INTRODUCTION
Adult hematopoietic stem cells (HSCs) have two main characteristics: they are able to make identical copies of themselves for long periods of time (known as long-term self-renewal), and they can give rise to mature cells with specialized functions. Primitive stem cells create intermediate cells called precursor cells. Under specific signals these cells divide and become differentiated cells that finally mature to specialized blood cells.
More than 30,000 autologous transplantations and more than 25,000 allogeneic transplantations are performed annually worldwide.1
Sources of Hematopoietic Stem Cells
HSC transplant (HSCT) is a general term referring to the reconstitution of a patient’s hematopoietic system by the administration of stored HSCs. The most common source of HSCs in adults is peripheral blood, accounting for ~70% of transplants. Cells are collected from peripheral blood through a process known as apheresis after mobilization of stem cells from the bone marrow into the peripheral circulation. Bone marrow is a source of HSCs in 20% of adult transplants. Cells are harvested directly from the bone marrow, usually from the iliac crests, under general anesthesia. Umbilical cord blood HSCs are currently used in 10% of transplants in adults, and the results are comparable to those achieved with adult unrelated donors (Fig. 31-1).2
Types of Hematopoietic Stem Cell Transplants
HSC transplants are divided into allogeneic and autologous transplants, depending on the relationship between the recipient and the donor.
Allogeneic transplant, where the donor is different from the recipient, can be classified as sibling-derived or matched unrelated donor. The two main sources of matched unrelated donor transplants are adult unrelated donorsand umbilical cord blood. In addition to the effect of the preparative high-dose chemo-therapy, the antitumoral effect of allogeneic transplants is mediated by the graft-versus-tumor effect (GvT), which consists in the immune destruction of residual tumor cells by the donor’s immune system. Syngeneic transplant is a sibling donor transplant from patient’s identical twin. Because of absence of GvHD, transplant related mortality associated with syngeneic transplantation is significantly lower than matched unrelated donor transplant. However because of lower GVT effect, relapse rate is substantially higher than similar patients who receive HLA-identical sibling donor transplantation; as a result overall survival is similar in syngeneic and HLA identical sibling donor transplants. In general, sibling transplants suffer fewer problems with rejection and graft-versus-host disease (GvHD) than matched unrelated donor transplants, and thus, recipients of the latter usually need more intensive immunosuppressive therapy in the posttransplant period (see Complications Related to Transplant, below).
FIGURE 31-1. Number and source of adult transplants facilitated by national marrow donor program. (Ballen KK, King RJ, Chitphakdithai P, et al. The national marrow donor program 20 years of unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14:2–7.)
Autologous transplant refers to the infusion of a patient’s own HSCs to reconstitute all of the hematopoietic lineages. This approach is used to allow very high doses of chemotherapy to be administered. Infusion of autologous HSCs rescues a patient’s bone marrow function from the effects of the myeloablative doses of chemotherapy.
Indications
Indications for autologous stem cell transplantation include malignancies (multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin lymphoma, acute myeloid leukemia, neuroblastoma, germ-cell tumors) and nonmalignant disorders (autoimmune disorders and amyloidosis). Indications for allogeneic stem cell transplantation include malignancies (leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes) and nonmalignant disorders (aplastic anemia, paroxysmal nocturnal hemoglobinuria, fanconi’s anemia, Blackfan–Diamond anemia, thalassemia major, sickle cell anemia, severe combined immunodeficiency, Wiskott–Aldrich syndrome, and inborn errors of metabolism).3 More than 50% of allogeneic transplantations are performed for treatment of acute leukemias, followed by NHL (14%), and MDS (14%).
Transplant Immunology
The major determinants of histocompatibility between donor and recipient, and thus risk for GvHD, are encoded by the human leukocyte antigen (HLA) system on chromosome 6. These proteins normally function in antigen presentation in adaptive immunity. The HLA class I antigens are called A, B, and C and are found on all nucleated cells. Class II proteins, called DR, DQ, and DP, are found only on dendritic cells, B lymphocytes, and macrophages. Mismatches at HLA-DP are not associated with increased mortality. The perfect match is 10/10 HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ match. With high resolution DNA based HLA typing overall survival of patients undergoing 10/10 fully matched transplantations is similar to patients receiving 8/8 HLA-A, HLA-B, HLA-C, and HLA-DR matched transplantations.4 According to NMDP guidelines, the minimal acceptable level of matching is 5 of 6 matches for HLA-A, HLA-B, and HLA-DRB.5 Cord blood transplantations have a lower risk of GvHD. Optimal cord blood transplant is 6/6 matches for HLA-A, HLA-B, and HLA-DR.6 The HLA locus can be considered a haplotype, so that all of the genes on one chromosome are inherited together (HLA A, B, and DR). Thus, for any given patient, the probability is one in four that a sibling will share the same two haplotypes and make a complete match.
Other antigens called minor histocompatibility antigens (MHCs) are peptides also presented by HLA proteins but that elicit weaker responses compared to major antigens. These antigens are related to both GvHD and GvT effect. MHCs expressed only on the recipient HSCs will cause a GvT effect. MHCs expressed on both epithelial cells and HSCs will cause both GvHD and GvT.
THE TRANSPLANT PROCEDURE
Mobilization and Collection of Hematopoietic Stem Cells
In order to collect the necessary number of HSCs from the donor and to ensure rapid engraftment in the recipient’s bone marrow, autologous and allogeneic HSCs are most commonly collected by leukapheresis from the peripheral blood after pretreatment with drugs that mobilize the HSCs from the bone marrow endosteal and vascular niches (mobilization). The most extensively studied mobilizing agent is granulocyte colony-stimulating factor (G-CSF). For G-CSF, the peak mobilization occurs after 4 to 6 days of daily treatment. Plerixafor, a small-molecule reversible CXC chemokine receptor 4 (CXCR4) inhibitor, can be added to G-CSF to improve stem cell collection. During the harvest procedure, called apheresis, stem cells are separated and removed from the other components of the blood by a cell-separator machine. The cells are then processed and stored for infusion into the patient.
Preparative Regimens
In allogeneic transplants, the traditional preparative regimens are ablative regimens, consisting of very high doses of chemotherapy drug combinations intended primarily to eliminate the tumor cells and secondarily to suppress the donor immune system. Due to the high toxicity associated with this approach, and in order to extend transplants to older patients or patients with comorbidities, reduced intensity and nonmyeloablative regimens have been developed. The basic principle is to give drugs that are immunosuppressive to allow the GvT effect.
In the autologous setting, the objective is to give high-dose chemotherapy to eliminate the tumor cells and then rescue the patient from aplasia with his or her own previously harvested and stored HSCs. In this case there is no GvT effect, and the disease control is exclusively due to the high-dose chemotherapy.
Among the most commonly used drugs are cyclophosphamide, busulfan, fludarabine, melphalan, etoposide, and antithymocyte globulin. Total-body irradiation-based regimens combine high-dose chemotherapy with irradiation to the whole body.
After the conditioning regimen is administered, patients will become profoundly pancytopenic (absolute neutrophil count, < 100; platelet count, < 10,000 cells/ μ L) for a period of between 12 and 24 days, depending on the source of HSCs (autologous or allogeneic) and preparative regimen used (ablative or nonablative).
Homing and Engraftment
After infusion, HSCs migrate to specific sites in the bone marrow called niches, where they reside and undergo self-renewal and differentiation. The process of migration and adhesion is called homing. The interaction between HSC and their niches will result ultimately in engraftment and long-term durable repopulation.
Neutrophil engraftment is defined as the first day of three consecutive days where the absolute neutrophil count is ≥500 cells/mm3. Platelet engraftment is defined as an achievement of a platelet count of >50,000 platelets/mm3sustained for 3 consecutive days unsupported by a platelet transfusion. Median time to neutrophil engraftment after peripheral blood stem cell transplantation, bone marrow transplantation and cord blood transplantations is 14, 21, and 28 days, respectively. Median time to platelet engraftment after peripheral blood stem cell transplantation and bone marrow transplantation is 13, and 20 days, respectively. Median time to neutrophil engraftment after autologous stem cell transplantation is 11 days. Factors affecting time to recovery include the use of G-CSF during mobilization and harvest, degree of pretreatment chemotherapy, use of peripheral blood HSCs instead of bone marrow HSCs, and presence of infections.
By days 18 to 21, natural killer cells are expanded and will provide antiviral responses. Within the first 30 days post transplant, natural-killer (NK) cells reach normal level and comprise the majority of lymphoid cells. Monocytes typically recover within a month after transplantation. B lymphocytes and CD8 T lymphocytes will reconstitute over months. CD4 T-lymphocyte recovery is usually prolonged over years (>5 years).7
Donor Lymphocyte Infusions (DLI)
Graft versus tumor mediated by donor T cells is a major component of the allogeneic HSCT anti tumor activity. DLI is defined as transfusion of nonmobilized lymphocyte concentrate or transfusion of mobilized peripheral blood stem cells without using immunosuppressant for GvHD prophylaxis. DLI can induce remissions in patients with relapse after allogeneic HSCT.8
SUPPORTIVE CARE
The posttransplant period is a critical time for patients who have undergone transplant. They become profoundly pancytopenic. During this time, there is significant potential morbidity and mortality from infectious agents, drug toxicity, and bleeding complications. Intensive care in a dedicated unit experienced in HSC transplant is required to support patients and provide optimal outcome.
Blood Products
All cytomegalovirus (CMV)-seronegative patients should receive CMV-negative blood and platelet products both prior to and during the transplant period. Blood products should also be irradiated or leukodepleted to avoid T-cell responses against host tissue (i.e., GvHD caused by the transfusion). Platelet products derived from a single donor are preferred to reduce alloantigen exposure.
Growth Factors
For both allogeneic and autologous transplants, hematopoietic growth factors have shown small reductions in the risk of documented infections, but with no effect on infection or treatment-related mortality. Specifically, in patients undergoing allogeneic HSC transplantation for myeloid leukemias, no long-term risk or benefit of using G-CSF after transplantation has been demonstrated. G-CSF shortens the post-transplantation neutropenic period by 4 to 5 days, without substantially affecting the hospitalization period or treatment-related mortality at days +30 and +100. Probabilities of acute and chronic GvHD, leukemia-free survival, and overall survival are similar whether or not G-CSF is given.
COMPLICATIONS RELATED TO TRANSPLANT
Graft-versus-Host Disease
GvHD corresponds to an immune response of the donor T cells against the recipient. It is the main cause of morbidity and mortality after allogeneic HSC transplants. The exact cause and pathogenesis are still not completely understood, but it is believed to be caused by a reaction of donor T cells against the receptor HLA class I antigens. This inflammatory response is augmented by intestinal damage caused by the preparative regimens, which cause leakage of bacterial lipopolysaccharides into the bloodstream, increasing and maintaining the cytokine storm and tissue damage.
GvHD has been divided into two phases, according to the timing of the symptoms. Acute GvHD occurs within 100 days after the transplant, and chronic GvHD occurs 100 days or more after the transplant, although the correlation between the two forms of GvHD is not very well understood. Moreover, not all cases of chronic GvHD are preceded by acute GvHD, although acute GvHD is the most important risk factor for chronic GvHD.
Acute GvHD occurs in 26% to 32% of recipients of sibling donor grafts, and 42% to 52% of recipients of unrelated donor grafts. It is graded as stages 0 to IV (most severe) according to the intensity of the symptoms. The usual organs compromised are the skin, mucous membranes, gastrointestinal tract, and liver. The risk factors for acute GvHD include HLA disparity, matched unrelated donors, older patients, gender-mismatched HLA, donors previously sensitized by transfusion or pregnancy, and CMV-positive donors.
The most effective measure to prevent GvHD is an accurate HLA matching between donor and receptor. Other measures include posttransplant immunosuppressive drugs (methotrexate, cyclosporine, tacrolimus) and in vivo and ex vivo T cell depletion.
Once GvHD is established, the first-line treatment remains corticosteroids. Topical corticosteroids and nonabsorbed steroid therapy are commonly used for skin GvHD and GI GvHD, respectively. There are a variety of second-line treatments, which generally have a low response rate.9
Chronic GvHD develops in >50% of long-term survivors after HSC transplantation and affects both quality of life and survival. Manifestations resemble autoimmune diseases, suggesting T-cell immune deregulation, and include dermal, hepatic, ocular, oral, pulmonary, gastrointestinal, and neuromuscular manifestations.
In contrast to acute GvHD, little is known about the causes and patho-biology of chronic GvHD. Presumably, MHCs are both responsible for and targets of this disease. It is also believed that chronic T-cell stimulation (as occurs in acute GvHD) could deregulate T cells, predisposing to chronic GvHD.
The most important risk factor for chronic GvHD is previous acute GvHD. Thirty percent of patients with grade 0 acute GvHD, versus 90% of grade IV acute GvHD patients, will develop chronic GvHD. Among patients with no or grade I acute GvHD, recipient age >20 years, use of non-T-cell-depleted bone marrow, and alloimmune female donors for male recipients predict a greater risk of chronic GvHD.
Prevention of chronic GvHD includes drugs such as cyclosporine, methotrexate, tacrolimus, corticosteroids, in vivo and ex vivo T cell depletion, and monoclonal and polyclonal antibodies. First line treatment of chronic GvHD includes a combination of corticosteroids and a calcineurin inhibitor (e.g., tacrolimus). Second-line therapies include ECP and mycophenolate mofetil.10
Sinusoidal Obstruction Syndrome (Veno-occlusive Disease)
Sinusoidal obstruction syndrome (SOS) is a feared complication with a high mortality rate that can occur after either allogeneic or autologous transplant. The incidence ranges from 0% to 50%, depending on the preparative regimen. SOS can occur in up to 50% of patients receiving high dose cyclophosphamide plus total-body irradiation. Recently, the frequency and severity of SOS have decreased significantly because of lower doses of TBI and replacement of cyclophosphamide by fludarabine. Experimental studies have shown that the main damage occurs in the hepatic sinusoid.
The major features accepted for diagnosis are jaundice, rising conjugated bili-rubin, tender hepatomegaly, and ascites with fluid retention 10 to 20 days after the start of preparative regimen. There are no other specific lab tests to confirm this complication.11
There is no satisfactory therapy for SOS. In 50% to 80% of patients, there is a gradual spontaneous resolution of the symptoms and signs in a 3-week period after onset of disease. During this period the focus of treatment should be management of fluid and electrolytes, and therapeutic paracentesis. Defibrotide, which has antithrombotic and profibrinolytic effects, is the best available treatment for sever SOS.
Pulmonary Complications
Pulmonary complications can occur in more than 60% of patients after HSCT. In the immediate post transplant period, infections (viral, bacterial, and fungal) are the most common causes of pulmonary complications. After engraftment, infections (viral, bacterial, and fungal), interstitial pneumonia syndrome (IPS) secondary to conditioning regimen and/or TBI, and diffuse alveolar hemorrhage (DAH) are the most common causes of pulmonary complications. Bronchiolitis obliterans is the most common late complication of HSCT, occurring more than 3 months after transplant.
IPS is defined as diffuse noninfectious lung injury after transplantation. Corticosteroid is not beneficial in treatment of IPS. Treatment with etanercept is associated with a significant improvement in these patients.
DAH is usually observed within the first month after HSCT, during periengraftment phase. High dose steroid is the treatment of choice for DAH, although its efficacy has not been proven in prospective clinical trials.
Bronchiolitis obliterans occurs in 6% to 26% of allogeneic stem cell recipient. Patients with bronchiolitis obliterans present with gradually worsening dyspnea, nonproductive cough, and wheezing. Patients are usually afebrile. Pulmonary function test shows persistent obstructive pattern. High resolution CT scan shows evidence of air trapping. Immunosuppressive agents are the treatments of choice.12
Mucositis
Mucositis is extremely common during the neutropenic period and corresponds to the painful desquamation of the gastrointestinal epithelium. Almost 100% of patients will develop some grade of mucositis after the conditioning regimen, usually starting 3 to 5 days after the preparative regimen and lasting for 7 to 14 days.
The only demonstrated preventive treatment currently available is Palifermin (keratinocyte growth factor), which is able to reduce the frequency of severe mucositis from 60% to 20%. It was also associated with significant reduction in the duration of mucositis, from 9 to 3 days.13 Others measures after mucositis is established include bland rinses, topical anesthetics, mucosal coating agents, and topical and systemic analgesics.
Engraftment Syndrome
Engraftment syndrome (ES) is characterized by a combination of noninfectious fever, erythematous rash, and noncardiogenic pulmonary edema occurring during neutrophil recovery phase following HSCT. It occurs most frequently after autologous HSCT. Treatment with a short course of corticosteroid is usually very effective especially in patients with significant pulmonary involvement.
Infections
Patients undergoing HSCT are at very high risk of infection due to the disease itself, previous chemotherapies, the preparative regimen, mucosal barrier breakdown, GvHD, and immunosuppressive drugs.
There are three periods of host defense recovery after HSC transplantation, and particular infections pose a threat in each period (Fig. 31-2).14
The phase I or preengraftment phase, <30 days post posttransplant, is marked by severe neutropenia and mucosal barrier damage. As such, the patient is at risk of infection with skin and gastrointestinal organisms. Gram-negative bacilli, Escherichia coli, Pseudomonas, Klebsiella, and other enterics may cause local infection or sepsis. Enterococci or viridans streptococci may also cause bacteremia. Catheter-related bloodstream infection can be caused by staphylococci, particularly Staphylococcus epidermidis. Fungi, including Candida species and Aspergillus, may cause disseminated disease. Viral reactivation with herpes simplex virus (HSV) is common, as is varicella zoster virus (VZV), causing shingles. Human herpesvirus 6 commonly reactivates and is implicated in graft failure. BK virus is associated with encephalitis, hepatitis, and cystitis. Adenovirus and rotavirus may cause enteritis. Respiratory pathogens include adenovirus, influenza, parainfluenza, and respiratory syncytial virus.
FIGURE 31-2. Phases of opportunistic infections among allogeneic HSCT recipients. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep. 2000;49: 1–128. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm.
Special consideration is given to nosocomial transmission of pathogens, including drug-resistant organisms. Thus, vigilance for methicillin-resistant Staphylococcus aureus is necessary, and broad coverage with vancomycin may be appropriate in the setting of neutropenic fevers without a known focus. Vancomycin-resistant enterococcus is commonly isolated from the stool but is often nonpathogenic; however, it requires treatment if isolated from the blood. Clostridium difficile causing colitis and diarrhea is problematic, as many patients receive broad antibiotics at some point during transplant. Contact isolation and strict adherence to routine hand washing are necessary to prevent outbreaks of nosocomial pathogens.
The phase II or postengraftment is from day 30 to 100 posttransplant. It is characterized by intense cellular and humoral immunodeficiency, the appearance of GvHD, and increased risk of CMV reactivation.
The phase III or late phase is after day 100 posttransplant. It is characterized by a T-cell-mediated immunodeficiency and the emergence of chronic GvHD. Several studies have demonstrated that although innate immunity recovers within several weeks, B cell and CD8 T cell counts take several months to normalize, and CD4 T cells can take several years or, indeed, may never recover in the presence of chronic GvHD.
Among the most common infections in the later stages after transplantation is recurrent encapsulated bacterial infection, CMV reactivation, which can cause interstitial pneumonia and retinal compromise, and VZV reactivation. Patients are also at risk of Pneumocystis jiroveci (formerly P. carinii) and Aspergillus sp. pneumonia.14,15
Prevention of Infections
Strict adherence to hand-washing procedures and isolation precautions (visitor screening, HEPA filtered air, no fresh flowers) is mandatory in the care of the HSC transplant patient. Avoidance of unwashed fruits, vegetables, unroasted nuts, and raw food is recommended but its impact on infection prevention is not known. Also, good oral and body hygiene is recommended. Gut decontamination with antibiotics is no longer recommended.
Routine prophylaxis includes trimethoprim-sulfamethoxazole, dapsone, or pent-amidine against Pneumocystis; acyclovir or valacyclovir against HSV and VZV; and fluconazole, itraconazole, or posaconazole against candidemia. Vaccination with inactivated vaccines can be started >12 months posttransplant, and patients will require a 23-valent pneumococcal vaccine as well as yearly influenza vaccinations (resuming 6 months posttransplant. Complete guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients can be found at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm.
General Principles of Treatment of Infections
Workup should be directed at the most likely organisms based on time after HSC transplant. Under the minimal suspicion of infection, rapid labs and imaging, such as blood and urine cultures, CMV or aspergillus serologies, chest x-ray, and sinus or chest CTs, should be done. Treatment often requires broad-spectrum antibiotics and antifungals, which should be started as soon as possible and normally without knowing the causative agent. Acyclovir is used for HSV and VZV at therapeutic doses. For CMV, ganciclovir or foscarnet is required. Human herpesvirus 6 is responsive to ganciclovir or foscarnet. Candida albicans and tropicalis are sensitive to fluconazole but disseminated infection may require echinocandins (caspofungin, micafungin, or anidulafungin) voriconazole, or amphotericin. Other Candida species, such as Candida glabrata and Candida krusei, respond to itraconazole, voriconazole, echinocandins, or amphotericin. For aspergillosis, amphotericin is the standard; however, voriconazole and caspofungin are very effective, with fewer side effects. If IV amphotericin is required, lipid formulations may be used to reduce renal toxicity.
Blood Group Incompatibility
The inheritance of ABO and HLA are unrelated. ABO incompatibility occurs in 30% to 40% of allogeneic HSCT. It can be categorized into 3 subtypes. Major mismatch is characterized by presence of ABO antibody in recipient plasma against donor RBC antigens (recipient O, donor A, B, AB or recipient A or B, donor B, A, or AB). Minor mismatch is defined by presence of ABO antibody in donor plasma against recipient RBC antigens (recipient A, B, or AB, donor O or recipient AB, donor A or B). Bidirectional mismatch is the presence of both major and minor mismatches (donor A, recipient B or vice versa).16
Major mismatch can lead to immediate hemolysis of RBCs in stem cell products, delayed hemolysis of donor RBCs or pure red cell aplasia (PRCA). Removal of RBCS from stem cell products can prevent immediate hemolysis. ABO antibodies are usually undetectable 2 months after major mismatch HSCT. Prolonged persistence of recipient B cells and plasma cells leading to persistence of ABO antibodies can occur for longer than 120 days after transplant. This can lead to delayed hemolysis or PRCA. Delayed hemolysis can be managed by transfusion of group O RBCs until anti-donor antibody has disappeared and recipient blood group has changed to donor blood group. PRCA can be managed by removal of recipient memory B cell and plasma cells by tapering immunosuppression permitting “graft versus plasma or B cell” or by using rituximab.
Minor ABO mismatch can cause “passenger lymphocyte syndrome” that is attributed to rapid proliferation of lymphocytes transfused with stem cells. Hemolysis starts between days 3 and 15 posttransplant, lasts 5 to 10 days, and then gradually resolves as the patient incompatible RBCs are destroyed and replaced by transfused group O RBCs and/or donor RBC derived from engrafted stem cells. Passenger lymphocyte syndrome can be managed by trans-fusion of group O RBCs and in extreme cases plasma exchange.
HEMATOPOIETIC STEM CELL TRANSPLANT PROGNOSIS
Over the past decade, there have been substantial advances in the care of patients undergoing HSCT, resulting in significant improvements in transplant related mortality, relapse rate, and overall survival.17 Despite significant advances in the knowledge of the biology and results of HSC transplantation, infections and other treatment-related complications are still a limiting factor in improving outcomes. Many complications are emergent and require admission to an ICU. Respiratory failure due to infections is common and may require mechanical ventilation. In addition, GvHD, infections and medication toxicities may contribute to multiple-organ dysfunction syndrome. The mortality rate is high in these situations, and overall prognosis should be discussed with the patient and family members promptly. Long-term survivors are at risk of complications such as chronic GvHD and secondary malignancies and should be closely followed. Factors such as age, comorbidities, and indication for and type of transplantation all contribute to the overall prognosis in each individual patient.
REFERENCES
1. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation. CIBMTR Summary Slides, 2010. Available at: http://www.cibmtr.org.
2. Ballen KK, King RJ, Chitphakdithai P, et al. The national marrow donor program 20 years of unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant.2008;14:2–7.
3. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–1826.
4. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576–4583.
5. Bray RA, Hurley CK, Kamani NR, et al. National marrow donor program HLA matching guidelines for unrelated adult donor hematopoietic cell transplants. Biol Blood Marrow Transplant. 2008;14:45–53.
6. Scaradavou A. Unrelated umbilical cord blood unit selection. Semin Hematol. 2010;47:13–21.
7. Geddes M, Storek J. Immune reconstitution following hematopoietic stem-cell transplantation. Best Pract Res Clin Haematol. 2007;20:329–348.
8. Huff CA, Fuchs EJ, Smith BD, et al. Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. Biol Blood Marrow Transplant. 2006;12(4):414–421.
9. Bacigalupo A. Management of acute graft-versus-host disease. Br J Haematol. 2007;137:87–98.
10. Schlomchik WD, Lee SJ, Couriel D, et al. Transplantation’s greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13:2–10.
11. McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. 2010;51:1450–1460.
12. Kotloff RM, Ahya VN, Crawford SW, et al. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respiratory Crit Care Med. 2004;170:22–48.
13. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351(25):2590–2598.
14. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep. 2000;49:1–128. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm.
15. Hiemenz JW. Management of infections complicating allogeneic hematopoietic stem cell transplantation. Semin Hematol. 2009;46(3):289–312.
16. Petz LD. Immune hemolysis associated with transplantation. Semin Hematol. 2005;42:145–155.
17. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–2101.