During the past two decades, significant advances have led to improved outcomes after allogeneic HSCT.[
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 that cover the most common pediatric allogeneic HSCT indications are provided below.
Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic hematopoietic stem cell transplantation (HSCT) (refer to Figure 1, Table 1, and Table 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., patients with African, Hispanic, Asian, or Pacific-Islander ancestry).[
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.[
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.[
|||Class I Antigens||Class II Antigens|
|BM = bone marrow; N/A = not applicable; PBSCs = peripheral blood stem cells.|
|a HLA antigen: A serologically defined, low-resolution method of defining an HLA protein. Differs from allele-level typing at least 40% of the time. Designated by the first two numbers (i.e., for HLA B 35:01, the antigen is HLA B 35).|
|b HLA allele: A higher-resolution method of defining unique HLA proteins by typing their gene through sequencing or other DNA-based methods that detect unique differences. Designated by at least four numbers (i.e., for HLA B 35:01, 35 is the antigen and 01 is the allele).|
| c Consensus recommendations for HLA typing, including extended class II typing of mismatched donors, have been published by the National Cancer Institute/National Heart, Lung, and Blood Institute–sponsored Blood and Marrow Transplant Clinical Trials Network.[
|d Siblings need confirmation that they have fully matched haplotypes with no crossovers in the A to DRB1 region. If parental typing is performed and haplotypes are established, antigen-level typing of class I is adequate. With no parental haplotypes, allele-level typing of eight alleles is recommended.|
|e Parent, cousin, etc., with a phenotypic match or near-complete HLA match.|
|Stem Cell Source||HLA A||HLA B||HLA C||HLA DRB1||HLA DQB1; HLA DPB1; HLA DRB3,4,5|
|Matched siblingd BM/PBSCs||Antigen or allele||Antigen or allele||Optional||Allele||N/A|
|Mismatched sibling/other related-donore BM/PBSCs||Allele||Allele||Allele||Allele||Recommended|
|Unrelated-donor cord blood||Antigen (allele recommended)||Antigen (allele recommended)||Allele recommended||Allele||N/A|
|If These HLA Antigens and Alleles Match:||Then the Donor Is Considered to be This Type of Match:|
|A, B, and DRB1||6/6|
|A, B, C, and DRB1||8/8|
|A, B, C, DRB1, and DQB1||10/10|
|A, B, C, DRB1, DQB1, and DPB1||12/12|
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.[
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).[
It is well understood that class II antigen DRB1 mismatches increase GVHD incidence and worsen survival.[
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.[
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 used to choose units for transplantation.
Although better outcomes occur when 6/6 or 5/6 HLA-matched units are used,[
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.[
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.[
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.[
If a single unit provides an adequate cell dose, there may be disadvantages to adding a second unit.[
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.[
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.[
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,[
Current approaches, however, are rapidly evolving, resulting in improved outcomes, with some pediatric groups reporting survival similar to that of standard approaches.[
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.[
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.[
Comparison of Stem Cell Products
Currently, the following three stem cell products are used from both related and unrelated donors:
Bone marrow or PBSCs, including 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 these products behave differently from other stem cell products. A comparison of stem cell products is presented in Table 3.
|||PBSCs||BM||Cord Blood||T-cell–Depleted BM/PBSCs||Haploidentical T-cell–Depleted BM/PBSCs|
|BM = bone marrow; EBV-LPD = Epstein-Barr virus–associated lymphoproliferative disorder; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; PBSCs = peripheral blood stem cells.|
|a Assuming no development of GVHD. If patients develop GVHD, immune reconstitution is delayed until resolution of the GVHD and discontinuation of immune suppression.|
|b If a haploidentical donor is used, longer times to immune reconstitution may occur.|
|T-cell content||High||Moderate||Low||Very low||Very low|
|CD34+ content||Moderate–high||Moderate||Low (but higher potency)||Moderate–high||Moderate–high|
|Time to neutrophil recovery||Rapid: median, 16 d (11–29 d)[
||Moderate: median, 21 d (12–35 d)[
||Slower: median, 23 d (11–133 d)[
||Rapid: median, 16 d (9–40 d)[
||Rapid: median, 13 d (10–20 d)[
|Early post-HSCT risk of infections, EBV-LPD||Low–moderate||Moderate||High||Very high||Very high|
|Risk of graft rejection||Low||Low–moderate||Moderate–high||Moderate–high||Moderate–high|
|Time to immune reconstitutiona||Rapid (6–12 mo)||Moderate (6–18 mo)||Slow (6–24 mo)||Slow (6–24 mo)||Slow (9–24 mo)b|
|Risk of acute GVHD||Moderate||Moderate||Moderate||Low||Low|
|Risk of chronic GVHD||High||Moderate||Low||Low||Low|
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 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.[
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.[
Other Donor Characteristics Associated With Outcome
HLA matching has consistently been the most important factor associated with improved survival in allogeneic HSCT, but a number of other donor characteristics have been shown to affect key outcomes. Higher cell dose from the donor has also been shown to be important when related, unrelated, or haploidentical bone marrow or PBSC donors are used (refer to the HLA Matching and Cell Dose Considerations for Unrelated Cord Blood HSCT section of this summary for more information).[
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.
Evidence (donor-recipient characteristics):
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.
Several 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,[
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.[
In the days just before infusion of the stem cell product (bone marrow, peripheral blood stem cells [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 graft-versus-leukemia (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.[
Existing preparative regimens vary tremendously in the amount of immunosuppression and myelosuppression they cause, with the lowest-intensity regimens relying heavily on a strong graft-versus-tumor (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 years, retrospective studies showed similar outcomes using reduced-intensity and myeloablative approaches.[
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,[
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 graft-versus-host disease (GVHD).[
Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). (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.[
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 graft-versus-host disease (GVHD). For standard approaches to HSCT, the highest survival rates have been associated with mild or moderate GVHD (grades I to II in acute myeloid leukemia [AML] and grades I to III in acute lymphoblastic leukemia [ALL]), compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.[
Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study 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 Allogeneic HSCT 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,[
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),[
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) or minimal residual disease 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.[
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:[
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 attacks 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.[
Decreased relapse and better survival have been noted with donor/recipient KIR-ligand incompatibility after cord blood HSCT, a relatively T-cell–depleted procedure.[
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.[
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):
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.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This is a new summary.
Immunotherapeutic Effects of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Added Verneris et al. as reference 23.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of allogeneic hematopoietic stem cell transplantation in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Allogeneic Hematopoietic Stem Cell Transplantation. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/hp-stem-cell-transplant/allogeneic. Accessed <MM/DD/YYYY>.
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Last Revised: 2022-02-11
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