The Washington Manual of Oncology, 3 Ed.

Principles of Hematopoietic Cell Transplantation

Jesse Keller • Rizwan Romee

 I. INTRODUCTION. Hematopoietic cell transplantation (HCT) involves the administration of dose-intense chemotherapy and/or radiation followed by the infusion of either autologous or allogeneic (donor-derived) hematopoietic cells. The number of hematopoietic cell transplants performed each year has been steadily increasing for both benign and malignant hematologic conditions. This chapter summarizes the underlying principles and clinical aspects of both autologous and allogeneic HCT.

1. TYPES OF TRANSPLANTS. Hematopoietic cell transplants are classified by the source of donor cells as (a) autologous, (b) syngeneic, and (c) allogeneic.
2. Autologous transplantation. In an autologous transplant, a patient’s hematopoietic cells are harvested and cryopreserved. Autologous hematopoietic cells, including hematopoietic stem cells (HSCs), are then reinfused after administration of high-dose chemotherapy and/or radiation therapy. Autologous transplantation (auto-HCT) allows the delivery of high doses of drugs to maximize efficacy in situations where myelosuppression would otherwise be dose-limiting.
3. Syngeneic transplantation. Transplantation from an identical twin is similar to an autologous transplant with the benefit of providing a “clean” graft of hematopoietic cells that are free of contaminating malignant cells. The advantage of using syngeneic over auto-HCT, however, has never been demonstrated in a large clinical trial. Syngeneic HCT is not associated with either the graft-versus-host or graft-versus-tumor (GvT) effect of an allogeneic transplant and does not require posttransplant immunosuppression. Even when available, syngeneic transplant is rarely done owing to the lack of GvT effect, a key component in preventing disease relapse.
4. Allogeneic transplantation. Allogeneic hematopoietic cell transplantation (allo-HCT) involves the infusion of hematopoietic cells including HSCs from a human leukocyte antigens (HLA) matched or mismatched donor. Allo-HCT can be performed either from a related family member or an unrelated donor. In addition to permitting myeloablative doses of chemotherapy and/or radiation therapy to be administered, an allo-HCT allows for potent immunologic effects mediated by donor lymphocytes (predominantly by T cells and NK cells). This effect is known as the GvT or the graft-versus-leukemia (GvL) effect. Allo-HCT has efficacy in the treatment of malignant and nonmalignant disorders, including congenital immune deficiencies, sickle-cell anemia, thalassemia, and some inborn errors of metabolism. The possible donor choices in allo-HCT are HLA-matched sibling donors, HLA-matched or HLA-mismatched unrelated donors, related HLA-haploidentical donors, and cord blood.
5. Matched sibling donors. For those requiring allo-HCT, use of a matched sibling is still considered an ideal graft source when available. An allo-HCT from an HLA-matching sibling donor is associated with the best survival rates and with less morbidity, including lower rates of acute and chronic GVHD. However, the availability of an appropriate donor is a concern, as roughly 70% of patients do not have a suitable HLA-matched sibling.
6. Matched unrelated donors (MUD). The majority of patients who do not have access to a matched sibling are eligible for an MUD. Donor searches, however, are costly and time-consuming. Notably, availability of appropriate donors for minority populations is limited. Currently, less than 25% of African American patients are able to find an appropriate HLA-matched donor.
7. Mismatched related donors. In some cases, transplantation may be performed with related donors mismatched at one or two HLA loci. Drawbacks to this approach include increased risks of GVHD and graft failure.
8. Related haploidentical donors. Related HLA-haploidentical donors are mismatched at three of the six possible loci (HLA-A, HLA-B, and HLA-DR) for which HLA typing is performed (in reality, they are mismatched for an entire maternal- or paternal-derived HLA haplotype, but the related family donors are typically tested only for the above-mentioned HLA loci). This is an expanding area of transplantation with emerging data supporting that outcomes may be equivalent to patients receiving an HLA-matched unrelated donor and possibly even HLA-matched sibling donor transplantation. Donor availability is simplified and expedited as usually multiple eligible donors can be found within a family.

 III. PATIENT SELECTION

1. Indications for transplantation. HCT has been successfully used in the treatment of a number of malignant and nonmalignant conditions (Table 8-1). The choice of autologous-versus-allogeneic transplantation largely depends on the disease being treated and the availability of a compatible donor. Currently, multiple myeloma and lymphomas are the most frequent indications for autologous transplants, whereas acute leukemia and myelodysplastic syndromes are the most frequent indications for allo-HCT. Guidelines for transplant referrals in adult patients have been published by the American Society for Blood and Marrow Transplantation (ASBMT) (Table 8-2).
2. Pretransplant evaluation of candidates for hematopoietic cell transplantation. Pretransplant evaluation of patients considered for HCT is required to identify candidates with comorbid conditions that may preclude the administration of high-dose therapy with their associated toxicity. Although the risk of transplant-related complications increases with advancing age, age alone is no longer considered an absolute contraindication, but rather one of many factors affecting the overall suitability of a patient for HCT. Guidelines for pretransplant evaluations are listed in Table 8-3.

 IV. DONOR SELECTION

1. HLA typing. For allo-HCT, donors are selected on the basis of their histocompatibility with the recipient. The major histocompatibility complex (MHC) locus, also called HLA locus, on chromosome 6 encodes class I and class II HLA antigens that allow for the immune recognition of foreign antigens. In hematopoietic and solid organ transplantation, HLA molecules function as alloantigens that can trigger immune recognition and graft rejection in mismatched recipients.

Autologous transplantation

Multiple myeloma

Hodgkin’s and non-Hodgkin’s lymphoma

Acute promyelocytic leukemia

Neuroblastoma

Germ cell tumors

Allogeneic transplantation

Acute and chronic myeloid leukemia

Acute and chronic lymphocytic leukemia

Myelodysplastic and myeloproliferative syndromes

Hodgkin’s and non-Hodgkin’s lymphoma

Multiple myeloma

Aplastic anemia and other bone marrow failure disorders

Hemoglobinopathies: thalassemia major and sickle-cell anemia

Immunodeficiency syndromes: severe combined immunodeficiency, Wiskott–Aldrich

Inborn errors of metabolism: Hurler’s syndrome, adrenoleukodystrophy

AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; WBC, white blood corpuscles; CNS, central nervous system; CR, complete remission; MDS, myelodysplastic syndromes; IPSS, International Prognostic Scoring System; CML, chronic myelogenous leukemia; IPI, International Prognostic Index.

1. HLA alleles. HLA antigens are defined serologically by testing for reactivity against a panel of monoclonal antibodies. DNA-based testing has largely replaced serologic testing and utilizes sequence-specific DNA primers and probes to define HLA alleles. High-resolution molecular typing of 10 HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1) is the current standard. High-resolution molecular typing permits precise HLA matching between donors and transplant patients, which has resulted in improved patient outcomes. Because the MHC complex is tightly clustered on chromosome 6, HLA alleles are inherited as a set also referred to as the patient’s haplotype. The chance of any individual sibling being HLA-matched is 25%, whereas the probability of having a fully HLA-matched sibling donor is 1–(3/4)ⁿ, where n is the number of full siblings.
2. HLA matching of unrelated donor transplants. In individuals who do not have an HLA-identical sibling, selection of an unrelated donor is required. Typing of HLA-A, -B, -C, -DR (DRB1), and DQB1 is routinely used to select unrelated donors. In addition, other class II loci HLA-DPB1 and -DRB3/4/5 are often tested although there is no definite association with the patient outcomes. In the United States, unrelated donor transplant searches are coordinated by the National Marrow Donor Program (NMDP). The likelihood of finding an unrelated donor for a given patient depends upon the frequency of the patient’s HLA haplotype in the general population. For all patients, the likelihood of finding a potential unrelated marrow or peripheral blood stem cells (PBSC) donor in the donor registries is largely tied to race. In the United States, Caucasians are much more likely to find a match than African Americans or Asian Americans.

HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; ECG, electrocardiogram; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; DLCO, carbon dioxide diffusion in the lung; CMV, cytomegalovirus; HSV, herpes simplex virus; HIV, human immunodeficiency virus; HTLV-I, human T-cell lymphoma virus type 1; TBI, total body irradiation.

3. HLA matching of haploidentical donor transplants. Haploidentical donors are matched at 3 of 6 loci (HLA-A, HLA-B, and HLA-DR). The likelihood of finding a successful haploidentical relative is significantly higher than that of finding a successful MUD match. Additionally, the time and expense of a donor search may be spared when seeking a haploidentical donor.
4. Non-HLA factors. Other factors are often considered when donors are selected, including cytomegalovirus (CMV)—negative serology (for patients with CMV-negative serology), male sex, younger age, ABO compatibility, larger body weight, and matched race. Multiparous female donors are associated with a higher risk of chronic graft-versus-host disease (cGVHD), but with no effect on overall survival.
5. SOURCES OF HEMATOPOIETIC STEM CELLS
6. Bone marrow. Historically, bone marrow was used as the sole graft source in transplantation. Bone marrow is collected from the posterior iliac crest by performing repeated aspirations while the donor is under general or regional anesthesia. The volume collected varies, but generally ranges from 10 to 15 mL/kg of donor weight. Improved survival has been correlated with higher transplanted HSC dose with more robust engraftment and fewer infectious complications. A total nucleated cell (TNC) dose of approximately 2 × 10⁸ cells/kg in the harvested bone marrow product is considered adequate for HCT. Side effects of marrow collection include fatigue and pain at the collection site and effects related to general anesthesia such as nausea and vomiting.
7. Peripheral blood as a graft source. HSCs normally circulate in low levels in the peripheral circulation, but can be recruited into the peripheral blood from the marrow in response to stressors such as inflammation or infection. In addition, the exogenous administration of hematopoietic growth factors can increase the numbers of peripheral blood stem cells by 40- to 80-fold in a process termed stem cell mobilization. These mobilized HSCs along with other mononuclear cells can then be harvested and used for HCT. Currently, the majority of autologous and allogeneic transplants are performed using peripheral blood as a graft source.
8. Stem cell mobilization. Although a number of cytokines and cytokine combinations can mobilize HSCs, the FDA-approved medications for stem cell mobilization include granulocyte-stimulating factor (G-CSF) (filgrastim, 10 to 16 µg/kg), granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim), and plerixafor. Donors may experience myalgia, bone pain, headache, nausea, and low-grade fevers with G-CSF. Splenic rupture due to extramedullary hematopoiesis has been reported as a rare complication.

 HSCs also increase in the peripheral circulation during neutrophil recovery after the administration of chemotherapy. For autologous stem cell collection, high-dose cyclophosphamide or other forms of chemotherapy may be used to mobilize HSCs, and this can be augmented with the administration of G-CSF or GM-CSF to increase the stem cell yield.

 Plerixafor is a CXCR4 antagonist used for the mobilization of stem cells. CXCR4 is a receptor for the chemokine CXCL12 (stromal-derived factor-1 [SDF-1]) produced by marrow stromal cells and is critical for the homing and retention of HSCs in the marrow. By disrupting the CXCR4/CXCL12 axis, plerixafor has been shown to be effective for the mobilization of stem cells either alone or in combination with G-CSF. Plerixafor is FDA-approved for use in combination with G-CSF for HSC mobilization for patients with a diagnosis of non-Hodgkin’s lymphoma (NHL) or multiple myeloma (MM) undergoing autologous transplantation.

2. HSC harvesting from peripheral blood. Following mobilization, HSCs are collected by large volume apheresis (up to 20 liters) through the antecubital veins or a central venous catheter. The mononuclear fraction containing the HSCs along with other mononuclear cells like lymphocytes and monocytes is retained, and the remainder is reinfused into the patient. Hypocalcemia from the anticoagulation with acid-citrate-dextrose solution used during apheresis may cause perioral numbness, paresthesias, and carpopedal spasm and is treated with calcium supplementation. A minimum of 2 × 10⁶ CD34⁺/kg recipient weight is required for an autologous transplant, whereas a goal of 5 × 10⁶ CD34⁺/kg increases the probability of early platelet recovery. Similarly ideal dose of CD34⁺ collected for allo-HCT is around 5 × 10⁶/kg recipient weight but doses ≥3 × 10⁶/kg are considered sufficient, especially in the absence of donor–recipient HLA mismatch. Most normal donors require only a single apheresis session to collect adequate numbers of stem cells, while autologous donors may require multiple (five or more) sessions, depending on their degree of exposure to previous chemotherapy.

Compared with marrow, PBSC contain higher numbers of CD34¹ cells than bone marrow and are associated with faster neutrophil and platelet recovery. In addition, PBSC grafts have approximately 10 times as many T lymphocytes, which are associated with higher rates of cGVHD but without an effect on overall survival. Aplastic anemia is an exception to the expanding use of peripheral blood as a graft source, as for these patients, bone marrow is the preferred graft source and has been associated with better outcomes.

2. Umbilical cord blood. Blood present in the umbilical cord and placenta following childbirth is a rich source of HSCs. After delivery of the placenta, the umbilical cord is clamped, and approximately 50 to 100 mL remaining in the placenta and umbilical cord is drained and cryopreserved. Cord blood typically contains about a 10- to 20-fold smaller dose of nucleated and CD34⁺ cells than an adult bone marrow. Because of the limitations in stem cell dose, cord blood transplants have been primarily performed in pediatric populations with a minimum of 2.0 × 10⁷ mononuclear cells/kg typically required for successful transplantation and greater than 3.0 × 10⁷mononuclear cells/kg for optimal results. In the adult population, typically two cord blood units (double cord allo-HCT) are pooled for a single recipient, which can result in a more rapid hematopoietic recovery. Of interest, in double cord allo-HCT, only one of the two cord blood units dominates hematopoiesis over the long term.

 Cord blood transplants are associated with lower of risks of GVHD and can be performed successfully with a greater degree of HLA mismatch than adult stem cell sources. In addition, cord blood units are more readily available than stem cells from adult donors and are associated with lower rates of viral transmission. Cord blood registries, unlike adult donor registries, do not suffer from loss to the donor pool due to advancing age or difficulties in locating potential donors. Major problems with cord blood transplantation include delayed engraftment, higher risk of posttransplant infections, mildly increased rates of graft failure, and the inability to collect additional donor cells for patients with graft failure and/or relapse.

 VI. CONDITIONING REGIMENS

4. Myeloablative conditioning. Traditional conditioning regimens used in HCT use myeloablative doses of alkylating agents (cyclophosphamide, busulfan, melphalan) with or without total body irradiation (TBI) before transplant to (a) eliminate residual disease and to (b) suppress immune function to allow engraftment of donor stem cells. Standard conditioning regimens vary by disease with commonly used regimens listed in Table 8-4. In addition to severe myelosuppression, agents used in HCT are typically associated with side effects such as mucositis, alopecia, nausea, and may cause significant organ damage including hepatic or pulmonary dysfunction.
5. Reduced intensity conditioning. In the allogeneic setting, nonmyeloablative or reduced intensity conditioning (RIC) regimens were designed to reduce the toxicity associated with high-dose therapy. These regimens do not attempt to completely eliminate malignant cells before transplant, but instead provide enough immunosuppression to allow donor engraftment and rely predominantly upon a GvT effect mediated by the donor-derived T cells to achieve their therapeutic goal. Some of the commonly used RIC regimens are listed in Table 8-5.

 RIC regimens allow the elderly and patients with significant comorbid conditions to be eligible for allo-HCT. In retrospective analyses conducted in myeloid malignancies, RIC regimens are associated with lower treatment-related mortality but with higher relapse rates and no change in overall survival. Rates of acute and cGVHD after RIC are comparable to those observed in standard high-dose transplants, but the onset of acute GVHD (aGVHD) is often delayed by weeks to months. In view of the increased risk of relapse, these regimens are best suited to patients who are otherwise in complete remission at the time of transplant.

TBI, total body irradiation; MESNA, [sodium-2]-mercaptoethane sulfonate; VP, vincristine/prednisone; CIVI, continuous intravenous infusion; BCNU, 1,3- bis-(2-chloroethyl)- 1-nitrosourea; Ara-C, acytosine arabinose.

RT, reverse transcription; ATG, antithymocyte globulin.

 VII. HEMATOPOIETIC CELL GRAFT INFUSIONS. Cells collected for autologous transplant are cryopreserved in the liquid or vapor phase of liquid nitrogen with 10% dimethyl sulfoxide (DMSO) used as a cryoprotectant. Before reinfusion of the cells, a bicarbonate infusion is used to alkalinize the urine to protect against renal injury caused by the hemolysis of contaminating red cells. Stem cells products are rapidly thawed at 37-degree water bath and typically infused over a 15-minute period as longer infusion times potentially subject the HSCs to DMSO toxicity. Side effects associated with DMSO include flushing, unpleasant taste, nausea, and vomiting with rare hypotension, atrial arrhythmias, and anaphylactic reactions. Allogeneic grafts are usually infused fresh, with patients monitored for any hypersensitivity reactions. Large volume bone marrow products should be infused over the period of 3 to 4 hours and the patient monitored for fluid overload. Also, the grafts for allo-HCT typically undergo RBC reduction in case of major ABO donor–recipient blood group mismatch prior to the cell infusion.

VIII. POSTTRANSPLANT CARE AND COMPLICATIONS

1. Hematopoietic
2. Engraftment. Following stem cell infusion, progenitor cells home to the marrow microenvironment, guided by interactions between adhesion molecules and their receptors expressed on hematopoietic cells and the marrow stroma. These cells must then proliferate and differentiate to repopulate the peripheral blood with mature blood cells in a process termed engraftment. Neutrophil engraftment (ANC greater than 500/mm³) typically occurs between 10 and 15 days’ posttransplant with PBSC transplants and slightly later in bone marrow transplants. The administration of colony-stimulating factors, either G-CSF or GM-CSF, posttransplant has been demonstrated to lessen the duration of neutropenia, though without improving survival. Platelet recovery tends to be much more variable posttransplant.

 Donor/recipient chimerism is evaluated post-HCT by analyzing either peripheral blood or bone marrow for differences in donor- and recipient-specific Short Tandem Repeats (STRs) using polymerase chain reaction (PCR)-based assays. In the case of sex-mismatched transplantation, chimerism can also be analyzed by the ratio of sex chromosome–specific fluorescence in situ hybridization (FISH) probes.

2. Transfusion support. Transfusions of red blood cells and platelets are common in HCT. Although transfusion parameters are somewhat arbitrary, it is reasonable to maintain hemoglobin levels greater than 8 g/dL and platelet counts greater than 10,000/mm³. To reduce the risk of transfusion-associated GVHD, all blood products should be irradiated with 2,500 cGy before administration.
3. ABO incompatibility. Because stem cell products are matched on the basis of HLA compatibility, ABO-incompatible HSCTs frequently occur. Red cell incompatibility is classified according to whether donor isoagglutinins, isoantigens, or both are incompatible with those of the recipient. Major incompatibility occurs when the recipient has antibodies directed against donor red blood cell antigens (e.g., A donor, O recipient); minor incompatibility occurs when donor plasma contains antibodies directed against patient red cells (e.g., O donor, A recipient). Mixed or bidirectional incompatibility occurs when there is both major and minor ABO incompatibility (e.g., A donor, B recipient, or vice versa). Red cells are typically reduced from the harvested grafts in major incompatible allo-HCT, especially when using bone marrow as the graft source to reduce the risk of clinically significant hemolysis of large quantities of red cells contained in the cell product. Immune-mediated hemolysis is indicated by a positive direct antiglobulin test (direct Coombs) in the setting of other markers of hemolysis such as an elevated lactate dehydrogenase (LDH) or indirect bilirubin. In cases of mild hemolysis, RBC transfusion support is adequate. In more severe cases, plasma exchange may be used. In contrast, patients receiving minor incompatible transplants have a risk of immediate hemolysis from the infusion of incompatible plasma. Immediate hemolysis can be prevented by removal of plasma from the bone marrow grafts by centrifugation. In transplants using peripheral blood mononuclear cells, apheresis used to collect the cells product effectively removes most of the donor plasma, and there is significantly less contamination with RBCs.
4. Graft failure. Rejection of the donor hematopoietic cells by the immune system of the recipient is termed graft failure and may be classified as primary (ANC <500/mm³ after 28 days posttransplant, although various definitions exist) or secondary (transient donor hematopoiesis). Causes of graft failure include HLA disparity at major and minor loci, inadequate conditioning of the host, inadequate number of donor stem cells, T cell depletion of the donor graft, inadequate immunosuppression, and presence of high titers of donor-specific antibodies (DSAs) caused by allo-sensitization to donor HLA antigens by blood transfusions, especially platelet products and multiple pregnancies before transplantation. Therapeutic options include more intensive immunosuppression, the administration of hematopoietic growth factors, donor lymphocyte infusions (DLIs), and even a second HCT.
5. Acute graft-versus-host disease (aGVHD)
6. Pathogenesis. aGVHD is caused by allo-reactive donor T cells that recognize recipient antigens as foreign, resulting in inflammatory disease affecting multiple organs. Cytokine storm in the early posttransplant period caused by either the conditioning regimen and/or infection is thought to further activate donor-derived lymphocytes, exacerbating the aGVHD-associated inflammation. Further, recipient antigen presenting cells (APCs), especially the dendritic cells, are thought to play an important role in initiating acute inflammatory cascade associated with aGVHD. aGVHD can be particularly severe in the setting of a major MHC class mismatch, but also occurs because of disparities in minor histocompatibility antigens.
7. Clinical manifestations. aGVHD typically manifests itself after the first 25 to 28 days after transplantation, and most commonly involves skin, liver, and gut, the three largest organs in our body. The skin manifestation of aGVHD varies from a mild maculopapular rash to overt sloughing. Liver involvement is commonly seen with a conjugated hyperbilirubinemia and elevation of the alkaline phosphatase as the biliary ductules are the first targeted components in the liver. Lower gastrointestinal (GI) involvement typically presents as diarrhea and abdominal cramping, while upper GI involvement usually presents as nausea and vomiting.

 Although several scoring systems are used to grade GVHD, most are based on the original Glucksberg criteria, with those having stage III and IV disease having a significantly poorer outcome (Table 8-6). Rates of grade III–IV aGVHD vary by study and donor source. Large studies have shown cumulative rates of aGVHD through 40 months of 39% and 49% respectively for sibling-allogeneic and unrelated donor transplants. For haploidentical transplantation using posttransplant cyclophosphamide, rates of grade III–IV aGVHD have ranged from 5% to 11%.

3. GVHD prophylaxis
4. Pharmacologic prophylaxis. Because of the high morbidity and mortality associated with the development of aGVHD, routine prophylaxis against GVHD is required in all patients undergoing allo-HCT. Although a number of different pharmacologic agents can be used, a typical regimen uses an antimetabolite agent like methotrexate (at a dose of 10 mg/m² on days 1, 3, 6 ± 9) or mycophenolate mofetil (MMF) continued until day 30 after allo-HCT combined with a calcineurin inhibitor, either cyclosporine or tacrolimus. Immunosuppression with a calcineurin inhibitor is generally continued until day 100 posttransplant and gradually tapered in the absence of GVHD or disease relapse. Recently, other novel regimens have included sirolimus plus tacrolimus, as well as vorinostat- and bortezomib-based regimens. Further GVHD prophylaxis using high-dose cyclophosphamide (50 mg/kg given on days 3 and 4 after allo-HCT) has revolutionized haploidentical transplantation as its use has dramatically reduced both aGVHD and cGVHD rates after haploidentical transplantation. This has also been successfully been used in HLA-matched sibling and unrelated donor transplants with very favorable GVHD rates.
5. T cell depletion. T cell depletion may be used as either an alternative or adjuvant to pharmacologic prophylaxis for GVHD. As donor-derived T cells are central to the pathogenesis of aGVHD, T cell depletion of the donor graft can effectively reduce the incidence of GVHD. A number of methods for T cell depletion have been used and include physical adsorption of T cells to proteins such as lectins, elutriation, or depletion with T cell or lymphocyte-specific antibodies. A loss of donor T cells is associated “however, with higher rates of graft rejection mediated by residual host T cells and a disease relapse due to partial loss of the GvT effect.” In addition, T cell depletion results in delayed immune reconstitution in recipients, leading to higher rates of viral infections and, in particular, cytomegalovirus (CMV) and Epstein–Barr virus (EBV).

4. Treatment. Corticosteroids are the primary treatment for aGVHD. For mild (grade I) GVHD of the skin, topical steroids may be sufficient. For grade II or higher disease, prednisone or methylprednisolone 1 to 2 mg/kg/day is usually initiated. Steroid doses are then generally tapered gradually after clinical improvement. For patients with steroid refractory disease, a number of agents have been used with modest success. These include agents such as mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, pentostatin, thalidomide, and monoclonal antibodies including daclizumab and infliximab. Recently, use of extracorporeal photopheresis (ECP) has also been tested for the treatment of aGVHD with variable results.
5. Infections
6. Timing of infectious complications. HCT recipients are at increased risk for opportunistic infections. The risk of developing specific types of infections seen in stem cell transplant recipients varies by the type of transplant (autologous or allogeneic) and the length of time since undergoing the transplant. Before neutrophil engraftment, patients are at increased risk for infection due to neutropenia caused by the conditioning regimen and breaks in mucosal barriers from chemotherapy or indwelling vascular access devices. During this period, febrile neutropenia caused from both gram-positive and gram-negative organisms are common. In addition, Candida infections and herpes simplex virus (HSV) reactivation may occur. The postengraftment period (days 30 to 100) is characterized by impaired cell-mediated immunity. After engraftment, the herpes viruses, particularly CMV, are major pathogens. Other dominant pathogens during this phase include Pneumocystis carinii and Aspergillus species.
7. Prophylaxis and management of specific infections
8. CMV. CMV infections in HSCT recipients most commonly present as fever or interstitial pneumonitis. Other clinical manifestations include bone marrow suppression, retinitis, or diarrhea. Patients at risk for developing CMV infection include those undergoing allogeneic HSCT where either the donor or recipient is CMV positive. Prevention of CMV disease in allogeneic transplant can be accomplished using either a prophylactic or a preemptive strategy. A prophylactic strategy of ganciclovir through day +100 posttransplant is effective at preventing CMV disease but may result in drug-induced marrow suppression and prevent reconstitution of CMV-specific T cell immunity, resulting in late occurrences of CMV disease. A preemptive strategy uses sensitive PCR techniques to detect viremia and initiates therapy with ganciclovir before the development of overt disease. For patients with resistant disease, foscarnet or cidofovir may be used.

 To reduce the risk of transfusion-acquired CMV infection, all donors and recipients are screened for their CMV serostatus. CMV antibody–negative blood products should be given to CMV-negative recipients. Alternatively, leukofiltration to reduce the white cell fraction in the transfused produce may be used as an alternative if no CMV-negative products are available.

1. HSV and VZV. Routine prophylaxis with either acyclovir 400 mg t.i.d. or valacyclovir 500 mg qd. to prevent reactivation of HSV and varicella zoster virus (VZV) is given to patients until neutrophil engraftment in autologous transplant patients and immunosuppression are discontinued in allogeneic transplant patients.
2. PCP prophylaxis. Prophylaxis with TMP-SMX one DS tablet b.i.d. 2× a week, dapsone 100 mg daily or aerosolized pentamidine should be given to all patients undergoing allogeneic transplant and selected patients undergoing autologous transplant. PCP prophylaxis is continued while patients remain on immunosuppressive medications.
3. Veno-occlusive disease of the liver. Veno-occlusive disease (VOD) of the liver is a clinical diagnosis based on the presence of hyperbilirubinemia associated with fluid retention and painful hepatomegaly. Histologically, VOD is associated with central vein occlusion, centrilobular hepatocyte necrosis, and sinusoidal fibrosis. Ultrasonography may reveal reversal of flow in the portal and hepatic veins. The etiology of VOD is believed to arise from damage to the hepatic endothelium secondary to high-dose chemotherapy and/or radiation.

 Risk factors for VOD include preexisting hepatic disease (e.g., viral hepatitis, cirrhosis), high-dose radiation as part of the conditioning, mismatched or unrelated donor HSCT, and the use of cyclosporine and methotrexate for GVHD prophylaxis. Spontaneous resolution of VOD is observed in approximately 70% of cases, but can frequently evolve into fatal multisystem organ failure. Low-dose heparin or ursodeoxycholic acid may provide some protection when used in a prophylactic manner. Supportive care measures are the mainstay of treatment for VOD with attention to fluid and electrolyte management. Other agents used for the treatment of VOD include defibrotide, alteplase and high-dose methylprednisolone, although the evidence supporting their use is mixed.

1. Management of relapsed disease. For relapsed disease following allogeneic transplant, maneuvers that attempt to maximize the GvL effect of the allograft may be useful. Withdrawal of immunosuppression is usually attempted first. If no effect is seen, a DLI can augment the immunologic effect of the allograft. DLI can result in significant toxicity including acute and cGVHD and severe pancytopenia. Responses are seen more frequently in diseases thought to be most sensitive to a graft-versus-disease effect such as chronic myeloid leukemia (CML) and in those patients who develop GVHD. Currently, the outcomes of patients who relapse after allo-HCT and are unable to achieve remission with salvage therapies remain extremely poor.

 IX. LATE COMPLICATIONS OF ALLOGENEIC TRANSPLANTATION

1. cGVHD
2. Clinical manifestations. The clinical manifestations of cGVHD are heterogeneous in terms of the organ systems involved, the disease severity, and the clinical course. Historically, GVHD was classified as chronic when it occurred after day +100 post-HSCT. However, currently if patients have features of aGVHD even after day +100 in the absence of features diagnostic of cGVHD, it is still classified as persistent, recurrent, or late-onset aGVHD. Based on NIH consensus guidelines, cGVHD includes classic cGVHD when patients have manifestations that are only present in cGVHD and overlap syndrome, which has diagnostic or distinctive features of cGVHD along with features typical of aGVHD (skin, GI tract, liver).

 Based on the NIH scoring system, cGVHD is classified into mild, moderate, or severe disease, depending on the number of affected organs and organ-specific severity (scored from 0 to 3). Mild cGVHD involves two or fewer organs/sites with no clinically significant organ impairment. Moderate cGVHD involves three or more organs/sites with no clinically significant impairment or at least one organ/site with clinically significant functional impairment, but no major disability. Severe cGVHD involves major disability caused by cGVHD.

 The most frequently affected organs in cGVHD include the skin, liver, GI tract (predominantly esophagus), and lungs. Epidermal involvement is characterized as an erythematous rash that may appear papular, lichen planus–like, papulosquamous, or poikiloderma. Dermal and subcutaneous involvement is characterized by sclerosis, fasciitis, and ulcerations. Oral manifestations of cGVHD include erythema, lichenoid hyperkeratosis, ulcerations, or mucoceles. Lacrimal gland dysfunction frequently results in keratoconjunctivitis sicca, also known as the dry eye syndrome, and can manifest as burning irritation, pain, blurred vision, and photophobia. GI symptoms include nausea, vomiting, anorexia, and unexplained weight loss. Liver involvement is characterized by rising bilirubin and transaminases. Pulmonary cGVHD can result in a debilitating bronchiolitis obliterans syndrome with pulmonary function testing often demonstrating decreases in the forced expiratory volume in the first second (FEV₁) and the diffusing capacity of the lung for carbon monoxide (DLCO).

2. Diagnosis and treatment. The diagnosis of cGVHD can often be made on the basis of classical features of skin involvement, manifestations of gastrointestinal involvement, and a rising serum bilirubin concentration. Often the diagnosis is less clear, in which case histologic confirmation may be desirable.

 Systemic immunosuppression with corticosteroids and other agents are often required to treat cGVHD. In addition, ancillary and supportive care measures tailored to the organ system involved are critical for the management of cGVHD, and in many circumstances reduce or eliminate the need for systemic immunosuppression.

1. Late infections. Autologous HCT patients have a more rapid recovery of immune function and a lower risk of opportunistic infections than allogeneic HSCT patients. Because of cell-mediated and humoral immunity defects and impaired functioning of the reticuloendothelial system, allogeneic HSCT patients with cGVHD are at risk for various infections during this phase. Late infections include EBV-related posttransplant lymphoproliferative disease, community-acquired respiratory virus infection, and infections with encapsulated bacteria. In addition, fungal infections with Aspergillus species and zygomycosis can be seen in the late period, particularly in patients with cGVHD.
2. Secondary malignancies. Patients undergoing both autologous and allogeneic transplantation are at risk for the development of either treatment-related myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) due to the high-dose alkylators and irradiation typically used as part of the conditioning regimens. Exposure to radiation and the photosensitizing effects of many commonly used transplantation-related medications increase the risk of skin cancers among recipients. Posttransplant lymphoproliferative disorders due to EBV can be observed particularly in patients receiving T cell–depleted grafts.
3. Other complications. Although stem cell transplantation can result in long-term survival with an excellent quality of life, late sequelae of the transplantation can result in significant morbidity. For example, TBI is associated with hypothyroidism and development of cataracts. Patients receiving prolonged corticosteroids can develop muscle weakness and bone loss. Recommendations for screening and preventative practices for long-term survivors of HSCT have been published.

SUGGESTED READINGS

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