Childhood Hematopoietic Cell Transplantation (PDQ®): Treatment - Health Professional Information [NCI]
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Childhood Hematopoietic Cell Transplantation
General Information About Hematopoietic Cell Transplantation (HCT)
Rationale for HCT
Blood and marrow transplantation (BMT) or HCT is a procedure that involves infusion of cells (hematopoietic stem cells [HSCs]; also called hematopoietic progenitor cells [HPCs]) that reconstitute the hematopoietic system of a patient. The infusion of HSCs generally follows a preparative regimen given to the patient consisting of agents designed to do the following:
- Suppress the patient's immune system to prevent rejection.
- Intensively treat malignant cells in patients with cancer.
HCT is currently used in the following three clinical scenarios:
|1.||Treatment of malignancies.|
|2.||Replacement or modulation of an absent or poorly functioning hematopoietic or immune system.|
|3.||Treatment of genetic diseases in which expression of the affected gene product in circulating hematopoietic cells alone is adequate to produce a clinically meaningful result.|
Principles of HCT
Autologous and Allogeneic HCT
The two major transplant approaches currently in use include autologous (using the patient's own hematopoietic stem cells [HSCs]) and allogeneic (using related or unrelated donor HSCs). Autologous transplant treats cancer by exposing patients to mega-dose (myeloablative) therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient's previously stored HSCs. In order for this approach to work, the following must apply:
- The higher chemotherapy/radiation therapy dose that can be used because of HSC support achieves a significantly higher cell kill of the disease. This may include increased tumor kill in areas where standard-dose chemotherapy has less penetration (CNS).
- Meaningful percentages of cure or long-term remission from the disease must occur without significant nonhematopoietic toxicities limiting the therapeutic benefit achieved.
Allogeneic approaches to cancer may involve high-dose therapy as well, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to mega-dose therapy alone and/or involve the bone marrow (BM), thus requiring allogeneic approaches for optimal outcome.
Determining when HCT is indicated: Comparison of HCT and chemotherapy outcomes
Because the outcomes using chemotherapy and hematopoietic cell transplantation (HCT) treatments tend to improve with time, regular comparisons should be performed between these approaches to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat using a human leukocyte antigen (HLA)-matched sibling donor have established the benefit of HCT by direct comparison.[1,2] However, for very high-risk patients such as those with early relapse of ALL, randomized trials have not been feasible due to investigator bias.[3,4] In general, HCT approaches only offer benefit to children at high risk for relapse with standard chemotherapy approaches; therefore, treatment schemes that accurately identify high-risk patients and offer HCT if reasonably HLA-matched donors are available, saving higher risk approaches to HCT (HLA haploidentical or significantly mismatched donors) for only the very highest risk patients, has come to be the preferred approach for many diseases.
When comparisons of similar patients treated with HCT or chemotherapy are made and randomized or intent-to-treat studies are not feasible, the following issues should be considered:
|1.||Remission status: Because patients failing to obtain remission do very poorly with any therapy, comparisons between HCT and chemotherapy should include only those who obtain remission, preferably after similar approaches to salvage therapy. In order to account for time-to-transplant bias, the chemotherapy comparator arm should only include patients who maintained remission until the median time to HCT. The HCT comparator arm should also only include patients who achieved the initial remission mentioned above and maintained that remission until the time of HCT.|
|2.||Past or current therapy approaches used: Disease- and era-appropriate chemotherapy and HCT approaches should be compared.|
|3.||HCT approach: HCT approaches that are very high risk or have documented lower rates of survival (i.e., haploidentical approaches) should not be combined for analysis with standard-risk HCT approaches (matched sibling and well-matched unrelated donors).|
|4.||Criteria for relapse: Risk factors for relapse should be carefully defined and analysis based upon the most current knowledge of risk should be performed. One should avoid combining high- and intermediate-risk patient groups because a benefit for HCT in the high-risk group can be masked when outcomes are similar in the intermediate-risk group.|
Selection Bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
One source of bias difficult to control for or detect is physician bias for or against HCT. The affect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.
HLA matching and hematopoietic stem cell sources
Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic HCT (see Table 1).
Figure 1. HLA Complex. Human chromosome 6 with amplification of the human leukocyte antigen (HLA) region. The locations of specific HLA loci for the class I B, C, and A alleles and the class II DP, DQ, and DR alleles are shown.
HLA class I (A, B, C, etc.) and class II (DRB1, DQB1, DPB1, etc.) alleles are highly polymorphic, therefore finding appropriately matched unrelated donors is a challenge for some patients, especially those of certain racial groups (e.g., African Americans and Hispanics). Because full siblings of cancer patients have a 25% chance of being HLA matched, they have been the preferred source of allogeneic HSCs. Early serologic techniques of HLA assessment defined a number of HLA antigens, but more precise DNA methodologies have shown HLA allele-level mismatches in up to 40% of serologic HLA antigen matches. These differences are clinically relevant, as use of donors with allele-level mismatches affect survival and rates of graft-versus-host disease (GVHD) to a degree similar to patients with antigen-level mismatches. Because of this, DNA-based allele-level HLA typing is standard when choosing unrelated donors.
Table 1. Level of Human Leukocyte Antigen (HLA) Typing Currently Used for Different Hematopoietic Stem Cell Sourcesa,b
|Class I Antigens||Class II Antigens|
|BM = bone marrow; PBSC = peripheral blood stem cell.|
|a HLA antigen: A serologically defined, low-resolution method of defining an HLA protein. Differs from allele-level typing half of the time. Designated by the first two numbers (i.e., HLA B 35:01—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., HLA B 35:01).|
|c 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|
|Matched Sibling BM/PBSC||Antigen||Antigen||Optional||Allele|
|Matched Sibling/Other Related Donorc BM/PBSC||Allele||Allele||Allele||Allele||Optional||Optional|
|Unrelated Donor BM/PBSC||Allele||Allele||Allele||Allele||Optional||Optional|
|Unrelated Cord Blood||Antigen (Allele Optional)||Antigen (Allele Optional)||Allele Optional||Allele||Optional||Optional|
Table 2. Definitions of the Numbers Describing Human Leukocyte Antigen (HLA) Antigens and Alleles Matching
|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 is HLA matched for HLA A, HLA B, and HLA DRB1 at a minimum, at the antigen level. Given the distance on chromosome 6 between HLA A and HLA DRB1, there is approximately a 1% possibility of a crossover event occurring in a possible sibling match. Because a crossover event could involve the HLA C antigen and because parents may share HLA antigens that actually differ at the allele level, many centers perform allele-level typing of possible sibling donors at all of the key HLA antigens (HLA A, B, C, and DRB1). Any related donor that is a nonfull sibling should have full HLA typing because similar haplotypes from different parents could differ at the allele level. Although single-antigen mismatched related donors (5/6 antigen matched) have been used interchangeably with matched sibling donors in some studies in the past, a large Center for International Blood and Marrow Transplant Research (CIBMTR) study in pediatric HCT recipients showed that use of 5/6 antigen matched related donors who are not siblings results in rates of GVHD and overall survival equivalent to 8/8 allele level matched unrelated donors and slightly inferior survival compared to fully matched siblings.
HLA matching considerations for unrelated donors
Optimal outcomes are achieved in unrelated allogeneic marrow transplantation when the pairs of antigens at HLA A, B, C, and DRB1 are matched between the donor and the recipient at the allele level (termed an 8/8 match). A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% to 10% with a similar increase in the amount of significant (grades III–IV) acute GVHD. Of these four antigen pairs, different reports have shown HLA A, C, and DRB1 mismatches to potentially be more highly associated with mortality than the other antigens,[8,10,11] but the differences in outcome are small and inconsistent, making it very difficult to conclude presently that one can pick a more favorable mismatch by choosing one type of antigen mismatch above another. Many groups are attempting to define specific antigens or pairs of antigens that are associated with poor outcome, but such studies require very large numbers of patients and exclusion of specific antigens or antigen pairs for donor choice is not widely practiced.
Although it is well understood that class II antigen DRB1 mismatches increase GVHD and worsen survival, the need to match for two other important class II antigens, DQB1 and DPB1, is controversial. DQB1 mismatches have been associated with significant increases in acute GVHD, but subsequent studies have not shown a difference in overall survival. Many centers have adopted a policy to attempt to match patients at DQB1 in addition to the other four pairs of antigens; full matches using this approach are thus termed 10/10 HLA matches. Such matching is possible for a high percentage of patients because of strong linkage disequilibrium between DRB1 and DQB1, resulting in many 8/8 matched donors also being 10/10 matches. DPB1 mismatches have similarly been shown to lead to increased GVHD without a change in survival.[13,14] Although some centers attempt to match for DPB1 (12/12 match), it is challenging, because due to less linkage disequilibrium, only about 15% of 10/10 matches will also be 12/12 matches; studies showing whether it is better to mismatch at DQB1 compared with DPB1 have not been performed. A study grouping DPB1 antigens into permissive groups allowed up to 50% of patients with 10/10 matches to choose a favorable DPB1 match, but this classification system is not yet generally accepted.
HLA matching and cell dose considerations for unrelated cord blood HCT
Another commonly used HSC source is that of unrelated umbilical cord blood (CB), which is harvested from donor placentas moments after birth and cryopreserved, HLA typed, and banked. Unrelated CB transplantation has been successful with less stringent HLA matching requirements compared with standard related or unrelated donors, probably due to limited antigen exposure experienced in utero and different immunological composition. CB matching is generally performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. This means that matching of only 6 antigens is necessary to choose units for transplantation. Although better outcomes occur when 6/6 or 5/6 HLA matched units are used, successful HCT has occurred even with 4/6 or less matched units in many patients. Many centers will type up to 10 alleles and use the best match possible, but this approach has not been shown to result in increased survival in patients with malignancies. Higher cell doses in CB units have been shown to improve outcomes, especially when the units have higher levels of HLA mismatch. One study showed that survival of recipients of 4/6 matched cords with cell doses greater than 5 × 107 total nucleate cells (TNC)/kg recipient weight is similar to 5/6 matched cord recipients receiving a cell dose of 2.5 to 5 × 107 TNC/kg. Although no clear improvement in survival occurred for cell doses above 5 × 107 TNC/kg, higher doses of cells improved outcomes for all levels of HLA mismatch.
Two aspects of umbilical CB HCT have made it more widely applicable. First, because a successful procedure can occur with multiple HLA mismatches, over 90% of patients from a wide variety of ethnicities are able to find a at least a 4/6 matched CB unit, allowing a method of performing HCT for populations that traditionally have not had HCT options because of having rare HLA haplotypes.[7,18] Second, as mentioned above, adequate cell dose (minimum 2–3 × 107 TNC/kg and 1.7 × 105 CD34+ cells/kg) has been shown to be associated with improved survival.[19,20] TNC is generally used to judge units because techniques to measure CD34+ doses have not been standardized. Because even large single umbilical CB units are only able to supply these minimum doses to recipients weighing up to 40 kg to 50 kg, early umbilical CB HCT focused mainly on smaller children. Later studies showed that this size barrier could be overcome by using two umbilical CB units as long as each of the units is at least a 4/6 HLA match with the recipient; because two cords result in much higher cell doses, umbilical CB transplantation is now used widely for larger children and adults. Single-center studies have suggested that the use of two umbilical CB units may decrease relapse in patients with malignancies; however, this has not been validated in multicenter studies. It has been shown that grades II to IV acute GVHD is higher when two versus one umbilical CB unit is used; but transplant-related mortality (TRM) has not been noted to be increased. One study comparing adult and older pediatric patients transplanted with either double 4/6 to 6/6 matched umbilical CB or unrelated BM/PBSCs showed survival to be equivalent.
Comparison of stem cell products
Currently, the three stem cell products used from both related and unrelated donors are BM, peripheral blood stem cells (PBSCs), and CB. In addition, BM 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 BM or PBSCs can be used after in vitro or in vivo T-cell depletion and this product also behaves differently compared with other stem cell products. A comparison of stem cell products is presented in Table 3.
Table 3. Comparison of Hematopoietic Stem Cell Products
|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; HCT = hematopoietic 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 source is used, you may see even longer time to immune reconstitution.|
|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 (13–25 d)||Moderate (15–25 d)||Slow (16–55 d)||Moderate (15–25 d)||Moderate (15–25 d)|
|Early post-HCT 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||High||Moderate||Low||Low|
The main differences between the products are associated with the numbers of T-cells and CD34+ progenitor cells present; very high levels of T-cells are present in PBSCs, intermediate numbers in BM, and low numbers in CB and T-cell depleted products. Patients receiving T-cell depleted products or CB generally have slower hematopoietic recovery, increased risk of infection, late immune reconstitution, higher risks of nonengraftment, and increased risk of Epstein-Barr virus–associated lymphoproliferative disorder (EBV-LPD). This is countered by lower rates of GVHD and an ability to offer transplantation to patients where full HLA matching is not available. Higher doses of T-cells in PBSCs result in rapid neutrophil recovery and immune reconstitution, but suffer from increased rates of chronic GVHD.
There are only a few studies directly comparing outcomes of different stem cell sources/products in pediatric patients. A retrospective registry study of pediatric patients undergoing HCT for acute leukemia compared those receiving related donor BM with related donor PBSCs. Although the BM and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and TRM associated with PBSC led to poorer survival in the PBSC group. This report, combined with lack of prospective studies comparing BM and PBSCs, has led most pediatric transplant protocols to prefer BM to PBSCs from related donors. For those requiring unrelated donors, a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial randomizing BM and PBSCs that included pediatric patients has recently completed and analysis of the outcomes will be forthcoming. In an attempt to determine whether unrelated BM or CB is better, a retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) study of pediatric acute lymphoblastic leukemia patients undergoing HCT who received 8/8 HLA allele-matched unrelated donor BM was compared with those receiving unrelated CB. The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched CB; survival after 8/8 HLA-matched unrelated BM was slightly less and was statistically identical to patients receiving 5/6 and 4/6 HLA-matched CB units. Based upon these studies, most transplant centers consider matched sibling BM to be the preferred stem cell source/product. If a sibling donor is not available, fully matched unrelated donor BM or PBSCs or HLA matched (4/6 to 6/6) CB lead to similar survival. Although adult studies of T-cell depleted unrelated BM or PBSC have shown outcomes similar to non-T-cell depleted approaches, large pediatric trials or retrospective studies comparing T-cell depleted matched or haploidentical BM or PBSCs have not occurred.
Early HCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival as the number of donor/recipient HLA mismatches increased. Studies have further demonstrated that even with very high numbers of donors in unrelated donor registries, patients with rare HLA haplotypes and patients with certain ethnic backgrounds (e.g., Hispanic, African American, Asian-Pacific Islander, etc.) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).
In order to allow access to HCT for patients without HLA matched donor options, investigators developed techniques allowing use of siblings, parents, or other relatives who share only a single haplotype of the HLA complex with the patient and are thus "half" matches. The majority of approaches developed to date rely on intense T-cell depletion of the product prior to infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery. This can result in lethal infections, increased risk of EBV-LPD, and high rates of relapse. This has generally lead to inferior survival compared with matched HCT and has resulted in the procedure being generally practiced only at larger academic centers with a specific research focus aimed at studying and developing this approach.
Current approaches are rapidly evolving, resulting in improved outcome, with some pediatric groups reporting survival similar to standard approaches.[30,31] Newer techniques of T-cell depletion and add back (i.e., CD3/19 negative selection), have decreased transplant-related mortality. Reduced toxicity regimens have led to improved survival, better supportive care has decreased the chance of morbidity from infection or EBV-LPD, and some patient/donor combinations that have specific killer immunoglobulin-like receptor (KIR) mismatches have shown decreased likelihood of relapse (refer to the Role of KIR mismatching in HCT section of this summary for more information). Finally, techniques such as using combinations of granulocyte-colony stimulating factor (G-CSF) primed BM and PBSCs with posttransplant antibody based T-cell depletion  or post-HCT cyclophosphamide (chemotherapeutic T-cell depletion)  have made these procedures more accessible to centers because expensive and complicated processing necessary for traditional T-cell depletion are not used. Reported survival using many different types of haploidentical approaches varies between 25% to 80% depending upon the technique used and the risk of the patient undergoing the procedure. Whether haploidentical approaches are superior to cord blood or other stem cell sources for a given patient group has not been determined because comparative studies have yet to be performed.
Immunotherapeutic Effects of HCT
Graft-Versus-Leukemia (GVL) Effect
Early studies in hematopoietic cell transplantation (HCT) focused on delivery of intense myeloablative preparative regimens followed by "rescue" of the hematopoietic system with either an autologous or allogeneic bone marrow. Investigators quickly showed that allogeneic approaches led to a decreased risk of relapse caused by an immunotherapeutic reaction of the new bone marrow graft against tumor antigens. This phenomenon came to be termed the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect, and has been shown to be associated with mismatches to both major and minor HLA antigens. The GVL effect is challenging to use therapeutically because of a strong association between GVL and clinical graft-versus-host disease (GVHD). For standard approaches to HCT, the highest survival rates have been associated with mild or moderate GVHD (overall grade I or II) compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.
Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study is comparing rates of relapse and survival between patients undergoing myeloablative HCT with autologous versus allogeneic donors for a given disease. In this setting, a clear advantage has been noted when allogeneic approaches are used for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). For ALL and AML specifically, autologous HCT approaches to most high-risk patient groups have shown results similar to chemotherapy, while allogeneic approaches have been superior.[1,2] Patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HCT.
Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens (refer to the Principles of HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL, as the intensity of the preparative regimen is not sufficient for cure in most cases. Although studies have shown benefit for patients pursuing this approach if they are ineligible for standard transplantation, because pediatric cancer patients can generally undergo myeloablative approaches safely, this approach has not been used for the majority of children with cancer who require HCT.
Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL
One can deliver GVL therapeutically through infusion of cells after transplant that either specifically or nonspecifically target tumor. The most common approach is the use of DLI. This approach relies on the persistence of donor T-cell engraftment after transplant to prevent rejection of donor lymphocytes infused to induce the GVL. Therapeutic DLI results in potent responses in patients with CML who relapse after transplant (60%–80% enter into long-term remission), but responses in other diseases (AML and ALL) have been less potent, with only 20% to 30% long-term survival. DLI works poorly in patients with acute leukemia who relapse early and who have high levels of active disease. Late relapse (>6 months after transplant) and treatment of patients into complete remission with chemotherapy prior to DLI have been associated with improved outcomes. Infusions of DLI modified to enhance GVL or other donor cells (natural killer [NK] cells, etc.) have also been studied, but have yet to be generally adopted.
Another method of delivering GVL therapeutically is the rapid withdrawal of immune suppression after HCT. Some studies have scheduled more rapid immune suppression tapers based upon donor type (related donors more quickly than unrelated donors due to GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient "chimerism") or minimal residual disease in order to assess risk of relapse and trigger rapid taper of immune suppression. A combination of early withdrawal of immune suppression after HCT with addition of DLI to prevent relapse in patients at high risk of relapse due to persistent/progressive recipient chimerism has been tested in patients transplanted for both ALL and AML. For patients with ALL, one study found increasing recipient chimerism in 46 of 101 patients. Thirty one of those patients had withdrawal of immune suppression and a portion went on to receive DLI if GVHD did not occur. This group had a 37% survival compared with 0% in the 15 patients who did not undergo this approach (P <.001). For patients with AML after HCT, about 20% experienced mixed chimerism after HCT and were identified as high risk. Of these, 54% survived if they underwent withdrawal of immune suppression with or without DLI; there were no survivors among those who did not receive this therapy.
Other approaches under evaluation
The role of killer immunoglobulin-like receptor (KIR) mismatching in HCT
Donor-derived NK cells in the post-HCT setting have been shown to promote engraftment, decrease GVHD, and lessen relapse of hematological malignancies.[10,11] NK cell function is modulated by interactions with a number of receptor families, including activating and inhibiting KIRs. The KIR effect in the allogeneic HCT setting hinges upon expression of specific inhibitory KIRs 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 of healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells and they may not have the appropriate inhibitory KIR ligand. This mismatch of ligand and receptor allows NK cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.
The original observation of decreased relapse with certain KIR receptor-ligand combinations was made in the setting of T-cell depleted haploidentical transplantation and was strongest after HCT for AML.[11,12] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate KIR receptor-ligand combinations. Many subsequent studies did not detect survival effects for KIR-incompatible HCT using standard transplantation methods,[13,14] 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 has been noted with donor/recipient KIR-ligand incompatibility after cord blood HCT, a relatively T-cell depleted procedure.[15,16] The role of KIR incompatibility in sibling donor HCT and in diseases other than AML is controversial.[17,18]
A current challenge associated with the KIR field is that several different approaches have been used to determine what is KIR compatible and incompatible.[12,19] Standardization of classification and prospective studies should help clarify the utility and importance of this approach. Currently, because a limited number of centers perform haploidentical HCT and the data in cord blood HCT are early, most transplant programs do not use KIR mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of KIR incompatibility remaining secondary.
NK cell transplantation
With low risk of GVHD and demonstrated efficacy in decreasing relapse in post-haploidentical HCT settings, NK cell infusions have been studied as a method of treating high-risk patients and consolidating patients in remission. The University of Minnesota group initially failed to demonstrate efficacy with autologous NK cells, but found that intense immunoablative therapy followed by purified haploidentical NK cells and IL-2 maintenance led to remission in 5 of 19 high-risk AML patients. Researchers at St. Jude Children's Research Hospital treated ten intermediate-risk AML patients who had completed chemotherapy and were in remission with lower-dose immunosuppression followed by haploidentical NK cell infusions and IL-2 for consolidation. Expansion of NK cells was noted in all nine of the KIR-incompatible donor/recipient pairs. All ten children remained in remission at 2 years. A follow-up phase II study is underway, as are many investigations into NK cell therapy for a number of cancer types.
Principles of HCT Preparative Regimens
In the days just prior to infusion of the stem cell product (bone marrow, peripheral blood stem cell, or cord blood), hematopoietic cell transplantation (HCT) recipients receive chemotherapy/immunotherapy sometimes combined with radiation therapy. This is called a preparative regimen and the original intent of this treatment was to:
- Create bone marrow space in the recipient for the donor cells to engraft.
- Suppress the immune system or eliminate the recipient T-cells to minimize risks of rejection.
- Intensely treat cancer (if present) with mega-dose therapy of active agents with the intent to overcome therapy resistance.
With the recognition that donor T-cells can facilitate engraftment and kill tumors through graft-versus-leukemia effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HCT approaches focusing on immune suppression rather than myeloablation have been developed. The resultant lower toxicity associated with these regimens has led to lower rates of transplant-related mortality (TRM) and an expansion eligibility for allogeneic HCT to older individuals and younger patients with pre-HCT comorbidities that put them at risk for severe toxicity after standard HCT approaches. The many preparative regimens available now vary tremendously in the amount of immunosuppression and myelosuppression that they cause, with the lowest intensity regimens relying heavily on a strong graft-versus-tumor effect.
Figure 2. Selected preparative regimens frequently used in pediatric HCT categorized by current definitions as non-myeloablative, reduced-intensity, or myeloablative. Although FLU plus Treosulfan and FLU plus Busulfan (full-dose) are considered myeloablative approaches, some refer to them as reduced toxicity regimens.
Although these regimens represent a spectrum of varying degrees of myelosuppression and immune suppression, they have been categorized clinically in the following three major categories:
- Myeloablative (MA): Intense approaches that cause irreversible pancytopenia requiring stem cell rescue for restoration of hematopoiesis.
- Nonmyeloablative (NMA): Regimens that cause minimal cytopenias and do not require stem cell support.
- Reduced-intensity conditioning (RIC): Regimens that are of intermediate intensity and do not meet the definitions of NMA or MA regimens.
Figure 3. 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, 15 (12), Andrea Bacigalupo, Karen Ballen, Doug Rizzo, Sergio Giralt, Hillard Lazarus, Vincent Ho, Jane Apperley, Shimon Slavin, Marcelo Pasquini, Brenda M. Sandmaier, John Barrett, Didier Blaise, Robert Lowski, Mary Horowitz, Defining the Intensity of Conditioning Regimens: Working Definitions, Pages 1628-1633, Copyright 2009, with permission from Elsevier.
The use of RIC and NMA regimens is well-established in older adults who cannot tolerate more intense myeloablative approaches,[3,4,5] but only a handful of younger patients with malignancies have been studied using these approaches.[6,7,8,9,10] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk for TRM with myeloablative regimens (e.g., history of previous myeloablative transplant, severe organ system dysfunction, or active invasive fungal infection) and successfully treated them with a reduced-intensity regimen. TRM was low in this high-risk group, and long-term survival occurred in most patients with minimal or no detectable disease present at the time of transplantation. Because the risks of relapse are higher with these approaches, their use in pediatric cancer is currently limited to patients ineligible for myeloablative regimens.
Establishing Donor Chimerism
Intense MA approaches almost invariably result in rapid establishment of hematopoiesis derived completely from donor cells upon count recovery within weeks of the transplant. The introduction of RIC and NMA approaches into HCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that is sometimes only partial. DNA-based techniques have been established to differentiate donor and recipient hematopoiesis, applying the word chimerism (from the Greek chimera, a mythical animal with parts taken from various animals) to describe whether all or part of hematopoiesis after HCT is from the donor or recipient.
There are several implications to the pace and extent of donor-chimerism eventually achieved by an HCT recipient. For patients receiving RIC or NMA regimens, rapid progression to full donor chimerism is associated with less relapse, but more graft-versus-host disease (GVHD). The delayed pace of obtaining full-donor chimerism after these regimens has led to late-onset acute GVHD, occurring as much as 6 months to 7 months after HCT (generally within 100 days after MA approaches). A portion of patients achieve stable mixed chimerism of both donor and recipient. Mixed chimerism is associated with more relapse after HCT for malignances and less GVHD; however, this condition is often advantageous for nonmalignant HCT, where usually only a percentage of normal hematopoiesis is needed to correct the underlying disorder and GVHD is not beneficial. Finally, serially measured decreasing donor chimerism, especially T-cell specific chimerism, has been associated with increased risk of rejection.
Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). These approaches are frequently used to address this issue, and have been shown in some cases to decrease relapse risk and stop rejection.[16,17] Timing of tapers of immune suppression and doses and approaches to the administration of DLI to increase or stabilize donor chimerism vary tremendously between transplant regimens and institutions.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with hematopoietic stem cell transplantation. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Changes to This Summary (04 / 12 / 2012)
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hematopoietic cell transplantation in treating childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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The lead reviewers for Childhood Hematopoietic Cell Transplantation are:
- Thomas G. Gross, MD, PhD (Nationwide Children's Hospital)
- Michael A. Pulsipher, MD (Primary Children's Medical Center)
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National Cancer Institute: PDQ® Childhood Hematopoietic Cell Transplantation. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childHCT/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-04-12
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