Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

117. Hematopoietic Stem Cell Transplantation

Susanne Liewer and Janelle Perkins


 Images Hematopoietic stem cell transplantation (HSCT) is a process that involves IV infusion of hematopoietic stem cells from a donor into a recipient, after the administration of chemotherapy with or without radiation. The rationale is to increase tumor cell kill by increasing the dose of chemotherapy. Immune-mediated effects also contribute to the tumor cell kill observed after allogeneic HSCT.

 Images Hematopoietic stem cells used for transplantation can come from the recipient (autologous) or from a related or unrelated donor (allogeneic). If the related donor is a twin, the transplant is referred to as a syngeneic transplant.

 Images Human leukocyte antigen (HLA) mismatching of allogeneic donor–recipient pairs at either class I or class II loci increases the risk of graft failure, graft-versus-host disease (GVHD), and worse survival. The ideal donor is one that is matched at HLA-A, -B, -C, and DRB1.

 Images Hematopoietic stem cells are found in the bone marrow, peripheral blood, and umbilical cord blood. Because of the rarity and similarity to other cells, hematopoietic stem cells are difficult to isolate and measure. These stem cells express the CD34 antigen, and measurement of the number of CD34+ cells is a clinically useful measure of the number of hematopoietic stem cells.

 Images Because of clinical and economic advantages, peripheral blood has replaced bone marrow as the source of hematopoietic stem cells in the autologous and adult allogeneic HSCT setting.

 Images The purpose of the preparative (or conditioning) regimen in traditional myeloablative transplants is twofold: (a) maximal tumor cell kill and (b) immunosuppression of the recipient to reduce the risk of graft rejection (allogeneic HSCT only).

 Images Reduced-intensity conditioning regimens (including those that are nonmyeloablative) have been developed in order to reduce early posttranslant morbidity and mortality while maximizing the GVT effect of the allogeneic graft. The advantage to this approach is that patients who would otherwise not be eligible for allogeneic HSCT can now be offered a potentially curative therapy.

 Images The transplant-related mortality rate associated with allogeneic HSCT ranges from 10% to 80% depending mostly on age and donor and disease status. Major causes of death include infection, organ toxicity, and GVHD. The most common cause of death after autologous HSCT is disease relapse; the transplant-related mortality rate is usually less than 5%, depending on the conditioning regimen, age, and disease status.

 Images Patients undergoing allogeneic HSCT are given prophylactic immunosuppressive therapy, which inhibits T-cell activation, proliferation, or both. The most commonly used GVHD prophylaxis regimens are cyclosporine or tacrolimus and methotrexate.

 Images Initial treatment of both acute and chronic GVHD consists of prednisone, either alone or combined with cyclosporine or tacrolimus. Treatment of patients with steroid-refractory GVHD is unsatisfactory.


Images Hematopoietic stem cell transplantation (HSCT) is a process that involves IV infusion of hematopoietic stem cells from a compatible donor into a recipient, usually after administration of high-dose chemotherapy with or without radiation (called conditioning or preparative regimens). The original rationale for HSCT for treatment of malignant disease is based on studies showing that most anticancer drugs have a steep dose–response relationship and that myelosuppression limits the chemotherapy dosage that can be safely administered. Although standard-dose chemotherapy can prolong survival in many cancer patients, most patients are not cured of their disease with this strategy alone. Infusion of hematopoietic stem cells allows administration of very high doses of chemotherapy (as much as 10-fold higher) by reestablishing hematopoiesis. If tumor cells that are resistant to standard doses are sensitive to higher doses of chemotherapy, then tumor cell kill will be greatly increased, and the likelihood of cure would be higher with HSCT compared with standard dose chemotherapy. However, the chemotherapy dose cannot be escalated indefinitely because of the risk for death caused by nonhematologic toxicity (Fig. 117-1). The success of reduced-intensity conditioning (RIC) regimens shows that immune-mediated effects of the donor cells also contribute to the antitumor effect of allogeneic HSCT.


FIGURE 117-1 Patients represented by the middle column are the best candidates for hematopoietic stem cell transplantation because the technique allows for administration of chemotherapy or radiation in doses that otherwise would be intolerable because of severe myelosuppression.

HSCT is an important modality for treatment of a variety of malignant and nonmalignant diseases. More than 16,000 transplants were performed in the United States in 2009, primarily for malignant diseases.1The most common malignancies treated with HSCT are multiple myeloma, lymphoma, and leukemia. The number of transplants has grown steadily over the past decade because of an increase in the number of patients receiving umbilical cord blood (UCB) transplants and patients older than 60 years undergoing transplantation.

Although HSCT is most commonly used for treatment of malignant diseases, many nonmalignant hematologic disorders, including aplastic anemia, thalassemia, and sickle cell anemia; immunodeficiency disorders; and other genetic disorders are also potentially curable with allogeneic HSCT. Transplantation is also being investigated as a treatment modality for patients with life-threatening autoimmune diseases, such as rheumatoid arthritis, systemic and multiple sclerosis, and systemic lupus erythematosus.

This chapter summarizes the procedures involved in HSCT and the common complications associated with HSCT. More detailed information on HSCT can be found in published reviews and books.25Information on HSCT also can be found on several websites, including (Center for International Blood and Marrow Transplant Research [CIBMTR]) and Marrow Donor Program).


Images Different types of donors are used in HSCT. The choice of donor depends on the diagnosis and disease status of the recipient as well as his or her age and comorbidities. The role and indications for HSCT are discussed in detail within individual disease chapters of this text. In autologous transplants, patients receive their own hematopoietic stem cells, which were collected and stored before administration of the transplant conditioning regimen. In syngeneictransplants, an identical twin serves as the donor. In allogeneic transplants, the donor is genetically not identical to the recipient but shares some common cell surface antigens called human leukocyte antigens (HLAs). These antigens are encoded by the major histocompatibility complex (MHC), a cluster of genes located on the sixth chromosome.6 The MHC contains three distinct regions designated as class I, class II, and class III. Class I and class II genes encode for HLA; products of class III genes have other important roles in the immune system. Class I and class II HLA antigens differ in their tissue distribution, structure, and function. Their primary function is to aid the immune system in recognizing cells or tissues as “self” or “nonself.” The genes (and the corresponding antigens they encode for) important in HSCT are HLA-A, HLA-B, and HLA-C (class I) and HLA-DRB1 (class II). Because of the polymorphism of the HLA system, there are many different HLA antigens within each different class of HLA. To reduce the chance of graft rejection and graft-versus-host disease (GVHD), a donor is chosen based on how many of these HLA antigens are the same as those of the recipient.

To identify a suitable allogeneic donor, both the recipient and potential donors are HLA typed (specific HLA antigens are identified); the potential donor who is most closely matched (has the most similar HLA antigens to the recipient) is generally chosen to be the transplant donor. HLA typing is accomplished by DNA-based techniques that use polymerase chain reaction (PCR) amplification of specific HLA genes from genomic DNA. DNA typing methods are categorized by the level of discrimination they provide in defining the sequence of an HLA gene. Low-resolution methods provide limited sequence information about a particular HLA gene and are typically used to identify sibling donors. However, low-resolution techniques cannot distinguish the extremely polymorphic nature of many of the HLA antigens. HLA antigens are characterized by thousands of genetic variations (alleles), and each allele may correspond to a unique HLA molecule. Different alleles can be distinguished only by high-resolution typing techniques; high-resolution methods are used to identify suitable unrelated donors.

Images The degree of HLA mismatching correlates with the risk of graft rejection, GVHD, and survival.6 In an analysis of 1,874 patients who received HLA-matched unrelated bone marrow donor transplants under the auspices of the National Marrow Donor Program (NMDP), low-resolution mismatches at HLA-A, HLA-B, HLA-C, and HLA-DRB1 were similarly associated with increased risk of GVHD and mortality.7 The observation concerning the prognostic value of HLA-C was particularly important because until that time, the locus was omitted from most matching algorithms. Based on these results, HLA-C typing is now included in standard typing protocols. High-resolution mismatches, particularly at HLA-A and HLA-DRB1, also were associated with increased mortality. These findings were confirmed in an analysis of more than 3,800 unrelated bone marrow donor–recipient pairs in which high-resolution matching for HLA-A, -B, -C, and DRB1 was associated with the overall survival.8

In the search for an allogeneic donor, the patient’s siblings are typed first. The odds that any one full sibling will match a patient are one in four. About 30% of Americans have an HLA-identical sibling. In an effort to offer allogeneic HSCT to patients who lack an HLA-identical sibling donor, alternative donors are being used. Rarely, a parent is HLA identical with his or her child. Although some patients who receive transplants from mismatched related donors experience long-term survival, their risks of graft failure and acute GVHD are higher than for recipients of matched-sibling transplants. It is estimated that only another 10% of patients will have a closely HLA-matched related donor.

The most common type of alternative donor is an individual unrelated to the recipient who is fully or closely HLA matched. To facilitate identification of these donors, the NMDP ( was started in 1986 with initial funding from a U.S. Navy contract. To date, the NMDP has registered more than 10 million donors in the United States and has facilitated more than 50,000 unrelated donor transplants. Donors outside the United States can also be accessed by the NMDP through agreements with international cooperative registries. About one-third of the allogeneic HSCTs performed worldwide are from unrelated donors.1 The NMDP currently requires that the recipient be typed by high-resolution methodology at HLA-A, -B, -C, and -DRB1. Although it is the transplant center’s responsibility to select the donor, the NMDP recommends that selected donor and recipient be matched at HLA-A, -B, -C, and -DRB1 by high-resolution typing when possible for bone marrow or peripheral blood HSCT; matching criteria are less stringent for UCB transplant.9 If more than one suitable HLA-matched unrelated donor is identified, other factors can be used to select the donor, such as younger age, being male or a nulliparous female, and negative cytomegalovirus (CMV) serostatus.

The likelihood of a recipient finding an HLA-matched donor ranges from one in 100 to one in 1,000,000, depending on the prevalence of the recipient’s HLA type, race, and ethnic background. With the current size of the NMDP registry, the matching likelihood is higher than 80% for whites. Because most minorities are not as well represented in the program, the likelihood of finding a donor for patients from some racial or ethnic groups is lower. Agreements between NMDP and international registries may improve the likelihood of finding donors for these patients. Another limitation is the time needed to search for a potential donor. Some donor searches take up to 3 to 4 months, and patients with acute leukemia can relapse while waiting for completion of the search. Cost is also a concern, with the cost for donor search and procurement ranging from $25,000 to $50,000. With improved HLA typing techniques and better supportive care, most reported outcomes with matched unrelated donors are no longer significantly different than those reported with related sibling donors.10,11


Hematopoietic stem cells serve as “mother” cells for all blood cells, including erythrocytes, leukocytes, and platelets (see eChap. 20). Stem cells have varying degrees of “stemness.” True pluripotent stem cells are capable of replicating indefinitely and can give rise to stem and progenitor cells of all tissues. Multipotent stem cells, such as hematopoietic stem cells, have the capacity for self-renewal and can differentiate into more than one cell type in a particular tissue lineage. Because of their capacity for self-renewal, hematopoietic stem cells are capable of repopulating the recipient’s marrow, which has been “emptied” by administration of high-dose chemotherapy, either alone or combined with radiation.

Images Hematopoietic stem cells are rare cells, comprising less than 0.01% of all bone marrow cells. Isolation and quantitative measurement of hematopoietic stem cells are extremely difficult because of their rarity and their similar appearance to other cells. For these reasons, surrogate markers are used to measure the number of stem cells. CD34 is an antigen expressed on hematopoietic stem cells and other early progenitor cells. Determination of the number of cells expressing the CD34 antigen (CD34+ cells), as determined by flow cytometry, has become the standard method of measuring hematopoietic stem cell content.

Hematopoietic stem cells are found in the bone marrow, peripheral blood, and UCB. Hematopoietic stem cells from the bone marrow are obtained by multiple aspirations from the anterior and posterior iliac crests while the donor is under general anesthesia. The procedure takes about 1 hour and yields 200 to 1,500 mL, depending on the size of the donor. The marrow is transferred into tissue culture medium containing preservative-free heparin. The pooled marrow is passed through a series of stainless steel screens to break up aggregated particles, resulting in an essentially single-cell suspension. In allogeneic HSCT, the marrow stem cells are given to the recipient 12 to 24 hours after harvest. In autologous HSCT, the marrow is frozen and stored until needed. After IV infusion, the marrow stem cells enter the systemic circulation and find their way to the bone marrow cavity, where they reseed and grow in the bone marrow microenvironment. Although the donor experiences local soreness for a few days, the procedure usually is well tolerated, with no delayed complications resulting from the marrow aspiration. The major risk of serving as a marrow donor is the risk of undergoing general anesthesia.

Hematopoietic stem cells in peripheral blood (peripheral blood stem cells [PBSCs]) are found in the mononuclear fraction of white blood cells (lymphocytes and monocytes) and are collected by a procedure called leukapheresis (or apheresis). This is an outpatient procedure that involves withdrawal of blood from a vein (through a specialized IV catheter), selective removal of mononuclear cells by an apheresis machine, and reinfusion of the unneeded blood components back to the patient. During this process, about 9 to 14 L of blood is processed over several hours during each daily apheresis session. Most of the blood cells are returned to the donor, and each apheresis yields about 200 mL of cells.

The number of hematopoietic stem cells that circulate in peripheral blood normally is too low for apheresis to be technically feasible. Without mobilization techniques, at least six aphereses usually are required to collect a sufficient number of PBSCs. Several methods have been used clinically to “mobilize” hematopoietic stem cells from the bone marrow into peripheral blood for use in autologous transplantation.12 Figure 117-2 shows representative schemas for mobilization and collection of PBSCs. One type of mobilization method is administration of chemotherapy, which can briefly increase the number of PBSCs as much as 100-fold. The more commonly used method is administration of a recombinant hematopoietic growth factor such as granulocyte colony-stimulating factor (G-CSF; filgrastim) or granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim). Each agent has its own potential advantages and disadvantages.12 Both agents are approved by the Food and Drug Administration (FDA) for this indication, but filgrastim is the most commonly used growth factor. Dosages are 10 mcg/kg/day (5–32 mcg/kg/day) for filgrastim and 250 mcg/m2/day for sargramostim. The combination of chemotherapy followed by a hematopoietic growth factor increases the number of PBSCs to a greater extent than either method alone. This approach is more expensive and is associated with more adverse effects than a growth factor alone, but the number of aphereses is reduced, and the additional chemotherapy may further reduce the tumor burden before transplant, which may reduce the likelihood of tumor cell contamination in the apheresis collection. Pegfilgrastim (pegylated filgrastim) has also been evaluated in the mobilization setting, either alone or after chemotherapy. Pegylation prolongs the half-life of filgrastim from 3 to 4 hours to 33 hours, allowing for single-dose administration. Both the 6- and 12-mg doses appear to be safe and at least as effective as filgrastim.13,14 Based on these studies, pegfilgrastim may be used in place of filgrastim for stem cell mobilization for patient convenience.


FIGURE 117-2 Schema for collection of peripheral blood progenitor cells after hematopoietic growth factor administration (top) or after chemotherapy and hematopoietic growth factor administration (bottom). Symbols with darker shading represent procedures performed only if adequate numbers of CD34+ cells have not been collected. (G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.)

Plerixafor is a novel inhibitor of the CXCR4 chemokine receptor that is FDA approved as a mobilizing agent in combination with filgrastim. Its approval was based on two multicenter, randomized, double-blinded trials that compared filgrastim plus plerixafor or placebo as primary mobilization in patients with multiple myeloma or non-Hodgkin lymphoma.15,16 In both studies, patients received filgrastim 10 mcg/kg/day for 4 days; on the evening of the fourth day, they received either 240 mcg/kg of plerixafor or placebo. In both studies, a significantly larger proportion of the filgrastim plus plerixafor–treated patients were able to collect the target number of CD34+ cells in no more than two aphereses procedures compared with the filgrastim plus placebo group. These initial trials demonstrated that plerixafor is very effective in increasing the number of CD34+ cells available for primary mobilization of hematopoietic stem cells.

Because most patients are able to mobilize efficiently with filgrastim alone and plerixafor is expensive, transplant centers generally use some type of risk-adapted approach to identify which patients are appropriate candidates for plerixafor. One approach is to give plerixafor to patients with certain characteristics that have been associated with a high risk of poor mobilization.17,18 These characteristics include previous exposure to extensive chemotherapy, lenalidomide, or radiation, older age, hypocellular bone marrow, or low platelet counts. Another approach is to monitor CD34+ cell counts in the peripheral blood on day 4 or 5 of filgrastim administration because low numbers of CD34+ cells after filgrastim have been associated with mobilization failure. Patients who do not have a minimal number of CD34+ cells receive plerixafor.1921 In general, these individualized approaches limit plerixafor administration to patients at high risk for poor mobilization.

In about 20% to 30% of autologous transplant candidates, an optimal number of CD34+ cells will not be obtained after the first attempt with standard mobilization regimens.22 Several strategies for overcoming the obstacle of poor mobilization have been evaluated, including remobilization with the same or higher doses of the same hematopoietic growth factor, a combination of hematopoietic growth factors (i.e., filgrastim and sargramostim), or a combination of chemotherapy and a hematopoietic growth factor. Bone marrow harvest is an option but often is of limited value. Plerixafor has been evaluated in patients who have failed primary mobilization. In a study of 115 patients who had failed at least one previous mobilization attempt, plerixafor and filgrastim were given with the objective of collecting at least 2 × 106 CD34+ cells/kg.23 Depending on diagnosis, about 60% to 75% of patients successfully mobilized with this regimen, which compares favorably with other secondary mobilization strategies. Although plerixafor with filgrastim may be effective for remobilization, it has been associated with a higher cost compared with other strategies, especially if multiple doses of plerixafor are required.24 The decision on which secondary mobilization regimen to be used should be based on patient-specific factors and clinician judgment.

Several studies show that the number of CD34+ cells infused correlates significantly with the rate of neutrophil and platelet recovery after high-dose chemotherapy.12 Rapid neutrophil recovery usually is observed in patients who receive at least 2 × 106 CD34+ cells/kg (body weight of recipient). More rapid platelet recovery is observed when at least 5 × 106 CD34+ cells/kg is transplanted compared with lower cell doses. As a result, most transplant centers use 2 × 106 CD34+ cells/kg as a minimum number to collect for autologous transplant, with an optimal target of 5 × 106 CD34+ cells/kg. For patients with multiple myeloma undergoing tandem transplants, cells for both transplants are collected before the first transplant. A minimum of 4 × 106 CD34+ cells/kg is required, and generally the entire cell dose collected is divided into two equal aliquots, one for each transplant.

Images Use of peripheral blood instead of bone marrow as a source of hematopoietic stem cells offers several clinical and economic advantages. The most clinically important advantage is that patients who receive mobilized PBSCs experience more rapid hematopoietic engraftment. Although engraftment of all lineages is more rapid when PBSCs are used, the most significant effect is observed with platelet recovery. Patients who receive mobilized PBSCs experience platelet recovery as much as 2 to 3 weeks earlier and require fewer platelet transfusions than those who receive bone marrow stem cells. As a result, patients usually are discharged earlier from the hospital, so the overall cost of autologous HSCT is reduced with the use of PBSCs. Another advantage is that the donor does not experience the discomfort associated with marrow aspirations and is not exposed to the risk associated with general anesthesia. PBSCs may be less likely to be contaminated with malignant cells compared with marrow stem cells. Finally, because PBSCs are collected from the mononuclear cell fraction, a fraction that also contains immunocompetent cells (e.g., natural killer [NK] cells and T lymphocytes), some investigators believe that infusion of PBSCs represents a form of “adoptive immunotherapy.” In this model, NK cells and lymphocytes targeted against tumor cells help to kill residual tumor cells. As a result of these clinical and economic advantages, peripheral blood has replaced bone marrow as the source of stem cells in the autologous setting.

Peripheral blood has also become the predominant source of hematopoietic stem cells in adult allogeneic HSCT.1,25 About 75% of allogeneic HSCTs performed in adults currently come from PBSCs harvested from normal donors. Concerns were raised initially over the safety and ethics of administering filgrastim to normal individuals volunteering as donors. Filgrastim is generally well tolerated. Short-term effects are similar to those seen in cancer patients receiving filgrastim (e.g., bone pain, headache, fever, arthralgias, malaise). Although there are concerns about increased risk of acute myelogenous leukemia (AML) in healthy subjects given filgrastim, no higher risk has been observed thus far.26 Because of the long latent period of drug-related AML and the very low incidence of AML in the general population, longer follow-up of thousands of healthy donors will be required to definitively conclude that an association between filgrastim and AML does not exist.

Randomized controlled trials and large registry studies show that patients who received allogeneic PBSC transplants from HLA-identical siblings experienced more rapid hematopoietic recovery and required fewer transfusions compared with patients receiving bone marrow.27 The difference in the rate of engraftment may be related to the threefold higher numbers of CD34+ cells infused in recipients of PBSC transplants. Although most of these studies did not report an increased risk of acute GVHD or transplant-related mortality in patients receiving allogeneic PBSC transplants, a higher risk of chronic GVHD has been observed. In a meta-analysis of nine randomized trials evaluating HLA-matched sibling donor transplants in adult patients, the risk of chronic GVHD was nearly twofold higher for patients who received allogeneic PBSC transplants compared with those who received bone marrow transplantation (BMT). However, the risk of relapse was higher in the patients receiving BMT, and no significant difference in overall survival was observed in the meta-analysis, although in some individual studies, disease-free and overall survival were improved with PBSC. When patients were analyzed based on disease status at the time of transplant, patients with hematologic malignancies at high risk of relapse had a better overall survival when transplanted with PBSC as compared with those who received BMT, which may be related in part to the lower risk of relapse in patients who received PBSC transplants.27 The Blood and Marrow Transplant Clinical Trials Network recently reported the results of a trial that randomized 551 patients to allogeneic PBSC or bone marrow from matched unrelated donors.28 At 2 years after transplant, there were no differences in overall survival, relapse, or mortality not related to relapse. Neutrophil and platelet engraftment were more rapid, and the risk of graft failure was reduced in the PBSC transplants compared with patients receiving BMT. The risk of acute GVHD was similar, but a higher incidence of chronic GVHD was reported in patients who received PBSC transplants. Two-year survival is an early outcome, and further follow-up will need to be done to determine if these results are maintained over time. Selection of the optimal source of hematopoietic stem cells for an individual patient should be based on the risk of relapse, chronic GVHD, graft failure, and donor preference. It is also important to note that most patients treated in the randomized trials of bone marrow versus peripheral blood transplants received myeloablative conditioning (MAC) regimens (discussed later), and it is unknown whether these results can be extrapolated to RIC regimens.

Several small studies have reported the engraftment and outcomes of patients receiving allogeneic bone marrow from donors who received filgrastim for 3 to 4 days before harvest. The use of the filgrastim was hypothesized to increase the yield of bone marrow from healthy donors. A meta-analysis of studies comparing filgrastim stimulated bone marrow to PBSCs showed similar rates of engraftment, acute GVHD, relapse, and overall survival but a greater risk of chronic GVHD with PBSCs. These initial studies suggest that filgrastim-stimulated bone marrow may result in early engraftment similar to PBSCs without the higher risk of GVHD.29 A large prospective randomized trial is comparing filgrastim–mobilized PBSCs with filgrastim-stimulated bone marrow.

In addition to bone marrow and peripheral blood, hematopoietic stem cells are found in UCB. UCB is an attractive source for several reasons.30 Because the stem cells are collected from placental blood, there is no risk to the mother or the baby and a very low risk of transmissible infectious diseases, such as cytomegalovirus and Epstein-Barr virus. The cells are available immediately because the donor does not have to be located and the stem cells harvested. UCB initially was obtained from siblings, but now recipients of transplants from unrelated donors account for almost all patients who receive UCB transplants. More than 600,000 UCB grafts are available in more than 100 UCB banks, and more than 20,000 unrelated UCB transplants have been performed worldwide.30

Recipients of UCB transplants usually receive a CD34+ cell dose more than 1 log lower than that given to recipients of BMT, and this difference in CD34+ cell dose may explain the delayed engraftment in recipients of UCB transplants. The number of infused total nucleated and CD34+ cells correlates with outcomes after UCB transplantation. Although no randomized comparisons have been performed, many retrospective studies have compared outcomes of UBC transplantation with more traditional stem cell sources such as bone marrow or PBSCs. Analysis of data from the CIBMTR and the New York Blood Center showed similar survival in children with acute leukemia who underwent either unrelated HLA-mismatched UCB transplantation or unrelated HLA-matched BMT. Children who received HLA-matched UCB transplants had better outcomes than those who received HLA-matched BMTs. However, higher transplant-related mortality was observed in children transplanted with a low UCB cell dose and a mismatched UCB graft.31 Similar studies of adults with hematologic malignancies have been conducted. The CIBMTR compared outcomes for adults with acute leukemia who were transplanted with unrelated BM or PBSC versus UCB. Both overall survival and leukemia-free survival were similar in all transplant groups. The risk of both acute and chronic GVHD was lower in UCB recipients compared with PBSC, and the risk of chronic GVHD was lower in UCB compared with bone marrow. However, transplant-related mortality was higher after UCB as compared with other stem cell sources. These data support the use of UBCs as a source of stem cells when matched PBSCs or bone marrow are not immediately available.32

A major limitation of UCB transplants is the small volume of blood collected, usually 60 to 150 mL with resultant low numbers of CD34+ cells. Although the relatively low numbers of hematopoietic cells may be adequate for hematopoietic engraftment in children and small adults, it may not be adequate for larger recipients. Efforts to expand the number of hematopoietic stem cells include “pooling” 2 or more units of UCB for one recipient (referred to as double cord transplant). The Seattle and Minnesota groups recently published their experience in more than 500 patients older than 10 years of age who received a matched related donor, matched unrelated donor, mismatched unrelated donor, or double cord transplant. Leukemia-free survival was similar in all groups, but the double cord transplant recipients had a higher risk of transplant-related mortality. Although the role of double cord transplantation has not yet been fully defined, the results of this study suggest that pooled UBCs may provide an option for patients in which no other appropriate donors are available.33


Conditioning Regimens

Images The purpose of the pretransplant conditioning regimen (also called the preparative regimen) depends on the type of transplant and the indication for its use. In the autologous setting, pretransplant conditioning is used to eradicate malignant cells. This is also the case in allogeneic transplantation for malignant diseases, but the conditioning regimen also serves a dual purpose to suppress the recipient’s immune system to allow for donor cell engraftment. Two types of conditioning regimens are used, myeloablative and reduced intensity. Myeloablative conditioning (MAC) regimens contain very high doses of chemotherapy with or without radiation that would lead to life-threatening or fatal myelosuppression if hematopoietic stem cells were not infused. Patients undergoing autologous transplantation receive MAC regimens. Reduced-intensity conditioning (RIC) regimens consist of lower doses or different types of chemotherapy or lower doses of radiation than used in MAC regimens. RIC regimens were developed after the observation was made that some of the antitumor effect of the allogeneic transplant was mediated by a reaction between the donor’s immune system and the recipient’s cancer cells. This meant that very high doses of chemotherapy, radiation, or both may not be needed. Because RIC regimens use lower doses of chemotherapy or radiation or less toxic drugs, older patients and those with comorbidities are now able to undergo allogeneic transplant. Both types of regimens are discussed in detail below.

Myeloablative Regimens

MAC regimens usually include at least one anticancer drug with a relatively steep dose-response curve and myelosuppression as their dose-limiting toxicity, such as alkylating agents. Cyclophosphamide, melphalan, busulfan, and carmustine are examples of chemotherapy agents commonly used in MAC regimens. Other agents are usually added that have additive or synergistic effects with these alkylating agents in specific types of cancers; other alkylating agents have also been used. Table 117-1 lists chemotherapeutic agents that are frequently used in MAC regimens as well as the doses used and their dose-limiting toxicity in the transplant setting.

TABLE 117-1 Dose-Limiting Nonhematologic Toxicities for Selected Chemotherapeutic Agents Included in Myeloablative Conditioning Regimens in Hematopoietic Stem Cell Transplantation


Total-body irradiation (TBI) is also used in some pretransplant conditioning regimens. In patients with malignant disease, the rationale of TBI is to eradicate malignant cells located in areas inaccessible to the systemic circulation and thus to the chemotherapeutic agents. TBI also has significant immunosuppressive activity. TBI doses for MAC regimens range from 10 to 15 Gy (1,000–1500 rads), which is more than twice the lethal dose of radiation for a normal person. TBI in these doses is typically fractionated (split over several days, once or twice a day) rather than given as a single-dose. Fractionated TBI has an improved therapeutic ratio compared with single-dose administration, that is, destruction of more leukemic cells and marrow stem cells while sparing other normal tissues. The acute toxicities of TBI consist of fever, nausea, vomiting, diarrhea, mucositis, and tender swelling of the parotid gland. Long-term complications of TBI-containing regimens include cataract formation, growth retardation, carcinogenesis, permanent reproductive sterility, and secondary malignancies.

Two of the most commonly used MAC regimens for allogeneic transplant are cyclophosphamide and TBI (CyTBI) or busulfan and cyclophosphamide (BuCy). When given with TBI, cyclophosphamide is usually given first as two doses of 60 mg/kg/day followed by TBI. In the original BuCy regimen, busulfan was given orally at a dosage of 1 mg/kg orally every 6 hours for 16 doses on days –9 to –6 (4 mg/kg/day for 4 days; day 0 being the day of transplant) followed by four doses of cyclophosphamide given IV once daily at a dosage of 50 mg/kg on days –5 to –2. In one widely used modification of the regimen (BuCy2), the total cyclophosphamide dosage is reduced from 200 (50 × 4) to 120 (60 × 2) mg/kg. Plasma busulfan concentrations are monitored at some centers because studies suggest that systemic exposure correlates with outcome, and use of a targeted busulfan and cyclophosphamide preparative regimen may improve patient outcome.34 The IV form of busulfan (Busulfex®) reduces some of the interpatient variability in systemic exposure and may also reduce the risk of hepatotoxicity. The dose of IV busulfan approved for pretransplant conditioning regimens is 0.8 mg/kg every 6 hours for 4 days, although once-daily dosing regimens have also been developed.

Several prospective randomized studies have compared CyTBI with BuCy in patients with acute or chronic myeloid leukemia (CML) undergoing allogeneic matched related donor HSCT.35,36 Early results of these studies showed that BuCy had similar or greater antileukemic activity than CyTBI in patients with CML and that CyTBI was associated with slightly better disease-free survival in patients with AML. However, with longer follow-up, similar survival rates were observed. In a large retrospective analysis of the CIBMTR in patients with myeloid malignancies receiving unrelated donor transplants, overall and disease-free survival were not significantly different between the two regimens.37 Long-term toxicities between the two regimens appear to be comparable. Since the publication of these studies, several improvements in clinical practice have been made (e.g., better supportive care, more specific HLA typing methodologies, use of PBSCs) that may have some effect on the comparison of these two commonly used regimens. For example, use of the IV form and pharmacokinetic monitoring of busulfan may optimize its use, giving an advantage to the use of BuCy. In addition, other MAC regimens have been developed that may be safer or more effective. Without definitive data showing the superiority of one regimen over another, the choice of regimens before allogeneic transplant generally is based on the experience of the transplant center, patient characteristics, diagnosis, and disease status.

Conditioning regimens used in autologous HSCT are exclusively myeloablative and generally include at least one alkylating agent with other agents added that may have specific activity against the tumor type being treated. TBI usually is not included in the conditioning regimen in patients who have received prior radiotherapy. MAC regimens used in patients with lymphoma generally include different combinations of cyclophosphamide, carmustine, etoposide, and cytarabine. Rituximab is commonly added to the high-dose chemotherapy regimen in patients with CD20-positive lymphomas. Many transplant treatment regimens also use rituximab at the time of stem cell collection to reduce the number of CD20-positive lymphoma cells in the stem cell product being collected. The availability of anti-CD20–radiolabeled monoclonal antibodies, iodine-131 tositumomab and yttrium-90 ibritumomab, offers the potential to deliver targeted radiation to CD20-positive tumor cells and less to normal organs. Based on the results of several promising phase II studies with these two agents, the Blood and Marrow Transplant Clinical Trials Network conducted a prospective comparative trial randomizing patients with diffuse large B cell lymphoma to receive high-dose chemotherapy with rituximab or iodine-131 tositumomab followed by autologous HSCT.38Progression-free survival (PFS) and overall survival were not significantly different between the two groups, and thus these agents are not used routinely as part of conditioning for patients with lymphoma undergoing autologous HSCT. Single-agent melphalan (200 mg/m2) is the standard conditioning regimen for patients undergoing autologous HSCT for myeloma. Studies are ongoing evaluating the addition of newer agents (e.g., bortezomib).

Reduced-Intensity Conditioning Regimens

Images Donor T cells contribute to the tumor cell kill and prevention of relapse observed after allogeneic HSCT, an effect referred to as the graft-versus-malignancy (GVM) effect. Evidence for the GVM effect is based on retrospective studies showing that patients who developed GVHD had a lower risk of leukemic relapse than those who did not develop GVHD. However, the overall survival rate was not different because of the increased nonrelapse mortality associated with GVHD. Other anecdotal evidence supporting a T cell–mediated GVM effect was the increased risk of relapse found with T cell–depleted transplants compared with unmodified transplants and the efficacy of donor lymphocyte infusions (DLIs) in producing responses in patients who have relapsed after allogeneic HSCT.

RIC regimens containing lower doses of chemotherapy or radiation or less toxic agents were developed to take advantage of the GVM effect but with a lower incidence of regimen-related toxicity than that of MAC regimens. Animal data demonstrated that MAC was not required for engraftment of donor cells (the other important role of conditioning in allogeneic HSCT), thus paving the way for the evaluation of RIC in humans.39,40 The major advantage of RIC is that potentially curative transplants can be offered to patients who typically would not be considered for allogeneic HSCT because of their unacceptably high risk of transplant-related complications because of increased age or moderately compromised organ function. Use of RIC regimens has steadily increased in patients aged 50 and older.1 In addition, because of the lower rate of toxicity, allogeneic HSCT with RIC can be offered to patients who have relapsed after traditional myeloablative autologous or allogeneic transplants. About 30% of allogeneic transplants are now being performed with RIC regimens.1

Because RIC regimens may not be completely myeloablative, host hematopoiesis can persist and lead to mixed chimerism (blood cells from both donor and recipient are present) (Fig. 117-3).39 Several studies have reported significant correlations between donor T-cell chimerism levels and the risk of graft rejection, GVHD, and relapse. For example, a low percentage of donor T and NK cells present on day 14 has been associated with graft rejection, but high T-cell donor chimerism on day 28 has been associated with acute GVHD. Achievement of full donor chimerism was associated with better PFS. These data suggest that monitoring donor chimerism after transplant may allow early interventions to prevent graft rejection or relapse.


FIGURE 117-3 Schema for nonmyeloablative transplantation for hematologic malignancy. Recipients (R) receive a reduced-intensity conditioning regimen and an allogeneic hematopoietic stem cell transplant (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 (DLIs) can be administered to enhance graft-versus-malignancy effects.

A number of RIC regimens that vary in their cytotoxic, myelosuppressive, and immunosuppressive activity have been developed.39,40 Most regimens include fludarabine (125–240 mg/m2) because of its potent immunosuppressive activity, combined with either low-dose TBI (at doses up to 8 Gy [800 rad]) or an alkylating agent, such as cyclophosphamide (2–3.6 g/m2 or 120–200 mg/kg), busulfan (up to 10 mg/kg), or melphalan (up to 180 mg/m2). Antithymocyte globulin or alemtuzumab is sometimes given for additional immunosuppression, and other purine analogs (e.g., pentostatin or clofarabine) are sometimes used instead of fludarabine. Rituximab has also been included in patients with CD20-positive lymphoid malignancies.41 Many of these regimens are myeloablative but are defined as RIC because of the reduced doses of chemotherapy.42

Some RIC regimens are considered nonmyeloablative because they result in little to no myelosuppression and do not require hematopoietic cell support for recovery of hematopoiesis. Nonmyeloablative regimens are associated with very little regimen-related toxicity but, similar to other RIC regimens, are immunosuppressive enough to result in full engraftment of important donor immune effector cells.42Two of the most common nonmyeloablative regimens are fludarabine (25 mg/m2/day for 3–5 days) combined with cyclophosphamide (60 mg/kg/day × 2 days) or with TBI (≤2 Gy [<200 rad]). Although these regimens are clearly nonmyeloablative, the distinction may be more difficult with other regimens as definitions remain somewhat arbitrary.

Progression-free and overall survival varies depending on the specific RIC regimen, disease type and status at the time of transplant, donor type, and patient age and comorbidities. Patients with indolent lymphoid malignancies generally have the lowest relapse rate after RIC transplants; those with advanced myeloid and lymphoid malignancies have higher relapse rates.43 Patients transplanted while in remission have lower relapse rates than those who were not in remission at the time of transplant. Studies evaluating “disease-targeted” therapy (radiolabeled monoclonal antibody, imatinib, or rituximab) combined with RIC transplants to improve outcomes in specific malignancies are ongoing.39 Several large retrospective registry-based studies have reported the results of RIC regimens.39,40,44 In general, regimen-related toxicity and nonrelapse mortality have been reported to be lower than that of historical or concurrent control participants receiving MAC regimens in nonrandomized comparisons. This is remarkable considering the older age and higher incidence of comorbidities in patients receiving RIC transplants. Of concern, however, has been an increased rate of relapse seen in some comparisons, resulting in similar overall survival being reported regardless of regimen intensity. Prospective randomized trials are needed to more fully define the role of RIC regimens in specific patient populations and to determine their relative safety and efficacy compared with standard MAC regimens. Until the results of those trials are available, most centers will continue to use RIC regimens because of better tolerability, especially in older patients and those with significant comorbidities.

Clinical Controversy…

Although RIC regimens reduce transplant-related mortality, whether this approach results in improved survival compared with MAC regimens is not clear. Direct comparison of the results of RIC versus MAC transplants is difficult because patients undergoing RIC transplants tend to be older and have more comorbidities. Randomized controlled trials addressing these questions are ongoing, and the results of these studies should better define the role of RIC transplants.

Posttransplant Therapy

Relapse of primary disease remains the most common cause of death for both allogeneic and autologous transplant patients. Several posttransplant therapies have been evaluated, including immunotherapy, conventional chemotherapy, and targeted therapy. Relapse after autologous transplant can often be treated with standard doses of chemotherapy, a second autologous transplant, or even an allogeneic transplant, depending on the diagnosis, disease status, side effects, response, and duration of response to the first transplant. Treatment options for most patients who relapse after allogeneic HSCT are limited, and prognosis is generally poor. Disease-specific chemotherapy can be considered for some patients. A second allogeneic HSCT may be considered but is associated with a mortality rate of up to 45%.45Newer strategies are needed to improve outcomes while limiting toxicity when treating relapsed disease. Because of the poor prognosis of relapse after transplant, efforts have been focused on treatment of molecular or cytogenetic disease markers, which generally appear before “full-blown” relapse or institution of maintenance therapy after transplant in patients at high risk of relapse.


Donor Lymphocyte Infusions The rationale for posttransplant immunotherapy after allogeneic HSCT is based on the GVM effect. To take advantage of the GVM effect in patients who relapse after allogeneic HSCT, immunosuppressive therapy being used for GVHD is withdrawn as quickly as possible without inducing a serious GVHD flare. In rare cases, this is enough to reinduce a remission, but in the majority of cases, further therapy is required. Perhaps the most commonly used form of posttransplant immunotherapy is DLIs.46,47 Lymphocytes are collected from the same donor who provided hematopoietic stem cells for the original transplant. Response to DLI is disease specific. More than 80% of patients with CML who are in cytogenetic or molecular relapse respond to DLI. The response rate of patients in more advanced phases is about 15% to 30%. Although the time to response is delayed (median, 3–4 months), patients often have a durable molecular remission to DLI. Response rates to DLI of patients with other myeloid malignancies, such as AML and myelodysplasia, are generally lower (25%–30%) than the rates of patients with CML.46,47 This may be related to the rapid proliferation of acute leukemia within the often prolonged time to response after DLI or to the lack of suitable target antigens on non-CML cells for recognition by donor cytotoxic T cells. Patients with relapsed AML after HSCT are more likely to achieve a complete response to DLI if they had a longer remission period after transplant and had some GVHD after the DLI; low tumor burden, remission at the time of DLI, and good-risk cytogenetics have also been shown to be favorable characteristics. Administration of induction chemotherapy before DLI administration may improve the antitumor activity of DLI in patients with AML, but this method has not been tested in a randomized study. DLI has been shown to have limited benefit in patients with relapsed acute lymphocytic leukemia (ALL) after transplant.

Donor lymphocyte infusion appears to be effective in patients with multiple myeloma who relapse after allogeneic HSCT, with reported response rates of 40% to 50%. Because it is relatively uncommon for a patient with multiple myeloma to be a candidate for allogeneic HSCT and patients have the option of treatment with lenalidomide or bortezomib after HSCT, the role of DLI in this population remains unclear. Chemotherapy followed by DLI may induce a GVM effect in patients with relapsed lymphoma. The highest response rates were reported in patients with indolent lymphoma while more aggressive malignancies had lower response rates.

The most serious complications of DLI are pancytopenia and GVHD, and DLI is not usually given to patients with GVHD. The cytopenias generally are transient and can be treated with hematopoietic growth factors. Some patients may have a more prolonged course of aplasia with associated risk of infection, bleeding, and anemia, and these patients may benefit from another infusion of donor hematopoietic stem cells. Acute GVHD (grade II or greater) occurs in 40% to 60% of patients receiving DLI. Although the severity of GVHD has been correlated with the GVM effect, complete responses have been seen in the absence of GVHD, suggesting that the effects can be separated. DLI is associated with 10% to 15% nonrelapse mortality rate at 1 year.

Monoclonal Antibodies Rituximab is being evaluated as adjuvant therapy in patients with non-Hodgkin lymphoma treated with autologous HSCT.48,49 The timing and number of doses of rituximab therapy vary. Promising results have included increased event-free survival and durable molecular remissions. Rituximab after autologous transplant appears to be fairly well tolerated. Prolonged suppression of immunoglobulin production and hematologic toxicities such as neutropenia can occur in patients who received rituximab after HSCT. Although these results have been encouraging, the use of rituximab after HSCT needs to be verified within large randomized trials.

Chemotherapy or Targeted Therapy

Tyrosine kinase inhibitors (TKIs), such as imatinib, have been shown to be effective in the prevention and treatment of relapse after allogeneic HSCT in patients with CML and Philadelphia chromosome–positive (Ph+) ALL.50 In patients with CML who experience hematologic relapse (presence of leukemic blasts in blood or bone marrow) after allogeneic HSCT, imatinib has been reported to induce complete hematologic responses (disappearance of leukemic blasts) and complete cytogenetic responses (disappearance of cytogenetic markers of disease) in a majority of these patients. Outcomes in patients with Ph+ ALL have also been encouraging. Second-generation TKIs, dasatinib and nilotinib, have also been used in both patient populations with relapsed disease. These agents appear to be effective with acceptable toxicity profiles.50 TKIs are also given soon after transplant to prevent relapse (maintenance therapy) or to treat early relapse described as minimal residual disease (preemptive therapy; i.e., appearance of molecular or cytogenetic markers of disease before appearance of leukemic blast in the bone marrow or peripheral blood).50,51 Patients with Ph+ ALL and CML without evidence of disease after transplant who are treated with imatinib to prevent relapse appear to have sustained cytogenetic remissions (without evidence of cytogenetic markers of disease). In a preemptive study of patients with Ph+ ALL, 50% of patients who had minimal residual disease detected after stem cell transplant had a complete response to TKI therapy.51 TKIs are generally well tolerated after transplant. Commonly reported side effects include neutropenia, thrombocytopenia, liver function abnormalities, edema, and muscle pain. Larger comparative studies will be required to clearly define the benefit of TKIs after transplant, as well as the optimal dosing, timing, and duration of therapy.

Based on its activity in AML and MDS, 5-azacitidine is being evaluated in the posttransplant setting to prevent or treat relapse in patients with these diagnoses. Investigators at the MD Anderson Cancer Center performed a dose and schedule finding study with 5-azacitidine in patients who were in a complete remission after HSCT. The dose-limiting toxicity was thrombocytopenia, and the optimal dose was 32 mg/m2 given subcutaneously for 5 days for 4 cycles. This study demonstrated that low-dose azacitidine may be administered in this population safely, and it may prolong event-free survival and overall survival, justifying further studies to optimize outcomes.52

Posttransplant therapy is also being evaluated in patients with multiple myeloma. Previous studies showed a potential benefit of thalidomide to prevent relapse after transplant, but its use is limited by neurotoxicity and other bothersome adverse effects. When given after autologous transplant in patients with nonprogressing disease, lenalidomide has been shown to prolong PFS compared with patients receiving placebo.53,54 However, a small but significant increased incidence of second primary cancers was reported in the lenalidomide-treated patients. Further study is needed to better define the risk of second malignancies. Patients should be aware of this potential safety issue when discussing treatment with lenalidomide after autologous HSCT. Bortezomib maintenance therapy after autologous HSCT has also been associated with prolonged PFS.55


Images Although many patients with cancer who are treated with high-dose chemotherapy and autologous or allogeneic HSCT experience long-term survival and cure of their disease, this modality is associated with many serious and potentially life-threatening complications. In the early 1970s, the posttransplant mortality rate was extremely high, and most allogeneic HSCT patients did not survive beyond 100 days because of infection, GVHD, organ toxicities, and leukemic relapse. Today, largely because of the availability of improved broad-spectrum antiinfective agents, immunosuppressive drugs, and hematopoietic growth factors, the transplant-related mortality rate after allogeneic HSCT with HLA-matched sibling donors has been reduced to less than 30%. The mortality rate is even lower with the use of RIC regimens. Causes of death are still related to transplant-related organ toxicity, GVHD, or immunosuppression. Until recently, allogeneic HSCT usually was restricted to patients younger than 50 years with an HLA-identical sibling donor and younger than 40 years with an HLA-matched unrelated donor. With advances in the prevention and treatment of transplant-related complications and the availability of RIC regimens, allogeneic HSCT now is being offered to patients up to the age of 70 years. The risk of transplant-related mortality after high-dose chemotherapy with autologous HSCT generally is less than 5%, depending on patient population and conditioning regimen. The mortality rate is lower with autologous transplants because of the lack of GVHD and associated complications of immunosuppression. Transplant-related mortality in autologous HSCT usually is caused by regimen-related toxicity or infection.

Table 117-1 lists the dose-limiting nonhematologic toxicities for several drugs that are commonly included in MAC regimens. These toxicities may be uncommon or rare with administration of conventional doses of specific drugs. When these agents are given in high doses, the toxicities seen with conventional doses (e.g., mucositis, enteritis, nausea, vomiting, hematuria) can be more frequent or severe. Several unusual and severe manifestations of regimen-related toxicities are discussed in this section.

Sinusoidal Obstruction Syndrome

Sinusoidal obstruction syndrome (SOS), formerly known as hepatic venoocclusive disease, occurs as a result of chemotherapy-induced damage to the sinusoidal endothelial cells of the liver, which leads to release of proinflammatory cytokines and further damage to the endothelium. Gaps develop between the endothelial cells allowing cellular debris to accumulate, causing the sinusoids to narrow and eventually become occluded. In addition, injury to the endothelial cells produces fibrin deposition and clot formation, further narrowing the sinusoids.56 These histologic changes can lead to obstruction of sinusoidal flow, reduced hepatic venous outflow, portal hypertension, and hepatic failure. Clinical signs of SOS include fluid retention (resulting in sudden weight gain and ascites), hepatomegaly (sometimes painful), and hyperbilirubinemia or jaundice. SOS usually occurs within the first 4 weeks after transplant, and the incidence of SOS ranges from 5% to 20% in most published series. Severe SOS is fatal in 50% to 75% of cases. Factors that have been reported to increase the risk of SOS include use of TBI-containing conditioning regimens (dose dependent), use of sirolimus for the prevention of GVHD, increased systemic exposure to busulfan, individual variability in cyclophosphamide metabolism, chronic viral hepatitis, and elevated liver function test results before transplant. Pretransplant exposure to gemtuzumab ozogamicin (Mylotarg®) has been implicated in the development of SOS in patients undergoing allogeneic HSCT, especially when given within a few months of transplant.

The pharmacokinetics of busulfan or cyclophosphamide may correlate with the risk of SOS.57 Because busulfan concentrations have been correlated with the risk of SOS, many HSCT centers adjust busulfan doses based on plasma concentrations. Exposure to the O-carboxymethyl-phosphoramide mustard metabolite of cyclophosphamide has been reported to correlate with the risk of SOS and nonrelapse mortality. In addition, when busulfan and cyclophosphamide are given in combination, the order in which they are given may contribute to the risk of SOS. Presumably because of the effect of busulfan on cyclophosphamide pharmacokinetics (increased exposure to active or toxic metabolites), liver toxicity appears to be worse when busulfan is given first, as traditionally given in the BuCy regimen. This effect appears to be ameliorated by reversing the order or delaying cyclophosphamide administration to 24 to 48 hours after busulfan.58

Some studies suggest that prostaglandin E1, unfractionated low-molecular-weight heparin, or ursodiol may be partially effective in preventing SOS.57 In a systematic review of three randomized trials comparing prophylactic ursodiol versus no treatment, Tay et al.59 found a reduced risk of SOS (relative risk [RR], 0.34; 95% confidence interval [CI], 0.17–0.66) with prophylactic ursodiol. These studies were conducted in patients undergoing myeloablative transplants. The transplant-related mortality rate was reduced (RR, 0.58; 95% CI, 0.35–0.95). Other outcomes, such as relapse and overall survival, were not affected. Defibrotide, a polydisperse oligonucleotide with fibrinolytic properties, is another agent that has been used successfully in the prophylaxis of SOS, mostly in pediatric transplant patients.56

Treatment is generally supportive, including fluid and electrolyte management. Mild to moderate disease generally resolves without specific therapy. Recombinant tissue plasminogen activator has been given to patients with severe SOS because of the possible role of the coagulation cascade in the pathogenesis of SOS. Responses have been reported, but patients also experienced a higher risk of bleeding.57 Some evidence supports the use of defibrotide in the treatment of patients with severe SOS, demonstrating improved response rates and lower mortality compared with historical control participants.56

Pulmonary Complications

Pulmonary complications after HSCT can be categorized as infectious and noninfectious (infectious complications are discussed in Chap. 100). Noninfectious complications can be caused by direct damage to the pulmonary tissue by chemotherapy or radiation used in the conditioning regimen, immune effects of the graft, or other causes not clearly understood. Early complications include diffuse alveolar hemorrhage, engraftment syndrome, and idiopathic interstitial pneumonitis. Diffuse alveolar hemorrhage is characterized by dyspnea, hypoxia, dry cough, and fever; chest radiography usually shows diffuse infiltrates in an alveolar pattern. Diffuse alveolar hemorrhage is diagnosed by examination of bronchoalveolar lavage fluid via bronchoscopy, which reveals progressively bloodier fluid with each instilled aliquot and negative findings on microbiologic analysis. Although the condition can be life-threatening or fatal, prompt treatment with high doses of corticosteroids is sometimes beneficial. A few patients have been treated successfully with recombinant human activated factor VIIa, desmopressin, or aminocaproic acid.60

Engraftment syndrome is characterized by fever, erythrodermatous skin rash, and noncardiogenic pulmonary edema can occur during neutrophil recovery after HSCT.61 The incidence of engraftment syndrome is not known because of the lack of uniform diagnostic criteria, although some series report that about 10% of patients who receive autologous HSCT develop the syndrome. Engraftment syndrome can progress to life-threatening respiratory failure with or without multiple organ failure. Corticosteroids are effective in some patients.

Idiopathic interstitial pneumonitis (also called idiopathic pneumonia syndrome) is defined as widespread alveolar injury in the absence of active lower respiratory tract infection after HSCT.62 Patients with idiopathic interstitial pneumonitis are clinically indistinguishable from patients with interstitial pneumonitis related to infection. Idiopathic interstitial pneumonitis is postulated to have a multifactorial etiology, including toxic effects of MAC, immunologic cell-mediated injury, inflammatory cytokine-induced lung damage, and occult pulmonary infections. The risk is similar in recipients of autologous or allogeneic HSCT but appears to be higher in patients who are conditioned with a TBI-containing regimen or who have acute GVHD. A mortality rate as high as 70% has been reported, and treatment consists of supportive care only. Etanercept has been beneficial in some patients with idiopathic interstitial pneumonitis.63

Late pulmonary complications cover a wide spectrum of disorders and include both obstructive and restrictive lung diseases.64 The most well-described of these disorders is bronchiolitis obliterans with or without organizing pneumonia. Although bronchiolitis obliterans is thought to be a result of chronic GVHD affecting the lungs, its pathogenesis has not been completely elucidated. Therapy consists of corticosteroids, which are approximately 50% effective. Patients with mild to moderate airflow impairment appear to have the best response. The survival rate at 5 years from diagnosis of bronchiolitis obliterans is less than 20%.

Graft Failure

Initial engraftment after high-dose chemotherapy conditioning regimens usually occurs in the first 2 to 4 weeks after transplant. Engraftment is evidenced by rising peripheral blood counts and the presence of hematopoietic precursor cells in the marrow. In allogeneic HSCT, the presence of donor cells (i.e., chimerism) is confirmed by PCR-based analysis of polymorphic DNA sequences of cells from the bone marrow and peripheral T cells. Full chimerism is defined as greater than 95% of cells of donor origin. In most patients, engraftment is sustained with complete recovery of hematopoiesis.

However, graft failure (loss of bone marrow function with resultant lose in peripheral blood counts) can occur. It can be the result of heavy pretreatment with chemotherapy or radiation therapy (or both); infusion of insufficient numbers of hematopoietic stem cells; viral infection; recurrence of primary hematologic malignancy; drug reaction (e.g., to ganciclovir); development of a secondary myelodysplasia; or in the allogeneic setting, an immunologic reaction between the donor and recipient caused by inadequate immunosuppression of the recipient (i.e., graft rejection). Two syndromes have been observed. Whereas early graft failure occurs when the rate of hematopoietic recovery is delayed or does not occur at all (primary graft failure or delayed engraftment), late graft failure is characterized by a decline in peripheral blood counts after initial engraftment (secondary graft failure). With widespread use of PBSCs and posttransplant growth factors, primary graft failure is rare after autologous and HLA-matched allogeneic HSCT but is not uncommon after UCB transplant. Graft failure that occurs after allogeneic HSCT, characterized by regrowth of immunocompetent recipient cells and a simultaneous loss of donor cells, is referred to as graft rejection. Graft rejection occurs rarely after HLA-matched allogeneic HSCT. An increased risk of graft rejection has been observed in recipients of hematopoietic stem cells from HLA-mismatched donors, recipients of T cell–depleted marrow, and patients with severe aplastic anemia. The long-term prognosis of patients with graft failure is poor. Despite supportive care and treatment with hematopoietic growth factors, death may result from infection or bleeding. In some patients with an allogeneic donor, a second infusion of stem cells can be attempted.

Hematopoietic growth factors usually are given after transplant to patients who receive autologous HSCT, although some clinicians believe that posttransplant filgrastim or sargramostim is unnecessary because of the already rapid engraftment seen after mobilized PBSC transplants.65,66 Sargramostim is dosed at 250 mcg/m2/day, and filgrastim is usually dosed at 5 or 10 mcg/kg/day. Growth factors can be initiated the day of, the day after, or as late as 7 days after the infusion of stem cells and are continued until neutrophil recovery to greater than an arbitrary number of neutrophils (500–1,000 cells/mm3 [0.5–1.0 × 109]). Pegfilgrastim appears to be equally efficacious to filgrastim in this setting.

Hematopoietic growth factors accelerate the rate of hematopoietic recovery in patients undergoing allogeneic HSCT. In a meta-analysis of 34 randomized controlled trials, no increased risk of acute GVHD or treatment-related mortality was observed when filgrastim or sargramostim was used after allogeneic HSCT.67 In another retrospective analysis of 2,719 patients from the CIBMTR, no association between filgrastim use and acute or chronic GVHD, transplant-related mortality, or survival was observed in recipients of HLA-identical sibling bone marrow, recipients of HLA-identical sibling peripheral blood, and recipients of HLA-matched unrelated donor bone marrow.68Filgrastim is most commonly used in patients receiving UCB transplants who are at increased of delayed engraftment and graft failure.

Results of studies with platelet growth factors, such as thrombopoietin and interleukin-11 (IL-11), given posttransplant have been disappointing. Platelet transfusions remain the standard of care in patients with thrombocytopenia below a given threshold (e.g., 10,000 cells/mm3 [10 × 109]) and in patients with significant bleeding.

Anemia may be problematic in the posttransplant setting, especially in patients receiving allogeneic HSCT. The etiology is unclear and most likely is multifactorial. Although erythropoietin administration may be useful in reducing the need for red blood cell transfusions, its use in cancer patients is associated with an increased risk of adverse events and is limited by FDA warnings and restrictions.

Graft-versus-Host Disease

GVHD is caused by immunocompetent allogeneic donor T cells reacting against recipient/host antigens presented by antigen-presenting cells (APCs). In that setting, donor T cells recognize unmatched major or minor histocompatibility antigens of the host as genetically foreign, become activated, proliferate, and attack recipient tissue, thereby producing the clinical syndrome of GVHD.

Two different clinical GVHD syndromes (acute and chronic) are recognized, depending on the time of onset and clinical presentation.69,70 Acute GVHD usually presents before day 100 after transplant (classic acute GVHD), but it can be persistent, recurrent, or late onset with clinical manifestations occurring after day 100. Acute GVHD observed after day 100 usually is the result of immunosuppression withdrawal for relapsed or persistent malignancy or administration of DLI or occurs in the setting of RIC. Chronic GVHD usually occurs after day 100, either with or without concurrent acute GVHD. Chronic GVHD without characteristics of acute GVHD (classic chronic GVHD) occurs after resolution of acute GVHD or de novo (no prior acute GVHD). An “overlap syndrome” may occur in which features of both acute and chronic GVHD are present simultaneously, usually when chronic GVHD develops before resolution of acute GVHD (also called progressive onset). Whereas acute GVHD usually is limited to the gastrointestinal tract, skin, and liver, signs and symptoms of chronic GVHD resemble an autoimmune disorder and can affect many organ systems.

A “hyperacute” form of GVHD may occur in patients with multiple HLA mismatches and in patients who receive T cell–replete transplants without adequate GVHD prophylaxis, especially after MAC regimens.71 Descriptions of hyperacute GVHD vary but usually include fever, generalized erythroderma, desquamation, and edema. More severe forms with accompanying organ failure have been seen in haploidentical donors. Hyperacute GVHD typically occurs about 1 week after transplant before engraftment of neutrophils. The response rate to first-line therapy appears to be lower in patients with hyperacute GVHD compared with patients who develop GVHD later after transplant, but no difference in survival has been observed.

Acute Graft-versus-Host Disease

The pathophysiology of acute GVHD has been described as a three-step process.72 In step 1, the conditioning regimen causes damage to the intestinal mucosa, leading to release of lipopolysaccharides into the systemic circulation. This stimulates secretion of inflammatory cytokines such as IL-1 and tumor necrosis factor-α (TNF-α). These cytokines upregulate MHC gene products and host APCs such as dendritic cells, which play a critical role in this immune response. In step 2, donor T cells are activated, and secretion of other cytokines (IL-2 and interferon-γ) by activated T cells results in recruitment of macrophages and alteration of target cells in the gastrointestinal tract and skin so that they are more susceptible to damage. In step 3, multiple cytotoxic effector cells (T cells and macrophages) are generated and contribute to target tissue injury by secreting more inflammatory cytokines that cause target cell apoptosis. The term “cytokine storm” is sometimes used to describe the critical role of inflammatory cytokines in this process.

Based on this three-step model, three general approaches have been used to prevent GVHD in humans. The first is to reduce host tissue damage with the use of RIC regimens. The second and most widely used approach is to modulate donor T cells by reducing T-cell numbers (T-cell depletion), activation (most immunosuppressive agents), or proliferation (antiproliferative agents). The third approach is to block inflammatory stimulation and effectors (e.g., TNF-α inhibition, IL-1 receptor blockade).

The principal target organs in acute GVHD are the skin, liver, and gastrointestinal tract.72 Acute GVHD is classified into four grades, depending on the number of organs involved and the degree of involvement of each organ (Table 117-2). Grade I disease involves only the skin. Grades II through IV involve the skin and the liver, gastrointestinal tract, or both. Acute skin GVHD usually is manifested as a generalized maculopapular rash that initially involves the face, ears, palms, soles, and upper trunk. The skin rash can spread to the rest of the body and, if untreated or refractory to treatment, will progress to bullae formation and desquamation similar to a burn injury. Gastrointestinal GVHD presents as a secretory diarrhea but may progress to abdominal pain or cramping and ileus; hemorrhage may also occur. GVHD of the upper intestinal tract appears as persistent nausea, vomiting, anorexia, and dyspepsia. The diagnosis of gastrointestinal GVHD should be made by biopsy of the intestinal tract (stomach, duodenum, or rectum). Hepatic GVHD usually is asymptomatic, consisting of hyperbilirubinemia and elevated alkaline phosphatase levels; increases in serum transaminases occur less consistently. The diagnosis can be made by biopsy, if possible.

TABLE 117-2 Consensus Grading of Acute Graft-versus-Host Disease


The overall incidence of moderate to severe (grades II–IV) acute GVHD ranges from 10% to more than 80%.72 Mortality directly attributable to acute GVHD or its treatment occurs in 10% to 20% of patients. The incidence of GVHD is related to the degree of histocompatibility, number of T cells in the graft, donor and recipient age and gender, intensity of the conditioning regimen, source of hematopoietic cells (bone marrow vs. peripheral blood), and prophylactic regimen. The most severe acute GVHD is observed in allogeneic HSCT with non–HLA-identical donors. In these settings, the incidence of grades II to IV acute GVHD can exceed 50% despite aggressive GVHD prophylaxis. Severe acute GVHD is a major cause of mortality with the risk of death increasing as the grade of GVHD increases. This risk is further increased if initial therapy is not effective.

Multiorgan acute GVHD and the drugs given to prevent or treat the disease are associated with delayed immunologic recovery and increased susceptibility to infections. Infection is often the primary cause of death in patients with GVHD. Patients with GVHD treated with an immunosuppressive regimen should receive prophylactic antiviral, antibacterial, and antifungal therapy and be monitored routinely for the occurrence of these infections.

Prevention of Acute Graft-versus-Host Disease Images Because treatment of established acute GVHD often is unsatisfactory, aggressive preventive measures usually are taken. The most common strategy used to prevent acute GVHD is to block the activation of T cells by administration of immunosuppressive agents.72 Several immunosuppressive agents have been used, including methotrexate, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, antithymocyte globulin, corticosteroids, and monoclonal antibodies directed at T cells. Table 117-3 shows the doses, toxicities, and monitoring of immunosuppressive agents used to prevent or treat GVHD. Most GVHD prophylaxis regimens combine immunosuppressive agents that affect different stages of T-cell activation. The most commonly used GVHD prophylaxis regimens are cyclosporine or tacrolimus and methotrexate. Another strategy is removing or depleting most T cells from donor bone marrow ex vivo before transplant by physical separation or by treatment with monoclonal antibodies directed at T cells.

TABLE 117-3 Immunosuppression for the Prevention and Treatment of GVHD


Despite standard prophylaxis with cyclosporine or tacrolimus and methotrexate, grade II to IV acute GVHD occurs in 30% to 50% in matched related donor transplants and 40% to 70% in matched unrelated donor transplants. IV cyclosporine or tacrolimus usually is started a few days before or on the day of transplant. Cyclosporine is given at an initial dosage of 3 to 5 mg/kg/day and tacrolimus at 0.02 to 0.03 mg/kg/day. Dosages are adjusted based on trough concentrations. Patients are converted to oral formulations when they can be tolerated. Cyclosporine and tacrolimus typically are given at full doses until days 50 to 100, gradually tapered in the absence of GVHD, and discontinued by day 180. Methotrexate is given IV on days 1, 3, 6, and 11 after transplant. The methotrexate dose is 10 mg/m2 except for the first dose given on day 1 (15 mg/m2). Alternatively, some centers use 5 mg/m2 (same schedule). The day 11 dose is sometimes omitted because of severe mucositis or hepatotoxicity or development of conditions that may prolong methotrexate systemic exposure (e.g., renal failure or third spacing). For patients who experience significant toxicity from methotrexate, monitoring of methotrexate levels with leucovorin rescue may be warranted.

Two large multicenter randomized trials, one in HLA identical sibling donors and the other matched unrelated donors, compared cyclosporine and methotrexate with tacrolimus and methotrexate.73,74 Both studies found the tacrolimus combination to be significantly superior to the cyclosporine combination in preventing grades II to IV acute GVHD. Survival did not differ between the two acute GVHD prophylaxis strategies, but the risk of renal impairment and need for hemodialysis were higher in patients receiving tacrolimus. The authors suggested that lowering the target blood levels to less than 20 ng/mL (20 mcg/L [24.8 nmol/L]) may reduce the renal toxicity of tacrolimus, and most centers currently use target trough tacrolimus levels of 5 to 15 ng/mL (5–15 mcg/L [6.2–18.6 nmol/L]). Based on the results of these two studies, many transplant centers use tacrolimus and methotrexate as first-line acute GVHD prophylaxis.

Because of the gastrointestinal and hematologic toxicities of methotrexate, other prophylactic regimens have been evaluated. Sirolimus has been successfully used for the prevention of rejection in solid organ transplant patients and has theoretical advantages for patients when used as prophylaxis of GVHD. This agent has been reported to have antiviral properties against CMV and Epstein-Barr virus and antitumor activity against some hematologic malignancies.75 Several studies have shown encouraging results with sirolimus when combined with a calcineurin inhibitor (tacrolimus or cyclosporine) in the prevention of GVHD, but the combination of tacrolimus and sirolimus is thought to be less toxic and more efficacious than cyclosporine and sirolimus. A typical dosing strategy for sirolimus includes a loading dose of 12 mg for 1 day followed the next day by 4 mg/day with further doses based on serum levels. In the initial studies evaluating tacrolimus and sirolimus, with the majority of patients receiving matched related donor transplants, the incidence of grade II to IV acute GVHD was 20% to 40% and grade III to IV was 5% to 15%.75 A phase III randomized trial was conducted through the Blood and Marrow Clinical Trials Network to compare tacrolimus and sirolimus versus tacrolimus and methotrexate as GVHD prophylaxis. Neutrophil and platelet engraftment were more rapid in the tacrolimus and sirolimus group. The incidence of grade II to IV and grade III to IV acute GVHD at 100 days were lower in the tacrolimus and sirolimus group (26 vs. 34%, P = 0.17; 8 vs. 15%, P= 0.05), but the primary end point of 114-day acute GVHD-free survival was not statistically different. Neither treatment-related mortality nor relapse at 2 years from transplantation was different between groups. Chronic GVHD was more common in the tacrolimus and sirolimus arm (54 vs. 43%, P = 0.044). Oral mucositis scores were lower in the tacrolimus and sirolimus arm, but the risk of SOS and thrombotic microangiopathy was higher in the tacrolimus and sirolimus arm. At 2 years from transplantation, disease-free and overall survival rates were not different between study arms. Tacrolimus and sirolimus can be used as an alternative to tacrolimus and methotrexate, but careful monitoring to minimize the risk of toxicities is required for both agents.76

Other methotrexate-sparing strategies have been evaluated for GVHD prophylaxis. Mycophenolate mofetil with tacrolimus was compared with tacrolimus and methotrexate in recipients of matched related and unrelated donors. The results of two small randomized trials have shown less toxicity with mycophenolate mofetil but little to no improvement in the rate of acute GVHD or overall survival.77,78 Single-agent cyclophosphamide (50 mg/kg on days 3 and 4 after transplant) also has been tested in patients receiving MAC. With single-agent cyclophosphamide posttransplant prophylaxis, 43% developed grade II to IV GVHD, and 10% had grade III to IV. The incidence of chronic GVHD was 10% at 26 months.79 Another novel GVHD prophylaxis regimen includes bortezomib given on days 1, 4, and 7 after transplant in addition to standard tacrolimus and methotrexate in RIC mismatched unrelated donor transplants. The incidence of grade II to IV GVHD was comparable to patients who received HLA-matched transplants.80The MD Anderson Cancer Center reported its results with the addition of pentostatin 1.5 mg/m2 weekly for 4 weeks combined with a calcineurin inhibitor and methotrexate. The addition of pentostatin to the standard GVHD prophylaxis regimen increased the proportion of patients alive without GVHD at day 100 compared with control participants.81 Although the addition of these novel agents is intriguing, it is difficult to compare outcomes because of different populations and study design. The CIBMTR is conducting a phase II trial evaluating the addition of agents like cyclophosphamide or bortezomib to standard prophylaxis regimens.

A reduction in the number of donor T cells in the stem cell donation decreases the risk of GVHD, but the role of ex vivo T-cell depletion is controversial.72 Earlier reports of this technique were associated with an increased risk of graft failure, delayed immune reconstitution, leukemic relapse, CMV reactivation, and Epstein-Barr virus–related lymphoproliferative disorders. Most of these studies occurred when bone marrow was the preferred stem cell source. The role of T-cell depletion is not well studied in patients who receive PBSC as a graft source. A recent study reported outcomes of a comparative analysis of among patients who received ex vivo T-cell depletion or the standard calcineurin inhibitor and methotrexate prophylaxis. Patients who received the T cell–depleted stem cells had lower rates of chronic GVHD. No differences in rates of graft rejection, leukemia relapse, treatment-related mortality, or overall survival rates were reported.82 Another approach is infusion of the T cells originally depleted from the graft later in the posttransplant period to prevent leukemic relapse. Because of the higher risk of GVHD in allogeneic HSCT with HLA-mismatched donors, T-cell depletion is sometimes included as part of the GVHD prophylaxis regimen in that setting.

Treatment of Acute Graft-versus-Host Disease Images Patients with mild skin-only acute GVHD (grade I) can be treated with topical corticosteroid preparations and counseled on the appropriate use of sunscreen. If a patient develops grades II to IV GVHD, prophylactic agents are continued, and high-dose corticosteroids in the form of IV methylprednisolone are given.72 The usual dosage is 1 to 2 mg/kg/day given in two divided doses; higher dosages have not been shown to be more efficacious. About 25% to 40% of patients with established acute GVHD respond to high-dose corticosteroids. If the patient responds, the corticosteroid dose is tapered gradually over several weeks to months, depending on response. In patients who experience a flare in GVHD during the taper phase, therapy consists of increasing the corticosteroid dose and then tapering more slowly. Oral beclomethasone dipropionate, a topically active corticosteroid, has been shown to reduce the frequency of gastrointestinal GVHD relapses when continued after prednisone taper.83 Administration of beclomethasone has been associated with a better survival at 200 days and 1 year after transplant. Budesonide, another nonabsorbable corticosteroid, has also been evaluated in uncontrolled studies and may also help to reduce the need for sustained use of high-dose systemic corticosteroid administration.84

GVHD-associated mortality is strongly correlated to response to initial treatment and ranges from about 25% in patients who had a complete response to about 80% in patients who had no response or progressive disease. Several randomized trials have evaluated other agents combined with methylprednisolone in an effort to improve response to initial therapy for acute GVHD.72 The combination of methylprednisolone and the anti–TNF-α monoclonal antibody infliximab has not been shown to increase response rate compared to methylprednisolone alone.85 The Blood and Marrow Transplant Clinical Trials Network randomized 180 patients to methylprednisolone 2 mg/kg/day combined with etanercept, mycophenolate mofetil, denileukin diftitox, or pentostatin.86 After 28 days of treatment, complete response rates were 60% for mycophenolate mofetil, 53% for denileukin diftitox, 38% for pentostatin, and 26% for etanercept. Efficacy and toxicity data suggested that the use of mycophenolate mofetil plus corticosteroids was the most promising regimen to compare with corticosteroids alone in a definitive phase III trial. This trial was halted early when a futility rule was met at a planned interim analysis. GVHD-free survival 56 days after randomization was not different between the groups. Based on the current published data, the use of glucocorticoid treatment with an additional agent for initial therapy of acute GVHD should only be done within the confines of a clinical trial.87

The mortality rate of patients with steroid-refractory GVHD is high. Criteria and indications for initiating secondary therapy for steroid-refractory acute GVHD have not been well defined in the literature. Although different centers may have varying criteria, in general, if the manifestations of acute GVHD in any organ worsen over 3 days of corticosteroid treatment or symptoms do not improve by 5 days, the patient likely will not respond to corticosteroids, and secondary therapy should be considered.87 From the available data, there is no standard treatment of patients with steroid-refractory acute GVHD because very few prospective comparative studies have been conducted to assess the efficacy of individual agents. Second-line therapy has consisted of continuation of corticosteroids with the addition of one or more of the following: antithymocyte globulin, mycophenolate mofetil, sirolimus, infliximab, etanercept, denileukin diftitox, alemtuzumab, or pentostatin.87,88 One approach that has shown benefit as corticosteroid-sparing therapy is extracorporeal photopheresis. During this procedure, the patient’s blood is exposed extracorporeally to 8-methoxypsoralen followed by ultraviolet A radiation and then returned to the patient. This process is thought to result in suppression of T-cell reactivity and induction of regulatory T cells. Clinical results have been positive, especially in patients with skin GVHD.89 The choice of a second-line regimen for acute GVHD should be based on the risk of potential toxicities, interactions with other agents, convenience, and cost.

Clinical Controversy…

Optimal treatment of steroid-refractory GVHD is unclear. Comparative trials are needed to determine a standard approach to this difficult condition.

Chronic Graft-versus-Host Disease

Chronic GVHD is the major determinant of late transplant-related morbidity and mortality.69,90 The pathophysiology of chronic GVHD is poorly understood but is generally thought to be a result of a persistence of pathogenic donor T cells that are responsible for tissue damage through direct cytolytic attack, lack of immune tolerance, stimulation of inflammatory cytokines, or B-cell activation and antibody production.90 Chronic GVHD is often considered an autoimmune disease because of its similarity to other autoimmune disorders.

The incidence of chronic GVHD in patients who survive more than 150 days ranges from 20% to 70%.91 The risk of chronic GVHD increases with increasing donor and recipient age and is higher in patients who receive transplants from HLA-nonidentical donors and in patients who receive PBSC transplants (especially with higher CD34+ cell doses). The incidence of chronic GVHD is rising because of increasing use of alternative donors, use of PBSCs as the graft source, use of DLI for treatment of recurrence, and older recipient age. Previous acute GVHD increases the risk of chronic GVHD, but about 20% to 30% of patients who develop chronic GVHD after HLA-matched allogeneic HSCT have no history of acute GVHD. Unlike acute GVHD, prophylactic immunosuppression does not appear to reduce the incidence or severity of chronic GVHD.

Chronic GVHD resembles autoimmune diseases and can affect any organ or tissue of the body. The most common sites involved are the skin, mouth, liver, and eye, but other sites include the gastrointestinal tract, joints, muscles, and lungs. The National Institutes of Health (NIH) Consensus Development Project developed standardized criteria for the diagnosis of chronic GVHD and proposed a clinical scoring system for the evaluation of patients with chronic GVHD based on the extent of organ damage and degree of functional impairment.70 The Working Group recommends that the diagnosis of chronic GVHD be made with the presence of at least one diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or a distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by biopsy or other test (e.g., Schirmer test).

The clinical scoring system categorizes chronic GVHD into mild, moderate, and severe.70 Mild chronic GVHD involves only one or two organs or sites (except the lung) with no clinically significant functional impairment. Moderate chronic GVHD involves at least one organ or site with clinically significant but no major disability, three or more organs or sites with no clinically significant functional impairment, or mild lung involvement. Severe chronic GVHD indicates major disability caused by chronic GVHD or at least moderate lung involvement.

Patients with mild skin-only chronic GVHD can be treated with a variety of topical preparations, such as clobetasol, tacrolimus, and pimecrolimus.90 Initial treatment of patients with more severe or systemic involvement of chronic GVHD consists of prednisone 1 mg/kg/day followed by taper with or without a calcineurin inhibitor. Although calcineurin inhibitors do not conclusively improve outcomes, it is often considered to reduce toxicities of prolonged steroid therapy, especially in patients who may be at high risk for prednisone-related complications.90 Prospective randomized trials evaluating the addition of mycophenolate mofetil to prednisone for initial therapy have shown limited to no benefit compared to prednisone alone.92 Treatment is continued until signs and symptoms of the disease have resolved and then are tapered gradually over an extended period of time. Patients with chronic GVHD may require prolonged immunosuppressive treatment for an average of 2 to 3 years from the initial diagnosis.

In addition to treatment specifically for chronic GVHD, ancillary therapies should be recommended to lessen the symptoms of chronic GVHD.93 Patients should be educated on the use of sunscreens (and avoidance of sun exposure) to reduce skin injury and exacerbation of GVHD skin lesions. Nonsclerotic skin lesions without erosions or ulcerations may respond well to emollients in addition to topical corticosteroids. Patients should be advised to maintain good oral hygiene with routine dental care. Saliva substitutes can be given for dry mouth symptoms, and topical corticosteroid gels can be used for localized and symptomatic oral lesions. Artificial tears or, if necessary for more severe symptoms, cyclosporine or corticosteroid eye drops are useful for patients with chronic GVHD manifesting as dry eyes or conjunctivitis. Physical therapy is recommended to reduce functional loss as a result of steroid myopathy, joint contractures, and deconditioning.

Patients who do not respond to initial therapy have a very poor prognosis. Uncontrolled trials have investigated several therapies with varying degrees of success. When choosing initial salvage therapy, clinicians should consider agents with documented activity and an adequate safety profile as well as agents that are steroid sparing.94 Agents with reported activity in refractory chronic GVHD include thalidomide, extracorporeal photophoresis, tacrolimus, sirolimus, pentostatin, mycophenolate mofetil, hydroxychloroquine, rituximab, imatinib and others.9496 The Blood and Marrow Clinical Trials Network has initiated a randomized phase II/III trial comparing the following three treatment strategies: sirolimus and prednisone; sirolimus, prednisone, and extracorporeal photophoresis; and sirolimus, prednisone, and a calcineurin inhibitor. Eligible subjects must have chronic GVHD, as diagnosed by NIH consensus criteria, and must be either untreated and high risk or not responding to standard therapy. The outcomes of this trial may help guide clinicians in the treatment of chronic GVHD.

Monitoring for long-term drug toxicities and infectious complications is critical during long-term immunosuppression. Infection is the primary cause of death in patients with chronic GVHD, and antimicrobial prophylaxis is an important component of the care of patients being treated for chronic GVHD.93,94 Patients should receive oral trimethoprim–sulfamethoxazole, penicillin, an antifungal azole agent, and acyclovir to prevent infections commonly seen in immunocompromised patients. Routine monitoring for CMV reactivation should be performed. Some HSCT centers also administer IV immunoglobulin to patients with low serum immunoglobulin G levels. Patients who remain on long-term steroids should be monitored for steroid-induced osteoporosis and diabetes mellitus. Other potential long-term complications of chronic GVHD therapies include hyperlipidemia, cataracts, myelosuppression, elevated blood pressure, and renal dysfunction.


Patients undergoing high-dose chemotherapy with autologous or allogeneic HSCT are severely immunocompromised and therefore are at high risk for bacterial, fungal, and viral infections. Management of these infections is discussed in detail in Chapters 99 and 100.

Late Complications

With the success of HSCT, the number of long-term survivors has grown. Many survivors experience delayed complications of transplantation and treatments used to prevent or treat those complications, including restrictive and obstructive pulmonary disease, bone and joint disease (including osteoporosis and avascular necrosis), cataract formation, endocrine dysfunction (including sterility and thyroid dysfunction), impaired growth and development, infections, cardiovascular disease, chronic renal and hepatic dysfunction, and secondary malignancies. These effects are more frequent after allogeneic compared with autologous and among allogeneic transplant patients, those with chronic GVHD tend to have a higher prevalence of multiple health conditions than those without chronic GVHD.97,98 Physical recovery tends to occur earlier than psychological or work recovery. Full recovery usually takes several years, and about two thirds of patients are without major limitations by 5 years. The Bone Marrow Transplant Survivor Study compared late mortality (2 years after HSCT) in allogeneic and autologous patients with that of the general population.99,100 Both types of transplants were associated with a several-fold increase in risk of premature death; relative mortality decreased with time but remained significantly elevated even 10 years after transplant. The leading cause of death was relapse of primary disease in both allogeneic and autologous patients, but allogeneic HSCT patients also continued to die from complications of chronic GVHD, but autologous HSCT patients frequently succumbed to secondary malignancies. Long-term monitoring of HSCT patients is required, both by transplant clinicians and primary care providers who are knowledgeable in the care of these patients, to prevent and treat late complications when such therapies are available.




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