Pediatric Allogeneic Hematopoietic Stem Cell Transplant (PDQ®)

References

1. Hahn T, McCarthy PL, Hassebroek A, et al.: Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol 31 (19): 2437-49, 2013. [PMC free article: PMC3691359] [PubMed: 23715573]
2. Horan JT, Logan BR, Agovi-Johnson MA, et al.: Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 29 (7): 805-13, 2011. [PMC free article: PMC3068057] [PubMed: 21220593]
3. Wood WA, Lee SJ, Brazauskas R, et al.: Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia. Biol Blood Marrow Transplant 20 (6): 829-36, 2014. [PMC free article: PMC4019683] [PubMed: 24607554]
4. MacMillan ML, Davies SM, Nelson GO, et al.: Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 14 (9 Suppl): 16-22, 2008. [PubMed: 18721776]
5. Harvey J, Green A, Cornish J, et al.: Improved survival in matched unrelated donor transplant for childhood ALL since the introduction of high-resolution matching at HLA class I and II. Bone Marrow Transplant 47 (10): 1294-300, 2012. [PubMed: 22343674]
6. Majhail NS, Chitphakdithai P, Logan B, et al.: Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant 21 (1): 142-50, 2015. [PMC free article: PMC4272902] [PubMed: 25445638]

HLA Overview

Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic hematopoietic stem cell transplant (HSCT) (see 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).[1,2] Full siblings of cancer patients have a 25% chance of being HLA matched.

Early serological 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 serological 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.[3] Because of this, DNA-based allele-level HLA typing is standard when unrelated donors are being chosen.

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.[4]

Table

Table 1. Level of HLA Typing Currently Used for Different Hematopoietic Stem Cell Sources^a,b,c.

Table

Table 2. Definitions of the Numbers Describing HLA Antigens and Alleles Matching.

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.[6] 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 bone marrow transplant 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) (see Table 2).[7] 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.[7] 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,[3,7,8] 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) produces outcomes similar to a match. Therefore, selection of this mismatch is desirable in an otherwise matched donor/pair combination.[9]

It is well understood that class II antigen DRB1 mismatches increase GVHD incidence and worsen survival.[8] 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.[10] 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 have worse survival than those with permissive mismatches or DPB1 matches.[11-13]

With these findings in mind, a 7/8- or 8/8-matched unrelated donor can be used routinely. However, outcomes may be further improved with the following:

• Extended typing of DQB1, DPB1, and DRB3,4,5.[4,11-13]
• Extended HLA testing to select appropriate donors in the context of HLA-sensitized patients to avoid the potential risk of graft failure.[14,15] HLA sensitization is detected by testing for the presence of specific anti-HLA antibodies and avoiding donors who have any HLA antigens associated with the antibodies present in the recipient.
• Use of younger donors.[5]
• Matching cytomegalovirus (CMV)-positive recipients with CMV-positive donors and matching CMV-negative recipients with CMV-negative donors.[16]
• Use of blood type–compatible unrelated donors.[5]

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, donor cells can detect a mismatch in a recipient which could cause GVHD) or a direction that promotes rejection (R-O, recipient cells can detect a mismatch in a donor that could lead to rejection). 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.[17] It is important to note that this observation in unrelated donors differs from observations in cord blood recipients, outlined below.

HLA Matching and Cell Dose Considerations for Unrelated Cord Blood 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 transplant 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. However, as outlined below, more extended typing can be helpful.

Although better outcomes occur when 6/6 or 5/6 HLA-matched units are used,[18] successful HSCT has occurred even with 4/6 or less HLA-matched units. 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, patients 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.[19] This observation was noted to be especially important in cord blood transplants for nonmalignant disorders, where any mismatching below 7/8 alleles led to inferior survival.[20] 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.[21,22] Evidence also suggests that selecting a mismatched cord blood unit, where the mismatch involves a noninherited maternal antigen, may improve survival.[23,24]

As with unrelated donors, individuals can occasionally have duplicate HLA alleles (e.g., the HLA A allele is 01:01 on both chromosomes). When this occurs in a donor product and the allele is matched to one of the recipient alleles, the recipient immune response will see the donor allele 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.[25] R-O mismatches have outcomes similar to those of bidirectional mismatches.[26] 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.[27]

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.[1,28] Second, as mentioned above, adequate cell dose (minimum 2.5–3 × 10⁷ total nucleated cells/kg and 1.5 × 10⁵ CD34+ cells/kg) has been shown to be associated with improved survival.[29,30] 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 smaller size could be overcome by using two umbilical cord blood units if 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 transplant is now used widely for larger children and adults.[31]

If a single unit provides an adequate cell dose, there may be disadvantages to adding a second unit.[32][Level of evidence A1] 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.[32,33]

Investigators have shown that by using combinations of cytokines and other compounds to expand cord blood before infusion, engraftment of cord blood cells can occur more rapidly than after standard approaches.[34-37] 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,[38] other studies are showing persistence of expanded cells, implying preservation of stem cells through the expansion process.[36,37] A number of these approaches are under investigation. The U.S. Food and Drug Administration (FDA) approved an approach that uses a single unit split into two fractions, expanding one in culture with nicotinamide and infusing the second fraction without manipulation (omidubicel). One randomized trial compared omidubicel with standard cord blood transplant. Patients who received omidubicel had faster neutrophil and platelet engraftment, fewer bacterial and fungal infections, and fewer hospital days in the first 3 months after HSCT.[39] Notably, there was no difference in survival and GVHD outcomes.

Haploidentical HSCT

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.[40] 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., patients with African, Hispanic, Asian, or Pacific-Islander ancestry) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).[2]

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 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,[41] increased risk of Epstein-Barr virus (EBV)–associated lymphoproliferative disorder, and high rates of relapse.[42] 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.

Improvements in haploidentical approaches, however, have resulted in better outcomes, with many groups reporting survival similar to that of unrelated marrow or cord blood approaches.[43-46] These improvements include the following:

• Newer techniques of T-cell depletion and add-back of specific cell populations (e.g., CD3 or alpha-beta CD3/CD19-negative selection) have decreased transplant-related mortality.[47]; [45,46,48,49][Level of evidence C2]
• Reduced toxicity preparative regimens have led to decreased transplant-related mortality.[45,50]
• Better supportive care has decreased the chance of morbidity from infection or EBV-associated lymphoproliferative disorder.[51]
• Patient-donor combinations that have specific killer immunoglobulin-like receptor mismatches have shown decreased likelihood of relapse in some studies. For more information, see the Role of killer immunoglobulin-like receptor (KIR) mismatching in HSCT section.
• Certain techniques, such as using combinations of granulocyte colony-stimulating factor–primed bone marrow and PBSCs with posttransplant antibody–based T-cell depletion [52] or post-HSCT cyclophosphamide (chemotherapeutic T-cell depletion),[45,46,53]; [54][Level of evidence C1] have made these procedures more accessible because they do not use the expensive and complicated processing necessary for traditional T-cell depletion.

Reported survival rates 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.[42,43,52,53]; [54][Level of evidence C1] Retrospective trials in adults have shown similar outcomes after haploidentical-donor transplants compared with matched-unrelated donor or cord blood transplants.[55,56] 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.[57] Pediatric trials using haploidentical donors have shown better outcomes with myeloablative preparative regimens, and survival is comparable to nonhaploidentical approaches.[45,46,49,58] One prospective trial in pediatric patients showed that disease-free survival (DFS) was superior using haploidentical approaches compared with mismatched unrelated-donor approaches. DFS rates in patients treated with haploidentical approaches were similar to those in patients treated with other stem cell sources.[45]

Patients who have been sensitized to HLA antigens and develop antibodies to HLA alleles that are present among the mismatched alleles of their haploidentical donor are at increased risk of rejection of their haploidentical graft. 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.[59]

Comparison of Stem Cell Products

Currently, the following three stem cell products are used from both related and unrelated donors:

• Bone marrow.
• PBSCs.
• Cord blood.

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.

Table

Table 3. Comparison of Hematopoietic Stem Cell Products.

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 transplant 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):

1. A retrospective registry study of pediatric patients who underwent HSCT for acute leukemia compared those who received related-donor bone marrow with those who received related-donor PBSCs.[63]

   • Although the bone marrow and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and transplant-related mortality associated with PBSCs led to poorer survival in the PBSC group.
2. A retrospective study of Japanese children with acute leukemia compared 90 children who received PBSCs with 571 children who received bone marrow.[64]

   • The study confirmed higher transplant-related mortality caused by GVHD and inferior survival among the children who received PBSCs.
3. A large Blood and Marrow Transplant Clinical Trials Network 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 the following:[65]

   • 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.

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.[66]

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):

1. In one study, pediatric patients with acute lymphoblastic leukemia (ALL) who underwent HSCT and received 8/8 HLA-matched unrelated-donor bone marrow were compared with those who received unrelated cord blood.[18]

   • The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched cord blood.
   • Survival after 8/8 HLA-matched unrelated bone marrow was slightly worse and was statistically identical to survival for patients receiving 5/6 and 4/6 HLA-matched cord blood units.
2. In another study from a single center consisting of mostly adult patients with acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and ALL, outcomes for cord blood recipients were compared with outcomes for recipients of matched and mismatched unrelated-donor bone marrow/PBSCs.[67]

   • Better survival because of less relapse was noted in cord blood recipients. This result was mainly due to superior survival in patients with minimal residual disease (MRD) present just before transplant.
   • No difference was seen in relapse or survival between patients with pre-HSCT MRD and patients without pre-HSCT MRD if they received cord blood.
   • These results are controversial because they contradict many other studies that showed that the presence of pre-HSCT MRD in cord blood recipients led to increased relapse and inferior survival rates.[68-71]
3. The CIBMTR compared outcomes of children with low-risk and intermediate-risk ALL and AML who underwent transplant between 2000 and 2014 using alternative donors (non–HLA-matched related or unrelated), including 7/8 HLA-matched bone marrow (n = 172) and 4/6 or greater HLA-matched umbilical cord blood (n = 1,613).[72]

   • In multivariate analysis, patients who received 7/8 HLA-matched bone marrow versus umbilical cord blood had similar GVHD-free, relapse-free survival (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.87–1.45; P = .39), chronic GVHD-free, relapse-free survival (HR, 1.06; 95% CI, 0.82–1.38; P = .66), and OS (HR, 1.07; 95% CI, 0.80–1.44; P = .66).
   • Relapse may have been higher in the 7/8 HLA-matched bone marrow group (HR, 1.44; 95% CI, 1.03–2.02; P = .03; the publication called this a trend as they chose a cutoff value of 0.01% to control for multiple comparisons).
   • The patients in the 7/8 HLA-matched bone marrow group had a significantly higher risk of grades III to IV acute GVHD (HR, 1.70; 95% CI, 1.16–2.48; P = .006) and chronic GVHD (HR, 6.17; 95% CI, 2.2–17.33; P = .0006) than did the patients in the umbilical cord blood group.

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, 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.[49][Level of evidence C2] For more information about the prevention of acute GVHD, see the Prevention and treatment of acute GVHD section in Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant.

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.[73,74] For more information, see the HLA Matching and Cell Dose Considerations for Unrelated Cord Blood HSCT section. 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:

• Donor age. The youngest donor available is generally preferred (when considering pediatric donors, the size and ability to obtain an adequate cell dose comes into consideration).[75,76]
• CMV status of the recipient. CMV-negative donor matched to CMV-negative recipient and CMV-positive donor matched to CMV-positive recipient are preferred.[77]
• Donor blood type. Matching of blood type between donor and recipient is preferred, although not required. If only blood type–mismatched donors are available, a minor mismatch is preferred over a major mismatch.[78-80]
• Donor sex and parity of female donors. Male or nonparous female donors are preferred over parous female donors.[76,81]

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):

1. A CIBMTR study examined 6,349 patients who underwent transplant for hematological malignancies from 1988 to 2006. The study tested the effect of donor characteristics while adjusting for disease risk and other key transplant characteristics. The data from this study showed the following:[76]

   • In addition to HLA mismatching, older donor age and major or minor ABO blood type mismatching increased overall mortality.
   • Parous female graft recipients experienced lower rates of relapse.
   • Recipients of younger donor grafts had lower rates of acute GVHD.
   • Recipients of parous female grafts had higher rates of chronic GVHD.
   • Recipient CMV status was more important than donor CMV status (recipients who are CMV positive are at higher risk of mortality independent of the donor CMV status), although a CMV-negative donor to a CMV-negative recipient combination improves survival.
2. A cohort of 4,690 patients who underwent transplant between 2007 and 2011 was tested by a multivariate analysis for independent predictors of survival in an EBMT study. The study demonstrated the following:[82]

   • Older donor age was confirmed to be independently associated with worse OS; every 10 years of donor age increased the risk of mortality by 5.5%.
   • HLA matching continued to have the most important effect on survival; ABO mismatching was not confirmed to have a continuing effect.
3. A study of over 10,000 matched donor-recipient pairs attempted to define a hierarchy that could prioritize the non-HLA characteristics (donor age, sex, blood type, CMV status, etc.) that have been described to affect outcomes.[83]

   • Although the study was unable to create a hierarchical algorithm of modifiable factors, it showed that, by far, younger donor age is the most important factor. The study found a decrease in OS of 3% for every 10-year increment of increased donor age.

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 transplant, 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,[84] but studies using posttransplant cyclophosphamide or intense immune suppression seem to favor male donors.[85,86] 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.[87] As with nonhaploidentical donors, significant improvement of outcomes was noted when younger donors were used for haploidentical procedures compared with older donors, with an HR of 1.13 for each decade of life that the donor is older.[88]

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39. Horwitz ME, Stiff PJ, Cutler C, et al.: Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood 138 (16): 1429-1440, 2021. [PMC free article: PMC9710469] [PubMed: 34157093]
40. Beatty PG, Clift RA, Mickelson EM, et al.: Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med 313 (13): 765-71, 1985. [PubMed: 3897863]
41. Aversa F, Tabilio A, Velardi A, et al.: Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339 (17): 1186-93, 1998. [PubMed: 9780338]
42. Barrett J, Gluckman E, Handgretinger R, et al.: Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant 17 (1 Suppl): S89-93, 2011. [PubMed: 21195317]
43. Leung W, Campana D, Yang J, et al.: High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 118 (2): 223-30, 2011. [PMC free article: PMC3138677] [PubMed: 21613256]
44. González-Vicent M, Molina B, Andión M, et al.: Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. Eur J Haematol 87 (1): 46-53, 2011. [PubMed: 21692851]
45. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PMC free article: PMC9918850] [PubMed: 35776909]
46. Merli P, Algeri M, Galaverna F, et al.: TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood 143 (3): 279-289, 2024. [PubMed: 37738655]
47. Handgretinger R, Chen X, Pfeiffer M, et al.: Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 1106: 279-89, 2007. [PubMed: 17442774]
48. Locatelli F, Merli P, Pagliara D, et al.: Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130 (5): 677-685, 2017. [PubMed: 28588018]
49. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PubMed: 30348653]
50. Bethge WA, Faul C, Bornhäuser M, et al.: Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells Mol Dis 40 (1): 13-9, 2008. [PubMed: 17869547]
51. Leen AM, Christin A, Myers GD, et al.: Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114 (19): 4283-92, 2009. [PMC free article: PMC2774556] [PubMed: 19700662]
52. Huang XJ, Liu DH, Liu KY, et al.: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38 (4): 291-7, 2006. [PubMed: 16883312]
53. Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47 (1-3): 65-77, 2010. [PMC free article: PMC2892158] [PubMed: 20066512]
54. Berger M, Lanino E, Cesaro S, et al.: Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study. Biol Blood Marrow Transplant 22 (5): 902-9, 2016. [PubMed: 26860636]
55. Baker M, Wang H, Rowley SD, et al.: Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies. Biol Blood Marrow Transplant 22 (11): 2047-2055, 2016. [PubMed: 27522040]
56. Rashidi A, Slade M, DiPersio JF, et al.: Post-transplant high-dose cyclophosphamide after HLA-matched vs haploidentical hematopoietic cell transplantation for AML. Bone Marrow Transplant 51 (12): 1561-1564, 2016. [PubMed: 27526282]
57. Fuchs EJ, O'Donnell PV, Eapen M, et al.: Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137 (3): 420-428, 2021. [PMC free article: PMC7819761] [PubMed: 33475736]
58. Symons HJ, Zahurak M, Cao Y, et al.: Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults. Blood Adv 4 (16): 3913-3925, 2020. [PMC free article: PMC7448587] [PubMed: 32813874]
59. Ciurea SO, Cao K, Fernandez-Vina M, et al.: The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone Marrow Transplant 53 (5): 521-534, 2018. [PMC free article: PMC7232774] [PubMed: 29335625]
60. Bensinger WI, Martin PJ, Storer B, et al.: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344 (3): 175-81, 2001. [PubMed: 11172139]
61. Rocha V, Cornish J, Sievers EL, et al.: Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 97 (10): 2962-71, 2001. [PubMed: 11342418]
62. Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014. [PubMed: 24869942]
63. Eapen M, Horowitz MM, Klein JP, et al.: Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 22 (24): 4872-80, 2004. [PubMed: 15520055]
64. Shinzato A, Tabuchi K, Atsuta Y, et al.: PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor. Pediatr Blood Cancer 60 (9): 1513-9, 2013. [PubMed: 23512888]
65. Anasetti C, Logan BR, Lee SJ, et al.: Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 367 (16): 1487-96, 2012. [PMC free article: PMC3816375] [PubMed: 23075175]
66. Shimosato Y, Tanoshima R, Tsujimoto SI, et al.: Allogeneic Bone Marrow Transplantation versus Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies in Children: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant 26 (1): 88-93, 2020. [PubMed: 31394270]
67. Milano F, Gooley T, Wood B, et al.: Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med 375 (10): 944-53, 2016. [PMC free article: PMC5513721] [PubMed: 27602666]
68. Ruggeri A, Michel G, Dalle JH, et al.: Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP-EBMT analysis. Leukemia 26 (12): 2455-61, 2012. [PubMed: 22555150]
69. Bachanova V, Burke MJ, Yohe S, et al.: Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant 18 (6): 963-8, 2012. [PMC free article: PMC3631589] [PubMed: 22430088]
70. Sutton R, Shaw PJ, Venn NC, et al.: Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia. Br J Haematol 168 (3): 395-404, 2015. [PubMed: 25312094]
71. Sanchez-Garcia J, Serrano J, Serrano-Lopez J, et al.: Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL. Bone Marrow Transplant 48 (3): 396-402, 2013. [PubMed: 22858507]
72. Mehta RS, Holtan SG, Wang T, et al.: GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia. Blood Adv 3 (9): 1441-1449, 2019. [PMC free article: PMC6517657] [PubMed: 31053571]
73. Pulsipher MA, Chitphakdithai P, Logan BR, et al.: Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose. Blood 114 (13): 2606-16, 2009. [PMC free article: PMC2756121] [PubMed: 19608747]
74. Aversa F, Terenzi A, Tabilio A, et al.: Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 23 (15): 3447-54, 2005. [PubMed: 15753458]
75. Kollman C, Howe CW, Anasetti C, et al.: Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98 (7): 2043-51, 2001. [PubMed: 11567988]
76. Kollman C, Spellman SR, Zhang MJ, et al.: The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 127 (2): 260-7, 2016. [PMC free article: PMC4713163] [PubMed: 26527675]
77. Boeckh M, Nichols WG: The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103 (6): 2003-8, 2004. [PubMed: 14644993]
78. Seebach JD, Stussi G, Passweg JR, et al.: ABO blood group barrier in allogeneic bone marrow transplantation revisited. Biol Blood Marrow Transplant 11 (12): 1006-13, 2005. [PubMed: 16338623]
79. Logan AC, Wang Z, Alimoghaddam K, et al.: ABO mismatch is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 21 (4): 746-54, 2015. [PMC free article: PMC4363312] [PubMed: 25572032]
80. Stussi G, Muntwyler J, Passweg JR, et al.: Consequences of ABO incompatibility in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 30 (2): 87-93, 2002. [PubMed: 12132047]
81. Loren AW, Bunin GR, Boudreau C, et al.: Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 12 (7): 758-69, 2006. [PubMed: 16785065]
82. Canaani J, Savani BN, Labopin M, et al.: ABO incompatibility in mismatched unrelated donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia: A report from the acute leukemia working party of the EBMT. Am J Hematol 92 (8): 789-796, 2017. [PubMed: 28439910]
83. Shaw BE, Logan BR, Spellman SR, et al.: Development of an Unrelated Donor Selection Score Predictive of Survival after HCT: Donor Age Matters Most. Biol Blood Marrow Transplant 24 (5): 1049-1056, 2018. [PMC free article: PMC5953795] [PubMed: 29454040]
84. Stern M, Ruggeri L, Mancusi A, et al.: Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 112 (7): 2990-5, 2008. [PMC free article: PMC2962448] [PubMed: 18492955]
85. Ciurea SO, Champlin RE: Donor selection in T cell-replete haploidentical hematopoietic stem cell transplantation: knowns, unknowns, and controversies. Biol Blood Marrow Transplant 19 (2): 180-4, 2013. [PMC free article: PMC4085130] [PubMed: 22892554]
86. Wang Y, Chang YJ, Xu LP, et al.: Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 124 (6): 843-50, 2014. [PubMed: 24916508]
87. Canaani J, Savani BN, Labopin M, et al.: Impact of ABO incompatibility on patients' outcome after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia - a report from the Acute Leukemia Working Party of the EBMT. Haematologica 102 (6): 1066-1074, 2017. [PMC free article: PMC5451338] [PubMed: 28255020]
88. DeZern AE, Franklin C, Tsai HL, et al.: Relationship of donor age and relationship to outcomes of haploidentical transplantation with posttransplant cyclophosphamide. Blood Adv 5 (5): 1360-1368, 2021. [PMC free article: PMC7948266] [PubMed: 33661299]

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-toxicity, reduced-intensity, and nonmyeloablative conditioning 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 partially long-term. 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).[17] 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 (acute GVHD generally occurs within 100 days after myeloablative approaches).[18] 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.[19] Finally, serially measured decreasing donor chimerism, especially T-cell–specific chimerism, has been associated with increased risk of rejection.[20]

Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). These approaches are frequently used to address this issue, and they have been shown to decrease relapse risk and stop rejection in some cases.[21-23] The timing of immune suppression and dose tapers and approaches to administration of DLI to increase or stabilize donor chimerism vary between stem cell sources. There is also a wide institutional variability, with some institutions proactively following chimerism and often intervening, and others having a more limited approach to interventions. For more information, see the Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL section.

References

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5. Scott BL, Pasquini MC, Logan BR, et al.: Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol 35 (11): 1154-1161, 2017. [PMC free article: PMC5455603] [PubMed: 28380315]
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7. Slavin S, Nagler A, Naparstek E, et al.: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91 (3): 756-63, 1998. [PubMed: 9446633]
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9. Bradley MB, Satwani P, Baldinger L, et al.: Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bone Marrow Transplant 40 (7): 621-31, 2007. [PubMed: 17660841]
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13. Roman E, Cooney E, Harrison L, et al.: Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia. Clin Cancer Res 11 (19 Pt 2): 7164s-7170s, 2005. [PubMed: 16203817]
14. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PubMed: 19528536]
15. Cseh A, Galimard JE, de la Fuente J, et al.: Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties. Br J Haematol 204 (1): e1-e5, 2024. [PubMed: 37795523]
16. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PMC free article: PMC9918850] [PubMed: 35776909]
17. Baron F, Baker JE, Storb R, et al.: Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104 (8): 2254-62, 2004. [PubMed: 15226174]
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21. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004. [PubMed: 15117992]
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23. Haines HL, Bleesing JJ, Davies SM, et al.: Outcomes of donor lymphocyte infusion for treatment of mixed donor chimerism after a reduced-intensity preparative regimen for pediatric patients with nonmalignant diseases. Biol Blood Marrow Transplant 21 (2): 288-92, 2015. [PubMed: 25464116]

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 transplant. 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.[1-3]; [4][Level of evidence C2]

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.

• Leukemia and myelodysplastic neoplasms (MDS): A clear advantage has been noted when allogeneic approaches are used for ALL, AML, chronic myelogenous leukemia (CML), and MDS. For ALL and AML specifically, autologous HSCT approaches for most high-risk patient groups have shown results similar to those obtained with chemotherapy, while allogeneic approaches produced superior results and are therefore useful for chemoresistant or relapsed patients.[5,6]
• Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL): Patients with HL or NHL generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HSCT.[7]

Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens. This approach to transplant 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 transplant,[8] this approach has not been used for most children with cancer who require HSCT because pediatric cancer patients can generally undergo myeloablative approaches safely. For more information, see the Allogeneic HSCT Preparative Regimens section.

References

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of allogeneic hematopoietic stem cell transplant 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.

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The lead reviewers for Pediatric Allogeneic Hematopoietic Stem Cell Transplant are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

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PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Allogeneic Hematopoietic Stem Cell Transplant. 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>. [PMID: 35133766]

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