text:
Childhood Hematopoietic Cell Transplantation (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Childhood Hematopoietic Cell Transplantation
General Information About Hematopoietic Cell Transplantation (HCT)
Rationale for HCT
Blood and marrow transplantation (BMT) or HCT is a procedure that involves infusion of cells (hematopoietic stem cells; 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:
|Treatment of malignancies.
|Replacement or modulation of an absent or poorly functioning hematopoietic or immune system.
|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:
|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.
|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.
|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).
|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]
Selection bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
One source of bias difficult to control for or detect is physician bias for or against HCT. The effect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.
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]
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 Sourcesa,b
|Class I Antigens
|Class II Antigens
|BM = bone marrow; PBSC = peripheral blood stem cells.
|a HLA antigen: A serologically defined, low-resolution method of defining an HLA protein. Differs from allele-level typing half of the time. Designated by the first two numbers (i.e., HLA B 35:01—antigen is HLA B 35).
|b HLA allele: A higher resolution method of defining unique HLA proteins by typing their gene through sequencing or other DNA-based methods that detect unique differences. Designated by at least four numbers (i.e., HLA B 35:01).
|c Parent, cousin, etc., with a phenotypic match or near-complete HLA match.
|Stem Cell Source
|Matched Sibling BM/PBSCs
|Matched Sibling/Other Related Donorc BM/PBSCs
|Unrelated Donor BM/PBSCs
|Unrelated Cord Blood
|Antigen (Allele Optional)
|Antigen (Allele Optional)
|Allele Optional
Table 2. Definitions of the Numbers Describing Human Leukocyte Antigen (HLA) Antigens and Alleles Matching
|If These HLA Antigens and Alleles Match
|Then the Donor is Considered to be This Type of Match
|A, B, and DRB1
|A, B, C, and DRB1
|A, B, C, DRB1, and DQB1
|A, B, C, DRB1, DQB1, and DPB1
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
|Cord Blood
|T-cell Depleted BM/PBSCs
|Haploidentical T-cell Depleted BM/PBSCs
|BM = bone marrow; EBV-LPD = Epstein-Barr virus–associated lymphoproliferative disorder; GVHD = graft-versus-host disease; HCT = hematopoietic cell transplantation; PBSCs = peripheral blood stem cells.
|a Assuming no development of GVHD. If patients develop GVHD, immune reconstitution is delayed until resolution of the GVHD and discontinuation of immune suppression.
|b If a haploidentical donor is used, longer times to immune reconstitution may occur.
|T-cell content
|Very low
|Very low
|CD34+ content
|Low (but higher potency)
|Time to neutrophil recovery
|Rapid (13–25 d)
|Moderate (15–25 d)
|Slow (16–55 d)
|Moderate (15–25 d)
|Moderate (15–25 d)
|Early post-HCT risk of infections, EBV-LPD
|Very High
|Very High
|Risk of graft rejection
|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
|Risk of chronic GVHD
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.
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 Indexa
|HCT-Charlson Comorbidity Index Score
|AST/ALT = aspartate aminotransferase/alanine aminotransferase; DLCO = diffusion capacity of carbon monoxide; FEV1 = forced expiratory volume in one second; ULN = upper limit of normal.
|a Adapted from Sorror et al.[1]
|b One or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass graft.
|Arrhythmia: Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias
|Moderate pulmonary: DLCO and/or FEV1 66%–80% or dyspnea on slight activity
|Heart valve disease: Excluding mitral valve prolapse
|Cardiac: Coronary artery disease,b congestive heart failure, myocardial infarction, or ejection fraction ≤50%
|Moderate/severe renal: Serum creatinine >2 mg/dL, on dialysis, or prior renal transplantation
|Moderate/severe hepatic: Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN
|Cerebrovascular disease: Transient ischemic attack or cerebrovascular accident
|Peptic ulcer: Requiring treatment
|Prior solid tumor: Treated at any time in the patient's history, excluding nonmelanoma skin cancer
|Diabetes: Requiring treatment with insulin or oral hypoglycemic agents but not diet alone
|Rheumatologic: Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, mixed connective tissue disease, or polymyalgia rheumatica
|Severe pulmonary: DLCO and/or FEV1 <65% or dyspnea at rest or requiring oxygen
|Hepatic, mild: Chronic hepatitis, bilirubin > ULN or AST/ALT > ULN to 2.5 × ULN
|Infection: Requiring continuation of antimicrobial treatment after day 0
|Inflammatory bowel disease: Crohn disease or ulcerative colitis
|Obesity: Body mass index >35 kg/m2
|Psychiatric disturbance: Depression or anxiety requiring psychiatric consult or treatment
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
|Liver (bilirubin)b
|GI/Gut (stool output/day)c
|BSA = body surface area; GI = gastrointestinal.
|a Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium consensus, adapted from the modified Glucksberg system.
|b There is no modification of liver staging for other causes of hyperbilirubinemia.
|c For GI staging: The "adult" stool output values should be used for patients weighing >50 kg. Use 3-day averages for GI staging based on stool output. If stool and urine are mixed, stool output is presumed to be 50% of total stool/urine mix.
|d If colon or rectal biopsy is positive, but stool output is <500 mL/day (<10 mL/kg/day), then consider as GI stage 0.
|e For stage 4 GI: the term "severe abdominal pain" will be defined as having both (a) pain control requiring treatment with opioids or an increased dose in ongoing opioid use; and (b) pain that significantly impacts performance status, as determined by the treating physician.
|No GVHD rash
|<2 mg/dL
|Child: <10 mL/kg/d; Adult: <500 mL/d
|Maculopapular rash <25% BSA
|2–3 mg/dL
|Adult: 500–999 mL/dd; Child: 10–19.9 mL/kg/d; Persistent nausea, vomiting, or anorexia, with a positive upper GI biopsy
|Maculopapular rash 25%–50% BSA
|3.1–6 mg/dL
|Child: 20–30 mL/kg/d; Adult: 1000–1500 mL/d
|Maculopapular rash >50% BSA
|6.1–15 mg/dL
|Child: >30 mL/kg/d; Adult: >1500 mL/d
|Generalized erythroderma plus bullous formation and desquamation >5% BSA
|>15 mg/dL
|Severe abdominal paine with or without ileus, or grossly bloody stool (regardless of stool volume)
Table 6. Overall Clinical Grade (Based on the Highest Stage Obtained)
|GI = gastrointestinal.
|Grade 0:
|No stage 1–4 of any organ
|Grade I:
|Stage 1–2 skin and no liver or gut involvement
|Grade II:
|Stage 3 skin or Stage 1 liver involvement or Stage 1 GI
|Grade III:
|Stage 0–3 skin, with Stage 2–3 liver or Stage 2–3 GI
|Grade IV:
|Stage 4 skin, liver, or GI involvement
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 Haira
|Organ or Site
|Other Featuresd
|Common (Seen with Both Acute and Chronic GVHD)
|a Reprinted from Biology of Blood and Marrow Transplantation, 11 (12), Alexandra H. Filipovich, Daniel Weisdorf, Steven Pavletic, Gerard Socie, John R. Wingard, Stephanie J. Lee, Paul Martin, Jason Chien, Donna Przepiorka, Daniel Couriel, Edward W. Cowen, Patricia Dinndorf, Ann Farrell, Robert Hartzman, Jean Henslee-Downey, David Jacobsohn, George McDonald, Barbara Mittleman, J. Douglas Rizzo, Michael Robinson, Mark Schubert, Kirk Schultz, Howard Shulman, Maria Turner, Georgia Vogelsang, Mary E.D. Flowers, 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, Pages 945-956, Copyright (2005), with permission from Elsevier.[36]
|b Sufficient to establish the diagnosis of chronic GVHD.
|c Seen in chronic GVHD, but insufficient alone to establish a diagnosis of chronic GVHD.
|d Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed.
|e In all cases, infection, drug effects, malignancy, or other causes must be excluded.
|f Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
|Sweat impairment
|Lichen planus-like features
|Sclerotic features
|Keratosis pilaris
|Maculopapular rash
|Morphea-like features
|Lichen sclerosus-like features
|Longitudinal ridging, splitting, or brittle features
|Pterygium unguis
|Nail loss (usually symmetric; affects most nails)e
|Scalp and body hair
|New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy)
|Thinning scalp hair, typically patchy, coarse, or dull (not explained by endocrine or other causes)
|Scaling, papulosquamous lesions
|Premature gray hair
Table 8. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Mouth and GI Tracta
|Organ or Site
|Other Featuresd
|Common (Seen with Both Acute and Chronic GVHD)
|ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ULN = upper limit of normal.
|Refer toTable 7footers for definitions ofa throughe.
|Lichen-type features
|Hyperkeratotic plaques
|Restriction of mouth opening from sclerosis
|Mucosal atrophy
|GI Tract
|Esophageal web
|Exocrine pancreatic insufficiency
|Strictures or stenosis in the upper to mid third of the esophaguse
|Weight loss
|Failure to thrive (infants and children)
|Total bilirubin, alkaline phosphatase >2 × ULNe
|ALT or AST >2 × ULNe
Table 9. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Eyesa
|Organ or Site
|Other Featuresd
|Common (Seen with Both Acute and Chronic GVHD)
|Refer toTable 7footers for definitions ofa throughf.
|New onset dry, gritty, or painful eyesf
|Blepharitis (erythema of the eyelids with edema)
|Cicatricial conjunctivitis
|Keratoconjunctivitis siccaf
|Confluent areas of punctate keratopathy
|Periorbital hyperpigmentation
Table 10. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Genitaliaa
|Organ or Site
|Other Featuresd
|Common (Seen with Both Acute and Chronic GVHD)
|Refer toTable 7footers for definitions ofa throughe.
|Lichen planus–like features
|Vaginal scarring or stenosis
Table 11. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Lung, Muscles, Fascia, Joints, Hematopoietic and Immune Systems, and Other Symptomsa
|Organ or Site
|Other Featuresd
|Common (Seen with Both Acute and Chronic GVHD)
|AIHA = autoimmune hemolytic anemia; BOOP = bronchiolitis obliterans–organizing pneumonia; ITP = idiopathic thrombocytopenic purpura; PFTs = pulmonary function tests.
|Refer toTable 7footers for definitions ofa throughf.
|Bronchiolitis obliterans diagnosed with lung biopsy
|Bronchiolitis obliterans diagnosed with PFTs and radiologyf
|Muscles, fascia, joints
|Myositis or polymyositisf
|Muscle cramps
|Arthralgia or arthritis
|Hematopoietic and immune
|Hypo- or hypergammaglobulinemia
|Autoantibodies (AIHA and ITP)
|Pericardial or pleural effusions
|Peripheral neuropathy
|Nephrotic syndrome
|Myasthenia gravis
|Cardiac conduction abnormality or cardiomyopathy
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]
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.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Hematopoietic Cell Transplantation are:
- Thomas G. Gross, MD, PhD (Nationwide Children's Hospital)
- Michael A. Pulsipher, MD (Primary Children's Medical Center)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Childhood Hematopoietic Cell Transplantation. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childHCT/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site's Contact Form.
Get More Information From NCI
Call 1-800-4-CANCER
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
Chat online
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
|NCI Public Inquiries Office
|Suite 3036A
|6116 Executive Boulevard, MSC8322
|Bethesda, MD 20892-8322
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
Find Publications
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
Last Revised: 2013-03-29
This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.


text:
Kohler K-3811-G9
Sandbar Santa Rosa 1.6 GPF One-Piece Elongated Comfort Height Toilet with AquaPiston Technology - Seat Included
Item # BCI1796258 | Model # K-3811-G9 | Santa Rosa Collection
Low Flow Toilet Restrictions - 1.28 GPF MaximumThis item cannot be shipped to the following location(s): CA, TX
Questions about Kohler K-3811-G9?
Contact us for advice or more details. Our product specialists are here to help.
This product has additional required/recommended options. To configure, add to your cart.
Wax Ring Kit Required
Santa Rosa
Santa Rosa Comfort Height 1 piece compact elongated 1.6 gpf toilet offers the exceptional functionality you expect from Kohler in a smaller footprint, so you can transform even the smallest of bathrooms into a well-designed, comfortable space.
Product Features:
- One-piece configuration provides a uniform look and simplifies installation
- Elongated bowl offers comfort and convenience, extending out an extra 1-1/2" compared to a round configuration
- Covered under Kohler's 1 year limited warranty
- The Santa Rosa toilet offers exceptional functionality with a small footprint
- Constructed of durable, easy to clean vitreous china
- Installs in a floor mounted configuration
- Features a powerful gravity flush with AquaPiston technology
- ADA compliant - complies with the standards for toilets set forth by the Americans with Disabilities Act
- Comfort Height - designed for ease of use, with a higher than average bowl
- Includes a Brevia Q2 seat and cover
Product Technologies / Benefits:
- AquaPiston: AquaPiston single flush canister technology uses the force of gravity and a precision-engineered tank, bowl, and trapway to create a strong, efficient siphon during flushing. The canister flush valve's 3:2 ratio optimizes flush performance and resists warping and deterioration, while its durable design features 90% less exposed seal material than a standard 3-inch flapper flush valve, guaranteeing leak-free performance. The light-touch canister requires lower activation force than a flapper, and once activated, allows water to flow into the bowl from all sides (360 degrees), increasing each flush's power and effectiveness.
- Comfort Height: Comfort Height toilets offer the greatest accessibility and ease of use with a bowl height of between 16-1/2" and 18", the same as a standard chair.
Product Specifications:
- Overall Height: 28-3/16" (measured from bottom of base to top of tank)
- Overall Depth: 27-3/4" (measured from back of tank to front of rim)
- Overall Width: 18-3/4" (measured from rightmost to leftmost edge of toilet)
- Bowl Height: 16-1/2" (measured from floor to bowl rim)
- Flow Rate: 1.6 GPF (gallons per flush)
- Water Area: 11" x 8-1/8" (inner rim dimensions of bowl, length x width)
- Water Depth (from Rim): 6-1/4"
- Tank Width: 18-3/4" (measured from leftmost to rightmost edge of tank)
- Tank Depth: 6-9/16" (measured from back edge to front edge of tank)
- Trapway (Discharge Passageway) Size: 2-1/8"
- Distance Between Toilet Seat Installation Holes: 5-1/2"
- Rough-In: 12"
1.28 GPF version of this model
About Kohler:
Gracious living is characterized by qualities of charm, good taste, generosity of spirit, and the enhancement of nature. It is Kohler's mission that you improve your sense of gracious living with every experience you have with a Kohler product or service. Kohler lives on the leading edge of design and technology, while maintaining a constant level of quality, regardless of price. It sets the standard of excellence in its field, and yet is constantly striving to improve. From sustainable products in the kitchen and bath to power systems that protect data centers and urban landscapes all over the world - this is what the Kohler company is all about.
Additional Kohler Links
This Kohler item can also be referenced by the following color/finish specific model #:
- Kohler K-3811-47
- Kohler K-3811-96
- Kohler K-3811-7
Black Black
- Kohler K-3811-K4*
- Kohler K-3811-NY
- Kohler K-3811-95
Ice Grey
- Kohler K-3811-55*
Innocent Blush
- Kohler K-3811-33*
Mexican Sand
- Kohler K-3811-G9
- Kohler K-3811-58*
Thunder Grey
- Kohler K-3811-0
*Discontinued model or finish
More Than Just a Store - Your Reasons to Shop
Discover the best online deals for the Kohler K-3811 and everything else for your home from the leading online home improvement store.
We're committed to providing you with the best assortment of Kohler products with over 400 warehouses across the country.
Our knowledgeable product specialists work to bring you the best prices on every product and provide unmatched customer service. Your satisfaction is our highest priority!
Manufacturer Resources
Product Videos
How to remove and install a ToiletIf you have been considering replacing your toilet, yet are wondering how complicated of a job this is? Take a moment and we'll show you just how simple this job can actually be.

subset: commoncrawl


text:
May 4, 2016
Officials of Topsail Island are disputing an online story which claims it's a prime location for a shark attack.
The StarNews of Wilmington reports the island appears in an online listing as one of five places in the U.S. where shark encounters are most likely to occur.
Locals say the story posted on Yahoo Travel doesn't have numbers to back up its claim. However, a girl was bitten at North Topsail Beach last month.
Florida's Icthyology Center reports that New Hanover County has had nine shark bites and no deaths since record-keeping began in 1935. Onslow and Carteret counties were next-highest in the state, each reporting eight bites and one death.
Florida had the most U.S. shark attacks in 2010, with 23. North Carolina was second with five.
Copyright 2016 by The Associated Press. All Rights Reserved.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or email@example.com.


text:
When We Dead Awaken
Random House Publishing Group, Nov 1, 1990 - Fiction - 272 pages
Newly married to Jack Parrish, Elsa finds her happiness transformed into a nightmare when Jack begins to suffer from horrifying dreams that lead him to question his sanity and to fear the return of his brother, dead for more than a year
From inside the book
74 pages matching tell in this book
Where's the rest of this book?
Results 1-3 of 74
What people are saying - Write a review
We haven't found any reviews in the usual places.
Other editions - View all
Common terms and phrases
ain't arms asked Bali Ha'i bedroom Behrman bike Billy and Jazzy Billy saw Billy's bitch blood Blue Lagoon Restaurant Bradenton brother Citrusville Cleo Cowboy crazy daddy damn dark Darth Vader door dream drink Edwina Elsa and Corky Elsa's Emerald City eyes face Father Steele feel felt Freddy goddamn going gonna getcha grinned guess Halloween Hammersmith hand happened head heard hell hurt I'm gonna getcha Jack Jack's Jazzy's Jenny Jonathan Kellerman kissed knew knife laughed Lee's looked married Mike mind mother never nice night Okay Parrish & Caine pulled Raggedy Ann remember Rosetta says scream sheriff sleep smile someone sorry Stephen Coonts stood sure talk Tamiami Trail tell there's thing thought told took tried trying turned Uncle Billy voice waiting what's woman Yeah


text:
This medication contains the hormone (FSH) and is used to treat certain fertility problems in women and men. In women, it helps stimulate healthy ovaries to produce eggs. This medication is usually used in combination with another hormone (hCG) to bring about the growth and release of a mature egg (ovulation). In men, it helps stimulate healthy testes to produce sperm. It is also used in combination with hCG.
This medication is not recommended for women whose ovaries no longer make eggs properly (primary ovarian failure) or for men whose testes no longer make sperm properly (primary testicular failure).
Read the Patient Information Leaflet before starting this medication and each time you get a refill of this medication because new information may be available. Learn all the preparation and usage instructions in the product package. You will be trained by a healthcare professional on how to properly use this medication. If any of the information is unclear, consult your healthcare professional.
There are different follitropin products available, but they are not interchangeable, and the doses may be different. Do not switch to a different brand or type without your doctor's approval.
Inject this medication under the skin or into a muscle as directed by your doctor. Dosage is based on your medical condition and response to therapy.
Wash your hands with soap and water before using this medication. Before injecting each dose, clean the injection site with rubbing alcohol. It is important to change the location of the injection site each time to avoid discomfort and problem areas under the skin.
If the medication is stored in the refrigerator, allow the medication to warm to room temperature before use.
Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.
Use this medication exactly as directed by your doctor in order to get the most benefit from it. Do not change the dose or use this drug for a longer period than prescribed unless instructed by your doctor.
Learn how to store and discard needles and medical supplies safely. Consult your pharmacist for more information.
Headache, stomach pain, bloating, redness/pain at the injection site, breast tenderness/pain, and dizziness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor right away if any of these serious side effects occur: flu-like symptoms (e.g., fever, chills, muscle aches, tiredness), swelling of ankles/hands/feet, bleeding from the vagina.
Seek immediate medical attention if any of these unlikely but very serious side effects occur: weakness on one side of the body, slurred speech, vision changes, sudden severe headache, pain/swelling of the calf muscles, chest pain, rapid breathing.
This medication may cause a condition known as ovarian hyperstimulation syndrome (OHSS). This condition may occur during therapy or after treatment has been discontinued. Rarely, serious OHSS causes fluid to suddenly build up in the stomach, chest, and heart area. Seek immediate medical attention if you develop the following side effects: severe pain or swelling in the lower abdominal (pelvic) area, nausea/vomiting, sudden/rapid weight gain, or a change in the amount of urine.
A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Before using this medication, tell your doctor or pharmacist if you are allergic to it; or to other products containing follicle-stimulating hormone (FSH), or to streptomycin, or neomycin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: abnormal bleeding from the vagina or uterus, thyroid problems, adrenal gland problems, cancer of the reproductive organs (breast, uterus, ovary, testis), tumors in the brain (e.g., pituitary tumor), ovarian cysts or enlargement, other fertility problems (e.g., primary ovarian failure).
Tell your doctor your medical history, especially of: blood clots, stroke, certain heart diseases (e.g., heart attacks), lung problems (e.g., asthma).
Multiple births may occur because of this treatment.
Stop using this medication when you become pregnant. This medication must not be used during pregnancy. If you think you may be pregnant, tell your doctor right away.
It is unknown if this drug passes into breast milk. Because of the possible harm to a nursing infant, consult your doctor before breast-feeding.
Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.
Some products that may interact with this drug include: gonadorelin.
If overdose is suspected, contact a poison control center or emergency room right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.
Laboratory tests and/or medical tests (e.g., vaginal ultrasound, hormone levels, semen test) will be performed to monitor your progress.
It is important to keep all regular medical and laboratory appointments so your doctor can closely monitor your response to help reduce the risk of serious side effects and determine the timing of your hCG dose.
Do not share this medication with others.
For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist to establish a new dosing schedule. Do not double the dose to catch up.
Store unopened vials in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light and moisture. Do not freeze. Discard any unused portion of the vial.
Brief storage at 77 degrees F (25 degrees C) is permitted for up to three months. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
Information last revised October 2015. Copyright(c) 2015 First Databank, Inc.
Sorry. No images are available for this medication.
With WebMD's Medicine Cabinet, you can check interactions with drugs.Go to medicine cabinet
©2005-2016 WebMD, LLC. All rights reserved.
WebMD does not provide medical advice, diagnosis or treatment. See additional information.


text:
Sunday may have been Veterans Day, but for 250 Fort Carson soldiers and their families, Monday is the real day to celebrate.
The soldiers, members of the 4th Brigade Combat Team, 4th Infantry Division, are returning home from a seven-month deployment in Afghanistan. Their welcome home ceremony is scheduled for 4:45 p.m. at the Special Events Center on post.
While deployed, the soldiers had responsibility over a 10,000 square mile area, in which they performed security operations and partnered with the four provincial governments presiding over the region.
For comparison, 10,000 square miles is roughly the size of the state of Maryland. More than three million Afghans live in the region.
Fort Carson reminds families that the homecoming time is subject to change. Keep checking here for any changes to the schedule.
KKTV firmly believes in freedom of speech for all and we are happy to provide this forum for the community to share opinions and facts. We ask that commenters keep it clean, keep it truthful, stay on topic and be responsible. Comments left here do not necessarily represent the viewpoint of KKTV 11 News.
If you believe that any of the comments on our site are inappropriate or offensive, please tell us by clicking "Report Abuse" and answering the questions that follow. We will review any reported comments promptly.powered by Disqus
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or firstname.lastname@example.com.


text:
Arek Sarkissian II, Tallahassee Democrat
A bill banning illegal activity in Internet cafés passed the state Senate this afternoon and now will head for the desk of Gov. Rick Scott.
SB 155 by state Sen. John Thrasher, R-St. Augustine, clears up some ambiguity in current law covering machines operated inside Internet cafes. If Scott signs the law, it will delineate the difference between games of skill and chance. It will not affect businesses like Chuck E. Cheese or those at Walt Disney World.
The bill was passed by the House on March 22 and was filed in response to a multistate investigation that led to arrest warrants of 57 people and the resignation of Lt. Gov. Jennifer Carroll, who was not suspected of any crime.
Tallahassee Democrat


text:
Looking good. Id drop the scale on the grass. At mo it looks like each blade is a few feet long. It could do with better blend onto the gravel too. How to do that. Well you can get a mask and fade it out and add two textures or you can generate a stamp type brush of some partial grass partial gravel and put some of those down on the blend line.
The house looks fine, the platform looks fine tho bare at mo. No theres not a lot wrong with it so far.
Theres lots of web sites with dioramas of 1940's stuff with model trains, tanks and so on. Because this is a station I would think that there would be some images of platforms as reference. Also a no end of holywood films set in 1940's around platforms too. You didnt say which country its based on but theres probably a selection of historical pics to reference too. I would think that all the trains were steam at that time (not an expert) so coal bunkers and water tanks and all that gear could be added.


text:
Flushing Meadows, NY (Sports Network) - Five-time champion Roger Federer
was an easy second-round winner Thursday at the U.S. Open.
The seventh-seeded former world No. 1 great blew past Argentine Carlos Berlocq
6-3, 6-2, 6-1 in 1 hour, 35 minutes at Ashe Stadium on the hardcourts at the
USTA Billie Jean King National Tennis Center. The Swiss icon tallied six aces
and broke Berlocq seven times en route to the third round.
The 17-time Grand Slam titlist Federer was the tennis king of New York from
2004-08 and runner-up in 2009.
Meanwhile, nifty eighth seed Richard Gasquet handled fellow Frenchman
Stephane Robert, 6-3, 7-5, 7-5, on Day 4. The capable Gasquet has only ever
reached one Grand Slam quarterfinal, when he landed in a semifinal at
Wimbledon six years ago.
In other action involving seeds, No. 18 Serb Janko Tipsarevic drilled Israeli
Dudi Sela 6-4, 6-4, 6-1 and No. 32 Russian Dmitry Tursunov topped France's
Guillaume Rufin 7-6 (7-4), 1-1, retired.
The Sports Network


text:
Party. Rinse. Repeat.
Pirate Bamboo Tableware for 8
Most party tableware goes from the package to the table to the landfill in record time, but our eco friendly bamboo sets show love for Mama Nature by being compostable.
Our organic bamboo veneerware plates and flatware packs for 8 are perfect for eco-friendly entertaining: indoor and outdoor use, formal or casual, at home or on the go.
- Sturdier than paper
- Compostable and biodegradable
- Contains no bleaches or dyes
- 100% certified organically grown bamboo
- 16 compostable bamboo plates: 8 9" plates, 8 7" plates
- 24 pieces of poplar flatware: 8 forks, 8 spoons, 8 knives
- Total: 40 pieces


text:
Monday, September 28, 2009
Pink Jacket, Warm Smile
Each time I run into this wonderful lady she brightens my day with her warm smile and colorful outfits.
Posted by Ari at 10:34 AM
7 comments:
- That's Not My Age said...
See what you mean - she has real warmth and charm
- September 28, 2009 at 4:13 PM
The smile, and the perky hat and the color combo of pink and turquoise with a bit of gold...
She's in harmony with herself.
- September 28, 2009 at 4:39 PM
- Regina said...
Me, I'm a teacher from fashion school here in Brazil and became an enthusiast of this blog.
Thank you very much.
- September 28, 2009 at 9:26 PM
- Nora said...
This is so cute.I really love this blog.I'm working in El Salvador at the moment and there is this cute Lady running the bakery over here.Her style is so awesome too, but I never catch her without pinafore so I could take a photo.
Once again, I love it.
- September 28, 2009 at 10:25 PM
- r l n ! said...
Pretty in pink, but beautiful in that smile :)
- September 29, 2009 at 12:14 AM
- thwany said...
i just want to give her a big hug.
- October 1, 2009 at 2:16 PM
- okiefeminist said...
I really want to know more of her story. You should interview her for us!
- October 4, 2009 at 12:21 PM
Subscribe to: Post Comments (Atom)