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; also called hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen given to the patient consisting of agents designed to do the following:

• Create marrow space.
• 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 an insufficient expression of the affected gene product by the patient can be partially or completely overcome by circulating hematopoietic cells transplanted from a donor with normal gene expression.

Autologous Versus Allogeneic HCT

The two major transplant approaches currently in use are autologous (using the patient's own hematopoietic stem cells) and allogeneic (using related or unrelated donor hematopoietic stem cells). 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 hematopoietic stem cells. It has also been used to attempt to reset the immune system in severe autoimmune disorders. In order for autologous transplant to work, the following must apply:

• The higher chemotherapy/radiation therapy dose that can be used because of hematopoietic stem cell 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 (central nervous system).


• Meaningful percentages of cure or long-term remission from the disease must occur without significant nonhematopoietic toxicities that would otherwise limit the therapeutic benefit achieved.

Allogeneic transplant approaches to cancer treatment also may involve high-dose therapy, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (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, thus requiring allogeneic approaches for optimal outcome. Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, and brain tumors.

Determining When HCT is Indicated: Comparison of HCT and Chemotherapy Outcomes

Because the outcomes using chemotherapy and HCT treatments have been changing with time, regular comparisons between these approaches should be performed 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 because of investigator bias. [3] [4] In general, HCT approaches offer benefit only to children at high risk for relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HCT if reasonably HLA-matched donors are available have come to be the preferred approach for many diseases. [5] Less well-established, higher-risk approaches to HCT (HLA haploidentical or significantly mismatched donors) are generally reserved for only the very highest-risk patients.

When comparisons of similar patients treated with HCT or chemotherapy are made and when randomized or intent-to-treat studies are not feasible, the following issues should be considered:

1. Remission status: Comparisons between HCT and chemotherapy should include only those who obtain remission, preferably after similar approaches to salvage therapy, because patients failing to obtain remission do very poorly with any therapy. 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. Therapy approaches used for comparison: Comparisons should be made with the best or most commonly used chemotherapy and HCT approaches utilized during the time frame under study.


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 should be based on the most current knowledge of risk. 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. [6]


5. Selection bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
   • Higher-risk patients preferentially undergoing HCT (i.e., patients who take several rounds to achieve remission or who relapse after obtaining remission and go back into a subsequent remission prior to HCT).
   • Sicker patients deferred from HCT because of comorbidities.
   • Patient/parent refusal.
   • Lack of or inability to obtain insurance approval for HCT.
   • Lack of access to HCT owing to distance/inability to travel.

One source of bias difficult to control for or detect is physician bias for or against HCT. The effect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.

References:

1. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999.
2. 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.
3. Lawson SE, Harrison G, Richards S, et al.: The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 108 (3): 531-43, 2000.
4. Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006.
5. Schrauder A, von Stackelberg A, Schrappe M, et al.: Allogeneic hematopoietic SCT in children with ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant 41 (Suppl 2): S71-4, 2008.
6. Pulsipher MA, Peters C, Pui CH: High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant? Biol Blood Marrow Transplant 17 (1 Suppl): S137-48, 2011.

Autologous HCT

Collection and Storage of Autologous Hematopoietic Stem Cells

Autologous procedures require collection of peripheral blood stem cells (PBSCs) from patients by the process of apheresis. Bone marrow can be used for the transplant, but PBSCs have been shown to lead to quicker recovery and less toxicity. Patients under consideration for autologous HCT are generally given chemotherapy to demonstrate tumor responsiveness and minimize risk of tumor contamination in their bone marrow. After a number of rounds of chemotherapy, they undergo the apheresis procedure, either as their blood counts recover from chemotherapy or during a break between chemotherapy treatments. Growth factors such as granulocyte colony-stimulating factor (G-CSF) are used to increase the number of circulating stem and progenitor cells (CD34+ cells). Collection centers monitor the CD34+ number in the patient and product each day to determine the best time to begin collection and when collection is complete. The collected PBSCs are cryopreserved for later use; after completion of an intensive preparative regimen using high-dose chemotherapy that varies according to tumor, the PBSCs are administered back to the patient at the time of transplant.

General Indications for Autologous Procedures/Preparative Regimens/Tumor Purging

In pediatrics, the most common autologous transplant indications are high-risk neuroblastoma, relapsed Hodgkin and non-Hodgkin lymphoma, high-risk and relapsed brain tumors, and relapsed or resistant germ cell tumors. Regimens specific to given tumors are described in disease-specific PDQ treatment summaries.

Preparative regimens for allogeneic transplant are mainly needed to ensure engraftment of the donor marrow or cord blood. Use of high-dose tumor-specific agents, however, has not shown benefit, especially if such agents add toxicity to the approach. Unlike allogeneic procedures, the tumor-specific activity and intensity of agents used for autologous regimens have been shown to be important in improving survival. One concern with autologous approaches to these and other tumor types has been the contamination of the collected stem cell product by persistent tumor cells. Although a wide variety of techniques have been developed to remove or “purge” tumor cells from products, most studies looking into these approaches have shown no benefit to tumor purging. [1]

References:

1. Kreissman SG, Villablanca JG, Seeger RC, et al.: A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study. [Abstract] J Clin Oncol 26 (Suppl 15): A-10011, 2008. Also available online. Last accessed March 22, 2013.

Allogeneic HCT

HLA Matching and Hematopoietic Stem Cell Sources

HLA overview

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). [1] 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, 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. [2] 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 Sources^a,b

Table 2. Definitions of the Numbers Describing Human Leukocyte Antigen (HLA) Antigens and Alleles Matching

HLA matching considerations for sibling and related donors

The most commonly used related donor is a sibling from the same parents who 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. [3]

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). [4] 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. [4] 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, [2] [4] [5] 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, [5] 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, [6] but subsequent studies have not shown a difference in overall survival. [4] 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. [7] [8] 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, [9] but this classification system is not yet generally accepted.

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 and 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 due to limited antigen exposure experienced in utero and different immunological composition. Cord blood 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, [10] successful HCT has occurred even with 4/6 or less matched units in many patients. Better matching of units (matching for HLA C, as well as A, B, and DRB1) has been shown to result in less transplant-related mortality, but has not been shown to have an impact on survival in children with malignancies. [11] Many centers will type up to 10 alleles and use the best match possible, but the impact of DQB1 mismatched has not been shown to affect outcome. Higher cell doses in cord blood 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/kg recipient weight is similar to 5/6 matched cord recipients receiving a cell dose of 2.5 to 5 × 10⁷ total nucleate cells/kg. Although no clear improvement in survival occurred for cell doses above 5 × 10⁷ total nucleate cells/kg, higher doses of cells improved outcomes for all levels of HLA mismatch. [12]

Occasionally, individuals can 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 unique type 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 compared with those with recipient direction only (R-O) mismatches. R-O mismatches have outcomes similar to those caused by bidirectional mismatches. [13] Current recommendations are for transplant centers to choose GVH-O mismatches above R-O or bidirectional mismatches.

Two aspects of umbilical cord blood 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 cord blood unit, allowing a method of performing HCT for populations that traditionally have not had HCT options because of having rare HLA haplotypes. [1] [14] Second, as mentioned above, adequate cell dose (minimum 2–3 × 10⁷ total nucleate cells/kg and 1.7 × 10⁵ CD34+ cells/kg) has been shown to be associated with improved survival. [15] [16] Total nucleate cells is generally used to judge units because techniques to measure CD34+ 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 result in much higher cell doses, umbilical cord blood transplantation is now used widely for larger children and adults. [17] Single-center studies have suggested that the use of two umbilical cord blood units may decrease relapse in patients with malignancies; however, this has not been validated in multicenter studies. [18] It has been shown that grades II to IV acute GVHD is higher when two versus one umbilical cord blood unit is used; but transplant-related mortality has not been noted to be increased. [19] One study comparing adult and older pediatric patients transplanted with either double 4/6 to 6/6 matched umbilical cord blood or unrelated bone marrow/PBSCs showed survival to be equivalent. [20]

Comparison of stem cell products

Currently, the three stem cell products used from both related and unrelated donors are bone marrow, peripheral blood stem cells (PBSCs), and 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 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

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 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. A retrospective registry study of pediatric patients undergoing HCT for acute leukemia compared those receiving related donor bone marrow with 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. [21] This report, combined with lack of prospective studies comparing bone marrow and PBSCs, has led most pediatric transplant protocols to prefer bone marrow to PBSCs from related donors. For those requiring unrelated donors, a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial randomizing bone marrow and PBSCs that included pediatric patients demonstrated that overall survival was identical using either source, but rates of chronic GVHD were significantly higher in the PBSC arm. [22] In an attempt to determine whether unrelated bone marrow or cord blood 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 bone marrow was compared with those receiving unrelated cord blood. [10] 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 patients receiving 5/6 and 4/6 HLA-matched cord blood units. Based upon 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 lead to similar survival. Although adult studies of T-cell depleted unrelated bone marrow 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 bone marrow or PBSCs have not occurred.

Haploidentical HCT

Early HCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival as the number of donor/recipient HLA mismatches increased. [23] 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). [1]

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, [24] increased risk of EBV-lymphoproliferative disorder, and high rates of relapse. [25] 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. [26] [27] Newer techniques of T-cell depletion and add-back of specific cell populations (i.e., CD3/19 negative selection) may decrease transplant-related mortality. [28] Reduced toxicity regimens have led to improved survival, better supportive care has decreased the chance of morbidity from infection or EBV-lymphoproliferative disorder, [29] and 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). Finally, techniques such as using combinations of granulocyte-colony stimulating factor (G-CSF) primed bone marrow and PBSCs with posttransplant antibody based T-cell depletion [30] or post-HCT cyclophosphamide (chemotherapeutic T-cell depletion) [31] 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. [25] [26] [30] [31] 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. [25]

Immunotherapeutic Effects of Allogeneic 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. [32] [33] 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. [34]

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, [35] 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), [36] but responses in other diseases (AML and ALL) have been less potent, with only 20% to 30% long-term survival. [37] 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. [38] 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). [39] 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. [40]

Other approaches under evaluation

The role of killer immunoglobulin-like receptor 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. [41] [42] 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 upon expression of specific inhibitory killer immunoglobulin-like receptors on donor-derived NK cells and either the presence or 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 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 killer immunoglobulin-like receptor 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 killer immunoglobulin-like receptor-ligand combinations was made in the setting of T-cell depleted haploidentical transplantation and was strongest after HCT for AML. [42] [43] 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, [44] [45] 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. [46] [47] 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. [48] The role of killer immunoglobulin-like receptor incompatibility in sibling donor HCT and in diseases other than AML is controversial. [26] [49]

A current challenge associated with the killer immunoglobulin-like receptor field is that several different approaches have been used to determine what is killer immunoglobulin-like receptor compatible and incompatible. [43] [50] 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 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 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. [51] 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. [52] 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 underway, as are many investigations into NK cell therapy for a number of cancer types.

Principles of Allogeneic 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 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. [53] 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: [54]

• Myeloablative: Intense approaches that cause irreversible pancytopenia requiring 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.

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 reduced-intensity conditioning and nonmyeloablative regimens is well-established in older adults who cannot tolerate more intense myeloablative approaches, [55] [56] [57] but only a handful of younger patients with malignancies have been studied using these approaches. [58] [59] [60] [61] [62] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk for 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. [35] 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 graft-versus-host disease (GVHD). [63] 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 myeloablative approaches). [64] 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. [65] Finally, serially measured decreasing donor chimerism, especially T-cell specific chimerism, has been associated with increased risk of rejection. [66]

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. [39] [67] 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.

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Complications After HCT

Pre-HCT Comorbidities that Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Charlson Comorbidity Index

Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, functional status, etc.) is associated with risk of transplant-related mortality. The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index. Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the Charlson Comorbidity Index elements were correlated with transplant-related mortality in adult and pediatric patients. They also determined several additional comorbidities that have predictive power specific to transplant patients. Successful validation defined what is now termed the HCT-Charlson Comorbidity Index. [1] Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (see Table 4).

Table 4. Definitions of Comorbidities Included in the Hematopoietic Cell Transplantation (HCT)-Charlson Comorbidity Index^a

The predictive power of this index for both transplant-related mortality and overall survival (OS) is strong, with a hazard ratio of 3.54 (95% confidence interval [CI], 2.0–6.3) for nonrelapse mortality (NRM) and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or more compared with those who have a score of 0. Although the original studies were performed with patients receiving intense, myeloablative approaches, the HCT-Charlson Comorbidity Index has been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens as well. [2] It has also been combined with disease status [3] and Karnofsky score, [4] leading to even better prediction of survival outcomes.

The large majority of patients assessed in the HCT-Charlson Comorbidity Index studies have been adults, and the comorbidities listed are skewed toward adult diseases. The relevance of this scale for pediatric and young adult recipients of HCT has been explored in two studies. A retrospective cohort study was conducted at four large centers of pediatric patients with a median age of 6 years and a wide variety of both malignant and nonmalignant disorders. [5] The HCT-Charlson Comorbidity Index was predictive of both NRM and survival, with 1-year NRM of 10%, 14%, and 28% and 1-year OS of 88%, 67%, and 62% for patients with scores of 0, 1–2, and 3+, respectively. A second study included young adults (aged 16–39 years) and demonstrated similar increases in mortality with higher HCT-Charlson Comorbidity Index scores (NRM 24% and 38% and OS 46% and 28% for patients with scores of 0–2 and 3+, respectively). [6] In both studies, more than three-quarters of the reported comorbidities were associated with respiratory or hepatic conditions and infection. [5] [6] Patients with pre-HCT pulmonary dysfunction were at particularly high risk for comorbidity, with a 2-year OS of 29% compared with 61% in those with normal lung function before HCT. [6]

Selected HCT-Related Acute Complications

Sinusoidal obstruction syndrome/veno-occlusive disease

Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is defined clinically by right upper quadrant pain with hepatomegaly, fluid retention (weight gain and ascites), and hyperbilirubinemia. Pathologically, the disease is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of myeloablative transplantations in children, and risk factors include the use of busulfan (especially before therapeutic pharmacokinetic monitoring), total-body irradiation, serious infection, graft-versus-host disease (GVHD), and pre-existing liver dysfunction due to hepatitis or iron overload. [7] [8] Life-threatening SOS/VOD generally occurs early after transplantation and is characterized by multiorgan system failure. [9] Milder, reversible forms can occur with full recovery expected.

Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied with mixed results, but recent studies have suggested prophylactic ursodiol may have an effect on SOS/VOD. [10] Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has been shown to decrease mortality in the treatment of severe VOD [11] [12] and seems to show efficacy in decreasing VOD incidence when used prophylactically. [13][Level of evidence: 1iiA] Defibrotide is not FDA approved but is routinely used by U.S. centers through a pre-approval protocol.

Transplant-associated microangiopathy

Although transplant-associated microangiopathy clinically mirrors hemolytic uremic syndrome, its causes and clinical course are different from other hemolytic uremic syndrome–like syndromes. Transplant-associated microangiopathy has most frequently been associated with the use of the calcineurin inhibitors, tacrolimus and cyclosporine, and has been noted to occur more frequently when either of these two medications are used in combination with sirolimus. [14] Diagnostic criteria for this syndrome have been standardized and include the presence of schistocytes on a peripheral smear and increased lactic dehydrogenase, decreased haptoglobin, and thrombocytopenia with or without anemia. [15] Suggestive symptoms consistent but not necessary for the diagnosis include a sudden worsening of renal function and neurologic symptoms. Treatment for transplant-associated microangiopathy includes cessation of the calcineurin inhibitor and substitution with other immune suppressants if necessary. In addition, careful management of hypertension and renal damage by dialysis, if necessary, is vital. Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most transplant-associated microangiopathy associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after stopping sirolimus, and in some cases, both medications. [14]

Idiopathic pneumonia syndrome

Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs within the first few months after transplantation. Diagnostic criteria include signs and symptoms of pneumonia, evidence of nonlobar radiographic infiltrates, and abnormal pulmonary function, all in the absence of documented infectious organisms. [16] With this in mind, early assessment by bronchioalveolar lavage to rule out infection is important. Time of onset ranges from 14 days to 90 days after the infusion of donor cells. Mortality rates of 50% to 70% have been reported, [17] although these estimates are from the mid-1990s and outcomes may have improved. Possible etiologies include direct toxic effects of the conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli. Traditional therapy has been high-dose methylprednisolone and pulmonary support. The addition of etanercept, a soluble interleukin-2 receptor, to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies, [18] but multicenter studies showing improved long-term survival are lacking. In recent years, the incidence of this complication appears to be decreasing, possibly due to less-intensive preparative regimens, better HLA matching, and better definition of occult infections through polymerase chain reaction (PCR) testing of blood and bronchioalveolar specimens.

Epstein-Barr virus–lymphoproliferative disorder

Epstein-Barr virus (EBV) infection increases through childhood from approximately 40% in 4-year olds to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk for reactivation of EBV when undergoing HCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin or alemtuzumab, and to a lesser degree, use of cord blood). [19] [20] [21] Patients experiencing EBV reactivation can vary from isolated increase in EBV titers in the bloodstream as measured by PCR to an aggressive monoclonal disease with marked lymphadenopathy presenting as lymphoma (lymphoproliferative disorder). Isolated bloodstream reactivation can improve in some cases without therapy as immune function improves; however, lymphoproliferative disorder may require more aggressive therapy. Treatment of EBV-lymphoproliferative disorder in the past has relied on decreasing immune suppression and treatment with chemotherapy such as cyclophosphamide. Recently, CD20-positive EBV-lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy, rituximab. [22] [23] In addition, some centers have found efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells. [24] Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.

Acute graft-versus-host disease (GVHD)

GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities present in the tissues of a recipient. [25] Acute GVHD usually occurs within the first 3 months of transplantation, although delayed acute GVHD has been noted in reduced-intensity conditioning and nonmyeloablative approaches, where achieving a high level of full donor chimerism is sometimes delayed. Typically, acute GVHD presents with at least one of three manifestations: skin rash, hyperbilirubinemia, and secretory diarrhea. Acute GVHD is classified by grading the severity of skin, gastrointestinal, and liver involvement and further combining the individual grading of these three areas into an overall stage that is prognostically significant (see Tables 5 and 6). [26] Patients with grade III or IV acute GVHD are at higher risk for mortality, generally due to organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Table 5. Grading and Staging of Acute Graft-Versus-Host Disease (GVHD)^a

Table 6. Overall Clinical Grade (Based on the Highest Stage Obtained)

Prevention and treatment of acute GVHD

Morbidity and mortality from acute GVHD can be reduced through immune suppressive medications given prophylactically or T-cell depletion of grafts, either ex vivo by actual removal of cells from a graft or in vivo with anti-lymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]). Approaches to GVHD prevention in non-T-cell–depleted grafts have included intermittent methotrexate, a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics), or various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil. When significant acute GVHD occurs, first-line therapy is generally methylprednisolone. [27] Patients with acute GVHD resistant to this therapy have a poor prognosis but a good percentage of cases respond to second-line agents (e.g., mycophenolate mofetil, infliximab, pentostatin, sirolimus, or extracorporeal photopheresis). [28] Complete elimination of acute GVHD with intense T-cell depletion approaches has generally resulted in increased relapse, more infectious morbidity, and increased EBV-lymphoproliferative disorder. Because of this, most HCT GVHD prophylaxis is given in an attempt to balance risk by giving sufficient immune suppression to prevent most severe acute GVHD but not completely removing GVHD risk.

Chronic Graft-versus-Host Disease

Chronic GVHD is a syndrome that may involve a single or several organ systems, with clinical features resembling autoimmune diseases. [29] [30] Chronic GVHD is usually first noted 2 to 12 months after HCT. Traditionally, symptoms occurring more than 100 days after HCT were considered to be chronic GVHD, and symptoms occurring earlier than 100 days post-HCT were considered to be acute GVHD. Because some approaches to HCT can lead to late-onset acute GVHD, and manifestations that are diagnostic for chronic GVHD can occur earlier than 100 days, the following three distinct types of chronic GVHD have been described:

• Classic chronic GVHD—occurs with diagnostic and/or distinct features of chronic GVHD (Tables 7–11) after a previous history of resolved acute GVHD.
• Overlap syndrome—an ongoing GVHD process when manifestations diagnostic for chronic GVHD occur while symptoms of acute GVHD persist.
• De novo chronic GVHD—new-onset GVHD generally occurring at least 2 months after transplant, with diagnostic and/or distinct features of chronic GVHD and no history of or features of acute GVHD.

Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT [31] and in 20% to 45% of children after unrelated donor HCT, with higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk with cord blood. [32] [33] The tissues that are commonly involved include skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may be involved.

Risk factors for the development of chronic GVHD include the following: [31] [34] [35]

• Patient’s age.
• Type of donor.
• Use of PBSCs.
• History of acute GVHD.
• Conditioning regimen.

The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive Schirmer test). [36] Tables 7 to 11 list organ manifestations of chronic GVHD with a specific listing of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsy of affected sites may be needed to confirm the diagnosis. [37]

Table 7. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Skin, Nails, Scalp, and Body Hair^a

Table 8. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Mouth and GI Tract^a

Table 9. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Eyes^a

Table 10. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Genitalia^a

Table 11. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Lung, Muscles, Fascia, Joints, Hematopoietic and Immune Systems, and Other Symptoms^a

Common skin manifestations include alterations in pigmentation, texture, elasticity, and thickness, with papules, plaques, or follicular changes. Patient-reported symptoms include dry skin, itching, limited mobility, rash, sores, or changes in coloring or texture. Generalized scleroderma may lead to severe joint contractures and debility. Associated hair loss and nail changes are common. Other important symptoms that should be assessed include dry eyes and oral changes such as atrophy, ulcers, and lichen planus. In addition, joint stiffness along with restricted range of motion, weight loss, nausea, difficulty swallowing, and diarrhea should be noted.

Several factors have been associated with increased risk of nonrelapse mortality (NRM) in children who develop significant chronic GVHD. Children who received HLA mismatched grafts, PBSCs, who were older than 10 years, or who had platelet counts of less than 100,000/µL at diagnosis of chronic GVHD have an increased risk of NRM. NRM was 17%, 22%, and 24% at 1, 3, and 5 years after diagnosis with chronic GVHD. Many of these children require long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died either of relapse or NRM, a third were off immune suppression, and a third still required some form of immune suppressive therapy. [38]

Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 proposed broadening the description of chronic GVHD to three categories in order to better predict long-term outcomes. [39] The three current NIH grading categories are as follows: [36]

• Mild disease—involving only one or two sites with no significant functional impairment (maximum severity score of 1 in a 0-to-3–point scale).
• Moderate disease—involving either more sites (>2) or is associated with higher severity score (maximum score of 2 in any site).
• Severe disease—indicating major disability (a score of 3 in any site or a lung score of 2).

Thus, high-risk patients include those with severe disease of any site or extensive involvement of multiple sites, especially those with symptomatic lung involvement, greater than 50% skin involvement, platelet count of less than 100,000/µl, poor performance score (<60%), weight loss greater than 15%, chronic diarrhea, progressive onset chronic GVHD, or a history of steroid treatment with greater than 0.5 mg/kg/day of prednisone for acute GVHD.

Treatment of chronic GVHD

Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including use of calcineurin inhibitors. [40] Topical therapy to affected areas is preferred for patients with limited disease. [41] A number of agents such as mycophenolate mofetil, [42] pentostatin, [43] sirolimus, [44] and rituximab, [45] have been tested with some success. Other approaches including extracorporeal photopheresis have been evaluated and show some efficacy in a percentage of patients. [46]

Besides significantly affecting organ function, quality of life, and functional status, infection is the major cause of chronic GVHD-related death. Therefore, all patients with chronic GVHD should receive prophylaxis against Pneumocystis jirovecii pneumonia, common encapsulated organisms, and varicella by using agents such as trimethoprim/sulfamethoxazole, penicillin, and acyclovir. While disease progression is the primary cause of death in long-term follow-up of hematopoietic stem cell transplantation patients with no chronic GVHD, transplant-related complications account for 70% of the deaths in patients with chronic GVHD. [31] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published. [41]

References:

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3. Sorror ML, Sandmaier BM, Storer BE, et al.: Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25 (27): 4246-54, 2007.
4. Sorror M, Storer B, Sandmaier BM, et al.: Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112 (9): 1992-2001, 2008.
5. Smith AR, Majhail NS, MacMillan ML, et al.: Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 117 (9): 2728-34, 2011.
6. Wood W, Deal A, Whitley J, et al.: Usefulness of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in predicting outcomes for adolescents and young adults with hematologic malignancies undergoing allogeneic stem cell transplant. Pediatr Blood Cancer 57 (3): 499-505, 2011.
7. Reiss U, Cowan M, McMillan A, et al.: Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol 24 (9): 746-50, 2002.
8. Cesaro S, Pillon M, Talenti E, et al.: A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 90 (10): 1396-404, 2005.
9. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85 (11): 3005-20, 1995.
10. Ruutu T, Eriksson B, Remes K, et al.: Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 100 (6): 1977-83, 2002.
11. Richardson PG, Murakami C, Jin Z, et al.: Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 100 (13): 4337-43, 2002.
12. Corbacioglu S, Kernan N, Lehmann L, et al.: Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol 5 (3): 291-302, 2012.
13. Corbacioglu S, Cesaro S, Faraci M, et al.: Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 379 (9823): 1301-9, 2012.
14. Cutler C, Henry NL, Magee C, et al.: Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (7): 551-7, 2005.
15. Ho VT, Cutler C, Carter S, et al.: Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (8): 571-5, 2005.
16. Clark JG, Hansen JA, Hertz MI, et al.: NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147 (6 Pt 1): 1601-6, 1993.
17. Kantrow SP, Hackman RC, Boeckh M, et al.: Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63 (8): 1079-86, 1997.
18. Yanik GA, Ho VT, Levine JE, et al.: The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112 (8): 3073-81, 2008.
19. Gerritsen EJ, Stam ED, Hermans J, et al.: Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant 18 (2): 377-82, 1996.
20. Shapiro RS, McClain K, Frizzera G, et al.: Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71 (5): 1234-43, 1988.
21. Brunstein CG, Weisdorf DJ, DeFor T, et al.: Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 108 (8): 2874-80, 2006.
22. Blaes AH, Cao Q, Wagner JE, et al.: Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant 16 (2): 287-91, 2010.
23. Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000.
24. Liu Z, Savoldo B, Huls H, et al.: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent Results Cancer Res 159: 123-33, 2002.
25. Ferrara JL, Levine JE, Reddy P, et al.: Graft-versus-host disease. Lancet 373 (9674): 1550-61, 2009.
26. Glucksberg H, Storb R, Fefer A, et al.: Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18 (4): 295-304, 1974.
27. Jacobsohn DA: Acute graft-versus-host disease in children. Bone Marrow Transplant 41 (2): 215-21, 2008.
28. Deeg HJ: How I treat refractory acute GVHD. Blood 109 (10): 4119-26, 2007.
29. Shlomchik WD, Lee SJ, Couriel D, et al.: Transplantation's greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (1 Suppl 1): 2-10, 2007.
30. Bolaños-Meade J, Vogelsang GB: Chronic graft-versus-host disease. Curr Pharm Des 14 (20): 1974-86, 2008.
31. Zecca M, Prete A, Rondelli R, et al.: Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood 100 (4): 1192-200, 2002.
32. Eapen M, Logan BR, Confer DL, et al.: Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant 13 (12): 1461-8, 2007.
33. 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.
34. Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007.
35. Arora M, Klein JP, Weisdorf DJ, et al.: Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood 117 (24): 6714-20, 2011.
36. Filipovich AH, Weisdorf D, Pavletic S, et al.: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11 (12): 945-56, 2005.
37. Shulman HM, Kleiner D, Lee SJ, et al.: Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 12 (1): 31-47, 2006.
38. Jacobsohn DA, Arora M, Klein JP, et al.: Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease. Blood 118 (16): 4472-9, 2011.
39. Pavletic SZ, Martin P, Lee SJ, et al.: Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 12 (3): 252-66, 2006.
40. Koc S, Leisenring W, Flowers ME, et al.: Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100 (1): 48-51, 2002.
41. Couriel D, Carpenter PA, Cutler C, et al.: Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 12 (4): 375-96, 2006.
42. Martin PJ, Storer BE, Rowley SD, et al.: Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood 113 (21): 5074-82, 2009.
43. Jacobsohn DA, Gilman AL, Rademaker A, et al.: Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood 114 (20): 4354-60, 2009.
44. Jurado M, Vallejo C, Pérez-Simón JA, et al.: Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 701-6, 2007.
45. Cutler C, Miklos D, Kim HT, et al.: Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108 (2): 756-62, 2006.
46. González Vicent M, Ramirez M, Sevilla J, et al.: Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol 32 (8): 589-93, 2010.

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 (03/29/2013)

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.

Autologous Hematopoietic Cell Transplantation (HCT)

Added Kreissman et al. as reference 1.

Allogeneic HCT

Added text to state that one study demonstrated that some killer immunoglobulin-like receptor mismatching combinations can lead to decreased relapse after acute myeloid leukemia HCT without T-cell depletion (cited Venstrom et al. as reference 48).

Complications After HCT

Added Corbacioglu et al. as reference 12.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

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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