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 (refer to Table 1).
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).[1,2] Because full siblings of cancer patients have a 25% chance of being HLA matched, they have been the preferred source of allogeneic hematopoietic stem cells. Early serologic techniques of HLA assessment defined a number of HLA antigens, but more precise DNA methodologies have shown HLA allele-level mismatches in up to 40% of serologic HLA antigen matches. These differences are clinically relevant because use of donors with allele-level mismatches affects survival and rates of graft-versus-host disease (GVHD) to a degree similar to that in patients with antigen-level mismatches. Because of this, DNA-based allele-level HLA typing is standard when unrelated donors are being chosen.
|Class I Antigens||Class II Antigens|
|BM = bone marrow; PBSC = peripheral blood stem cells.|
|aHLA 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).|
|bHLA 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).|
|cSiblings need confirmation that they have fully matched haplotypes with no crossovers in the A to DRB1 region. If parental typing is performed and haplotypes are established, antigen-level typing of class I is adequate. With no parental haplotypes, allele-level typing of eight alleles is recommended.|
|dParent, cousin, etc., with a phenotypic match or near-complete HLA match.|
|Stem Cell Source||HLA A||HLA B||HLA C||HLA DRB1||HLA DQB1; HLA DPB1; HLA DR3,4,5|
|Matched siblingc BM/PBSCs||Antigen or allele||Antigen or allele||Optional||Allele|
|Mismatched sibling/other related donord BM/PBSCs||Allele||Allele||Allele||Allele||Recommended, if mismatches are present|
|Unrelated donor BM/PBSCs||Allele||Allele||Allele||Allele||Recommended, if mismatches are present|
|Unrelated donor cord blood||Antigen (allele recommended )||Antigen (allele recommended )||Allele recommended||Allele||--|
|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 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) have been used interchangeably with matched sibling donors in some studies, 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 rates in 8/8 allele level matched unrelated donors and slightly inferior survival than in fully matched siblings.
HLA matching considerations for unrelated donors
Optimal outcomes are achieved in unrelated allogeneic marrow transplantation when the pairs of antigens at HLA A, B, C, and DRB1 are matched between the donor and the recipient at the allele level (termed an 8/8 match). A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% and 10%, with a similar increase in the amount of significant (grades III–IV) acute GVHD. Of these four antigen pairs, different reports have shown HLA A, C, and DRB1 mismatches to potentially be more highly associated with mortality than the other antigens,[3,5,6] 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 either good or poor outcomes. It has been established that a specific HLA C mismatch (HLA-C*03:03/03:04) has outcomes similar to a match; therefore, selection of this mismatch is desirable in an otherwise matched donor/pair combination.
It is well understood that class II antigen DRB1 mismatches increase GVHD and worsen survival. Subsequent data have also shown that multiple mismatches of DQB1, DPB1, and DR3,4,5 lead to worse outcomes in the setting of less than 8/8 matches. DPB1 mismatches have been extensively studied and classified as permissive or nonpermissive based on T-cell epitope matching. Patients with 10/10 matches and nonpermissive DPB1 mismatches have more transplant-related mortality, but have survival rates similar to those with DPB1 matches or permissive matches. Those with 9/10 matches who have nonpermissive DPB1 mismatches had worse survival than did those with permissive mismatches or DPB1 matches.[9-11] With these findings in mind, although a 7/8 or 8/8 matched unrelated donor can be used routinely, centers may be able to further improve outcomes by the use of extended typing of DQB1, DPB1, and DR3,4,5, especially in the context of a less-than-8/8-matched donor.[9-11] In addition, extended HLA testing can also allow the selection of appropriate donors in the context of HLA-sensitized patients to avoid the potential risk of graft failure.[12,13] HLA sensitization is detected by testing for the presence of specific anti-HLA antibodies and avoidance of donors who have any HLA antigens associated with the antibodies present in the recipient. Finally, the use of younger donors and blood type–compatible unrelated donors may further improve outcomes.
If a donor or recipient has a duplication of one of their HLA alleles, they will have a half match and a mismatch only in one direction. Figure 2 illustrates that these mismatches will occur in either a direction that promotes GVHD (GVH-O) or a direction that promotes rejection (R-O). When 8/8 matched unrelated donors are compared with 7/8 donors mismatched in the GVH-O direction, 7/8 mismatched in the R-O direction, or 7/8 mismatched in both directions, the mismatch in the R-O direction leads to rates of grades III and IV acute GVHD similar to rates in the 8/8 matched and better than in the other two combinations. The 7/8 mismatched in only the R-O direction is preferred over GVH-O and bidirectional mismatches. It is important to note that this observation in unrelated donors differs from observations in cord blood recipients outlined below.
HLA matching and cell dose considerations for unrelated cord blood HCT
Another commonly used hematopoietic stem cell source is that of unrelated umbilical cord blood, which is harvested from donor placentas moments after birth. The cord blood is processed, cryopreserved, HLA typed, and banked. Unrelated cord blood transplantation has been successful with less-stringent HLA matching requirements compared with standard related or unrelated donors, probably because of limited antigen exposure experienced in utero and different immunological composition. Cord blood matching has traditionally been performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. This means that attempted matching of only six antigens is necessary to choose units for transplantation.
Although better outcomes occur when 6/6 or 5/6 HLA matched units are used, successful HCT has occurred even with 4/6 or less matched units in many patients. In a large CIBMTR/Eurocord study, better matching at the allele level using eight antigens (matching for HLA A, B, C, and DRB1) resulted in less transplant-related mortality and improved survival. Best outcome was noted with 8/8 allele matching versus 4/8 to 7/8 matches, with poor survival in patients with five or more allele mismatches. Patients receiving 8/8 matched cord blood did not require higher cell doses for better outcomes;however, those with one to three allele mismatches had less transplant-related mortality with total nucleated cell counts greater than 3 × 107/kg, and those with four allele mismatches required a total nucleated cell count greater than 5 × 107/kg to decrease transplant-related mortality. Many centers will type additional alleles and use the best match possible, but the impact of DQB1, DPB1, and DR3,4,5 mismatches has not been studied in detail.
As in unrelated PBSC 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.[18,19] Evidence also suggests that selecting a mismatched cord blood unit, where the mismatch involves a noninherited maternal antigen, may improve survival.[20,21]
As with unrelated donors, individuals can occasionally have duplicate HLA antigens (e.g., the HLA A antigen is 01 on both chromosomes). When this occurs in a donor product and the antigen is matched to one of the recipient antigens, the recipient immune response will see the donor antigens as matched (matched, in the rejection direction), but the donor immune response will see a mismatch in the recipient (mismatch 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 (GVH-O) lead to lower transplant-related mortality and overall mortality than in those with recipient direction only (R-O) mismatches. R-O mismatches have outcomes similar to those caused by bidirectional mismatches. Although some recommend using unidirectional mismatching as a criteria for cord blood selection, a Eurocord-EBMT analysis disputes the value of this type of mismatching.
Two aspects of umbilical cord blood HCT 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.[1,25] Second, as mentioned above, adequate cell dose (minimum 2–3 × 107 total nucleated cells/kg and 1.7 × 105 CD34+ cells/kg) has been shown to be associated with improved survival.[26,27] 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 HCT focused mainly on smaller children. Later studies showed that this size barrier could be overcome by using two umbilical cord blood units, as long as each of the units is at least a 4/6 HLA match with the recipient; because two cords provide higher cell doses, umbilical cord blood transplantation is now used widely for larger children and adults. If a single unit provides an adequate cell dose, there may be disadvantages to adding a second unit. A large randomized trial demonstrated 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 worse platelet recovery and higher rates of grades III and IV acute GVHD and extensive chronic GVHD.
Comparison of stem cell products
Currently, the following three stem cell products are used from both related and unrelated donors:
- Bone marrow.
- Cord blood.
In addition, bone marrow or PBSCs can be T-cell depleted by several methods, and the resultant stem cell product has very different properties. Finally, partially HLA-matched (half or more antigens [haploidentical]) related bone marrow or PBSCs can be used after in vitro or in vivo T-cell depletion, and this product also behaves differently from other stem cell products. A comparison of stem cell products is presented in Table 3.
|PBSCs||BM||Cord Blood||T-cell–Depleted BM/PBSCs||Haploidentical T-cell–Depleted BM/PBSCs|
|BM = bone marrow; EBV-LPD = Epstein-Barr virus–associated lymphoproliferative disorder; GVHD = graft-versus-host disease; HCT = hematopoietic cell transplantation; PBSCs = peripheral blood stem cells.|
|aAssuming no development of GVHD. If patients develop GVHD, immune reconstitution is delayed until resolution of the GVHD and discontinuation of immune suppression.|
|bIf a haploidentical donor is used, longer times to immune reconstitution may occur.|
|T-cell content||High||Moderate||Low||Very low||Very low|
|CD34+ content||Moderate–high||Moderate||Low (but higher potency)||Moderate–high||Moderate–high|
|Time to neutrophil recovery||Rapid: median, 16 d (11–29 d) ||Moderate: median, 21 d (12–35 d) ||Slower: median, 23 d (11–133 d) ||Rapid: median, 16 d (9–40 d) ||Rapid: median, 13 d (10–20 d) |
|Early post-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||Moderate||Low||Low||Low|
The main differences between the products are associated with the numbers of T cells and CD34-positive progenitor cells present; very high levels of T cells are present in PBSCs, intermediate numbers in bone marrow, and low numbers in cord blood and T-cell–depleted products. Patients receiving T-cell–depleted products or cord blood generally have slower hematopoietic recovery, increased risk of infection, late immune reconstitution, higher risks of nonengraftment, and increased risk of Epstein-Barr virus (EBV)–associated lymphoproliferative disorder. This is countered by lower rates of GVHD and an ability to offer transplantation to patients where full HLA matching is not available. Higher doses of T and other cells in PBSCs result in rapid neutrophil recovery and immune reconstitution, but also increased rates of chronic GVHD.
There are only a few studies directly comparing outcomes of different stem cell sources/products in pediatric patients. The following results have been observed:
- A retrospective registry study of pediatric patients who underwent HCT for acute leukemia compared those who received related donor bone marrow with those who received related donor PBSCs. Although the bone marrow and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and transplant-related mortality associated with PBSC led to poorer survival in the PBSC group.
- A retrospective study of Japanese children with acute leukemia compared 90 children who received PBSCs with 571 children who received bone marrow; the study confirmed higher transplant-related mortality due to GVHD and inferior survival among the children who received PBSCs.
These reports, combined with 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.
For those requiring unrelated donors, a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial that included a few pediatric patients randomly assigned patients to receive either bone marrow or PBSCs. This trial demonstrated that overall survival was identical using either source, but rates of chronic GVHD were significantly higher in the PBSC arm.
In an attempt to determine whether unrelated bone marrow or cord blood is better, a retrospective CIBMTR study was conducted. Pediatric patients with acute lymphoblastic leukemia who underwent HCT and received 8/8 HLA allele–matched unrelated donor bone marrow were compared with those who received unrelated cord blood. The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched cord blood; survival after 8/8 HLA-matched unrelated bone marrow was slightly less and was statistically identical to survival for patients receiving 5/6 and 4/6 HLA-matched cord blood units.
On the basis of these studies, most transplant centers consider matched sibling bone marrow to be the preferred stem cell source/product. If a sibling donor is not available, fully matched unrelated donor bone marrow or PBSCs or HLA-matched (4/6 to 6/6) cord blood leads to similar survival. Although adult studies of T-cell–depleted unrelated bone marrow or PBSCs have shown outcomes similar to non–T-cell–depleted approaches, large pediatric trials or retrospective studies comparing T-cell–depleted matched or haploidentical bone marrow or PBSCs have not been conducted.
Early 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).
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. Most approaches developed to date rely on intense T-cell depletion of the product before infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery, which can result in lethal infections, increased risk of EBV-lymphoproliferative disorder, and high rates of relapse. This has generally led 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 on studying and developing this approach.
- Newer techniques of T-cell depletion and add-back of specific cell populations (e.g., CD3 or alpha-beta CD3/CD19-negative selection) may decrease transplant-related mortality.[32,41]
- Reduced toxicity regimens have led to improved survival.
- Better supportive care has decreased the chance of morbidity from infection or EBV-lymphoproliferative disorder.
- Some patient-donor combinations that have specific killer immunoglobulin-like receptor mismatches have shown decreased likelihood of relapse (refer to the Role of killer immunoglobulin-like receptor mismatching in HCT section of this summary for more information).
- Certain techniques, such as using combinations of granulocyte-colony stimulating factor (G-CSF)–primed bone marrow and PBSCs with posttransplant antibody–based T-cell depletion  or post-HCT cyclophosphamide (chemotherapeutic T-cell depletion), have made these procedures more accessible to centers because expensive and complicated processing necessary for traditional T-cell depletion are not used.
Reported survival using many different types of haploidentical approaches varies between 25% and 80%, depending on the technique used and the risk of the patient undergoing the procedure.[38,39,43,44] Whether haploidentical approaches are superior to cord blood or other stem cell sources for a given patient group has not been determined because comparative studies have yet to be performed.
Immunotherapeutic Effects of Allogeneic HCT
Graft-versus-leukemia (GVL) effect
Early studies in 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 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 either autologous or allogeneic donors for a given disease.
- Leukemia and myelodysplastic syndrome (MDS): 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 MDS. For ALL and AML specifically, autologous HCT approaches for most high-risk patient groups have shown results similar to those obtained with chemotherapy, while allogeneic approaches produced superior results.[45,46]
- 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 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 Allogeneic HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL because the intensity of the preparative regimen is not sufficient for cure in most cases. Although studies have shown benefit for patients pursuing this approach when they are ineligible for standard transplantation, because pediatric cancer patients can generally undergo myeloablative approaches safely, this approach has not been used for most 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 before 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 on donor type (related donors are tapered more quickly than are unrelated donors because of less GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient chimerism) or minimal residual disease to assess 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 rate, compared with 0% in the 15 patients who did not undergo this approach (P < .001). For patients with AML after HCT, about 20% experienced mixed chimerism after HCT and were identified as high risk. Of these, 54% survived if they underwent withdrawal of immune suppression with or without DLI; there were no survivors among those who did not receive this therapy.
Other approaches under evaluation
The role of killer immunoglobulin-like receptor mismatching in HCT
- Decreased GVHD.
- Fewer relapses of hematological malignancies.
- Improved survival.
NK cell function is modulated by interactions with a number of receptor families, including activating and inhibiting killer immunoglobulin-like receptors. The killer immunoglobulin-like receptor effect in the allogeneic HCT setting hinges on expression of specific inhibitory killer immunoglobulin-like receptors on donor-derived NK cells and either the presence or the absence of their matching HLA class I molecules (killer immunoglobulin-like receptor ligands) on recipient leukemic and normal cells. Normally, the presence of specific killer immunoglobulin-like receptor ligands interacting with paired inhibitory killer immunoglobulin-like receptor molecules prevents NK cell attack on healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells, and they may not have the appropriate inhibitory killer immunoglobulin-like receptor ligand. Mismatch of ligand and receptor allows NK cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.
The original observation of decreased relapse with certain killer immunoglobulin-like receptor-ligand combinations was made in the setting of T-cell–depleted haploidentical transplantation and was strongest after HCT for AML.[55,57] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate killer immunoglobulin-like receptor-ligand combinations. Many subsequent studies did not detect survival effects for killer immunoglobulin-like receptor-incompatible HCT using standard transplantation methods,[58,59] which has led to the conclusion that T-cell depletion may be necessary to remove other forms of inhibitory cellular interactions. Decreased relapse and better survival have been noted with donor/recipient killer immunoglobulin-like receptor-ligand incompatibility after cord blood HCT, a relatively T-cell–depleted procedure.[60,61] In contrast to this notion, one study demonstrated that some killer immunoglobulin-like receptor mismatching combinations (activating receptor KIR2DS1 with the HLA C1 ligand) can lead to decreased relapse after AML HCT without T-cell depletion. The role of killer immunoglobulin-like receptor incompatibility in sibling donor HCT and in diseases other than AML is controversial.[39,63]
A current challenge associated with studies of killer immunoglobulin-like receptor is that several different approaches have been used to determine what is killer immunoglobulin-like receptor compatible and incompatible.[57,64] Standardization of classification and prospective studies should help clarify the utility and importance of this approach. Because a limited number of centers perform haploidentical HCT and the results of the data in cord blood HCT are preliminary, most transplant programs do not use killer immunoglobulin-like receptor mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of killer immunoglobulin-like receptor incompatibility remaining secondary.
NK cell transplantation
With low risk of GVHD and demonstrated efficacy in decreasing relapse in posthaploidentical 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 interleukin-2 (IL-2) maintenance led to remission in 5 of 19 high-risk AML patients. Researchers at St. Jude Children’s Research Hospital treated ten intermediate-risk AML patients who had completed chemotherapy and were in remission with lower-dose immunosuppression followed by haploidentical NK cell infusions and IL-2 for consolidation. Expansion of NK cells was noted in all nine of the killer immunoglobulin-like receptor-incompatible donor/recipient pairs. All ten children remained in remission at 2 years. A follow-up phase II study is under way, as are many investigations into NK cell therapy for a number of cancer types.
Chimeric antigen receptor (CAR) T-cell therapy
In order for T cells are to attack cellular targets (viruses or cancer cells), they must to bind to class I major histocompatibility complex (MHC) molecules on the surface of the target cells and avoid suppressor signals sent by regulatory T cells and other surface molecule interactions. Gene transfer technologies can modify T cells to express MHC-independent antibody-binding domains (CAR molecules) aimed at specific target proteins on the surface of tumors. To minimize the chance of suppressor mechanisms affecting CAR T-cell function, lymphodepleting chemotherapy is generally given before CAR T-cell infusions. CAR T-cell–mediated responses can be further enhanced by the addition of intracellular costimulatory domains (e.g.., CD28, 4-1BB), which cause significant CAR T-cell expansion and may increase the lifespan of these cells in the recipient.
Use of this technology has targeted a variety of tumors/surface molecules but the best-studied experience has been CAR T cells aimed at CD19, a surface receptor on B cells. Several groups have reported significant rates of remission (70%–90%) in children and adults with refractory B-cell ALL,[68-70] and one group has reported persistence of CAR T cells and remission beyond 6 months in most patients studied. Responses have been associated with a significant increase in inflammatory cytokines (termed cytokine release syndrome) that has given a sepsis-like picture that can be successfully treated with anti–IL-6 therapies (tociluzumab). Early loss of the CAR T cells is associated with relapse, and the best use of this therapy (bridge to transplant vs. definitive therapy) is under study.
Principles of Allogeneic HCT Preparative Regimens
In the days before infusion of the stem cell product (bone marrow, peripheral blood stem cells, or cord blood), 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 GVL effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HCT approaches focusing on immune suppression rather than myeloablation have been developed. The resultant lower toxicity associated with these regimens has led to lower rates of transplant-related mortality and an expanded eligibility for allogeneic HCT to older individuals and younger patients with pre-HCT comorbidities that put them at risk of severe toxicity after standard HCT approaches. The 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.
Although these regimens represent a spectrum of varying degrees of myelosuppression and immune suppression, they have been grouped clinically into the following three major categories:
- Myeloablative: Intense approaches that cause irreversible pancytopenia that requires stem cell rescue for restoration of hematopoiesis.
- Nonmyeloablative: Regimens that cause minimal cytopenias and do not require stem cell support.
- Reduced-intensity conditioning: Regimens that are of intermediate intensity and do not meet the definitions of nonmyeloablative or myeloablative regimens.
The use of reduced-intensity conditioning and nonmyeloablative regimens is well established in older adults who cannot tolerate more-intense myeloablative approaches,[75-77] but these approaches have been studied in only a handful of younger patients with malignancies.[78-82] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk of transplant-related mortality with myeloablative regimens (e.g., history of previous myeloablative transplant, severe organ system dysfunction, or active invasive fungal infection) and successfully treated them with a reduced-intensity regimen. Transplant-related mortality was low in this high-risk group, and long-term survival occurred in most patients with minimal or no detectable disease present at the time of transplantation. Because the risks of relapse are higher with these approaches, their use in pediatric cancer is currently limited to patients ineligible for myeloablative regimens.
Establishing donor chimerism
Intense myeloablative approaches almost invariably result in rapid establishment of hematopoiesis derived completely from donor cells upon count recovery within weeks of the transplant. The introduction of reduced-intensity conditioning and nonmyeloablative approaches into HCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that is sometimes only partial. DNA-based techniques have been established to differentiate donor and recipient hematopoiesis, applying the word chimerism (from the Greek chimera, a mythical animal with parts taken from various animals) to describe whether all or part of hematopoiesis after HCT is from the donor or recipient.
There are several implications to the pace and extent of donor chimerism eventually achieved by an HCT recipient. For patients receiving reduced-intensity conditioning or nonmyeloablative regimens, rapid progression to full donor chimerism is associated with less relapse but more GVHD. The delayed pace of obtaining full donor chimerism after these regimens has led to late-onset acute GVHD, occurring as long as 6 months to 7 months after HCT (generally within 100 days after myeloablative approaches). A portion of patients achieve stable mixed chimerism of both donor and recipient. Mixed chimerism is associated with more relapse after HCT for malignancies and less GVHD; however, this condition is often advantageous for nonmalignant HCT, where usually only a percentage of normal hematopoiesis is needed to correct the underlying disorder and GVHD is not beneficial. Finally, serially measured decreasing donor chimerism, especially T-cell–specific chimerism, has been associated with increased risk of rejection.
Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and DLI. (Refer to the Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL section of this summary for more information.) These approaches are frequently used to address this issue, and have been shown in some cases to decrease relapse risk and stop rejection.[52,87] Timing of tapers of immune suppression and doses and approaches to the administration of DLI to increase or stabilize donor chimerism vary tremendously among transplant regimens and institutions.
- Barker JN, Byam CE, Kernan NA, et al.: Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant 16 (11): 1541-8, 2010. [PUBMED Abstract]
- Gragert L, Eapen M, Williams E, et al.: HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 371 (4): 339-48, 2014. [PUBMED Abstract]
- Woolfrey A, Klein JP, Haagenson M, et al.: HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 17 (6): 885-92, 2011. [PUBMED Abstract]
- Shaw PJ, Kan F, Woo Ahn K, et al.: Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 116 (19): 4007-15, 2010. [PUBMED Abstract]
- Flomenberg N, Baxter-Lowe LA, Confer D, et al.: Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 104 (7): 1923-30, 2004. [PUBMED Abstract]
- Petersdorf EW, Kollman C, Hurley CK, et al.: Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience. Blood 98 (10): 2922-9, 2001. [PUBMED Abstract]
- Fernandez-Viña MA, Wang T, Lee SJ, et al.: Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood 123 (8): 1270-8, 2014. [PUBMED Abstract]
- Fernández-Viña MA, Klein JP, Haagenson M, et al.: Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood 121 (22): 4603-10, 2013. [PUBMED Abstract]
- Fleischhauer K, Shaw BE, Gooley T, et al.: Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 13 (4): 366-74, 2012. [PUBMED Abstract]
- Crocchiolo R, Zino E, Vago L, et al.: Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation. Blood 114 (7): 1437-44, 2009. [PUBMED Abstract]
- Pidala J, Lee SJ, Ahn KW, et al.: Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 124 (16): 2596-606, 2014. [PUBMED Abstract]
- Spellman S, Bray R, Rosen-Bronson S, et al.: The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood 115 (13): 2704-8, 2010. [PUBMED Abstract]
- Ciurea SO, Thall PF, Wang X, et al.: Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood 118 (22): 5957-64, 2011. [PUBMED Abstract]
- Howard CA, Fernandez-Vina MA, Appelbaum FR, et al.: Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant 21 (1): 4-7, 2015. [PUBMED Abstract]
- Hurley CK, Woolfrey A, Wang T, et al.: The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors. Blood 121 (23): 4800-6, 2013. [PUBMED Abstract]
- Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007. [PUBMED Abstract]
- Eapen M, Klein JP, Ruggeri A, et al.: Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 123 (1): 133-40, 2014. [PUBMED Abstract]
- Takanashi M, Atsuta Y, Fujiwara K, et al.: The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood 116 (15): 2839-46, 2010. [PUBMED Abstract]
- Cutler C, Kim HT, Sun L, et al.: Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 118 (25): 6691-7, 2011. [PUBMED Abstract]
- Rocha V, Spellman S, Zhang MJ, et al.: Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy. Biol Blood Marrow Transplant 18 (12): 1890-6, 2012. [PUBMED Abstract]
- van Rood JJ, Stevens CE, Smits J, et al.: Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci U S A 106 (47): 19952-7, 2009. [PUBMED Abstract]
- Kanda J, Atsuta Y, Wake A, et al.: Impact of the direction of HLA mismatch on transplantation outcomes in single unrelated cord blood transplantation. Biol Blood Marrow Transplant 19 (2): 247-54, 2013. [PUBMED Abstract]
- Stevens CE, Carrier C, Carpenter C, et al.: HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection. Blood 118 (14): 3969-78, 2011. [PUBMED Abstract]
- Cunha R, Loiseau P, Ruggeri A, et al.: Impact of HLA mismatch direction on outcomes after umbilical cord blood transplantation for hematological malignant disorders: a retrospective Eurocord-EBMT analysis. Bone Marrow Transplant 49 (1): 24-9, 2014. [PUBMED Abstract]
- Barker JN, Rocha V, Scaradavou A: Optimizing unrelated donor cord blood transplantation. Biol Blood Marrow Transplant 15 (1 Suppl): 154-61, 2009. [PUBMED Abstract]
- Wagner JE, Barker JN, DeFor TE, et al.: Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 100 (5): 1611-8, 2002. [PUBMED Abstract]
- Rubinstein P, Carrier C, Scaradavou A, et al.: Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 339 (22): 1565-77, 1998. [PUBMED Abstract]
- Barker JN, Weisdorf DJ, DeFor TE, et al.: Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105 (3): 1343-7, 2005. [PUBMED Abstract]
- Wagner JE Jr, Eapen M, Carter S, et al.: One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med 371 (18): 1685-94, 2014. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001. [PUBMED Abstract]
- Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007. [PUBMED Abstract]
- Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010. [PUBMED Abstract]
- 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 Abstract]
- Porter DL, Collins RH Jr, Shpilberg O, et al.: Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transplant 5 (4): 253-61, 1999. [PUBMED Abstract]
- Levine JE, Barrett AJ, Zhang MJ, et al.: Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population. Bone Marrow Transplant 42 (3): 201-5, 2008. [PUBMED Abstract]
- Warlick ED, DeFor T, Blazar BR, et al.: Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 18 (3): 480-6, 2012. [PUBMED Abstract]
- 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 Abstract]
- Rettinger E, Willasch AM, Kreyenberg H, et al.: Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 118 (20): 5681-8, 2011. [PUBMED Abstract]
- Ruggeri L, Capanni M, Urbani E, et al.: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295 (5562): 2097-100, 2002. [PUBMED Abstract]
- Giebel S, Locatelli F, Lamparelli T, et al.: Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102 (3): 814-9, 2003. [PUBMED Abstract]
- Bari R, Rujkijyanont P, Sullivan E, et al.: Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 31 (30): 3782-90, 2013. [PUBMED Abstract]
- Ruggeri L, Mancusi A, Capanni M, et al.: Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110 (1): 433-40, 2007. [PUBMED Abstract]
- Davies SM, Ruggieri L, DeFor T, et al.: Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 100 (10): 3825-7, 2002. [PUBMED Abstract]
- Farag SS, Bacigalupo A, Eapen M, et al.: The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant 12 (8): 876-84, 2006. [PUBMED Abstract]
- Cooley S, Trachtenberg E, Bergemann TL, et al.: Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood 113 (3): 726-32, 2009. [PUBMED Abstract]
- Willemze R, Rodrigues CA, Labopin M, et al.: KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 23 (3): 492-500, 2009. [PUBMED Abstract]
- Venstrom JM, Pittari G, Gooley TA, et al.: HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 367 (9): 805-16, 2012. [PUBMED Abstract]
- Leung W: Use of NK cell activity in cure by transplant. Br J Haematol 155 (1): 14-29, 2011. [PUBMED Abstract]
- Leung W, Iyengar R, Triplett B, et al.: Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol 174 (10): 6540-5, 2005. [PUBMED Abstract]
- Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al.: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105 (8): 3051-7, 2005. [PUBMED Abstract]
- Rubnitz JE, Inaba H, Ribeiro RC, et al.: NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 28 (6): 955-9, 2010. [PUBMED Abstract]
- Kalos M, Levine BL, Porter DL, et al.: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3 (95): 95ra73, 2011. [PUBMED Abstract]
- Grupp SA, Kalos M, Barrett D, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368 (16): 1509-18, 2013. [PUBMED Abstract]
- Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al.: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385 (9967): 517-28, 2015. [PUBMED Abstract]
- Davila ML, Riviere I, Wang X, et al.: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6 (224): 224ra25, 2014. [PUBMED Abstract]
- Maude SL, Frey N, Shaw PA, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371 (16): 1507-17, 2014. [PUBMED Abstract]
- Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124 (2): 188-95, 2014. [PUBMED Abstract]
- Deeg HJ, Sandmaier BM: Who is fit for allogeneic transplantation? Blood 116 (23): 4762-70, 2010. [PUBMED Abstract]
- Bacigalupo A, Ballen K, Rizzo D, et al.: Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15 (12): 1628-33, 2009. [PUBMED Abstract]
- Giralt S, Estey E, Albitar M, et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89 (12): 4531-6, 1997. [PUBMED Abstract]
- 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 Abstract]
- Storb R, Yu C, Sandmaier BM, et al.: Mixed hematopoietic chimerism after marrow allografts. Transplantation in the ambulatory care setting. Ann N Y Acad Sci 872: 372-5; discussion 375-6, 1999. [PUBMED Abstract]
- 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 Abstract]
- Del Toro G, Satwani P, Harrison L, et al.: A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant 33 (6): 613-22, 2004. [PUBMED Abstract]
- Gómez-Almaguer D, Ruiz-Argüelles GJ, Tarín-Arzaga Ldel C, et al.: Reduced-intensity stem cell transplantation in children and adolescents: the Mexican experience. Biol Blood Marrow Transplant 9 (3): 157-61, 2003. [PUBMED Abstract]
- Pulsipher MA, Woolfrey A: Nonmyeloablative transplantation in children. Current status and future prospects. Hematol Oncol Clin North Am 15 (5): 809-34, vii-viii, 2001. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- Vigorito AC, Campregher PV, Storer BE, et al.: Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood 114 (3): 702-8, 2009. [PUBMED Abstract]
- Marsh RA, Vaughn G, Kim MO, et al.: Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 116 (26): 5824-31, 2010. [PUBMED Abstract]
- McSweeney PA, Niederwieser D, Shizuru JA, et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97 (11): 3390-400, 2001. [PUBMED Abstract]
- Horn B, Soni S, Khan S, et al.: Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 43 (6): 469-76, 2009. [PUBMED Abstract]