Amber P. Lawson
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the rationale for using hematopoietic stem cell transplant (HSCT) to treat cancer
2. Compare the different types of HSCTs, specifically (a) the types of donors (i.e., autologous and allogeneic), (b) the source of hematopoietic cells (i.e., umbilical cord, peripheral blood progenitor cells [PBPCs], and bone marrow), and (c) the type of preparative regimen (i.e., myeloablative and nonmyeloablative).
3. List the nonhematologic toxicity to high-dose chemotherapy used in myeloablative preparative regimens, specifically busulfan-induced seizures, hemorrhagic cystitis, GI toxicities, and sinusoidal obstruction syndrome.
4. Develop a plan for monitoring and managing engraftment of hematopoiesis.
5. Explain graft-versus-host disease (GVHD).
6. Recommend a prophylactic and treatment regimen for GVHD.
7. Choose an appropriate regimen to minimize the risk of infectious complications in HSCT patients.
8. Evaluate the long-term health care of HSCT survivors.
KEY CONCEPTS
Hematopoietic stem cell transplantation (HSCT) is a procedure used mainly to treat hematologic malignancies via high-dose chemotherapy and/or a graft-versus-tumor effect.
An autologous HSCT involves the infusion of a patient’s own hematopoietic cells and allows for the administration of higher doses of chemotherapy, radiation, or both to treat the malignancy. Infusion of another’s hematopoietic cells is an allogeneic HSCT; these cells can be from donors related or unrelated to the recipient.
Umbilical cord blood, peripheral blood progenitor cells (PBPCs), and bone marrow can serve as the source of hematopoietic cells. The optimal cell source differs based on the donor and recipient characteristics.
A myeloablative preparative regimen involves the administration of sublethal doses of chemotherapy to the recipient in order to eradicate residual malignant disease. The recipient will not regain his or her own hematopoiesis and will be at risk for substantial life-threatening nonhematologic toxicity.
A nonmyeloablative preparative regimen is less toxic than a myeloablative regimen in hopes of being able to offer the benefits of an allogeneic HSCT to more patients. A nonmyeloablative HSCT is based on the concept of donor immune response having a graft-versus-tumor effect.
Nonhematologic toxicity differs based upon the preparative regimen administered.
Engraftment is the reestablishment of functional hematopoiesis. It is commonly defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of greater than 500 cells/mm3 (0.5 × 109/L) and a sustained platelet count of greater 20,000/mm3 (20 × 109/L) lasting for three or more consecutive days without transfusions.
Graft-versus-host disease (GVHD) is caused by the activation of donor lymphocytes leading to immune damage to the skin, gut, and liver in the recipient. An immunosuppressive regimen is administered to prevent GVHD in recipients of an allogeneic graft; this regimen is based on the type of preparative regimen and the source of the graft.
Recipients of HSCT are at higher risk of bacterial, viral, and fungal infections and usually receive a prophylactic or preemptive regimen to minimize the morbidity and mortality owing to infectious complications.
Long-term survivors of HSCT should be monitored closely, particularly for infections and secondary malignant neoplasms.
INTRODUCTION
Hematopoietic stem cell transplantation (HSCT) is a procedure used mainly to treat hematologic malignancies via high-dose chemotherapy and/or a graft-versus-tumor effect. An essential component of this procedure is the infusion of hematopoietic cells into the recipient to facilitate an immunologic response against the residual malignancy and/or restore normal hematopoiesis and lymphopoiesis. The first HSCTs were performed using allogeneic bone marrow, which involved administration of high-dose chemotherapy and/or radiation aimed at eradicating residual malignant disease followed by transplantation of bone marrow from one individual to another in order to “rescue” the recipient’s immune system from the myelotoxic effects of the treatment. Bone marrow contains pluripotent stem cells and post-thymic lymphocytes, which are responsible for long-term hematopoietic reconstitution, immune recovery, and its associated graft-versus-host disease (GVHD). Subsequently, the dose-intensity concept for cancer treatment was expanded to using myeloablative preparative regimens followed by autologous HSCT.
The type of HSCT performed depends on a number of factors, including type and status of disease, availability of a compatible donor, patient age, performance status, and organ function. In addition to bone marrow, hematopoietic stem cells may be obtained from the peripheral blood progenitor cells (PBPCs) and umbilical cord blood. The essential properties of the hematopoietic cells are their ability to engraft, the speed of engraftment, and the durability of engraftment.
Examples of diseases treated with HSCT are listed in Table 98–1. Autologous HSCT, or infusion of a patient’s own hematopoietic cells, allows for the administration of higher doses of chemotherapy, radiation, or both to treat the malignancy or autoimmune disorder. In this setting, the hematopoietic cells “rescue” the recipient from otherwise dose-limiting hematopoietic toxicity. Autologous HSCT is used to treat intermediate- and high-grade non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), autoimmune diseases, and relapsed or refractory Hodgkin’s disease.1
Allogeneic HSCT involves the transplantation of hematopoietic cells obtained from a different person’s (donor) bone marrow, peripheral blood, or umbilical cord blood to the recipient. Unless the donor and the recipient are identical twins (referred to as a syngeneic HSCT), they are dissimilar genetically. Allogeneic HSCT is used to treat both nonmalignant conditions and hematologic malignancies such as acute and chronic leukemias.1
The infusion of hematopoietic cells follows the administration of a combination of chemotherapy and/or radiation, termed the conditioning or preparative regimen. A myeloablative preparative regimeninvolves the administration of sublethal doses of chemotherapy to the recipient in order to eradicate residual malignant disease. The recipient will not regain his or her own hematopoiesis and will be at risk for substantial life-threatening nonhematologic toxicity. For those undergoing an autologous HSCT, their hematopoietic cells must be harvested and stored before the myeloablative preparative regimen is administered. After the administration of the myeloablative preparative regimen, these hematopoietic cells serve as a rescue intervention to reestablish bone marrow function and avoid long-lasting, life-threatening marrow aplasia. In the setting of an allogeneic HSCT, the preparative regimen is designed to suppress the recipient’s immunity, eradicate residual malignancy, or create space in the marrow compartment. Improved survival outcomes have been observed with both autologous and allogeneic HSCT when the hematologic malignancy is in complete remission at the time of HSCT.2 At most HSCT centers, age younger than 65 years and normal renal, hepatic, pulmonary, and cardiac function are considered eligibility requirements for myeloablative allogeneic HSCT. A myeloablative or nonmyeloablative preparative regimen may be used for allogeneic HSCT; only myeloablative preparative regimens are used for autologous HSCT. Allogeneic HSCT offers the potential for a graft-versus-tumor effect in which immune effector cells from the donor recognize and eliminate residual tumor in the recipient.1
Table 98–1 Diseases Commonly Treated With HSCT
The recognition of graft-versus-tumor effect, which likely is caused by cytotoxic T lymphocytes in the donor stem cells, led to investigations with nonmyeloablative transplants, in which less toxic preparative regimens are used in the hope of expanding the availability of HSCT to recipients whose medical condition or age prohibits use of myeloablative regimens.
EPIDEMIOLOGY AND ETIOLOGY
Each year, the number of allogeneic HSCTs is less than the number of autologous HSCTs. Worldwide, approximately 35,000 autologous HSCTs and 20,000 allogeneic HSCTs are performed per year, with 40% of allogeneic HSCTs employing reduced-intensity preparative regimens. In the late 1990s, the number of allogeneic HSCTs reached a plateau, most likely related to the introduction of imatinib (Gleevec) for treatment of newly diagnosed chronic-phase chronic myelogenous leukemia (CML). Furthermore, the limited availability of suitable donors may have contributed to the plateau effect. Recently, however, the number of allogeneic transplants for hematologic malignancies other than CML appears to be increasing.2
Autologous PBPC use has increased and essentially has replaced bone marrow as a graft source in many transplant centers. From years 2002 through 2006, over 95% of autologous HSCTs in adults and 80% in children used PBPCs as the source of hematopoietic cells.2 Patients do not benefit from an immunologic graft-versus-tumor effect while undergoing an autologous transplant; instead, the administration of high-dose chemotherapy followed by an autologous stem cell transplant in chemotherapy-sensitive malignancies relies on the preparative regimen alone to eradicate the malignant disease. Autologous HSCT is used to treat a variety of malignancies; Hodgkin’s lymphoma, NHL, and MM are the most common indications for this procedure and represent over one-half of all autologous HSCTs.2 Autologous HSCT circumvents the need for histocompatible donors, is associated with lower mortality, and is not restricted to younger patients.3 The use of allogeneic PBPCs is increasing; from years 2002 through 2006, 75% of allogeneic HSCTs performed worldwide used PBPCs as the source of hematopoietic cells rather than bone marrow in adult patients.3
PATHOPHYSIOLOGY
For an allogeneic HSCT, the recipient and the donor are dissimilar genetically unless they are identical twins (a transplant between twins is referred to as a syngeneic HSCT). The transplanted tissue is immunologically active, and thus there is potential for bidirectional graft rejection. In the first scenario, cytotoxic T cells and natural killer (NK) cells belonging to the host (recipient) recognize minor histocompatibility (MHC) antigens of the graft (donor hematopoietic stem cells) and lead to a rejection response. In the second scenario, immunologically active cells in the graft recognize host MHC antigens and elicit an immune response. The former is referred to as host-versus-graft disease and the latter is referred to as GVHD. Host-versus-graft effects are more common in solid-organ transplantation. When host-versus-graft effects occur in allogeneic HSCT, they are referred to as graft failure or rejection,which results in ineffective hematopoiesis (i.e., adequate ANC and/or platelet counts were not obtained). Engraftment is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of greater than 500 cells/mm3 (0.5 × 109/L) and a sustained platelet count of greater than or equal to 20,000/mm3 (20 × 109/L) lasting greater than or equal to three consecutive days without transfusions.4 Therefore, an essential first step for patients eligible for HSCT is finding a human leukocyte antigen (HLA)–compatible graft with an acceptable risk of graft failure and GVHD.
Histocompatibility
Histocompatibility differences between the donor and the recipient necessitate immunosuppression after an allogeneic HSCT because considerable morbidity and mortality are associated with graft failure and GVHD. Rejection is least likely to occur with a syngeneic donor, meaning that the recipient and host are identical (monozygotic) twins. In patients without a syngeneic donor, initial HLA typing is conducted on family members because the likelihood of complete histocompatibility between unrelated individuals is remote. Siblings are the most likely individuals to be histocompatible within a family. The chance for complete histocompatibility occurring in an individual with only one sibling is 25%. Approximately 40% of patients with more than one sibling will have an HLA-identical match. Having a matched-sibling donor is no longer a requirement for allogeneic HSCT because improved immunosuppressive regimens and the National Marrow Donor Program have allowed an increase in the use of unrelated or related matched or mismatched HSCTs. The use of alternative sources of allogeneic hematopoietic cells, such as related donors mismatched at one or more HLA loci or phenotypically (i.e., serologically) matched unrelated donors, has been evaluated.5 Establishment of the National Marrow Donor Program has helped to increase the pool of potential donors for allogeneic HSCT. Through this program, an HLA-matched unrelated volunteer donor might be identified. Recipients of an unrelated graft are more likely to experience graft failure and acute GVHD relative to recipients of a matched-sibling donor. Determination of histocompatibility between potential donors and the patient is completed before allogeneic HSCT. Initially, HLA typing is performed using blood samples and compatibility for class I MHC antigens (i.e., HLA-A, HLA-B, and HLA-C) is determined through serologic and DNA-based testing methods. In vitro reactivity between donor and recipient also can be assessed in mixed-lymphocyte culture, a test used to measure compatibility of the MHC class II antigens (i.e., HLA-DR, HLA-DP, and HLA-DQ). Currently, most clinical and research laboratories are also performing molecular DNA typing using polymerase chain reaction methodology to determine the HLA allele sequence.6
The preparative regimen or GVHD prophylaxis may be altered based on the mismatch between the donor and the recipient. The risk of graft failure decreases with better matches such that those with a class I (i.e., HLA-A, -B, or -C) antigen mismatch have the highest risk of rejection; those with just one class I allele mismatch have a minimal risk. Graft failure does not appear to be associated with mismatch at a single class II antigen or allele.6 GVHD and survival have been associated with disparity for class I and II antigens and alleles.7
Stem Cell Sources
Autologous hematopoietic stem cells are obtained from bone marrow or peripheral blood. The technique for harvesting autologous hematopoietic cells depends on the anatomic source (i.e., bone marrow or peripheral blood). A surgical procedure is necessary for obtaining bone marrow. Multiple aspirations of marrow are obtained from the anterior and posterior iliac crests until a volume with a sufficient number of hematopoietic stem cells is collected (i.e., 600–1,200 mL of bone marrow). The bone marrow then is processed to remove fat or marrow emboli and usually is infused IV into the patient like a blood transfusion.
The shift to the use of PBPCs over bone marrow for autologous HSCT is primarily because of the more rapid engraftment and decreased health care resource use. Because the harvest occurs before administering the preparative regimen, autologous hematopoietic cells must be cryopreserved and stored for future use.
Transplantation with PBPCs essentially has replaced bone marrow transplantation (BMT) as autologous rescue after myeloablative preparative regimens. Autologous PBPCs are obtained by administering a mobilizing agent(s) followed by apheresis, which is an outpatient procedure similar to hemodialysis. Hematopoietic growth factors (HGFs) alone or in combination with myelosuppressive chemotherapy are used for mobilization of autologous PBPCs with similar results. The HGFs granulocyte-macrophage colony-stimulating factor (sargramostim, Leukine) and granulocyte colony-stimulating factor (filgrastim, Neupogen) are used as mobilizing agents. The use of pegylated granulocyte colony-stimulating factor (pegfilgrastim, Neulasta) for mobilization of PBPCs appears more convenient and is promising as a mobilization agent; however, further data are needed regarding graft composition, HSCT outcomes, and donor safety in allogeneic donations before widespread use of this agent can be recommended.
The combination of chemotherapy with an HGF enhances PBPC mobilization relative to HGF alone.1 In addition to treating the underlying malignancy, this approach lowers the risk of tumor cell contamination and the number of apheresis collections required, but there is a greater risk of neutropenia and thrombocytopenia. The HGF is initiated after completion of chemotherapy and is continued until apheresis is complete. Many centers monitor the number of cells that express the CD34 antigen (i.e., CD34+ cells) to determine when to start apheresis. The CD34 antigen is expressed on almost all unipotent and multipotent colony-forming cells and on precursors of colony-forming cells, but not on mature peripheral blood cells. Apheresis is continued daily until the target number of PBPCs per kilogram of the recipient’s weight is obtained. For adult recipients, the number of CD34+ cells correlates with time to engraftment. Lower yield of CD34+ cells is associated with administration of stem cell toxic drugs (e.g., carmustine and melphalan) and intensive prior chemotherapy or radiotherapy.
If patients are unable to obtain an adequate yield of CD34+ cells per kilogram after mobilization attempts fail, then allogeneic transplant may be considered as an alternative. In 2008, plerixafor (Mobozil) was FDA approved for use in combination with granulocyte colony-stimulating factor to mobilize PBPCs for collection and subsequent autologous transplantation in patients with NHL and MM. Plerixafor is an inhibitor of the CXCR4 chemokine receptor which results in more circulating PBPCs in the peripheral blood due to the inability of CXCR4 to assist in anchoring hematopoietic stem cells to the bone marrow matrix. Since administration of plerixafor with granulocyte colony-stimulating factor results in increased yield of CD34+ cells per kilogram compared to granulocyte colony-stimulating factor alone, this combination may serve as an alternative mobilization strategy in patients deemed to be at risk for mobilization failure with conventional methods.
TREATMENT
Desired Outcome
The desired outcome with HSCT is to cure the patient of his or her underlying disease while minimizing the short- and long-term morbidity associated with HSCT.
Nonpharmacologic Therapy
Harvesting, Preparing, and Transplanting Allogeneic Hematopoietic Cells
Bone marrow, PBPCs, and umbilical cord blood can serve as the source of hematopoietic cells. The optimal cell source differs based on the donor and recipient characteristics.
Bone Marrow Harvesting the bone marrow from an allogeneic donor is conducted via the same process as for an autologous HSCT. The harvest occurs on day 0 of the HSCT such that it is infused into the recipient immediately after processing. The marrow may need additional processing if the donor and recipient are ABO-incompatible, which occurs in up to 30% of HSCTs. Red blood cells (RBCs) may need to be removed before infusion into the recipient to prevent immune-mediated hemolytic anemia and thrombotic microangiopathic syndromes.
Peripheral Blood Progenitor Cells The allogeneic donor first undergoes mobilization therapy with an HGF to increase the number of hematopoietic cells circulating in the peripheral blood. The most commonly used regimen to mobilize allogeneic donors is a 4- to 5-day course of filgrastim, 10 to 16 mcg/kg/day, administered subcutaneously, followed by leukopheresis on the fourth or fifth days when peripheral blood levels of CD34+ cells peak. An adequate number of hematopoietic cells usually are obtained with one to two apheresis collections, with the optimal number of CD34+ collected being a minimum of 5 × 106cells/kg of recipient body weight. Higher numbers of CD34+ cells are associated with more rapid neutrophil and platelet engraftment; patients who receive less than 2 × 106/kg CD34+ cells experience a higher mortality rate and a decreased overall survival compared to patients who receive at least 2 × 106/kg CD34+ cells.8 Hematopoietic stem cells obtained from the peripheral blood are processed like bone marrow–derived stem cells and may be infused immediately into the recipient or frozen for future use. In comparison with bone marrow donation, allogeneic PBPC donation leads to quicker hematopoietic recovery. Neutrophil engraftment occurs 2 to 6 days earlier and platelet engraftment occurs approximately 6 days earlier with PBPC grafts compared to bone marrow grafts.9 The donor may experience musculoskeletal pain, headache, mild increases in hepatic enzyme or lactate dehydrogenase levels related to filgrastim administration. Hypocalcemia may also occur owing to citrate accumulation, which decreases ionized calcium concentrations during apheresis.
Allogeneic PBPC grafts contain approximately 10 times more T and B cells than bone marrow grafts. Historically, there has been significant concern that the greater T- and B-cell content of PBPCs could increase the risk of acute and/or chronic GVHD. In patients with a hematologic malignancy who have an HLA-matched sibling donor, a PBPC graft is optimal relative to bone marrow graft because the PBPC graft is associated with quicker neutrophil and platelet engraftment and potentially improved disease-free survival rates.10 Grafts from PBPCs are associated with a similar incidence of acute GVHD but an approximately 20% increase in the incidence of extensive-stage and overall chronic GVHD.10 Similar trends for engraftment and GVHD have been found with unrelated donors.11
Umbilical Cord Blood Transplant with umbilical cord blood offers an alternative stem cell source to patients who do not have an acceptable matched related or unrelated donor. When allogeneic hematopoietic cells are obtained from umbilical cord blood, the cord blood is obtained from a consenting donor in the delivery room after birth and delivery of the placenta. The cord blood is processed, a sample is sent for HLA typing, and the cord blood is frozen and stored for future use. Numerous umbilical cord blood registries exist, with the goal of providing alternative sources of allogeneic stem cells. One potential limitation to the use of umbilical cord blood transplants is the inability to employ donor-lymphocyte infusions in the event of relapse. Engraftment is slower in umbilical cord blood transplants, with a potential lower risk of GVHD and similar survival rates relative to BMT.1,12 In children receiving an umbilical cord blood graft from an unrelated donor, cell dose (e.g., nucleated cells) is related to engraftment, transplant-related morbidity, and survival.13 Although there were initial concerns regarding whether a umbilical cord blood transplant could provide enough nucleated cells to engraft adequately within an adult, there is growing experience to indicate that a umbilical cord blood transplant is feasible when at least 1 × 107 nucleated cells per kilogram of recipient body weight are administered.13 The prospective use of dual umbilical cord units and ex vivo expansion of umbilical cord units to obtain adequate engraftment are methods currently under exploration.
T-Cell Depletion Immunocompetent T lymphocytes may be depleted from the donor bone marrow ex vivo before infusion (referred to as T-cell–depleted hematopoietic cells) into the recipient as a means of preventing GVHD. Depletion of T lymphocytes in donor hematopoietic cells is completed ex vivo using physical (e.g., density-gradient fractionation) and/or immunologic (e.g., antithymocyte globulin [ATG] and CAMPATH-1 antibodies) methods. Functional recovery of T cells in the recipient is delayed, and the risk of Epstein-Barr virus–associated lymphoproliferative disorders is higher with the use of T-cell–depleted bone marrow. The use of T-cell–depleted grafts reduces the incidence of GVHD, but graft failure and relapse are more common. The use of donor lymphocyte infusion in patients who relapse after receiving a T-cell–depleted HSCT is being investigated.
Engraftment After chemotherapy and radiation, pancytopenia lasts until the infused stem cells reestablish functional hematopoiesis. The median time to engraftment is a function of several factors, including the source of stem cells such as PBPCs, which can result in earlier engraftment than bone marrow.9 Myeloablative preparative regimens have significant regimen-related toxicity and morbidity and thus usually are limited to healthy, younger (i.e., usually younger than 50 years) patients. Alternatively, nonmyeloablative transplants are being performed with the hope of curing more patients with cancer by increasing the availability of HSCT with less regimen-related toxicity and by using the graft-versus-tumor effect.1
A delicate balance exists between host and donor effector cells in the bone marrow environment. Residual host-versus-graft effects may lead to graft failure, which is also known as graft rejection. Graft failureis defined as the lack of functional hematopoiesis after HSCT and can occur early (i.e., lack of initial hematopoietic recovery) or late (i.e., in association with recurrence of the disease or reappearance of host cells after initial donor cell engraftment). Engraftment usually is evident within the first 30 days in patients undergoing an HSCT; however, rejection can occur after initial engraftment. Therapeutic options for the treatment of graft rejection are limited; a second HSCT is the most definitive therapy, although the toxicities are formidable.14
Graft-Versus-Tumor Effect
A graft-versus-tumor effect occurs owing to the donor lymphocytes, as supported by three observations after myeloablative allogeneic HSCT; namely, (a) lower relapse rates in patients with GVHD relative to those who did not have GVHD; (b) a higher rate of leukemia relapse after T-cell–depleted, autologous, or syngeneic HSCT, and (c) the effectiveness of donor lymphocyte infusions in reinducing a remission in patients who relapsed after allogeneic HSCT. Rapid taper of immunosuppression in patients with residual disease may induce a graft-versus tumor effect. In donor lymphocyte infusion, lymphocytes are collected from the peripheral blood of the donor and administered to the recipient. Eradication of the recurrent malignancy is due to either specific targeting of the tumor antigens or to GVHD, which may affect cancer cells preferentially. Patients with hematologic malignancies (e.g., CML and AML) and certain solid tumors (e.g., renal cell carcinoma) appear to benefit from a graft-versus-tumor effect. These data gave rise to the use of nonmyeloablative preparative regimens.
Pharmacologic Therapy
Preparative Regimens for HSCT
Examples of commonly used preparative regimens are included in Table 98–2. The nonhematologic toxicity differs based on the preparative regimen administered.
Myeloablative Preparative Regimens In both autologous and allogeneic HSCT, infusion of stem cells circumvents dose-limiting myelosuppression, maximizing the potential value of the steep dose-response curve to alkylating agents and radiation, suppressing the host immune system, and creating space in the marrow compartment to facilitate engraftment. The preparative regimen is designed to eradicate immunologically active host tissues (lymphoid tissue and macrophages) and to prevent or minimize the development of host-versus-graft reactions. Most allogeneic preparative regimens for the treatment of hematologic malignancies contain either cyclophosphamide, radiation, or both. The combination of cyclophosphamide and total-body irradiation (TBI) was one of the first preparative regimens developed and is still used widely today. This regimen is immunosuppressive and has inherent activity against hematologic malignancies (e.g., leukemias and lymphomas). TBI has the added advantage of being devoid of active metabolites that might interfere with the activity of donor hematopoietic cells. In addition, TBI eradicates residual malignant cells at sanctuary sites such as the CNS. Modifications of the cyclophosphamide-TBI preparative regimen include replacing TBI with other agents (e.g., busulfan) or adding other chemotherapeutic or monoclonal agents to the existing regimen in hopes of minimizing long-term toxicities. In the case of a mismatched allogeneic HSCT with a substantially increased chance of graft rejection, ATG also may be added to the preparative regimen to further immunosuppress the recipient.
Table 98–2 Commonly Used Preparative Regimens for HSCTa
The optimal myeloablative preparative regimen remains elusive. The long-term outcomes of busulfancyclophosphamide (BU-CY) and cyclophosphamide-TBI (CY-TBI) in patients with AML and CML, the more common indications for allogeneic HSCT, have been compared in a meta-analysis of four clinical trials.18 Equivalent rates of long-term complications were present between the two preparative regimens, except that there was a greater risk of cataracts with CY-TBI and alopecia with BU-CY. Overall and disease-free survivals were similar in patients with CML, whereas there was a trend for improved disease-free survival with CY-TBI in AML patients. Thus, the preparative regimen can be tailored to the primary disease and to the degree of HLA compatibility.
Nonmyeloablative Preparative Regimens A nonmyeloablative preparative regimen is less toxic than a myeloablative regimen in hopes of being able to offer the benefits of an allogeneic HSCT to more patients. A nonmyeloablative HSCT is based on the concept of donor immune response having a graft-versus-tumor effect.
Because of the severe regimen-related toxicity of a myeloablative preparative regimen, the use of HSCT traditionally was limited to younger patients with minimal comorbidities. Most patients diagnosed with cancer are elderly and thus, myeloablative HSCT could not be offered to a substantial portion of cancer patients. The concept of donor immune response having a graft-versus-tumor effect gave rise to the theory that a strongly immunosuppressive, but not myeloablative, preparative regimen (i.e., a nonmyeloablative transplant may result in a state of chimerism in which the recipient and donor are coexisting. The toxicity and efficacy of nonmyeloablative transplants are being evaluated in patients with malignant and nonmalignant conditions who are not eligible for a myeloablative HSCT.
FIGURE 98–1. Schema for nonmyeloablative transplantation. Recipients (R) receive a nonmyeloablative preparative regimen and an allogeneic HSCT. Initially, mixed chimerism is present with the coexistence of donor (D) cells and recipient-derived normal and leukemia/lymphoma (RL) cells. Donor-derived T cells mediate a graft-versus-host hematopoietic effect that eradicates residual recipient-derived normal and malignant hematopoietic cells. Donor-lymphocyte infusions may be administered to enhance graft-versus-tumor effects. (From Ref. 19.)
A nonmyeloablative preparative regimen allows for development of mixed chimerism (defined as 5% to 95% peripheral donor T cells) between the host and recipient to allow for a graft-versus-tumor effect as the primary form of therapy (Fig. 98–1). Chimerism is assessed within peripheral blood T cells and granulocytes and bone marrow using conventional (e.g., using sex chromosomes for opposite-sex donors) and molecular (e.g., variable number of tandem repeats) methods for same-sex donors.
The nonmyeloablative preparative regimen does not completely eliminate host normal and malignant cells. Donor cells eradicate residual host hematopoiesis, and the graft-versus-tumor effects generally occur after the development of full donor T-cell chimerism. After engraftment, mixed chimerism should be present and is shown by the presence of both donor- and recipient-derived cells. Autologous recovery should occur promptly if the graft is rejected. The intensity of immunosuppression required for engraftment depends on the immunocompetence of the recipient and the histocompatibility and composition of the HSCT.19 More intensive cond it i oning regimens that are required for engraftment in the setting of unrelated-donor- or HLA-mismatched-related HSCT recently have been termed reduced-intensity myeloablative transplants. After chimerism develops, donor-lymphocyte infusion can be administered safely in patients without GVHD to eradicate malignant cells.
Nonmyeloablative preparative regimens typically consist of a purine analog (e.g., fludarabine) in combination with an alkylating agent or low-dose TBI. Adverse effects in the early post-transplant period are decreased because of the lower-intensity preparative regimen, thus making HSCT available to patients who in the past were not healthy or young enough to receive a myeloablative preparative regimen. The risk of GVHD remains with nonmyeloablative transplant; the GVHD prophylaxis regimens are reviewed in the GVHD section below. Presently, nonmyeloablative transplant is not indicated as first-line therapy for any malignant or nonmalignant conditions although research is ongoing. Nonmyeloablative transplantation is being evaluated for cancers sensitive to a graft-versus-tumor effect (e.g., CML and AML), in older patients, or for those with comorbidities who would not be able to tolerate a myeloablative HSCT.
Toxicities and Management of Preparative Regimens
Myelosuppression is a frequent dose-limiting toxicity for antineoplastics when administered in the conventional doses used to treat cancer. However, because myelosuppression is circumvented with hematopoietic rescue in the case of patients receiving HSCT, the dose-limiting toxicities of these myeloablative preparative regimens are nonhematologic and vary with the preparative regimen used. Most patients undergoing HSCT experience toxicities commonly associated with chemotherapy (e.g., alopecia, mucositis, nausea and vomiting, and infertility), albeit these toxicities are magnified in the HSCT population.
Busulfan Seizures Seizures have been reported in both adult and pediatric patients receiving high-dose busulfan for HSCT preparative regimens. Anticonvulsants are used to minimize the risk of seizures. Anticonvulsants are begun shortly before busulfan, with the loading dose completed at least 6 hours prior to the first busulfan dose. Oral loading and maintenance regimens generally are sufficient because target phenytoin concentrations of 10 to 20 mcg/mL (40–79 µmol/L) can be achieved by the peak time of seizure risk. If patients are experiencing significant vomiting or have difficulty maintaining therapeutic phenytoin concentrations, IV phenytoin should be substituted. Benzodiazepines such as lorazepam or clonazepam also have been used for seizure prophylaxis during high-dose busulfan therapy before HSCT. Antiseizure medications usually are discontinued 24 to 48 hours after administration of the last dose of busulfan. Seizures still can occur despite the use of prophylactic anticonvulsants and usually do not result in permanent neurologic deficits.
Adaptive Dosing of Busulfan The considerable interpatient variability in the clearance of both oral and IV busulfan, along with the identified concentration-effect relationships, has led to the adaptive dosing of busulfan. Adjusting the oral busulfan dose to achieve a target concentration minimizes the toxicities of the BU-CY regimen, particularly hepatic sinusoidal obstruction syndrome (formerly referred to as veno-occlusive disease), while improving engraftment and relapse rates. Complete reviews of these relationships after oral busulfan administration are available elsewhere.20 An IV busulfan product, Busulfex, was approved by the FDA in February 1999 in combination with cyclophosphamide as a preparative regimen prior to allogeneic HSCT for CML. Recent data with Busulfex in combination with either cyclophosphamide or fludarabine suggest that therapeutic drug monitoring may be needed.21
Hemorrhagic Cystitis High-dose cyclophosphamide causes moderate to severe hemorrhagic cystitis; acrolein, a metabolite of cyclophosphamide, is the putative bladder toxin. Preventive measures to lower the risk of hemorrhagic cystitis include vigorous hydration, continuous bladder irrigation, and/or concomitant use of the uroprotectant mesna. The American Society of Clinical Oncology (ASCO) Guidelines for the Use of Chemotherapy and Radiotherapy Protectants recommends the use of mesna plus saline diuresis or forced saline diuresis to lower the incidence of urothelial toxicity with high-dose cyclophosphamide in the setting of HSCT.22 The optimal mesna dose with high-dose cyclophosphamide in preparation for myeloablative HSCT is unknown.
Chemotherapy-Induced GI Effects Preparative regimens for myeloablative HSCT result in other end-organ toxicities, such as renal failure and idiopathic pneumonia syndrome. In addition, recipients of myeloablative preparative regimens are at risk for severe GI toxicity, specifically chemotherapy-induced nausea and vomiting (CINV), diarrhea, and mucositis. CINV can be due to administration of highly emetogenic chemotherapy over several days, TBI, and also poor control of CINV prior to HSCT. Thus, patients who are undergoing a myeloablative HSCT should receive a prophylactic corticosteroid with a serotonin antagonist, with higher doses of serotonin antagonists potentially being needed in this patient population. In addition, these patients are at high risk for delayed CINV in the immediate post-transplant period and these issues should be addressed accordingly as per published clinical practice guidelines.23
Diarrhea is also an adverse effect experienced by a majority of patients undergoing HSCT. Chemotherapy-induced diarrhea occurs due to the effects of the preparative regimen, which results in inflammation and damage to the cells lining the GI tract. Diarrhea caused by the preparative regimen is usually apparent within the first week after the initiation of chemotherapy and/or radiation. Treatment strategies for chemotherapy-induced diarrhea include the administration of antidiarrheals after excluding infectious causes of diarrhea and the prevention of dehydration.
Virtually all patients receiving a myeloablative preparative regimen experience severe mucositis owing to its effects on rapidly dividing cells of the oral epithelium and subsequent inflammation of the oropharyngeal cavity. Routine oral care protocols are indicated to reduce the severity of mucositis, which may onset within the first week of HSCT and persist for up to approximately two weeks. Recently, the FDA approved palifermin (Kepivance), a recombinant human form of keratinocyte growth factor that specifically acts on epithelial cells. In recipients of an autologous HSCT, palifermin lowered the incidence and average duration of severe oral mucositis as well as the incidence and duration of opioid use.24 Patients still may require parenteral opioid analgesics for pain relief owing to mucositis and total parenteral nutrition may be necessary to prevent the development of nutritional deficiencies.
Sinusoidal Obstruction Syndrome Hepatic sinusoidal obstruction syndrome is a life-threatening complication that may occur secondary to preparative regimens or radiation. The pathogenesis of sinusoidal obstruction syndrome is not understood completely, although several mechanisms have been proposed. The key event appears to be endothelial damage caused by the preparative regimen. The primary site of the toxic injury is the sinusoidal endothelial cells; the endothelial damage initiates the coagulation cascade, induces thrombosis of the hepatic venules, and eventually leads to fibrous obliteration of the affected venules.25
The clinical manifestations of sinusoidal obstruction syndrome are hyperbilirubinemia, jaundice, fluid retention, weight gain, and right upper quadrant abdominal pain. To make a clinical diagnosis of sinusoidal obstruction syndrome, these features must occur in the absence of other causes of post-transplant liver failure, including GVHD, viral hepatitis, fungal abscesses, or drug reactions. Most cases of sinusoidal obstruction syndrome occur within three weeks of HSCT and clinical diagnosis can be confirmed histologically via liver biopsy.
Patients with mild sinusoidal obstruction syndrome have an excellent prognosis, whereas those with more severe disease (i.e., bilirubin greater than 20 mg/dL [342 µmol/L] or weight gain greater than 15%) have a high mortality rate. Pretransplant risk factors for sinusoidal obstruction syndrome include a mismatched or unrelated graft, increased age, prior abdominal radiation or stem cell transplant, and increased transaminases prior to HSCT.25 Interpatient variability in the metabolism and clearance of the chemotherapy (i.e., busulfan and cyclophosphamide) used within the preparative regimen also may be associated with a poor outcome, although the relationships vary within the various preparative regimens.20 The association of sinusoidal obstruction syndrome with busulfan concentrations is discussed in the section on adaptive dosing of busulfan. Preliminary data suggest that IV busulfan may be associated with a lower risk of sinusoidal obstruction syndrome, although more data are needed.26 Use of ursodiol, unfractionated heparin, or low molecular weight heparin have been associated with a lower incidence of sinusoidal obstruction syndrome in a limited number of small, randomized studies and may be recommended for sinusoidal obstruction syndrome prophylaxis.25
The mainstay of treatment for established sinusoidal obstruction syndrome is supportive care aimed at sodium restriction, increasing intravascular volume, decreasing extracellular fluid accumulation, and minimizing factors that contribute to or exacerbate hepatotoxicity and encephalopathy. Recombinant tissue plasminogen activator administered with or without heparin has been investigated for treatment of sinusoidal obstruction syndrome but life-threatening risk of bleeding precludes any potential benefit.25 Defibrotide, an oligonucleotide with antithrombotic, anti-ischemic, and anti-inflammatory activity, has shown promising results in the treatment of sinusoidal obstruction syndrome in clinical trials.25
Myelosuppression and Hematopoietic Growth Factor Use Hematopoietic growth factors (HGFs) may be administered in order to mobilize PBPCs prior to an HSCT, to hasten hematopoietic recovery during the period of aplasia after an autologous HSCT, and to stimulate hematopoietic recovery in cases where the patient fails to engraft.27
Autologous HSCT is associated with profound aplasia owing to the myeloablative preparative regimen. Aplasia typically lasts 7 to 14 days after an autologous PBPC transplant. During this period of aplasia, patients are at high risk for complications such as bleeding and infection. Filgrastim and sargramostim exert their effects by stimulating the proliferation of committed progenitor cells and accelerating recovery on hematopoiesis. Once engraftment occurs HGFs may be discontinued. The anatomic source of hematopoietic cells predicts the degree of benefit, with the greatest benefit reached when bone marrow is the graft source. With autologous PBPC transplant, the effect of HGF on neutrophil recovery is variable.
The use of HGF after allogeneic HSCT—whether from bone marrow or PBPC grafts—is controversial. The amount of data with sargramostim is limited in this setting; data with filgrastim have shown more rapid neutrophil but slower platelet engraftment in those receiving grafts from bone marrow or PBPCs.28 The effects of post-HSCT filgrastim use on acute and chronic GVHD have been conflicting, with either no effect or increases in both the incidence of acute and chronic GVHD and treatment-related mortality.28 Thus, there is little reason to treat allogeneic BMT with filgrastim as prophylaxis after HSCT.
Graft Failure A delicate balance between host and donor effector cells in the bone marrow is necessary to ensure adequate engraftment because residual host-versus-graft effects may lead to graft rejection. The incidence of graft rejection is higher in patients with aplastic anemia and those undergoing HSCT with histoincompatible marrow or T-cell–depleted marrow.1 Graft rejection is uncommon in leukemia patients receiving myeloablative preparative regimens with a histocompatible allogeneic donor.
Therapeutic options for the treatment of graft rejection or graft failure are limited. A second HSCT is the most definitive therapy, although the associated complications and toxicities may preclude its use. Graft rejection is best managed with immunosuppressants such as ATG. Primary graft failure occasionally can be treated successfully using HGFs, although patients who received purged autografts are less likely to respond.
Clinical Presentation and Diagnosis of Sinusoidal Obstructive Syndrome
General
• Sinusoidal obstructive syndrome (SOS) usually occurs within the first 3 weeks after HSCT
• Busulfan, cyclophosphamide, pretransplant exposure to gemtuzumab, TBI-containing preparative regimens, and pretransplant abnormalities in liver function tests may increase risk for SOS
Symptoms
• Patients may complain of weight gain and abdominal pain
Signs
• Fluid retention: Weight gain due to ascites greater than 2% compared to pretransplant weight
• Hepatomegaly: May result in right upper quadrant pain
• Hepatic: Jaundice due to hyperbilirubinemia defined as a bilirubin greater than 2 mg/dL (34.2 µmol/L)
Laboratory Tests
• Hepatic: Elevation of bilirubin, alkaline phosphatase, and γ-glutamyltransferase (GGT)
• Hematologic: CBC with differential may reveal thrombocytopenia, elevated plasminogen activator-1 levels, decreased antithrombin III, protein C, and protein S
Other Diagnostic Tests
• Reversal of blood flow in portal and hepatic veins on Doppler ultrasonography
• Liver biopsy for pathologic review
Patient Encounter 1
LL, a 47-year-old male, was diagnosed with high-risk diffuse large cell B-cell non-Hodgkin’s lymphoma (NHL) 12 months ago. LL had a complete response to his initial treatment of six cycles of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). LL is participating in a clinical trial and is randomized to receive a myeloablative autologous HSCT: TBI days –8 to –5, etoposide day –4, rest day –3, cyclophosphamide day –2, rest day –1, with infusion of autologous PBPC on day 0.
What nonhematologic toxicity should be monitored? How long should the patient be monitored for these toxicities?
What pharmacologic management is necessary during administration of the preparative regimen?
It is day +1, and LL has a WBC with differential of 0/mm3, ANCs 0/mm3 (0 × 109/L), platelets 30,000/mm3 (30 × 103/µL), and hemoglobin 9 g/dL (5.6 mmol/L). Renal clearance and liver function are within normal limits. Vital signs are bp 130/80, RR 18, and T 39°C (102.2°F). Medications include meropenem 2 g IV every 8 hours and filgrastim 480 mcg subcutaneously daily.
Develop a monitoring plan for LL’s hematologic function. Identify your treatment goals for LL’s hematologic function.
Graft-Versus-Host Disease
GVHD is caused by the activation of donor lymphocytes, leading to immune damage to the skin, gut, and liver in the recipient. Immune-mediated destruction of tissues, a hallmark of GVHD, disrupts the integrity of protective mucosal barriers and thus provides an environment that favors the establishment of opportunistic infections. An immunosuppressive regimen is administered to prevent GVHD in recipients of an allogeneic graft; this regimen is based on the type of preparative regimen and the source of the graft. The combination of GVHD and infectious complications are leading causes of mortality for allogeneic HSCT patients. GVHD is divided into two forms (i.e., acute and chronic) based on clinical manifestations. Traditionally, the boundary between acute and chronic GVHD was set at 100 days after HSCT; however, more recent definitions hinge upon different clinical symptoms rather than the time of onset.29
Acute GVHD The degree of histocompatibility between donor and recipient is the most important factor associated with the development of acute GVHD. The pathophysiology for acute GVHD is a multistep phenomenon, including (a) the development of an inflammatory milieu that results from host tissue damage induced by the preparative regimen, (b) both recipient and donor antigen-presenting cells and inflammatory cytokines triggering activation of donor-derived T cells, and (c) the activated donor T cells mediate cytotoxicity through a variety of mechanisms, which leads to tissue damage characteristic of acute GVHD.30
Clinically relevant grades II to IV acute GVHD occurs in up to 30% of HLA-matched sibling grafts and 50% to 80% of HLA-mismatched sibling or HLA-identical unrelated donors.30 Other factors that increase the risk of acute GVHD include increasing recipient or donor age (older than 20 years), female donor to a male recipient, and mismatches in minor histocompatibility antigens in HLA-matched transplants.30 T-cell depletion or receipt of an umbilical cord blood graft appears to lower the risk of acute GVHD.1
Clinical Presentation and Staging of Acute GVHD Acute GVHD must be distinguished accurately from other causes of skin, liver, or GI toxicity in the HSCT patient. Other causes of toxicities affecting the skin, liver, or GI tract may include a drug reaction or an infectious process. A staging system based on clinical criteria is used to grade acute GVHD (Fig. 98–2). The severity of organ involvement is scored on an ordinal scale from 0 (no symptoms) to IV (severe symptoms), and then an overall grade is established based on the number and extent of involved organs.
Immunosuppressive Prophylaxis of Acute GVHD GVHD is a leading cause of morbidity and mortality after allogeneic HSCT and thus, efforts have focused on preventing acute GVHD. The donor graft and preparative regimen influence the prophylactic regimen for acute GVHD, with two approaches having been taken by clinicians over time. One approach involves T-cell depletion, which was discussed more fully in the section on T-cell depletion earlier. The more common method is to use two-drug immunosuppressive therapy that typically consists of a calcineurin inhibitor (i.e., cyclosporine or tacrolimus) with methotrexate after myeloablative HSCT and a calcineurin inhibitor with mycophenolate mofetil after nonmyeloablative HSCT.
After myeloablative conditioning, acute GVHD rates have been similar or lower with triple-drug regimens, but infectious complications are higher and overall survival is similar to that with two-drug regimens.31 With the two-drug regimen, a short-course of low-dose methotrexate (e.g., on days +1, +3, +6, and day +11) is used and thus, can delay engraftment, increase the incidence and severity of mucositis, and cause LFT elevations. The methotrexate dose is reduced in the setting of renal or liver impairment. The calcineurin inhibitors (i.e., cyclosporine and tacrolimus) should be initiated before donor cell infusion (e.g., day –1) when used for GVHD prophylaxis. This schedule is recommended because of the known mechanism of action of cyclosporine, which entails blocking the proliferation of cytotoxic T cells by inhibiting production of T-helper-cell-derived interleukin 2 (IL-2). Administering cyclosporine before the donor cell infusion allows inhibition of IL-2 secretion to occur before a rejection response has been initiated. Studies comparing cyclosporine and tacrolimus in combination with methotrexate have shown that tacrolimus administration is associated with a lower incidence of grade II to IV acute GVHD and a similar incidence of chronic GVHD, but variable effects on overall survival.32,33 Because of the mucosal toxicity from myeloablative preparative regimens, the calcineurin inhibitors are administered IV until the GI toxicity from a myeloablative preparative regimen has resolved (e.g., for 7–21 days). Most centers use a 1:2 to 1:3 ratio for conversion of IV to oral cyclosporine with the Neoral formulation; the ratio for tacrolimus conversion from IV to oral is often 1:4. Different conversion ratios for IV to oral regimens may be used when patients are receiving concomitant medications that affect cytochrome P-450 3A or p-glycoprotein; these pathways are involved in the metabolism and transport of the calcineurin inhibitors (e.g., voriconazole).
FIGURE 98–2. Clinical grading of acute GVHD. The left panel summarizes the grading of one organ system; the right panel shows the overall clinical grade. With grade I, only the skin can be involved. With more extensive involvement of the skin or involvement of liver and intestinal tract and impairment of the clinical performance status, either alone or in any combination, the severity grade advances from II to IV. (From Perkins JB, Yee GC. Hematopoietic stem cell transplantation. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;2005:2552.)
Clinical Presentation and Diagnosis of Acute GVHD
General
• Patients may present with any or all of the following: skin rash, GI complaints, or jaundice
• Signs and symptoms present after engraftment when donor lymphoid elements begin to proliferate
Symptoms
• Patients may complain of nausea, vomiting, bloody diarrhea or itching from skin rash
Signs
• Skin: Maculopapular skin rash on the face, truck, extremities, palms, soles, and ears which may progress to generalized total-body erythroderma, bullous formation, and skin desquamation
• GI: Ileus, malnutrition, dehydration and electrolyte abnormalities due to nausea, vomiting, and diarrhea
• Hepatic: Jaundice due to hyperbilirubinemia
Laboratory Tests
• Hepatic: Elevation of bilirubin, alkaline phosphatase, and hepatic transaminases
• GI: send stool for bacterial, viral, and parasitic cultures to rule out infectious causes
Other Diagnostic Tests
• Biopsy of affected site for pathologic review
Prophylaxis of acute GVHD for nonmyeloablative preparative regimens is varied, but a calcineurin inhibitor with either methotrexate or mycophenolate mofetil is used.3 To date, trials evaluating the optimal acute GVHD prophylaxis regimen have not been conducted.
Adaptive Dosing of the Calcineurin Inhibitors Most HSCT centers have their own standardized approach to dose adjust the calcineurin inhibitors cyclosporine and tacrolimus to target concentration ranges. Cyclosporine trough concentrations are associated with the acute GVHD and nephrotoxicity. Cyclosporine trough concentrations usually are maintained between 150 and 400 ng/mL (125–333 nmol/L) in patients undergoing allogeneic HSCT. Tacrolimus trough concentrations are targeted to a range of 10 to 20 ng/mL (10–20 mcg/L).34 Dosage adjustments to either calcineurin inhibitor also should be made for elevated serum creatinine (SrCr) regardless of their serum concentrations. Nephrotoxicity can occur despite low or normal concentrations of the calcineurin inhibitor cyclosporine and may be a consequence of other drug- or disease-related factors known to influence the development of nephrotoxicity (e.g., genetic risk factors, concurrent use of other nephrotoxic agents, and sepsis). Careful monitoring for drug interactions via cytochrome P-450 3A4 and p-glycoprotein is also warranted. The calcineurin inhibitor doses are adjusted based on serum drug levels and the calculated creatinine clearance. Common adverse effects to these agents include neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and/or nephrotoxicity (which may lead to an impaired clearance of methotrexate).
Tapering schedules for the calcineurin inhibitors after myeloablative HSCT vary widely. In patients without GVHD, the calcineurin inhibitor doses usually are stable to day +50 and then are tapered slowly with the intent of discontinuing all immunosuppressive agents by 6 months after HSCT. By this time, immunologic tolerance has developed and patients no longer require immunosuppressive therapy. There is a paucity of information regarding the optimal duration of GVHD prophylaxis after nonmyeloablative HSCT, with data suggesting that a two month duration of cyclosporine with a four month taper lowers the rate of severe acute GVHD.35
Treatment of Acute GVHD The most effective way to treat GVHD is to prevent its development. Corticosteroids, usually in combination with a calcineurin inhibitor, are the first-line therapy for treatment of established acute GVHD. Corticosteroids indirectly halt the progression of immune-mediated destruction of host tissues by blocking macrophage-derived IL-1 secretion. IL-1 is a primary stimulus for T-helper-cell-induced secretion of IL-2, which, in turn, is responsible for stimulating proliferation of cytotoxic T lymphocytes. The recommended dosage of methylprednisolone in this setting is 2 mg/kg/day; there is no advantage to higher corticosteroid doses (i.e., 10 mg/kg/day).30A partial or complete response is seen in approximately 50% of patients treated with corticosteroids. Once a clinical improvement occurs, there is no consensus on the optimal method for tapering the corticosteroids. Patients with steroid-refractory acute GVHD have a poor prognosis and a number of medications are being studied for salvage therapy.
Chronic GVHD Occurring in 20% to 70% of HSCT recipients surviving over 100 days, chronic GVHD is the most frequent and serious late complication of allogeneic HSCT.36 Chronic GVHD is the major cause of nonrelapse mortality and morbidity. The clinical course of chronic GVHD is multifaceted, involving almost any organ in the body and its symptoms resemble autoimmune and immunologic disorders (e.g., scleroderma). Chronic GVHD symptoms usually present within 3 years of allogeneic HSCT and often are preceded by acute GVHD.29 Traditionally, the boundary between acute and chronic GVHD was set at 100 days after HSCT; however, more recent definitions hinge on different clinical symptoms rather than the time of onset.36 A consensus document regarding the diagnosis and scoring of chronic GVHD has been published recently which proposes a clinical scoring system to describe chronic GVHD as opposed to historical descriptions of chronic GVHD which described the phenomenon as being “limited” versus “extensive” in nature.29 The diagnosis of chronic GVHD requires (a) distinction from acute GVHD, (b) presence of at least one diagnostic clinical sign of chronic GVHD or presence of at least one distinctive manifestation confirmed by pertinent biopsy or other relevant tests, and (c) exclusion of other possible diagnoses.
Prevention and Treatment of Chronic GVHD Chronic GVHD is not a continuation of acute GVHD and separate approaches are needed for its prevention and management. Prevention of chronic GVHD through prolonged use of immunosuppressive medications has been unsuccessful.36 Thus, its prevention is focused on minimization of factors associated with higher rates of chronic GVHD. Several recipient, donor, and transplant factors are relevant. Recipient risk factors that are not modifiable include older age, certain diagnoses (e.g., chronic myeloid leukemia), and lack of an HLA-matched donor. Modifiable factors that may lower the risk of chronic GVHD include selection of a younger donor, avoidance of a multiparous female donor, use of umbilical cord blood or bone marrow grafts rather than PBPCs, and limitation of CD34+ and T-cell dose infused.36 Development of acute GVHD is a major predictor for chronic GVHD, with 70% to 80% of those with grade II to IV acute GVHD developing chronic GVHD.36
Relative to no treatment, survival in those with chronic GVHD is improved by extended corticosteroid therapy; however, multiple long-term adverse effects are associated with corticosteroid use. The prednisone dosage is 1 mg/kg/day administered orally in divided doses for 30 days and then slowly converted to an alternate-day therapy by increasing the “on day” and decreasing the “off day” dose until a total of 2 mg/kg/day on alternate days is administered. Once therapy is initiated, one to two months may pass before an improvement in clinical symptoms is noted and therapy usually is continued for 9 to 12 months. Therapy can be tapered slowly after resolution of signs and symptoms of chronic GVHD. If a flare of chronic GVHD occurs during the tapering schedule or after therapy is discontinued, immunosuppressive therapy is restarted. Other potential approaches for patients who are refractory to initial therapy include etanercept (Embrel), infliximab (Remicade), mycophenolate mofetil (Cellcept), rituximab (Rituxan), extended use of calcineurin inhibitors, or extracorporeal photochemotherapy.36 When immunosuppressive therapy is administered for long periods, the patient must be monitored closely for chronic toxicity. Cushingoid effects, aseptic necrosis of the joints, and diabetes can develop with long-term corticosteroid use. Other severe complications include a high incidence of infection with encapsulated organisms and atypical pathogens such as Pneumocystis jiroveci, cytomegalovirus (CMV), and varicella-zoster virus (VZV).
Patient Encounter 2
AS is a 65-year-old female with relapsed acute myeloid leukemia. PMH is significant for type II diabetes and renal hypertension. She is day +1 from a nonmyeloablative HSCT with fludarabine (30 mg/m2/day IV for 3 days) and total-body irradiation (TBI) preparative regimen and a graft from a full HLA-matched sibling.
What preventive measures are needed for the complications of HSCT?
How would you monitor AS for GVHD?
What would you recommend for treatment of GVHD?
Infectious Complications
Recipients of HSCT are at higher risk of bacterial, viral, and fungal infections and usually receive a prophylactic or preemptive regimen to minimize the morbidity and mortality owing to infectious complications. After myeloablative and nonmyeloablative HSCT, opportunistic infections are a major source of morbidity and mortality. There are three periods of infectious risks, early (days 0–30), middle (engraftment to day +100), and late (after day +100). From days 0 to 30 after HSCT, particularly for patients undergoing myeloablative HSCT, the primary pathogens are aerobic bacteria, Candida, and herpes simplex virus (HSV). Respiratory viruses such as respiratory syncytial virus (RSV), influenza, adenovirus, and parainfluenza virus are recognized increasingly as pathogens causing pneumonia, particularly during community outbreaks of infection with these organisms. To reduce potential exposure of HSCT recipients to such respiratory viruses, visitors and staff members with respiratory signs and symptoms of a viral illness may not be allowed direct contact with patients.
The second period of infectious risk occurs after engraftment to post-transplant day +100. Bacterial infections are still of concern, but pathogens such as CMV, adenovirus, and Aspergillus species are common. A common manifestation of infection is interstitial pneumonitis (IP), which can be caused by CMV, adenovirus, Aspergillus, and P. jiroveci. Suppression of the immune system from acute GVHD and corticosteroids contributes to the risk of such infections during this period. Therefore, patients undergoing nonmyeloablative transplant who are receiving corticosteroids to treat GVHD can be expected to have a similar risk for infection as those undergoing myeloablative HSCT.37 Invasive fungal infections over the first year after HSCT occur at a similar rate in nonmyeloablative transplant when compared with historical controls receiving a myeloablative preparative regimen.38
During the late period (after day +100), the predominant organisms are the encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis), fungi, VZV. The encapsulated organisms commonly cause sinopulmonary infections. The risk of infection during this late period is increased in patients with chronic GVHD as a result of prolonged immunosuppression.
Prevention and Treatment of Bacterial and Fungal Infections Due to the need to administer chemotherapy, blood products, antibiotics, and other adjunctive medications, the placement of a semipermanent double- or triple-lumen central venous catheter is necessary prior to HSCT. However, the indwelling IV central catheters put HSCT recipients at increased risk for Staphylococcus infections.
Between the time of administration of the preparative regimen and successful engraftment, allogeneic myeloablative HSCT patients undergo a period of pancytopenia that can last from two to six weeks. During this time, multiple transfusions of blood and platelet products are needed to support the patient through the pancytopenic period. Transfusions with multiple blood products place patients at risk for blood product–derived infection (e.g., CMV and hepatitis) and sensitization to foreign leukocyte HLA antigens (i.e., alloimmunization) which can lead to immune-mediated thrombocytopenia. Thus, blood product support in the myeloablative allogeneic HSCT patient must incorporate strategies that reduce the risk of viral infection and alloimmunization by minimizing the number of pretransplant infusions, using of single-donor (rather than pooled-donor) blood products, irradiating blood products in order to inactivate T cells in the product, or filtering blood products with leukocyte-reduction filters. The risk of infection in autologous and allogeneic myeloablative HSCT patients is minimized through a variety of measures. Private reverse isolation rooms equipped with positive-pressure HEPA filters and adherence to strict hand-hygiene techniques reduce the incidence of bacterial and fungal infections.4 To reduce exposure to exogenous sources of bacteria, immunosuppressed-patient (low-microbial) diets are used and live plants or flowers are not allowed in the patient’s room. Chemotherapy-induced mucosal damage serves as a portal of entry for many organisms (e.g., Streptococcus viridans, aerobic gram-negative bacteria, and fungi) into the bloodstream. The mouth should be kept clean by using frequent (at least four to six times daily) mouth rinses with sterile water, normal saline, or sodium bicarbonate.4 Soft toothbrushes may be employed for oral hygiene during periods of neutropenia and thrombocytopenia. The risk of infection is also reduced by aggressive use of antibacterial, antifungal, and antiviral therapy both prophylactically and for the treatment of documented infection. The antibacterial prophylactic regimens vary substantially among HSCT centers. Some HSCT centers use a prophylactic fluoroquinolone (e.g., levofloxacin) on admission for HSCT and then switch to a broad-spectrum IV antibiotic (e.g., meropenem) when the patient experiences his or her first neutropenic fever. Although fluoroquinolones reduce the incidence of gram-negative bacteremia, they have not been shown to affect mortality; the possibility of developing clostridium difficile-associated diarrhea exists with fluoroquinolone use and infectious causes should be ruled out if diarrhea occurs.4 Concerns with fluoroquinolone use in the prophylactic setting during HSCT include the emergence of resistant organisms and an increased risk for streptococcal infection.4 Broad-spectrum IV antibiotics should be initiated immediately at the time of the first neutropenic fever under the treatment guidelines endorsed by the Infectious Disease Society of America for management of fever of unknown origin in the neutropenic host.39
Prevention of HSV and VZV Patients who are HSV-antibody seropositive before HSCT are at high risk for reactivation of their HSV infection. Acyclovir is highly effective in preventing HSV reactivation, and thus, prophylactic acyclovir is used commonly in HSV-seropositive patients who are undergoing an allogeneic or autologous HSCT.4 In the setting of HSV prophylaxis, dosing regimens for prophylactic acyclovir vary widely and most centers discontinue acyclovir at the time of hematopoietic recovery.4 Valacyclovir (Valtrex), a prodrug of acyclovir with improved bioavailability, may allow for adequate serum concentrations to prevent HSV in patients undergoing HSCT as well.
In those with a history of VZV infection, VZV disease occurs in 30% of allogeneic HSCT recipients.40 The appropriate duration of VZV prophylaxis is controversial. Although VZV infections are reduced by prophylactic acyclovir administered from one to two months until one year after HSCT, the risk of VZV persists in those on continued immunosuppression.40
Prevention and Preemptive Therapy of CMV Disease After allogeneic HSCT, CMV disease is common and has high morbidity and mortality rates. Allogeneic patients are at greater risk than autologous recipients primarily because the latter more efficiently reconstitute their immune system after transplantation. However, autologous HSCT recipients who are CMV-seropositive before HSCT are at risk for CMV infection and prophylaxis should be considered in a select minority of patients.4 Infection due to CMV is usually asymptomatic and develops when CMV replication occurs primarily in body fluids such as the blood (viremia), bronchoalveolar fluid, or urine (viruria). Cytomegalovirus disease is symptomatic and occurs when the virus invades an organ or tissue. Pneumonia and gastritis are the most common types of CMV disease after allogeneic HSCT. The presence of a CMV infection substantially increases the risk for developing invasive CMV disease. Strategies to prevent CMV infection have resulted in dramatic reductions in the incidence of CMV disease.
Primary CMV can be prevented with CMV seromatching, which includes transplanting PBPCs or bone marrow from CMV-seronegative donors and infusing CMV-negative blood products to CMV-negative recipients. Antivirals are essential in those who are CMV-seropositive or have a CMV-seropositive graft, with two available approaches to minimize the morbidity associated with CMV. The first is universal prophylaxis, in which ganciclovir is begun at the time of engraftment and is continued until approximately day +100. The second approach is called preemptive therapy, for which ganciclovir is selectively administered based on detection of CMV reactivation.
Preemptive therapy is the most commonly used strategy for preventing CMV disease after allogeneic HSCT because ganciclovir is used only in patients at highest risk for developing CMV disease. This approach minimizes administration of ganciclovir, thus lowering the risk of ganciclovir-induced neutropenia with its subsequent increased risk of invasive bacterial and fungal infections. With a decreased risk of ganciclovir-induced neutropenia, fewer interruptions of ganciclovir therapy due to myelosuppression may occur with a preemptive approach and the subsequent use of filgrastim to maintain adequate neutrophil counts may be limited. Preemptive therapy hinges on the ability to detect early reactivation of CMV using shell vial cultures, assays of blood for CMV antigens (such as pp65), or viral nucleic acids using polymerase chain reaction (PCR). Antigenemia-based preemptive therapy has similar efficacy in preventing CMV disease as universal ganciclovir prophylaxis and preemptive therapy also has been associated with a significant reduction in CMV mortality. Preemptive strategies typically use an induction course of ganciclovir for 7 to 14 days, followed by a maintenance course until 2 or 3 weeks after the last positive antigenemia result or until day +100 after HSCT.4 Oral valganciclovir (Valcyte) is an orally bioavailable prodrug of ganciclovir that is converted to ganciclovir in vivo after intestinal absorption and has been used for preemptive therapy. Foscarnet may be given as an alternative to ganciclovir to prevent CMV disease, although its use is complicated by nephrotoxicity and electrolyte wasting.
Fungal Infections
Prevention of Fungal Infections. The widespread use of fluconazole prophylaxis since the early 1990s has led to a significant decline in the morbidity and mortality associated with invasive candidiasis in HSCT recipients. However, invasive aspergillosis (IA), zygomycetes, and fluconazole-resistant Candida species, such as C. krusei and C. glabrata, have increased markedly in incidence.41 Itraconazole, another azole antifungal agent, has better in vitro activity against fluconazole-resistant fungi (e.g., Aspergillus and some Candida spp.) and is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic HSCT; however, itraconazole is used less often due to frequent GI side effects and concern for potential drug interactions.42 Posaconazole (Noxafil) is a triazole antifungal that has recently been FDA approved for prophylaxis against IA in HSCT patients with GVHD and is now the recommended prophylactic agent for this subset of HSCT patients on immunosuppression.43Posaconazole should be given with food for adequate absorption. Micafungin (Mycamine), an agent of the newer class of antifungals known as the echinocandins, has been FDA approved for prophylaxis of Candida infections in patients undergoing HSCT.
Risk Factors for Invasive Mold Infections. Invasive mold infections (e.g., Aspergillus spp., Fusarium spp., Zygomycetes, and Scedosporium spp.) are an increasing cause of morbidity and death after allogeneic and autologous HSCT. It has been estimated that up to one-third of febrile neutropenic patients who do not respond to antibiotic therapy after one week are harboring a fungal infection.39 In HSCT recipients, risk factors for invasive fungal infections include (a) previous history of IA; (b) recipient factors including older age, CMV seropositivity, and type of stem cell transplant; (c) treatment factors (e.g., a fludarabine-based preparative regimen); (d) transplant complications (e.g., prolonged neutropenia, graft failure, and higher-grade GVHD); and (e) host factors (e.g., diabetes, iron overload).44 Infections with Aspergillus species remain the most common mold infections diagnosed in the HSCT population and optimal treatment must be promptly initiated if indicated.
Treatment of Invasive Aspergillosis. Early diagnosis and initiation of appropriate therapy may reduce the high mortality of IA. Outcomes also depend on recovery of the recipient’s immune system and reduction of immunosuppression. Diagnosis is difficult with the use of CT scans and cultures. Research is ongoing to evaluate the benefit of using nonculture-based methods, such as galactomannan and (1,3)-β-d-glucan antigen detection, which are components of the fungal cell wall that can be detected by commercially available assays.
Practice guidelines are available for the treatment of invasive Aspergillus infections in immunocompromised patients.43 Available mold-active agents include triazole antifungals (itraconazole, voriconazole, and posaconazole), echinocandins (caspofungin, micafungin, and anidulafungin), and amphotericin B formulations. Historically, conventional amphotericin B (c-AmB) has been considered the “gold standard” antifungal therapy for any IA infection although the majority of responders eventually died of their infection. Significant toxicity occurs with c-AmB administration, with nephrotoxicity, electrolyte wasting (e.g., potassium and magnesium), and infusion-related reactions being the most troublesome side effects. Lipid analogs of amphotericin B were developed with the specific intent of reducing nephrotoxicity associated with conventional amphotericin B while retaining therapeutic efficacy, albeit at a higher acquisition cost.45 These products include amphotericin B lipid complex (Abelcet, ABLC), liposomal amphotericin B (Ambisome, L-Amb), and amphotericin B colloidal dispersion (Amphotec, ABCD).
With significant toxicity limiting the overall utility of conventional amphotericin B, voriconazole (Vfend) was compared to c-AmB for treatment of IA. For initial therapy of IA, voriconazole had higher response and survival rates than c-AmB and is now considered the primary option for patients with IA.46 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive alternative. Common toxicities reported with voriconazole include infusion-related reactions, transient visual disturbances, skin reactions, elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache. In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors); concomitant use of voriconazole and sirolimus should be carefully monitored. Due to pharmacokinetic and pharmacodynamic relationships, antifungal therapy with triazole antifungals such as voriconazole may be optimized for efficacy and toxicity through the practice of therapeutic monitoring of serum levels of these agents.43
In patients who have failed initial therapy (i.e., salvage), lipid formulations of amphotericin products, itraconazole, posaconazole, or an agent from the echinocandin class may be used. The echinocandins have a unique target for their antifungal activity—specifically, β-1,3-glucan synthase, an enzyme that produces an important component of the fungal cell wall. Three agents in the echinocandin class (caspofungin, micafungin, and anidulafungin) are currently FDA approved and are only available as IV formulations. Caspofungin (Cancidas) is the only member of the echinocandin class approved for use in pediatric patients, for patients with persistent neutropenic fever, and for patients with probable or proven IA that is refractory to or intolerant of other approved therapies. The most common adverse effects observed include increased liver aminotransferase enzyme levels, mild to moderate infusion reactions and headache, with a smaller number of patients experiencing dermatologic reactions related to histamine release (e.g., flushing, erythema, and wheals).
The optimal duration of appropriate antifungal therapy for treating IA is individualized to the reconstitution of the patient’s immune system and his or her response to antifungal treatment. Most clinicians will continue aggressive antifungal therapy until the infection has stabilized radiographically and may continue with less aggressive “maintenance” therapy (e.g., oral voriconazole) until immunosuppression is lessened or completed. In general, it is not uncommon to require several months of antifungal therapy to treat IA.
P. jiroveci After allogeneic HSCT, prophylaxis for P. jiroveci (formerly P. carinii) pneumonia (PCP) is used because Pneumocystis is a common infection with a high mortality rate if left untreated. The optimal prophylactic regimen in this setting is unclear, with most centers using cotrimoxazole for 6 to 12 months after HSCT.4 Aerosolized or IV pentamidine and oral dapsone are alternatives for patients who are allergic to sulfa drugs or who do not tolerate cotrimoxazole. Because PCP most often occurs after engraftment, cotrimoxazole usually is begun after neutrophil recovery because of its myelosuppressive effects. Patients receiving prophylactic cotrimoxazole should be monitored closely for rash and unexplained neutropenia or thrombocytopenia. Cotrimoxazole usually is avoided on days of methotrexate administration because the sulfonamides can displace methotrexate from plasma binding sites and decrease renal methotrexate clearance, resulting in higher methotrexate concentrations. Autologous HSCT patients do not receive post-transplant immunosuppression, and thus, their risk of developing PCP is lower.4 Thus PCP prophylaxis is used often after autologous HSCT in patients with a hematologic malignancy.
Issues of Survivorship after HSCT
The number of long-term HSCT survivors is increasing as 5-year disease-free survival rates improve. Since nonmyeloablative preparative regimens were developed over the past decade, the late effects reported in HSCT survivors describe those resulting from myeloablative preparative regimens.47 HSCT recipients—with either an autologous or an allogeneic graft—have higher mortality than the general population.48 
Long-term survivors of HSCT should be monitored closely, particularly for infections and secondary malignant neoplasms.
Patient Encounter 3
JM is a 44-year-old female who is currently day + 8 following an HSCT from a full HLA-matched sibling for AML in first complete remission. Her preparative regimen consisted of busulfan and cyclophosphamide; tacrolimus and methotrexate are being administered for GVHD prophylaxis. She is currently receiving fluconazole 400 mg daily and acyclovir 400 mg three times daily for infection prophylaxis. She is currently day 4 of cefepime 2 g IV every 8 hours and vancomycin 1,000 mg (15 mg/kg) IV every 12 hours for neutropenic fever; all cultures remain negative. Her ANC today is 20 cells/mm3 (0.02 × 109/L). She remains persistently febrile. Her latest vital signs reveal a temperature of 38.9°C, (102°F), blood pressure 106/70 mm Hg, heart rate 112 bpm, respiration rate of 20 breaths per minute, and an oxygen saturation of 95% on room air. She has no other complaints other than she is experiencing grade II mucositis.
What diagnostic measures are needed to address JM’s current signs and symptoms?
Are any changes to JM’s anti-infective regimen warranted? What options are available in terms of medication management and what monitoring parameters are necessary with each medication?
HSCT survivors are at higher risk for secondary malignant neoplasms.47 Long-term impairment of end-organ function, including kidney, liver, and lungs, may be due to the preparative regimen, infectious complications, and/or post-transplant immunosuppression. Many HSCT recipients experience endocrine dysfunction, such as hypothyroidism from TBI, adrenal insufficiency from long-term corticosteroids to treat GVHD, and infertility from radiation and/or high doses of alkylating agents in myeloablative preparative regimens. Osteopenia has been found in over half of HSCT recipients, most likely from gonadal dysfunction and/or corticosteroid administration.
Close monitoring of HSCT recipients for infections is necessary because recovery of immune function is slow, sometimes requiring over two years, even in the absence of immunosuppressants.47 Fevers should be assessed and treated rapidly to minimize the likelihood of a fatal infection. HSCT recipients—both autologous and allogeneic—lose protective antibodies to vaccine-preventable diseases; the CDC and the European Group for BMT have issued recommendations for reimmunization for HSCT recipients.49
HSCT survivors should be monitored routinely for signs of relapse and, if an allogeneic graft was used, chronic GVHD. They should be advised regarding revaccination and obtaining prompt medical care for fevers or signs of infection. Routine evaluations of organ function (i.e., renal, hepatic, thyroid, and ovarian) and osteopenia should occur and the appropriate management strategies initiated if necessary.
OUTCOME EVALUATION
Monitor for symptoms and signs of the disease that is being treated by HSCT in order to assess the effectiveness of the HSCT. For example, the monitoring plan for a patient with CML would be to monitor disease response by PCR of the BCR-ABL transcript. The actual clinical outcome monitored, along with the frequency of monitoring, is based on the underlying disease.
Monitor for nonhematologic toxicity of the preparative regimen during its administration. Monitor these symptoms at least daily, with more frequent monitoring if the patient is experiencing these nonhematologic effects. The goal is to prevent or minimize these adverse effects. Specifically,
• Busulfan: Seizures, busulfan concentrations if being used with the BU-CY preparative regimen, number of vomiting episodes, and nausea by patient self-report, total bilirubin, and sudden weight changes (sinusoidal obstruction syndrome [SOS])
• Cyclophosphamide: ECG during IV administration, RBCs in urine, frequency of urination, pain on urination, urinary output, number of vomiting episodes, and nausea by patient self-report, total bilirubin, and sudden weight changes (sinusoidal obstruction syndrome [SOS])
• Etoposide: Blood pressure, respiratory rate, serum pH, serum bicarbonate with arterial blood gases, and evaluation of anion gap if necessary
• Total-body irradiation: Number of vomiting episodes, nausea by patient self-report, sudden weight changes (SOS), total bilirubin, and skin assessment for presence of irritation or blister formation
Until the patient has achieved engraftment, monitor the patient for engraftment with at least daily CBCs with differentials; these tests may be needed more often if the patient is critically ill or had a prior low hemoglobin. Patients will require transfusion support with blood products and platelets until engraftment occurs if hemoglobin and/or platelets drop below unsafe levels. Transfusion parameters may differ for individual patients but typically patients will be transfused if the hemoglobin drops below 8 g/dL (4.96 mmol/L); platelets are maintained at least above 10,000/mm3 (10 × 109/L) to prevent spontaneous bleeding.
Until engraftment has occurred, monitor the patient’s temperature every 4 to 8 hours for signs of infection. Also guide monitoring signs of focal point of infection based on clinical symptoms. For example, if the patient develops shortness of breath, then imaging of the lungs should occur to assess pulmonary infection. Monitor for the toxicity of prophylaxis and/or treatment of bacterial, fungal, or viral infections.
Patient Care and Monitoring
1. Assess the patient regarding the indication for HSCT, the type of preparative regimen, and the type of donor. Determine the nonhematologic toxicity of the preparative regimen, the expected timing of engraftment after the graft is infused, along with the need for GVHD prophylaxis.
2. Determine the supportive care needs during administration of the preparative regimen, including use of indwelling central venous catheters, blood product support, and pharmacologic management of CINV, mucositis, and pain.
3. After the graft is infused, monitor CBC with differential at least daily to evaluate engraftment. Allogeneic HSCT patients experience an initial period of pancytopenia followed by a more prolonged period of immunosuppression, which substantially increases the risk of bacterial, fungal, viral, and other opportunistic infections.
4. Counsel the patient regarding adherence to prophylactic antibiotic, antifungal, and antiviral regimens. Evaluate the patient for infection and adverse drug reactions to antibiotics, antifungals, and antivirals. Ensure that the patient is appropriately immunized after recovery from HSCT.
5. Counsel the patient regarding adherence to GVHD prophylaxis and treatment. Monitor and manage for adverse drug reactions.
Monitor for acute nonhematologic toxicity to the preparative regimen to approximately day +30. Specifically,
• Monitor the inside of the mouth and assess patient’s the mouth pain for signs and symptoms of mucositis.
• Monitor weight and skin color daily to observe sudden weight changes suggesting sinusoidal obstruction syndrome. Obtain a total bilirubin determination at least twice weekly or more frequently if sinusoidal obstruction syndrome is suspected based upon weight change.
Monitor for signs of acute GVHD at least daily during engraftment and more often if GVHD is suspected or diagnosed. The patient and his or her caregivers should be educated regarding the signs and symptoms to self-monitor for GVHD. The signs and symptoms for acute GVHD that occur between day +0 and day +100 are rash, nausea, diarrhea, jaundice, elevated liver function tests, and elevated bilirubin.
Abbreviatons Introduced in This Chapter
|
AML |
Acute myeloid leukemia |
|
ANC |
Absolute neutrophil count |
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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