity, which can be measured by staging. The American Society for Transplantation and Cellular Therapy Consensus guidelines for CRS have now been broadly adopted (refer to Table 4). While treatment of grade 1 and early grade 2 CRS is generally not offered, patients with some forms of grade 2 and all patients with grades 3 and 4 CRS require therapy.
Neurotoxicities, including aphasia, altered mental status, and seizures, have also been observed with CAR T-cell therapy. This clinical syndrome (immune effector cell-associated neurotoxicity syndrome [ICANS]) is graded according to the most severe five measures that are not attributable to causes other than CAR T-cell therapy, as follows:
Most neurological toxicities after CD19-targeted CAR T-cell therapy have been short lived (1–5 days), but rare, fatal events such as severe cerebral edema have been reported. The pathophysiology of central nervous system (CNS) toxicity is likely related to disruption of the blood-brain barrier secondary to systemic cytokine release, high levels of cytokines in the cerebrospinal fluid, and/or direct attack of CD19-positive brain mural cells in the CNS tissue by the CAR T cells. CNS symptoms have not responded well to IL-6R–targeting agents and have generally been treated with high-dose steroids or other approaches. Exactly when treatment is required for ICANS is controversial, but concerns about its rare, fatal form have led to near-uniform recommendations for the treatment of patients with grade 3 or higher ICANS.
Other CAR T-cell therapy side effects include coagulopathy, hemophagocytic lymphohistiocytosis–like laboratory changes, and cardiac dysfunction. Early studies of patients with high levels of disease and delayed CRS therapy resulted in 20% and 40% of patients requiring treatment in the intensive care unit (mostly pressor support, with 10% to 20% of patients requiring intubation and/or dialysis);[124,127,128] however, current real-world data show that intensive care unit requirements are now less than 10% to 20%.
An international trial in children led to FDA approval of tisagenlecleucel for multiply relapsed or refractory, CD19-positive, B-cell ALL for patients aged 1 to 25 years. Tisagenlecleucel has also been approved for adults with B-cell lymphoma, as has axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel.[137,138]
Principles of Allogeneic HSCT Preparative Regimens
In the days just before infusion of the stem cell product (bone marrow, PBSCs, or cord blood), HSCT 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 GVL effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HSCT approaches focusing on immune suppression rather than myeloablation have been developed. The resulting lower toxicity associated with these regimens has led to lower rates of transplant-related mortality and expanded eligibility for allogeneic HSCT to older individuals and younger patients with pre-HSCT comorbidities that put them at risk of severe toxicity after standard HSCT approaches.
The preparative regimens available now vary tremendously in the amount of immunosuppression and myelosuppression they cause, with the lowest-intensity regimens relying heavily on a strong GVT effect (refer to Figure 3).
Figure 3. Selected preparative regimens frequently used in pediatric HSCT categorized by current definitions as nonmyeloablative, reduced intensity, or myeloablative. Although FLU plus treosulfan and FLU plus busulfan (full dose) are considered myeloablative approaches, these and similar approaches are called reduced-toxicity regimens.
Although these regimens lead to varying degrees of myelosuppression and immune suppression, they have been grouped clinically into the following three major categories (refer to Figure 4):
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.
For a number of years, retrospective studies showed similar outcomes using reduced-intensity and myeloablative approaches.[75,141] However, a BMT CTN trial of adult patients with AML and MDS who were randomly assigned to receive either myeloablative or reduced-intensity HSCT approaches demonstrated the importance of regimen intensity.
With this in mind, the use of reduced-intensity conditioning and nonmyeloablative regimens is well established in older adults who cannot tolerate more intense myeloablative approaches,[143,144,145] but these approaches have been studied in a limited number of younger patients with malignancies.[146,147,148,149,150] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk of 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 these patients 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 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 and is most likely to be successful when patients have achieved MRD-negative remissions.
Establishing donor chimerism
Intense myeloablative approaches almost invariably result in hematopoiesis derived from donor cells upon count recovery after the transplant. The introduction of reduced-intensity conditioning and nonmyeloablative approaches into HSCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that sometimes remains partial. DNA-based techniques have been established to differentiate donor from recipient hematopoiesis, applying the word chimerism to describe whether all or part of hematopoiesis after HSCT is from the donor or recipient.
There are several implications regarding the pace and extent of donor chimerism achieved by an HSCT recipient. For patients receiving reduced-intensity conditioning or nonmyeloablative regimens, rapid progression to full donor chimerism is associated with lower relapse rates but more GVHD. The delayed pace of obtaining full donor chimerism after reduced-intensity regimens has led to late-onset acute GVHD, occurring as late as 6 to 7 months after HSCT (generally occurs 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 HSCT for malignancies and less GVHD; however, this condition is often advantageous for nonmalignant HSCT, 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 DLI. (Refer to the Using donor lymphocyte infusions [DLI] or early withdrawal of immune suppression to enhance GVL section of this summary for more information.) These approaches are frequently used to address this issue, and they have been shown to decrease relapse risk and stop rejection in some cases.[104,155,156] The timing of tapers of immune suppression and doses and approaches to administration of DLI to increase or stabilize donor chimerism vary among transplant approaches and institutions.
Indications for HSCT vary over time as risk classifications for a given malignancy change and the efficacy of primary therapy improves. It is best to include specific indications in the context of complete therapy for any given disease. With this in mind, links to sections in specific PDQ summaries where HSCT indications are discussed are provided below.
HSCT Indications for Hematologic Malignancies
HSCT Indications for Solid Tumors
Chimeric Antigen Receptor (CAR) T-Cell Therapy Indications
Pre-HSCT Comorbidities That Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Specific 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, and functional status) is associated with a 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 (CCI). Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the CCI 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 hematopoietic cell transplantation–specific comorbidity index (HCT-CI).[1,2] Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (refer to Table 5).
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 and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or higher, compared with those who have a score of 0. Although the original studies were performed with patients receiving intense myeloablative approaches, the HCT-CI has also been shown to predict outcomes for patients receiving reduced-intensity and nonmyeloablative regimens. It has also been combined with disease status  and Karnofsky score, leading to even better prediction of survival outcomes. In addition, high HCT-CI scores (>3) have been associated with a higher risk of grades 3 to 4 acute graft-versus-host disease (GVHD).
Most patients assessed in the HCT-CI 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 HSCT has been explored in the following studies:
Most of the reported comorbidities in these studies were with respiratory or hepatic conditions and infections.[7,8] In the adolescent and young adult study, patients with pre-HSCT pulmonary dysfunction were at particularly high risk of comorbidity, with a 2-year OS rate of 29%, compared with 61% in those with normal lung function before HSCT.
Selected HSCT-Related Acute Complications
Infectious risks and immune recovery after transplantation
Defective immune reconstitution is a major barrier to successful HSCT, regardless of graft source.[10,11] Serious infections have accounted for a significant percentage (4%–20%) of late deaths after HSCT.
Factors that can significantly slow immune recovery include the following:
Figure 5 illustrates the immune defects, contributing transplant-related factors, and types and timing of infections that occur after allogeneic transplantation.
Figure 5. Phases of predictable immune suppression with their opportunistic infections among allogeneic hematopoietic stem cell transplantation recipients. Adapted from Burik and Freifeld. This figure was published in Clinical Oncology, 3rd edition, Abeloff et al., Chapter: Infection in the severely immunocompromised patient, Pages 941–956, Copyright Elsevier (2004).
Bacterial infections tend to occur in the first few weeks after transplant during the neutropenic phase, when mucosal barriers are damaged from the conditioning regimen; there is significant ongoing study about the role of prophylactic antibacterial medications during the neutropenic phase.
Guidelines for prevention of infections after HSCT have been established by a joint effort of the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Transplantation and Cellular Therapy. Approaches include preventive or prophylactic antivirals, antifungals, and antibiotics; escalation to heightened empiric therapy for signs of infection; and continued careful monitoring through the full duration of the immunocompromised period after HSCT.
Prophylaxis against fungal infections is standard during the first several months after transplantation and may be considered for patients with chronic GVHD who are at high risk of fungal infection. Antifungal prophylaxis must be tailored to the patient's underlying immune status. Pneumocystis infections can occur in all patients after bone marrow transplants, and prophylaxis is mandatory.; [Level of evidence: 3iiiB]
After HSCT, viral infections can be a major source of mortality, especially after T-cell–depleted or cord blood procedures. Types of viral infections include the following:
Careful viral monitoring is essential during high-risk allogeneic procedures.
Late bacterial infections can occur in patients who have central lines or patients with significant chronic GVHD. These patients are susceptible to infection with encapsulated organisms, particularly pneumococcus. Despite reimmunization, these patients can sometimes develop significant infections, and continued prophylaxis is recommended until a serological response to immunizations has been documented. Occasionally, postallogeneic HSCT patients can become functionally asplenic, and antibiotic prophylaxis is recommended. Patients should remain on infection prophylaxis (e.g., Pneumocystis jirovecii pneumonia prophylaxis) until immune recovery. Time to immune recovery varies but ranges from 3 months to 9 months after autologous HSCT, and 9 months to 24 months after allogeneic HSCT without GVHD. Patients with active chronic GVHD may have persistent immunosuppression for years. Many centers monitor T-cell subset recovery after bone marrow transplants as a guide to infection risk.
Vaccination after transplantation
International transplant and infectious disease groups have developed specific guidelines for the administration of vaccines after autologous and allogeneic transplantation.[15,19,20] Comparative studies aimed at defining ideal timing of vaccination after transplantation have not been performed, but the vaccine guidelines outlined in Table 6 result in protective titers in most patients who receive vaccinations. These guidelines recommend that autologous transplant recipients receive immunizations beginning at 6 months after stem cell infusion and receive live vaccines 24 months after the transplant. Patients undergoing allogeneic procedures can begin immunizations as soon as 6 months after transplant. However, many groups prefer to wait either until 12 months after the procedure for patients who continue to receive immunosuppressive drugs or until patients are no longer receiving immunosuppressants.
Vaccination recommendations should be reconsidered at times of local endemic or epidemic disease outbreaks. In those settings, earlier vaccination with killed vaccines may be implemented, acknowledging limited host responses.
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD)
Pathologically, SOS/VOD of the liver 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 pediatric myeloablative transplantation patients.[22,23]
Risk factors for SOS/VOD include the following:[22,23]
SOS/VOD is defined clinically by the following:
Life-threatening SOS/VOD generally occurs soon after transplantation and is characterized by multiorgan system failure. Milder, reversible forms can occur, with full recovery expected. Pediatric patients who have severe SOS/VOD without increased bilirubin have been reported; therefore, it is important to be vigilant about monitoring patients who have other symptoms without increased bilirubin.
Prevention and treatment of SOS/VOD
Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied, with mixed results. One small, retrospective, single-center study showed a benefit from corticosteroid therapy, but further validation is needed. Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Studies of defibrotide have shown the following:
Defibrotide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients who have hepatic SOS/VOD with renal or pulmonary dysfunction after HSCT.
The British Society for Blood and Marrow Transplantation (BSBMT) published evidence-guided recommendations for the diagnosis and management of SOS/VOD. They recommend that biopsy be reserved for difficult cases and be performed using the transjugular approach. The BSBMT supports the use of defibrotide for the prevention of SOS/VOD (defibrotide prophylaxis is not currently part of the FDA indication) but maintains there is insufficient data to support the use of prostaglandin E1, pentoxifylline, or antithrombin. For treatment of SOS/VOD, they recommend aggressive fluid balance management, early involvement of critical care and gastroenterology specialists, and the use of defibrotide and possibly methylprednisolone. However, they concluded there is insufficient evidence to support the use of tissue plasminogen activator or N-acetylcysteine.[31,35] More detailed consensus recommendations for the diagnosis and management of SOS/VOD in children after HSCT have been published by the Pediatric Blood and Marrow Transplant Consortium, which worked with the Pediatric Acute Lung Injury and Sepsis Investigators.[36,37,38]
Transplant-associated microangiopathy (TA-TMA)
Although TA-TMA clinically mirrors hemolytic uremic syndrome, its causes and clinical course differ from those of other hemolytic uremic syndrome–like diseases. Studies have linked this syndrome with dysregulation of complement pathways. TA-TMA has most frequently been associated with the use of the calcineurin inhibitors tacrolimus and cyclosporine, and it has been noted to occur more frequently when either of these medications is used in combination with sirolimus.
Diagnostic criteria for this syndrome have been standardized and include the following:
Suggestive symptoms consistent with, but not necessary for, the diagnosis include a sudden worsening of renal function or neurologic symptoms.
Treatment of TA-TMA
Treatment for TA-TMA includes the following:
Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most TA-TMA that is associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after sirolimus is discontinued, and in some cases, after both medications are stopped.
Some evidence suggests a role for complement modulation (c5, eculizumab therapy) in preserving renal function; further assessment of the role of this medication in treating this complication is ongoing.[42,43,44]
Idiopathic pneumonia syndrome (IPS)
IPS is characterized by diffuse, noninfectious lung injury that occurs from 14 to 90 days after the infusion of donor cells. Possible etiologies include direct toxic effects of conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli.
The incidence of this complication appears to be decreasing, possibly because of less intensive preparative regimens, better HLA matching, and better definition of occult infections through PCR testing of blood and bronchioalveolar specimens. Mortality rates of 50% to 70% have been reported; however, these estimates are from the mid-1990s, and outcomes may have improved.
Diagnostic criteria include the following signs and symptoms in the absence of documented infectious organisms:
Early assessment by bronchioalveolar lavage to rule out infection is important.
Treatment of IPS
The traditional therapy for IPS has been high-dose methylprednisolone and pulmonary support.
Etanercept is a soluble fusion protein that joins the extracellular ligand-binding domain of the tumor necrosis factor (TNF)–alpha receptor to the Fc region of the immunoglobulin G1 antibody. It acts by blocking TNF-alpha signaling. The addition of etanercept to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies. A large phase II trial of this approach in pediatric patients showed promising results, with overall survival rates of 89% at 1 month and 63% at 12 months.
Autoimmune cytopenias (AIC)
AIC after allogeneic HSCT can be restricted to one cell lineage (e.g., autoimmune hemolytic anemia), two cell lineages, or three cell lineages. Most data about AIC in pediatric patients after HSCT are reported from single-center experiences, with the number of cases ranging from 20 to 30, over a 10- to 20-year period.[49,50,51] The incidence of AIC is about 5% after allogeneic HSCT. Risk factors for developing AIC seem to be age younger than 10 years and having a nonmalignant disease as an HSCT indication. At least one study has identified use of serotherapy, use of cord blood as the donor source, and severe GVHD as risk factors, but this finding has not been confirmed in other studies. One study demonstrated that patients who develop AIC have inferior outcomes compared with patients who did not develop AIC. However, other studies did not demonstrate an inferior outcome.[49,50]
Treatment of AIC
The most common first-line therapy for AIC has been corticosteroids.[49,50,51] This treatment is effective in only 15% of patients, and additional immunosuppression or B-cell targeting monoclonal antibodies have been used. Intravenous immunoglobulin is used frequently as adjunct treatment for AIC and/or immunoglobulin replacement.
EBV-associated lymphoproliferative disorder
After HSCT, EBV infection incidence increases through childhood, from approximately 40% in children aged 4 years to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk of EBV reactivation when undergoing HSCT 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).[52,53,54]
Features of EBV reactivation can vary, from an 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 of EBV can improve in some cases without therapy as immune function improves; however, lymphoproliferative disorder requires more aggressive therapy. Treatment of EBV-associated lymphoproliferative disorder has relied on decreasing immune suppression and treatment with chemotherapy agents such as cyclophosphamide. CD20-positive EBV-associated lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy rituximab.[55,56,57] In addition, some centers have shown efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[58,59]
Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.
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 posttransplantation, 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 the following three manifestations:
Acute GVHD is classified by staging the severity of skin, liver, and gastrointestinal involvement and further combining the individual staging of these three areas into an overall grade that is prognostically significant (refer to Tables 7 and 8). Patients with grade III or grade IV acute GVHD are at higher risk of mortality, generally resulting from organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.
Because of variation in outcomes of patients with different grades of acute GVHD, investigators have sought to define a more precise determination of acute GVHD risk based on serum biomarkers. A study that included both adults and children used a score calculated on the basis of the levels of a combination of three biomarkers (tumor necrosis factor receptor 1 [TNFR1], suppression of tumorigenicity 2 [ST2], and regenerating islet-derived 3-alpha [REG3-alpha]) measured at the onset of acute GVHD. Investigators were able to define patients with low (8%), intermediate (27%), and high (46%, P < .0001) risk of 6-month mortality. The biomarker score was more sensitive and specific for predicting survival than clinical staging. Additional refining of the prediction algorithm showed that measurement of only two biomarkers (ST2 and REG3-alpha) reliably predicts outcome. In addition, after 4 weeks of therapy, changes in the biomarker score were able to further refine prediction of survival outcomes. These findings have led to several studies targeting biomarker high-risk or low-risk subsets of patients with acute GVHD and are influencing clinicians regarding the timing and intensity of acute GVHD therapies.
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 antilymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]).
Approaches to GVHD prevention in non–T-cell-depleted grafts have included the following:[65,66]; [Level of evidence: 3iiiA]
When significant acute GVHD occurs, first-line therapy is generally methylprednisolone. Patients with acute GVHD who are 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). Ruxolitinib was approved in 2019 for the treatment of children aged 12 years and older with steroid-refractory acute GVHD, with an overall response rate of 55% and a complete response rate of 27% at day 28 after initiation of therapy. Comparative trials of these agents have not been performed; therefore, a best option for steroid-refractory GVHD has not been identified.[70,71]
Complete elimination of acute GVHD with intense T-cell depletion has generally resulted in increased relapse, more infectious morbidity, and increased EBV-associated lymphoproliferative disorder. Because of this result, most HSCT GVHD prophylaxis attempts to balance risk by giving sufficient immune suppression to prevent severe acute GVHD but not completely remove GVHD risk.
Chronic GVHD is a syndrome that may involve a single organ system or several organ systems, with clinical features resembling an autoimmune disease.[72,73] Chronic GVHD is usually first noted 2 to 12 months after HSCT. Traditionally, symptoms occurring more than 100 days after HSCT were considered chronic GVHD, and symptoms occurring sooner than 100 days after HSCT were considered acute GVHD. Because some approaches to HSCT can lead to late-onset acute GVHD, and manifestations that are diagnostic for chronic GVHD can occur sooner than 100 days post-HSCT, the following three distinct types of chronic GVHD have been described:
Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HSCT  and in 20% to 45% of children after unrelated-donor HSCT, with a higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk associated with cord blood and selected approaches to haploidentical HSCT.[75,76,77] The tissues that are commonly involved include the skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may also be involved.
Risk factors for the development of chronic GVHD include the following:[74,78,79]
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 results of a Schirmer test). Tables 9 to 13 list organ manifestations of chronic GVHD, with a description of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsies 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 in children who develop significant chronic GVHD. Children who received HLA-mismatched grafts, received PBSCs, were older than 10 years, or had platelet counts lower than 100,000/µL at diagnosis of chronic GVHD have an increased risk of nonrelapse mortality. Nonrelapse mortality was 17% at 1 year, 22% at 3 years, and 24% at 5 years after diagnosis of chronic GVHD. Many of these children required long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died of either relapse or nonrelapse mortality, 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 broadened the description of chronic GVHD to three categories to better predict long-term outcomes. The three 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 the following:
One study demonstrated a much higher chance of long-term GVHD-free survival and lower treatment-related mortality in children with mild and moderate chronic GVHD than in children with severe chronic GVHD. At 8 years, the probability of continued chronic GVHD in children with mild, moderate, and severe chronic GVHD was 4%, 11%, and 36%, respectively. In another large prospective trial with central review that used the NIH consensus criteria, about 28% of patients were misclassified as having chronic GVHD when they actually had late-acute GVHD. Additionally, there were significant challenges when using the NIH consensus criteria for bronchiolitis obliterans in children.
Treatment of chronic GVHD
Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including the use of calcineurin inhibitors. Topical therapy to affected areas is preferred for patients with limited disease. The following agents have been tested with some success:
Other approaches, including extracorporeal photopheresis, have been evaluated and show some efficacy in some 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 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 seen in long-term follow-up of HSCT 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.[87,94]
Late Mortality After HSCT
The highest incidence of mortality after HSCT occurs in the first 2 years and is mostly caused by relapse. A study of late mortality (≥2 years) in children with malignancies who underwent HSCT showed that approximately 20% of the 479 patients who were alive at 2 years suffered a late death. Late mortality in the allogeneic group was 15% (median follow-up, 10.0 years; range, 2.0–25.6 years), mainly caused by relapse (65%). A total of 26% of patients suffered a late death after autologous HSCT (median follow-up, 6.7 years; range, 2.0–22.2 years), and recurrence of the primary malignancy accounted for 88% of these deaths. Nonrelapse mortality is less common in children than in adults. Death caused by chronic GVHD and secondary malignancies is less common in children. Another study reviewed the causes of late mortality after second allogeneic transplantation. Of the children who were alive and relapse free 1 year after a second HSCT, 55% remained alive at 10 years. The most common cause of mortality at 10 years in this group was relapse (77% of deaths), generally occurring in the first 3 years after transplantation. The cumulative incidence of nonrelapse mortality for this cohort at 10 years was 10%. Chronic GVHD occurred in 43% of children in this study and was the leading cause of nonrelapse mortality.
A study focused on late mortality after autologous HSCT in children showed that mortality rates remained elevated compared with those of the general population more than 10 years after the procedure, but they approached the rates of the general population at 15 years. The study also showed a decrease in late mortality in the more current treatment eras (before 1990, 35.1%; 1990–1999, 25.6%; 2000–2010, 21.8%; P = .05).
Data from studies of child and adult survivors of hematopoietic stem cell transplantation (HSCT) have shown a significant impact of treatment-related exposures on survival and quality of life. In one study of patients who were alive 2 years after undergoing HSCT, survivors had a 9.9-fold increased risk of premature death compared with age- and sex-matched controls in the U.S. general population.
Methodological Challenges Specific to HSCT
Although the main cause of death in patients who have undergone HSCT is from relapse of the primary disease, a sizeable number of these patients die from infections related to graft-versus-host disease (GVHD), second malignancies, or cardiac or pulmonary issues.[2,3,4,5] In addition, other studies have revealed that up to 40% of HSCT survivors experience severe, disabling, and/or life-threatening events or die because of an adverse event associated with primary or previous cancer treatment.[6,7]
Before studies aimed at decreasing the incidence and severity of these effects are initiated, 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 on the basis of genetic differences in both the donor and recipient.[8,9,10]
Cardiovascular System Late Effects
Although cardiac dysfunction has been studied extensively in non-HSCT settings, less is known about the incidence and predictors of congestive heart failure following HSCT in childhood. Potentially cardiotoxic exposures unique to HSCT include the following:
HSCT survivors are at increased risk of developing cardiovascular risk factors such as hypertension and diabetes, partly as a result of exposure to TBI and prolonged immunosuppressive therapy after allogeneic HSCT or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[7,11] In a study of 661 pediatric patients who survived at least 2 years after allogeneic HSCT, 52% of patients were obese or overweight at their most recent examination, 18% of patients had dyslipidemia (associated with pre-HSCT anthracycline or cranial or chest irradiation), and 7% of patients were diagnosed with diabetes.
Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) who were 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 the following:
Survivors also had an increased cumulative incidence of related conditions that increased their risk of developing more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).
In addition, cardiac function and pre-HSCT exposures to chemotherapy and radiation therapy have been shown to significantly impact post-HSCT cardiac function. In evaluating post-HSCT patients for long-term issues, it is important to consider levels of pre-HSCT anthracycline and chest irradiation. Although more specific studies are needed to verify this approach, current evidence suggests that the risk of late-occurring cardiovascular complications after HSCT may largely result from pre-HSCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[15,16]
(Refer to the Late Effects of the Cardiovascular System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Central Nervous System Late Effects
A preponderance of studies report normal neurodevelopment after HSCT, with no evidence of decline.[17,18,19,20,21,22,23,24]
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.[20,21,22] This research group reported poorer outcomes in patients who underwent unrelated-donor transplant when the patients received TBI and when they experienced GVHD. But these effects on outcomes were small compared with the much larger effects of socioeconomic status on cognitive function. Most published studies report similar outcomes. Normal cognitive function and academic achievement were reported in a cohort of 47 patients monitored prospectively through 2 years post-HSCT. Stable cognitive function was also noted in a large cohort monitored from pretransplant to 2 years post-HSCT. A smaller study reported similar normal functioning and the absence of declines over time in HSCT survivors. HSCT 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. On the basis of the findings to date, it appears that HSCT poses low-to-minimal risk of late cognitive and academic deficits in survivors.
A number of studies, however, have reported some decline in cognitive function after HSCT.[25,26,27,28,29,30,31] 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-HSCT, deficits that were maintained at 3 years post-HSCT.[26,27] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who underwent transplant with TBI.[29,30] Another study from St. Jude Children's Research Hospital reported that while all children younger than 3 years had a decline in IQ at 1 year after transplant, patients who did not receive TBI during conditioning recovered later. However, patients who received TBI had a significantly lower IQ at 5 years (P = .05) than did those who did not receive TBI.
(Refer to the Hematopoietic stem cell transplantation (HSCT) section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
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 14). (Refer to the Hepatobiliary section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
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 these from GVHD presenting with hepatocellular injury.
Iron overload occurs in almost all patients who undergo HSCT, especially if the procedure is for a condition associated with transfusion dependence before HSCT (e.g., thalassemia, bone marrow failure syndromes) or pre-HSCT 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-HSCT have not been well studied; however, reducing iron levels after HSCT for thalassemia has been shown to improve cardiac function. Non-HSCT 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 HSCT) 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 HSCT vary, with larger series reporting an average incidence of about 30%.[64,65,66,67,68,69,70,71,72,73] A lower incidence in adults (on average, 15%) and a notable increase in incidence in children younger than 10 years who underwent HSCT suggest that a developing thyroid gland may be more susceptible to damage.[64,66,70]
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 showed similar rates of thyroid dysfunction, suggesting a role for high-dose chemotherapy in thyroid damage.[67,68,69] Rates of thyroid dysfunction associated with newer combinations of busulfan/fludarabine or reduced-intensity regimens have yet to be reported. (Refer to the Posttransplant thyroid dysfunction section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Higher rates of thyroid dysfunction occur with single-drug prophylaxis than with three-drug GVHD prophylaxis. Increased rates of thyroid dysfunction occur after unrelated-donor HSCT than after related-donor HSCT (36% vs. 9%), suggesting a role for alloimmune damage in causing thyroid dysfunction.[69,76]
Growth impairment is generally multifactorial. Factors that play a role in failure to achieve expected adult height in young children who have undergone HSCT 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.[71,72,77,78,79,80] Risk factors include the following:[67,68,78,81]
Patients younger than 10 years at the time of HSCT are at the highest risk of growth impairment, but they 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.
(Refer to the Growth hormone deficiency section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Abnormal body composition/metabolic syndrome
After HSCT, adult survivors have a 2.3-fold higher risk of premature cardiovascular-related death compared with the general population.[83,84] The exact etiology of cardiovascular risk and subsequent death is largely unknown, although the development of metabolic syndrome (a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), especially insulin resistance, as a consequence of HSCT has been suggested.[85,86,87]
In studies of conventionally treated leukemia survivors compared with those who underwent HSCT, transplant survivors are significantly more likely to manifest metabolic syndrome or multiple adverse cardiac risk factors, including central adiposity, hypertension, insulin resistance, and dyslipidemia.[33,88,89] The concern over time is that survivors who develop metabolic syndrome after HSCT will be at higher risk of significant cardiovascular-related events and/or premature death from cardiovascular-related causes.
(Refer to the Metabolic Syndrome section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
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 HSCT. However, despite having a normal BMI, HSCT 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, termed sarcopenic obesity, 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.[90,91,92]
Preliminary data from 119 children and young adult survivors and 81 healthy sibling controls found that HSCT survivors had significantly lower weight but no differences in BMI or waist circumference when compared with siblings. HSCT survivors had a significantly higher percent fat mass and lower lean body mass than did controls. HSCT survivors were significantly more insulin resistant than were controls, and they also had a higher incidence of other cardiovascular risk factors, such as elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides. 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 HSCT in children.[94,95,96,97,98,99,100] 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 sex, 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]), most reported populations have been too small for multivariate analysis to test the relative importance of each factor.[101,102,103,104,105,106,107,108,109,110,111]
Some studies in adults have shown improvement over time in low bone mineral density after HSCT;[99,112,113] however, this has yet to be shown in children.
Treatment for children has generally included a multifactorial approach, with vitamin D and calcium supplementation, minimization of corticosteroid therapy, participation in weight-bearing exercise, and resolution of other endocrine problems. The role of bisphosphonate therapy in children with this condition is unclear.
(Refer to the Osteoporosis and Fractures section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Reported incidence of osteonecrosis in children after HSCT has been 1% to 14%; however, these studies were retrospective and underestimated actual incidence because patients may be asymptomatic early in the course of the disease.[114,115,116] Two prospective studies showed an incidence of 30% and 44% with routine MRI screening of possible target joints.[98,117] Osteonecrosis generally occurs within 3 years after HSCT, 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.[74,114,118,119]
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-HSCT 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 HSCT. A Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective nested control study of 160 cases and 478 control children suggested older age (>5 years), female sex, and the presence of chronic GVHD as risk factors for developing osteonecrosis.
Treatment has generally consisted of minimization of corticosteroid therapy and surgical joint replacement. Most patients are not diagnosed until they present with symptoms. In one study of 44 patients with osteonecrosis lesions in whom routine yearly MRI was performed, 4 resolved completely and 2 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.
(Refer to the Osteonecrosis section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Reproductive System Late Effects
Delayed, absent, or incomplete pubertal development commonly occurs after HSCT. 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.[73,121] Boys who received more than 24 Gy of radiation to the testicles developed azoospermia and also experienced 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 25 g/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 HSCT.[123,124,125,126] 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 HSCT is associated with a higher chance of menarche and ovulation.[127,128] (Refer to the Ovarian function after HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Studies of pregnancy are challenging because data seldom 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 HSCT, 48% to 85% of men will experience gonadal failure.[123,129,130] 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. (Refer to the Testicular function after HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Effect of reduced-toxicity/reduced-intensity/nonmyeloablative regimens
On the basis of clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, the use of reduced-intensity/reduced-toxicity/nonmyeloablative regimens will likely lead to a higher chance of preserved fertility after HSCT. Because 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. In addition, a single-center study compared myeloablative busulfan/cyclophosphamide with reduced-intensity fludarabine/melphalan.[Level of evidence: 3iiiC] Spontaneous puberty occurred in 56% of girls and 89% of boys after busulfan/cyclophosphamide, whereas 90% of girls and all of the boys in the fludarabine/melphalan group entered puberty spontaneously (P = .012). Significantly more girls (61%) conditioned with busulfan/cyclophosphamide required hormone replacement than did girls in the fludarabine/melphalan group (10.5%; P = .012). In boys, no difference was noted between the two conditioning groups in time to follicle-stimulating hormone elevation (median, 4 years in the fludarabine/melphalan group vs. 6 years in the busulfan/cyclophosphamide group). While the two regimens have similar effects on testicular function, ovarian function seems to be better preserved in girls undergoing HSCT with reduced-intensity conditioning approaches.
A second study compared serum concentrations of antimüllerian hormone (AMH) and inhibin B in 121 children who survived more than 1 year following a single HSCT and received a treosulfan-based regimen (treosulfan; low-toxicity), a fludarabine/melphalan regimen (Flu/Mel; reduced-intensity), or a busulphan/cyclophosphamide regimen (Bu/Cy; myeloablative). Mean age at HSCT was 3.6 years; mean age at follow-up was 11.8 years. Mean length of follow-up was 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher after treosulfan (-1.047) and Flu/Mel (-1.255) than after Bu/Cy (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu/Mel than after Bu/Cy. Mean serum AMH concentration was significantly better with treosulfan (>1.0 μg/l) than with Flu/Mel or Bu/Cy. In males, mean inhibin B SDS was significantly higher after treosulfan (-0.506) than after Flu/Mel (-2.53) or some Bu/Cy (-1.23). The authors concluded that treosulfan-based regimens may confer a more favorable outlook for gonadal reserve in both sexes than Flu/Mel or Bu/Cy regimens.
Respiratory System Late Effects
Chronic pulmonary dysfunction
The following two forms of chronic pulmonary dysfunction are observed after HSCT:[133,134,135,136,137,138]
The incidence of both forms of lung toxicity can range from 10% to 40%, depending on donor source, the time interval after HSCT, definition applied, and presence of chronic GVHD. In both conditions, collagen deposition and the development of fibrosis in either the interstitial space (restrictive lung disease) or the peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.
Obstructive lung disease
The most common form of obstructive lung disease after allogeneic HSCT is bronchiolitis obliterans.[135,138,140,141] 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 HSCT. Pulmonary function tests show obstructive lung disease with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in 1 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:[133,140]
The clinical course of bronchiolitis obliterans is variable, but patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression.
Standard treatment for obstructive lung disease combines enhanced immunosuppression with supportive care, including antimicrobial prophylaxis, bronchodilator therapy, and supplemental oxygen, when indicated. The potential role for tumor necrosis factor-alpha in the pathogenesis of obstructive lung disease suggests that neutralizing agents such as etanercept may have promise.
Restrictive lung disease
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 HSCT 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 HSCT are associated with an increase in nonrelapse mortality. Early reports suggested that the incidence of restrictive lung disease increases with advancing recipient age, but subsequent studies have revealed significant restrictive lung disease in children receiving HSCT.
The most recognizable form of restrictive lung disease is bronchiolitis obliterans organizing pneumonia (BOOP), more recently called cryptogenic organizing pneumonia (COP). Clinical features include dry cough, shortness of breath, and fever. Radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in fewer than 10% of HSCT recipients, the development of BOOP/COP is strongly associated with previous acute and chronic GVHD.
Patients with restrictive lung disease have limited responses to multiple agents such as corticosteroids, cyclosporine, tacrolimus, and azathioprine. The potential role for tumor necrosis factor-alpha in the pathogenesis of restrictive lung disease suggests that neutralizing agents such as etanercept may have promise.
(Refer to the Respiratory complications associated with HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
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 HSCT, approximately 16.6% of patients (range, 3.6% to 89%) 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.[146,147] Mortality rates among patients with chronic kidney disease in this setting are higher than those in transplant recipients who retain normal renal function, even when studies have controlled for comorbidities.
It is important to aggressively treat hypertension in patients post-HSCT, especially in those treated with prolonged courses of calcineurin inhibitors. Whether post-HSCT 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 and well-being, with reference to the impact of health issues on overall quality of life.[150,151] Many studies have shown that HRQL varies according to the following:
Pre-HSCT factors, such as family cohesion and a child's adaptive functioning, have been shown to affect HRQL. Several groups have also identified the importance of pre-HSCT parenting stress on parental ratings of children's HRQL post-HSCT.[153,154,155,156,157] A report of the trajectories of HRQL over the 12 months after HSCT noted that the poorest HRQL was seen at 3 months post-HSCT, 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-HSCT. Longitudinal studies identified an association of the following additional baseline risk factors with the trajectory of HRQL after HSCT:
A report that investigated the impact of specific HSCT complications 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 HSCT survivors of 5 years or longer is reasonably good, although psychological, cognitive, or physical problems appear to negatively influence HRQL. Female sex, causal diagnosis for HSCT (acute myelogenous leukemia, worse HRQL), and intensity of pre-HSCT therapy were all identified as affecting HRQL post-HSCT.[164,165] Finally, another cross-sectional study of children 5 to 10 years post-HSCT 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 HSCT survivors suggest that the prevalence and severity of functional loss is low.
Self-reported physical performance
Self-reported and proxy data among survivors of childhood HSCT indicated similar low rates of functional loss in the following studies:
Other studies that have reported functional limitations include the following:
Measured physical performance
Objective measurements of function in the pediatric HSCT patient and survivor population hint that loss of physical capacity may be a bigger problem than revealed in studies that rely on clinician or self-report data. Studies measuring cardiopulmonary fitness have observed the following:
Predictors of poor physical performance
The BMTSS found associations between chronic GVHD, cardiac conditions, immune suppression, or treatment for a second malignant neoplasm and poor physical performance outcomes. In 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 published consensus guidelines for follow-up for late effects after HSCT. The CIBMTR, along with the American Society of Blood and Marrow Transplant (ASBMT) and in cooperation with five other international transplant groups, published consensus recommendations for screening and preventive practices for long-term survivors of HSCT.
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 (United Kingdom, Scotland, and Netherlands). The COG has also published more specific recommendations for late effects surveillance after HSCT. To address the lack of detailed, pediatric-specific, late-effects data and guidelines for long-term follow-up after HSCT, 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 United Kingdom), along with expert recommendations for pediatric-specific issues.[8,33,63,177,178,179]
Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are under way, the PBMTC summary and guideline recommendations provide the most current outline for monitoring children for late effects after HSCT.
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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.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hematopoietic Cell Transplantation. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/child-hct-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389503]
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Last Revised: 2021-07-13
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