Hematopoietic Stem Cell Transplantation
Introduction
Hematopoietic stem cell transplantation (HSCT) is a procedure in which progenitor cells capable of reconstituting normal bone marrow function are administered to a patient. This procedure is often performed as part of therapy to eliminate a bone marrow infiltrative process, such as leukemia, or to correct congenital immunodeficiency disorders. Recent work in this field has expanded its use to allow patients with cancer to receive higher doses of chemotherapy than the bone marrow can usually tolerate; bone marrow function is then salvaged by replacing the marrow with previously harvested stem cells.
The basic process of hematopoietic stem cell transplantation has been around for more than 50 years. The earliest work in the field was performed using animal models in the mid 1950s. During the 1960s, the first few successful hematopoietic stem cell transplants used in the treatment of congenital immunodeficiency disorders and end-stage leukemia were reported. These early attempts were marred by high morbidity and mortality, in large part due to toxicity related to the chemotherapy (called conditioning) administered prior to bone marrow transplantation, posttransplant infectious complications, and graft versus host disease.
Subsequent studies have been dedicated to improving conditioning regimens with improved outcomes, decreasing transplantation-related morbidity and mortality, improving survival, and increasing the understanding of the immune mechanisms associated with both the adverse effects and the antitumoral effects of the transplanted graft.
Transplantation of hematopoietic stem cells as a procedure involves a series of events that are fairly constant in theme, although the specifics of these events may widely vary depending on the disease being treated. First, a source of stem cells must be identified for the patient. Then, a means of conditioning (ie, clearing the bone marrow of its current contents and preparing the marrow space to receive donor marrow) must be determined. This conditioning may clear the bone marrow as its primary desired effect or may be a secondary effect related to giving increased doses of chemotherapy to destroy a tumor that may not even occupy the bone marrow. Next, stem cells are infused. Finally, recovery from the physiologic effects of the conditioning regimen must take place.
This article summarizes the types of hematopoietic stem cell transplantation, methods of collection of stem cells, indications for hematopoietic stem cell transplantation, complications of hematopoietic stem cell transplantation, and survival data, with emphasis on current research with particular reference to pediatrics.
Types of Hematopoietic Stem Cell Transplantation
Types of hematopoietic stem cell transplantation (HSCT) are typically categorized based on the source of progenitor cells used in the transplant. These cells have 3 main sources: the patient (an autologous transplant), someone besides the patient (an allogeneic transplant), or donated umbilical cord blood (a cord blood or umbilical cord blood transplant). Each of these sources of cells has specific advantages and disadvantages, and each has found particular applications in the care of children with oncologic or immunologic disorders.
Autologous transplantation is typically used as a method of returning the patient's own stem cells as a rescue therapy after high-dose myeloablative therapy. This is generally used in chemosensitive hematopoietic and solid tumors to eliminate malignant cells by administering higher-dose chemotherapy than could normally be tolerated by the bone marrow of the patient, with the hope of increasing the chances of killing remaining tumor cells. The high dose chemotherapy is then followed with subsequent rescue of the host's bone marrow with previously collected autologous stem cells. Immunosuppression is not required after autologous transplantation because the immune system that is reconstituted is that of the original host. For this same reason, this technique is not typically used for immunologic disorders.
Allogeneic transplantation refers to the use of stem cells from a human leukocyte antigen (HLA)–matched donor. These donors may be genetically related or unrelated. This type of transplant is used for various malignant and nonmalignant disorders to replace a defective host marrow or immune system with the (presumably) normal donor marrow and immune system. The degree of HLA match between the donor and the recipient is perhaps the most important factor in these transplants; well-matched transplants decrease risks of graft rejection and graft versus host disease (GVHD), both of which are among the most serious sequelae of transplantation. See below for further description of HLA matching.
Cord blood transplantation refers to the use of hematopoietic stem cells collected from the umbilical cord and placenta. The use of cord blood transplantation has rapidly increased because of several favorable factors, including ease of collection, expanded and prompt availability, no risk to the donors, a decreased risk of adverse effects (eg, GVHD, transmission of infections), increased tolerance to HLA-mismatch, and no risk of donor loss at the time of transplantation.1 Cord blood banking has become increasingly important, and the classification and documentation of the cord blood available is increasing.
Use of cord blood as a source of donor stem cells is somewhat constrained by the quantity of cells available in a typical sample. Improved collection techniques have increased the size of aliquots available from a given donor and are making this source available to more patients. Additional research is exploring the use of multiple cord blood transplants, in which multiple cord blood donors are used during the same transplantation procedure to improve engraftment times.2
The traditional source of hematopoietic stem cells for use in autologous and allogeneic transplantations was bone marrow. The use of peripheral blood as a source of these cells later replaced bone marrow for most autologous transplantations and a significant proportion of allogeneic transplantations.3 Table 1 lists the differences in the cellular characteristics of these commonly used sources of stem cells, and Table 2 lists the clinical differences.
Table 1. Cellular Characteristics of Various Sources of Stem Cells
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| Cellular Characteristics | Source | ||
|---|---|---|---|
| Bone Marrow | Peripheral Blood | Cord Blood | |
| Stem-cell content | Adequate | Good | Low |
| Progenitor-cell content | Adequate | High | Low* |
| T-cell content | Low | High | Low, functionally immature |
| Risk of tumor cell contamination | High † | Low † | Not applicable ‡ |
| Cellular Characteristics | Source | ||
|---|---|---|---|
| Bone Marrow | Peripheral Blood | Cord Blood | |
| Stem-cell content | Adequate | Good | Low |
| Progenitor-cell content | Adequate | High | Low* |
| T-cell content | Low | High | Low, functionally immature |
| Risk of tumor cell contamination | High † | Low † | Not applicable ‡ |
* Studies have shown that the cord blood progenitor cells have greater proliferative potential than that of peripheral blood and marrow progenitor cells.
† Risk of tumor cell contamination from bone marrow or from an autologous source would be high; an allogeneic source should have negligible risk.
‡ Risk of tumor contamination from cord blood from an allogeneic source should be negligible.
Table 2. Clinical Characteristics With Various Sources of Stem Cells
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| Cellular Characteristics | Source | ||
|---|---|---|---|
| Peripheral Blood | Bone Marrow | Cord Blood | |
| HLA matching | Close matching required | Close matching required | Less restrictive than others |
| Engraftment | Fastest | Faster than cord blood but slower than peripheral blood | Slowest |
| Risk of acute GVHD | Same as in bone marrow | Same as in peripheral blood | Lowest |
| Risk of chronic GVHD | Highest | Lower than peripheral blood | Lowest |
| Cellular Characteristics | Source | ||
|---|---|---|---|
| Peripheral Blood | Bone Marrow | Cord Blood | |
| HLA matching | Close matching required | Close matching required | Less restrictive than others |
| Engraftment | Fastest | Faster than cord blood but slower than peripheral blood | Slowest |
| Risk of acute GVHD | Same as in bone marrow | Same as in peripheral blood | Lowest |
| Risk of chronic GVHD | Highest | Lower than peripheral blood | Lowest |
Human Leukocyte Antigen Matching
Human leucocyte antigens (HLAs) are expressed on the surface of various cells, in particular WBCs. These antigens are also known as the major histocompatibility complex (MHC) and occupy the short arm of chromosome 6.4 This genetic region has been divided into chromosomal regions, called classes. Classes I, II, and III have been defined, although class III information is still too sparse to include here.
Class I is made up of HLA-A, HLA-B, and HLA-C, as well as other genes less frequently discussed (eg, HLA-E, HLA-F, and HLA-G). Class II is made up of HLA-DR, HLA-DP, and HLA-DQ, as well as variations on these genes. Traditionally, the loci critical for matching are HLA-A, HLA-B, and HLA-DR. HLA-C and HLA-DQ have recently gained importance and are now considered in determining the appropriateness of a donor.
A completely matched sibling donor is generally considered the ideal donor. For unrelated donors, a completely matched or a single mismatch is considered acceptable for most transplantation protocols, although, in certain circumstances, a greater mismatch is tolerated. Syngeneic transplantation is a form of allogeneic transplantation in which the donor is an identical twin sibling of the patient. Graft rejection is less of an issue for such transplants when compared with other allogeneic transplants.
Collection of Stem Cells
Bone marrow
Stem cells are obtained from the bone marrow by repeated aspirations of the posterior iliac crests of the donor under general or local anesthesia. Adverse effects are generally rare and include discomfort at the harvesting site that typically lasts 1-2 weeks. This can be a difficult procedure in donors who are smaller than the recipient, such as sibling donors, and several aspirations may be required for an adequate mononuclear cell dose.
Bone marrow primed with granulocyte colony-stimulating factor (G-CSF; filgrastim [Neupogen]) has been used in both pediatric and adult patients to increase the stem cell count and, thus, to reduce the number of aspirations from the donor and speed engraftment in the recipient.5 Filgrastim and chemotherapy can be used alone or in combination to mobilize stem cells. Interleukin-2 increases T-cell function but is not a stem cell mobilizer.
Studies have suggested that the risk of chronic graft versus host disease (GVHD) from G-CSF–primed bone marrow may be less than that from G-CSF–primed peripheral blood stem cells. A randomized trial suggested that G-CSF–primed marrow does not have an increased risk of GVHD and does not affect engraftment.6 The potential risks of G-CSF use include increased bone pain, rare events (eg, splenic rupture), and the theoretical risk of leukemia.
Peripheral blood
Stem cells in the bone marrow can be mobilized into the peripheral blood and then collected via leukocytopheresis.7 Stem cells are collected postrecovery, after a cycle of chemotherapy; their number can be increased using hematopoietic growth factors like G-CSF. Along with increasing the number of cells, G-CSF also causes the release of proteases that degrade the proteins that anchor the stem cells to the marrow stroma, causing their release into the peripheral blood. Studies have shown that a combination of G-CSF and AMD3100, an inhibitor of chemokine receptor 4 (CXCR4), is superior to G-CSF alone in mobilizing stem cells.8
The dosage of G-CSF is 5-20 μ g/kg/d. In most regimens, 10 μ g/kg/d is used until harvesting. After mobilization, an apheresis machine collects the cells. Two ports of venous access are necessary to allow for continuous blood processing. In most adults, venous access is accomplished by using 2 antecubital lines. In 5-10% of adults and in most children, percutaneous antecubital large-bore access is not possible, and an apheresis catheter is used instead. Apheresis catheters placed in cervical vessels can be used in children who weigh as little as 10 kg. Lighter children generally require a femoral catheter.
The WBC count (or CD34 count) in the peripheral blood determines the timing of collection. CD34 is a cell surface marker on hematopoietic stem cells. Studies have reported a good correlation between the CD34 count in the peripheral blood and the number of cells harvested. The recommended CD34 count is 20-50 cells/μ L of blood.
Collected stem cells are counted by flow cytometric analysis. Although the minimum number required for engraftment is considered to be 1 X 106 cells per kilogram of body weight, the preferred number is 2-2.5 X 106 cells/kg. Most people prefer to have a collection goal of 5-10 X 106 cells/kg to freeze the extra cells for potential future use.9
Peripheral blood stem cells can be cryopreserved for infusion months to years after collection.
Peripheral blood stem cells have 10-fold more T cells than bone marrow and increase the risk of chronic GVHD. Peripheral blood stem cells speed engraftment and reduce toxicity in patients undergoing autologous transplantation.
Issues in the collection of peripheral-blood stem cells
Two issues in the collection of peripheral blood stem cells require special consideration in children: priming and anticoagulation. Although devices to minimize extracorporeal volume are used, priming of the apheresis machine with RBCs is required for children younger than 6 years. This step prevents unacceptable dilutional anemia during the procedure and fluid overload associated with the return of red cells from the centrifuge chamber at the end of the procedure.
Second is the issue of anticoagulation. In older patients, anticoagulation required for the apheresis procedure is accomplished using anticoagulant citrate dextrose (ACD). Although ACD does not result in systemic anticoagulation, the citrate component of ACD increases the risk of symptomatic hypocalcemia in young patients. Citrate toxicity often limits the rate of blood processing, prolonging the procedure. Pediatric patients can also be treated with a combination of ACD and heparin. The heparin can allow use of decreased amounts of ACD, making symptomatic hypocalcemia rare. However, the patient treated with heparin and ACD may be fully anticoagulated by the end of the procedure, slightly increasing the bleeding risk and possibly requiring reversal of heparinization at the end of the procedure.
Cord blood
Blood from umbilical cord and placenta is rich in hematopoietic stem cells. Cord blood has relatively immature donor T cells compared with allogeneic stem cells; therefore, they are more immunotolerant to host's immune system. This property decreases the risk of GVHD and graft rejection. About 40-70 mL of fetal cord blood is collected immediately after the cord is clamped and cut. These units are cryopreserved and stored in private and public cord blood banks worldwide until future use. This type of collection has no risk to the donor if the cord is appropriately clamped.
Indications for Hematopoietic Stem Cell Transplantation
More than 30,000 autologous and 15,000 allogeneic transplantation procedures are performed every year worldwide. The list of diseases for which hematopoietic stem cell transplantation (HSCT) is being used is rapidly increasing. More than half of the autologous transplantations are performed for multiple myeloma and non-Hodgkin lymphoma, and a vast majority of allogeneic transplants are performed for hematologic and lymphoid cancers.
Table 3 summarizes the common indications for hematopoietic stem cell transplantation. Cord blood transplants are being used for many of the allogeneic transplant indications whenever a suitable human leukocyte antigen (HLA)–matched donor is unavailable or whenever time for identifying, typing, and harvesting a transplant from an unrelated donor is limited.
Table 3. Common Indications for Hematopoietic Stem Cell Transplantation10
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| Autologous Transplantation | Allogeneic Transplantation | ||
|---|---|---|---|
| Malignant Disorders | Nonmalignant Disorders | Malignant Disorders | Nonmalignant Disorders |
|
|
|
|
| Autologous Transplantation | Allogeneic Transplantation | ||
|---|---|---|---|
| Malignant Disorders | Nonmalignant Disorders | Malignant Disorders | Nonmalignant Disorders |
|
|
|
|
*Uncommon in children; common reasons for transplantation in adults
Conditioning Regimens
Conditioning regimens can be classified as myeloablative, nonmyeloablative, and reduced intensity.
Myeloablative regimens are designed to kill all residual cancer cells in autologous or allogeneic transplantation and to cause immunosuppression for engraftment in allogeneic transplantation. Total-body irradiation (TBI) and cyclophosphamide or busulfan and cyclophosphamide are the commonly used myeloablative therapies. These regimens are especially used in aggressive malignancies, such as leukemias.
With nonmyeloablative regimens, use doses of chemotherapy drugs and radiation substantially lower than those of myeloablative regimens. These regimens are immunosuppressive but not myeloablative and rely on a graft-versus-tumor effect to kill tumor cells with donor T lymphocytes. Because of their decreased acute and chronic toxicity, these regimens can be used in patients aged 55 years or older and in patients with notable comorbidities.
Such regimens are usually beneficial for slow-growing tumors, such as those of chronic lymphocytic leukemia or chronic myelogenous leukemia, and are also beneficial for various nonmalignant disorders, such as thalassemia and autoimmune disorders. Currently, a combination of autologous transplantation followed by nonmyeloablative allogeneic transplantation is being studied for both pediatric and adult tumors, the most common of which is multiple myeloma.
Reduced-intensity regimens can range in intensity from myeloablative to nonmyeloablative, and involve drugs such as fludarabine, melphalan, antithymocyte globulin, and busulfan. Such regimens also reduce acute and chronic toxicity compared with myeloablative regimens, although the incidence of graft versus host disease (GVHD) is comparable with that of myeloablative regimens. The onset of GVHD is delayed with this compared with other regimens.
Outcome Data
Transplantation-related mortality and morbidity rates have considerably decreased because of improved conditioning regimens, human leukocyte antigen (HLA) typing, supportive care, and prevention and treatment of serious infections. However, overall and event-free survival rates are based on the individual's disease pathology and on the stage of disease. Table 4 lists the survival rates of different diseases after hematopoietic stem cell transplantation (HSCT).
Patients undergoing HLA-matched sibling allogeneic transplantation have the best 5-year survival rate of all treated patients. These data need to be interpreted carefully because methods of data collection, the way in which survival is counted, and the length of follow-up can be important. Still, this table constitutes a useful starting place for survival in children who undergo transplantation.
Table 4. Five-Year Survival Data by Disease*
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Table
| Disease | Stage | Survival Rate (%) | ||
|---|---|---|---|---|
| Autologous Transplantation | Allogeneic Transplantation | |||
| Sibling Donor | Unrelated Donor | |||
| Acute lymphoblastic leukemia (ALL) | Complete response (CR)1 | N/A | 65 | 45 |
| CR2 | N/A | 55 | 35 | |
| Acute myeloid leukemia (AML) | CR1 | 60 | 65 | 30 |
| CR2 | 40 | 45 | 50 | |
| No remission | 20 | N/A | 25 | |
| Chronic myeloid leukemia (CML) | Chronic phase <1> | N/A | 70 | 55 |
| Chronic phase >1 y | N/A | 60 | 50 | |
| Hodgkin disease | CR1 | 80 | N/A | N/A |
| CR2 | 70 | N/A | N/A | |
| No remission | 45 | N/A | N/A | |
| Diffuse large-cell lymphoma | CR1 | 65 | 25 | 30 |
| 50 | 25 | N/A | ||
| 45 | 20 | N/A | ||
| Neuroblastoma | 40 | N/A | N/A | |
| Disease | Stage | Survival Rate (%) | ||
|---|---|---|---|---|
| Autologous Transplantation | Allogeneic Transplantation | |||
| Sibling Donor | Unrelated Donor | |||
| Acute lymphoblastic leukemia (ALL) | Complete response (CR)1 | N/A | 65 | 45 |
| CR2 | N/A | 55 | 35 | |
| Acute myeloid leukemia (AML) | CR1 | 60 | 65 | 30 |
| CR2 | 40 | 45 | 50 | |
| No remission | 20 | N/A | 25 | |
| Chronic myeloid leukemia (CML) | Chronic phase <1> | N/A | 70 | 55 |
| Chronic phase >1 y | N/A | 60 | 50 | |
| Hodgkin disease | CR1 | 80 | N/A | N/A |
| CR2 | 70 | N/A | N/A | |
| No remission | 45 | N/A | N/A | |
| Diffuse large-cell lymphoma | CR1 | 65 | 25 | 30 |
| 50 | 25 | N/A | ||
| 45 | 20 | N/A | ||
| Neuroblastoma | 40 | N/A | N/A | |
* Based on Kaplan-Meier curves of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National Marrow Donor Program (NMDP) data.
Acute lymphoblastic leukemiaHematopoietic stem cell transplantation is recommended in high-risk ALL for patients who have various chromosomal abnormalities. In particular, patients who are known to be positive for the Philadelphia chromosome t(9;22) have a definite survival benefit with hematopoietic stem cell transplantation compared with patients who do not receive this therapy.11 Patients who have hypodiploidy (<44>12 Many oncologists have traditionally referred very high-risk patients for transplantation, and a recent Children's Oncology Group (COG) study, AALL0031, seeks to quantify benefit of hematopoietic stem cell transplantation to these very high-risk patients. Results from this study are not yet available.
Infants with ALL, particularly those with the 11q23 rearrangement, frequently undergo transplantation; however, the role for transplantation in these infants is still under intense investigation. Some studies have indicated a benefit, although these studies have often been single institution and limited in nature.13,14,15 Other studies have been less clear that hematopoietic stem cell transplantation provides a benefit to these children.16 Subgroups of children with 11q23 rearrangements may benefit from transplant because a heterogeneity of response is observed.17,18 This is an area of continued investigation.
Other children for whom hematopoietic stem cell transplantation may be a good option include those who have experienced induction failure19 and patients with early relapse within 18 months of diagnosis.20,21
Acute myelogenous leukemia
Recently, allogeneic hematopoietic stem cell transplantation was recommended in pediatric patients with AML in CR1 if a matched sibling was available.22 A positive graft-versus-leukemia effect has been reported in patients who received this therapy, and patients who had mild graft versus host disease (GVHD) experienced improved relapse-free survival.23
Despite these results, recent data suggest that subpopulations of patients with AML do not experience significant benefit from hematopoietic stem cell transplantation in CR1. These include patients with inv(16) and t(8;21).24,25 Patients with acute promyelocytic anemia often have t(15;17); these patients are not treated with up-front transplant regimens because they respond to newer regimens involving all-trans retinoic acid (ATRA) and, increasingly, arsenic trioxide.26 Poor-risk cytogenetic features include monosomy5, monosomy7, or induction failure; continuing COG studies suggest hematopoietic stem cell transplantation in children with these features if a donor is available. For patients in CR2, transplant is a viable option, although outcomes are worse than for children who were transplanted in CR1.27
In a COG study, 2891 patients who did not have an HLA-matched family donor were randomized to autologous transplant or consolidation chemotherapy.28 This study reported that autologous stem cell transplant can be an effective strategy, but its superiority to chemotherapy only is questionable.22
Chronic myeloid leukemia
Allogeneic transplantation had long been the standard of care for patients with CML because it offered the only potential for cure; however, with the advent of imatinib this has changed.29 In current treatment models, imatinib is considered first-line therapy for CML.30 Patients who are treated with imatinib can experience lasting cytogenetic remission.
Hematopoietic stem cell transplantation is used for failure of imatinib therapy or for those who have not achieved an optimal response to imatinib.31 Alternatives to imatinib, such as dasatinib, have extended spectra of activity against the BCR/ABL fusion product and may rescue some patients who have failed or lost response to imatinib.32 Therapy with imatinib does not appear to change the transplant outcome.30
Hodgkin disease
Autologous transplantation is the standard of care for chemosensitive relapsed Hodgkin disease and primary refractory Hodgkin disease.33 Chemoresistant relapsed disease is under investigation, and some evidence suggests that patients may benefit from transplantation in this situation as well,34 although the subset of patients who receive the most benefit from such transplantation is not yet clear. The role of allogeneic transplant in refractory or relapsed nonchemosensitive Hodgkin disease is still under investigation.
Reduced intensity allogeneic transplantation in refractory Hodgkin disease in adults is also an area of current research, with modest improvements in overall survival for patients undergoing reduced intensity transplantation balanced against increased rates of relapse.35,36
Non-Hodgkin lymphoma
Refractory or relapsed non-Hodgkin lymphoma therapy continues to be a challenge. Autologous transplantation has offered some improvement in survival for these children,37 and many consider this the standard of care. Allogeneic transplantations with HLA-matched sibling donors are comparable to autologous transplantations but are associated with increased related morbidity and mortality rates.38Purging of autologous grafts may be important in decreasing relapse rates, although this has been controversial.39
Neuroblastoma
Autologous transplantation is the current backbone of therapy for patients with high-risk neuroblastoma in CR1.40,41 A study of long-term survival of patients with high-risk neuroblastoma treated with tandem cycles of myeloablative therapy and hematopoietic stem cell transplantation reported a 5-year progression-free survival of 47% and a 7-year progression-free survival of 45%.36 Allogeneic transplantation is reported in patients with relapsing or refractory disease, but no standard guidelines for its use are available.
Complications
Hematopoietic stem cell transplantation (HSCT)–related complications can be classified into early and late effects.
Early effects
Mucositis
Mucositis is one of the most common adverse effects of transplantation. It can involve the entire GI tract, leading to painful mouth sores, diarrhea, nausea, and abdominal pain. It is usually managed symptomatically with narcotics and topical anesthetics. A novel keratinocyte growth factor, palifermin, reduces the incidence of mucositis in adults.42
Graft versus host disease
Acute graft versus host disease (GVHD) is a common complication of allogeneic transplantation and occurs within the first 100 days after the procedure. It is an immune response of donor T lymphocytes against host cells. The skin, GI tract, and liver are the organs typically involved.43,44
Preventive and therapeutic measures include immunosuppression with drugs such as cyclosporine, corticosteroids, tacrolimus, mycophenolate mofetil (MMF), and methotrexate. Nonmyeloablative regimens and graft T-cell depletion are other techniques used to decrease the incidence of GVHD. Current research focuses on improving our understanding of the pathophysiologic pathways of GVHD to design targeted therapies. Eventually, genetic modifications of donor T cells may help prevent and treat GVHD.
The severity of GVHD is inversely related to the risk of relapse because GVHD and graft versus leukemia (GVL) effect are interrelated. Therefore, strategies reducing GVHD may increase relapse rates. New strategies are being developed to separate these effects to decrease the incidence and severity of GVHD without increasing the risk of relapse.
Hemorrhagic cystitis
Hemorrhagic cystitis is a disorder that manifests as dysuria and hematuria. Hematuria may be microscopic or may be gross. Clots may form within the bladder, occluding the urethral exit of urine, and may be severe. This disorder may occur in the immediate posttransplant period or may appear much later. Medications used in conditioning (especially cyclophosphamide) are well known to be associated with the disorder, especially earlier in the transplant timeline; a bladder protectant (MESNA) is often used to help prevent this problem, but hemorrhagic cystitis may still occur. Later onset is associated with infections such as adenovirus or BK virus.45 Therapy is largely supportive, with hyperhydration, bladder irrigation, pain medications, and, in the most severe cases, surgery. Cidofovir may be helpful in viral infection with BK virus.46
Veno-occlusive disease
Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a potentially fatal syndrome of tender hepatomegaly, direct hyperbilirubinemia, ascites, and weight gain. VOD is caused by damage to the sinusoidal endothelium, which results in sinusoidal obstruction. Total-body irradiation (TBI) and drugs such as oral busulfan and cyclophosphamide predispose individuals to this syndrome.
It typically occurs within the first 20 days after hematopoietic stem cell transplantation, and preexisting liver disease and certain genetic mutations that alter drug metabolism may increase the risk of VOD. Incidence in children has been found to range between 27-40%.46 . No standard effective therapy is currently available. Defibrotide is a novel, porcine-derived agent that elicits some responses in severe VOD;47 however, it is under investigation in a phase III trial. VOD has an overall mortality rate of as much as 50%.
Transplantation-related lung injury
Transplantation-related lung injury (TRLI) is an acute inflammatory response that leads to severe lung injury. TRLI is seen in allogeneic transplants. Early treatment with corticosteroids and etanercept, an anti–tumor-necrosis factor (TNF) agent, can reduce the extent of this injury.
Transplantation-related infections
Life-threatening bacterial, fungal, and viral infections (eg, those due to Aspergillus or cytomegalovirus) are common in patients undergoing hematopoietic stem cell transplantation. Causes include prolonged neutropenia, use of steroids, and immunodeficiency associated with GVHD. Bacterial sepsis occurs early in the course of transplantation, whereas viral infections such as those caused by cytomegalovirus usually occur after engraftment. Fungal infections such as those caused by Aspergillus may occur after 7-10 days of onset of neutropenia until engraftment. Early recognition and treatment are vital. Following engraftment, the ongoing risk of infection relates to the degree of immunosuppression.
Late effects
Chronic graft versus host disease
Chronic GVHD is most common in patients who develop acute GVHD but can develop in its absence. Chronic GVHD is characterized by an immune phenomenon that clinically resembles lupus, scleroderma, or Sjögren syndrome. It is thought to result from 2 potential mechanisms: thymic injury during conditioning, resulting in loss of negative selection of autoreactive T cells, and the alloreactivity of mature postthymic donor T lymphocytes.
Immunosuppression with corticosteroids, tacrolimus, and MMF are the mainstays of treatment. Hydroxychloroquine, an antimalarial drug, is effective in several autoimmune disorders, including chronic GVHD. Some studies have suggested that the use of keratinocyte growth factors prevents GVHD,48 presumably by preventing host thymic injury.49,50 Other studies have not confirmed this finding.51
Ocular effects
Posterior subcapsular cataract formation is common in hematopoietic stem cell transplant recipients. TBI is the predisposing risk factor. Fractionation of the dose substantially decreases the risk. Keratoconjunctivitis sicca, or dry eyes, is part of the chronic GVHD syndrome. Other adverse effects include retinopathy, infectious retinitis, and hemorrhage. Treatment includes the use of topical lubricants and steroids.52
Endocrine effects
Infertility is common in both male and female individuals. Secondary amenorrhea affects most women after hematopoietic stem cell transplantation. In children, growth and development are impaired; these children may require growth hormone supplements. Hypothyroidism, both overt and subclinical, is also common in these patients; they should be screened for low levels of thyroid hormone.52
Pulmonary effects
Pulmonary effects include restrictive and chronic obstructive lung disease. Conditioning regimens, infections, and GVHD are important risk factors.53 Bronchiolitis obliterans is a specific form of obstructive lung disease seen in hematopoietic stem cell transplant recipients and has a fatality rate of 50%. Corticosteroids are generally not helpful. Some patients respond to azathioprine and MMF.52
Musculoskeletal effects
Osteopenia, osteoporosis, and avascular necrosis are common adverse effects in hematopoietic stem cell transplantation recipients.54 Bisphosphonate therapy may be able to reverse some of the effects of this early onset osteoporosis.55
Neurocognitive and neuropsychological effects
Lower intelligence quotient (IQ) scores, sleep disorders, fatigue, memory problems, and developmental delays and declines have all been reported. Greatest declines in these functional areas occur in patients who have received cranial radiation either as part of their oncologic therapy or as part of their hematopoietic stem cell transplantation conditioning. These issues must be addressed appropriately to improve the person's overall quality of life.56
Immune effects
Host immunity is suppressed for months to years after hematopoietic stem cell transplantation. This effect is more pronounced in allogeneic transplantation than in autologous transplantations. Factors responsible for depressed immunity include severe myelosuppression due to the myeloablative conditioning of the host, acute GVHD that further suppresses host immunity, and the use of immunosuppressants to prevent or treat GVHD.57
In allogeneic transplant recipients, complete immune reconstitution takes a few years and depends on the ability of naïve prethymic donor T cells to mature in the host's thymus and to become host tolerant and antigen specific. This process is most efficient in children and young adults because they have an active thymus. Older patients may never completely recover their immunity because their thymic tissue might not be fully functional.
These immune effects should be considered because these patients are prone to serious infections long after the initial procedure. Revaccinatiion of these patients is also an issue. Guidelines for revaccinating these patients are based on consensus opinion in general, and little comprehensive data are available. Some studies suggest that most vaccine-acquired immunity wanes after hematopoietic stem cell transplantation.
Most killed vaccines are considered safe, but use of live virus vaccines is generally contraindicated until at least 18 months posttransplantation. Appropriate timing for revaccinating is 12-18 months after transplantation, although this period may need to be individualized on the basis of the patient's immune function, especially in the presence of GVHD. Vaccinations earlier than this may not result in an appropriate immune response.
Table 5 (expanded and adapted from Patel et al) summarizes recommendations and guidelines orignially published by the Royal College of Paediatrics and Child Health in 2002, which was, in turn, based on a combination of expert opinion and limited clinical literature.57
Table 5: Guidelines for Reimmunization After Hematopoietic Stem Cell Transplantation57
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Period After Hematopoietic Stem Cell Transplantation | Stem Cell Source | |
Human Leukocyte Antigen (HLA) Identical Sibling/Autologous/Syngeneic | Other Source | |
| 6 mo | Influenza vaccination each autumn | ... |
| 12 mo | Commence if no evidence of active or chronic GVHD observed 3 doses at intervals of 1-2 mo: diphtheria/tetanus/acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type B (HIB) conjugate, meningococcal C-conjugate (MCC), meningococcal quadrivalent conjugate (MQC) | ... |
| 3 doses at intervals of 0, 1, and 6 mo intervals: Hepatitis B vaccine | ||
| 18 mo | Measles, mumps, and rubella (MMR)-1 | Commence if no evidence of active or chronic GVHD observed 3 doses at intervals of 1-2 mo: DTaP, IPV, HIB conjugate, MCC, MQC |
| 3 doses at intervals of 0, 1, and 6 mo: Hepatitis B vaccine | ||
| >18-21 mo | ... | 2 doses at 1-2 month intervals: Pneumococcal heptavalent conjugate vaccination (PCV)7 |
| 24 mo | MMR-2 | MMR-1 |
| 30 mo | ... | MMR-2, 23 valent pneumococcal conjugate (PN-PS23) |
Period After Hematopoietic Stem Cell Transplantation | Stem Cell Source | |
Human Leukocyte Antigen (HLA) Identical Sibling/Autologous/Syngeneic | Other Source | |
| 6 mo | Influenza vaccination each autumn | ... |
| 12 mo | Commence if no evidence of active or chronic GVHD observed 3 doses at intervals of 1-2 mo: diphtheria/tetanus/acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type B (HIB) conjugate, meningococcal C-conjugate (MCC), meningococcal quadrivalent conjugate (MQC) | ... |
| 3 doses at intervals of 0, 1, and 6 mo intervals: Hepatitis B vaccine | ||
| 18 mo | Measles, mumps, and rubella (MMR)-1 | Commence if no evidence of active or chronic GVHD observed 3 doses at intervals of 1-2 mo: DTaP, IPV, HIB conjugate, MCC, MQC |
| 3 doses at intervals of 0, 1, and 6 mo: Hepatitis B vaccine | ||
| >18-21 mo | ... | 2 doses at 1-2 month intervals: Pneumococcal heptavalent conjugate vaccination (PCV)7 |
| 24 mo | MMR-2 | MMR-1 |
| 30 mo | ... | MMR-2, 23 valent pneumococcal conjugate (PN-PS23) |
These guidelines suggest that vaccination may recommence approximately 1 year after autologous or HLA-identical stem cell transplantation. Patients transplanted with other sources of stem cells should wait until about 18 months posttransplantation to revaccinate. These guidelines stipulate that no evidence of active chronic GVHD can be present and that the patient is not taking immunosuppressive therapy for at least 6 months (12 mo for live vaccines). The patient should not have received intravenous immunoglobulin for at least 3 months. Autologous and allogeneic hematopoietic stem cell transplantation recipients should receive complete reimmunization with the full schedule of primary routine childhood vaccinations. The influenza vaccination (killed) should be administered each autumn while the patient is considered immunocompromised. These vaccination guidelines should be altered to fit current vaccination recommendations and schedules in each country.
Other guidelines are also available, including those of the European Blood and Marrow Transplantation Infectious Disease Working Party. These were originally published in 1995, and were updated in 2005.58 These are similar to the above guidelines but suggest starting reimmunization for all transplant patients at 6 months posttransplantation for killed vaccinations and suggest live vaccinations (eg, MMR) should start at 24 months posttransplantation.
Future of Hematopoietic Stem Cell Transplantation
Substantial progress has been made in the field of hematopoietic stem cell transplantation (HSCT) since its inception 50 years ago. Hematopoietic stem cell transplantation currently offers the only potential cure for a large number of malignant and nonmalignant disorders.
Future research will focus on decreasing the transplantation-related morbidity and mortality and on increasing relapse-free survival. The work will include designing effective, reduced-intensity conditioning regimens; discovering targeted therapies to prevent and treat graft versus host disease (eg, cytokine antagonists, genetically modified donor T cells); in-depth human leukocyte antigen (HLA)-typing at the allelic level; advances in cord blood transplantation; and in vitro expansion and modification of stem cells.
Further work is underway to help define those risk groups that receive the greatest benefit from transplant. Future work will also focus on increasing the use and safety of transplantation for nononcologic indications, such as sickle cell disease, other hemoglobinopathies, and inborn errors of metabolism.
Keywords
hematopoietic stem cell transplantation, stem cells, autologous stem cell transplant, allogeneic stem cell transplant, cord blood transplant, leukemia, umbilical cord blood transplant, graft versus host disease, GVHD, human leukocyte antigen matching, HLA matching, single mismatch, syngeneic transplantation, graft rejection, splenic rupture, dilutional anemia, multiple myeloma, non-Hodgkin lymphoma, non-Hodgkin's lymphoma, Hodgkin disease, Hodgkin's disease, acute myeloid leukemia, AML, medulloblastoma, germ-cell tumors, amyloidosis, acute lymphoblastic leukemia, ALL, chronic myeloid leukemia, CML, myelodysplastic syndromes, chronic lymphocytic leukemia, aplastic anemia, Fanconi anemia, severe combined immunodeficiency, thalassemia major, Diamond-Blackfan anemia, sickle cell anemia, Wiskott-Aldrich syndrome, osteopetrosis, inborn errors of metabolism
More on Hematopoietic Stem Cell Transplantation |
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