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1938 Section XIV: Transplantation

67. Fisbein TN, Kaufman SS, Florman SS, et al: Isolated intestinal transplanta-tion: proof of clinical efficacy. Transplantation 76(4):636, 2003.

68. Sudan DL, Kafman SS, Shaw BW Jr, et al: Isolated intestinal transplantationfor intestine failure. Am J Gastroenterol 95(6):1506, 2000.

69. Pascher A, Kohler S, Neuhaus P, et al: Present status and futureperspectives of intestinal transplantation. Transpl Int 21(5):401414,2008.

70. Abu-Elmagd KM, Costa G, Bond GJ, et al: Evolution of the immunosup-pressive strategies for the intestinal and multivisceral recipients with specialreference to allograft immunity and achievement of partial tolerance. TransplInt 22(1):96109, 2009.

71. Abu-Elmagd KM, Costa G, Bond GJ, et al: Five hundred intestinal and mul-tivisceral transplantations at a single center: major advances with new chal-lenges. Ann Surg 250(4):567581, 2009.

CHAPTER 188 HEMATOPOIETIC CELLTRANSPLANTATIONPAUL A. CARPENTER, MARCO MIELCAREK AND ANN E. WOOLFREY

GENERAL PRINCIPLESHematopoietic cell transplantation (HCT) typically is per-formed in patients with life-threatening disorders of thehematopoietic system. The procedure has considerable risks oftransplant-related morbidity and mortality with a substantialproportion of patients requiring intensive medical care [1,2](Fig. 188.1). Thus, knowledge of the basic principles of thetransplant procedure and an understanding of potential com-plications including their differential diagnosis are importantfor improving the outcome of critically ill patients after trans-plantation.

HCT is potentially curative treatment for diseases includ-ing leukemia, lymphoma, myelodysplasia, multiple myeloma,aplastic anemia, hemoglobinopathies, and congenital immunedeficiencies. In selected cases, HCT may also have a role inthe treatment of solid tumors such as germ cell tumors, renalcell cancer, and breast cancer, and as a type of immunosup-pression for patients with life-threatening autoimmune diseases(Table 188.1). In preparation for HCT, high-dose chemother-apy alone, or combined with irradiation therapy, is used toeradicate the underlying disease and to induce transient im-munosuppression in the recipient to prevent graft rejection, apossible complication mediated by immunologic host-versus-graft reactions after allogeneic HCT. High-dose chemoradia-tion is followed by intravenous infusion of the graft, whichcontains hematopoietic stem cells (HSCs) that home to thebone marrow and reconstitute the hematopoietic system ofthe patient. In contrast to autologous HCT, allogeneic HCTrequires prophylactic immunosuppressive therapy after trans-plant to prevent or mitigate graft-versus-host disease (GVHD),an inflammatory syndrome that primarily affects the skin, gas-trointestinal (GI) tract, and liver.

Classification

HCT can be categorized according to the source of stem cells,the type of donor, or the intensity of the preparative regimen.The type of HCT used in an individual patient is a complex de-cision based on the patients age, diagnosis, disease stage, priortreatments, donor availability, and presence of comorbidities.

Stem Cell Source

HSCs capable of reconstituting hematopoiesis in recipi-ents given myeloablative therapy can be obtained from bone

marrow, peripheral blood, or umbilical cord blood (UCB). Thestem cell products obtained from each of these sources are char-acterized by distinct kinetics of engraftment and recovery of im-mune function after transplantation. These features may affectthe risks of developing infectious complications and GVHDduring the posttransplant period.

Bone Marrow. Bone marrow was historically the most com-mon source of stem cells for HCT but is now used very infre-quently for autologous HCT. Bone marrow is harvested fromthe iliac crest under general anesthesia, from appropriate vol-unteer donors. Engraftment after bone marrow transplant isevidenced by rising neutrophil and platelet counts and occursbetween 3 and 4 weeks after transplant.

Mobilized Peripheral Blood. Growth factormobilized pe-ripheral blood stem cells (PBSC) are the predominant source ofHSC for allogeneic HCT in adults and are almost always usedas HSC rescue for autologous HCT [3]. PBSCs are recognizedon the basis of their expression of the CD34 surface markerand can be collected from the blood by a semiautomated proce-dure called leukapheresis. To promote peripheral blood mobi-lization of PBSC for autologous HCT, patients typically receivechemotherapy followed by administration of G-CSF, which hasthe benefit of chemotherapy-mediated tumor debulking priorto stem cell collection [4]. For allogeneic HCT, PBSCs are mo-bilized from healthy donors using growth factor alone.

Engraftment after PBSC transplantation occurs approxi-mately 1 week earlier compared with bone marrow trans-plantation, which is likely related to the greater proliferativepotential of stem and progenitor cells in PBSC. PBSC allograftscontain approximately 10 times more T cells than marrow,which influences the development of GVHD, graft rejection,and rate of relapse for malignancies after HCT [5]. Random-ized studies of allografts donated from HLA-matched siblingshave shown a higher risk for relapse and lower risk for chronicGVHD among recipients of marrow compared with PBSC[3,6].

Umbilical Cord Blood. UCB contains HSC sufficient for recon-stitution of hematopoiesis, which can be collected from the pla-centa and umbilical cord immediately after delivery of a baby.UCB banking has increased the likelihood of donor availabil-ity for patients with rare HLA haplotypes. T cells containedin UCB are immunologically naive, which allows for less strin-gent HLA matching between donor and recipient. The numberof HSC contained in a typical UCB unit is several orders of



Chapter 188: Hematopoietic Cell Transplantation 1939

FIGURE 188.1. Complications after myeloablative allogeneic hematopoietic cell transplantation. BOOP,bronchiolitis obliterans with organizing pneumonia; DAH, diffuse alveolar hemorrhage; GVHD, graft-versus-host disease; HHV6, human herpes virus 6; HSV, herpes simplex virus; IPS, idiopathic pneumoniasyndrome; SOS, sinusoidal obstruction syndrome.

TA B L E 1 8 8 . 1

INDICATIONS FOR ALLOGENEIC OR AUTOLOGOUSTRANSPLANTS

Allogeneic Autologous

High-risk acute leukemiaAcute myeloid leukemiaAcute lymphoblastic leukemia

Chronic leukemiaChronic myeloid leukemiaChronic lymphocyticleukemia

Juvenile myelomonocyticleukemia

Chronic myelomonocyticleukemia

Myelodysplastic syndromes

Bone marrow failure syndromesSevere aplastic anemia

Severe immunodeficiencysyndromes

Inborn errors of metabolism

HemoglobinopathiesThalassemia majorSymptomatic sickle celldisease

High-risk lymphomaNon-Hodgkins

lymphomaHodgkins lymphoma

Multiple myeloma

Solid tumorsNeuroblastomaPoor-risk breast cancerPoor-risk sarcoma

InvestigationalOther poor-prognosis

tumorsRefractory autoimmune

disorders

magnitude lower compared with typical bone marrow or PBSCharvests. The smaller number of HSC may result in delayed en-graftment, increased risk for graft rejection, and infection [7,8].Recent studies have shown that infusion of two UCB units in-creases the total number of HSC, which seems to decrease therisk of graft rejection, thus giving adults as well as children theoption of UCB transplantation [9].

Donor Type

Autologous. Transplantation of HSC donated by the patient istermed autologous HCT. Most commonly, autologous PBSCare cryopreserved and then thawed and reinfused once thehigh-dose preparative therapy has been completed. High-dosechemoradiation is given to kill tumor cells that may not be sus-ceptible to conventional-dose cytotoxic therapy. The success ofthe autologous transplant procedures relies exclusively on thetumor-eradicating potential of the preparative regimen [10].The effect the conditioning regimen has on extrahematopoietictissues determines the dose-limiting toxicity of the procedure.Relapse after autologous HCT may occur from tumor cells thathave survived the conditioning therapy or from those that con-taminated the graft, although the former mechanism appearsto be more important.

Syngeneic. Transplantation of HSCs donated from identical(monozygotic) twins is termed syngeneic HCT. When thereis no genetic disparity between donor and recipient, the biol-ogy of the transplant is similar to autologous HCT. Comparedwith allogeneic HCT from HLA-matched related or unrelateddonors, relapse rates are higher after syngeneic HCT, whichhas been attributed to the absence of malignancy-eradicatinggraft-versus-host reactions.

Allogeneic. Transplantation of HSCs cells donated by anotherindividual is termed allogeneic HCT. Allogeneic HCT requires




availability of an HLA-compatible related or unrelated donor.Because of the inheritance pattern of HLA haplotypes, thestatistical likelihood of two siblings being genotypically HLAidentical is 25%. Donor-recipient HLA genotypic identity isassociated with the lowest risks for immunologically medi-ated complications such as graft rejection and GVHD [11].For approximately 70% of patients who do not have an HLA-identical sibling donor, a search for a suitable unrelated donorcan be considered. HCT from HLA-matched unrelated donors,however, has traditionally been associated with higher risksof transplant-related morbidity and mortality compared withHCT from HLA-identical related donors. Use of unrelateddonors who are matched using molecular HLA typing methodscan improve outcomes considerably, and, for some diseases,survival of patients with unrelated grafts has approached thatwith HLA-identical sibling grafts [12,13].

The worldwide development of donor registries has in-creased the number of available HLA-matched unrelateddonors and umbilical cord blood units for patients withoutsuitable related donors. Another alternative source of HSC is ahaploidentical relative, such as a parent, defined by the inher-itance of one identical haplotype and mismatching of one ormore HLA loci with the noninherited haplotype. Over the pastdecade, technological advances have improved the outcome forrecipients of HLA-disparate grafts. When more than a singleHLA antigen disparity is present, depletion of T cells from thegraft is necessary to prevent life-threatening GVHD. Depletionof T cells from the marrow may be accomplished ex vivo byusing immunologic or physical methods to target T cells for re-moval. Because T cells play an important role in establishmentof the graft, early immune reconstitution, and tumor control,T-cell depletion has been associated with higher rates of graftfailure, opportunistic infections, and relapse. Strategies to se-lectively deplete alloreactive T cells remain an active area ofresearch.

Intensity of the Preparative Regimen

Myeloablative

In myeloablative HCT, the preparative regimen ablates thehematopoietic system of the patient and leads to transientbut profound myelosuppression with pancytopenia. The trans-planted hematopoietic cells reconstitute the ablated hematopoi-etic system in the recipient. High-dose chemotherapy regimens,with or without doses of total body irradiation (TBI) thatexceed 6 Gy, combine different drug combinations that havenonadditive toxicities with radiation. The aim of high-dosetherapy is to overcome the genetic heterogeneity of tumorsby employing agents with different mechanisms of action. Al-though the myeloablative regimens used for autologous HCTtypically consist of drugs that provide maximum tumor erad-ication with tolerable toxicity to the patient, regimens usedfor allogeneic HCT also must provide sufficient recipient im-munosuppression to prevent graft rejection. Myeloablativepreparative regimens are associated with substantial risks oftransplant-related toxicity and mortality, particularly amongolder or medically ill patients [14].

Nonmyeloablative

Nonmyeloablative preparative regimens for allogeneic HCTare mainly immunosuppressive and aimed at preventing graftrejection. The underlying malignancy is eliminated through theensuing immunologic graft-versus-tumor effects, provided thetumor expresses antigens that make it a target for immune at-tack. Compared with myeloablative allogeneic HCT, the ex-trahematopoietic toxicity from nonmyeloablative preparativeregimens is considerably milder, an important consideration

for older patients or those with comorbidities [15,16]. Typicalpost-HCT complications such as GVHD and infections, how-ever, are not prevented by nonmyeloablative conditioning butmay have a delayed onset.

Epidemiology

Current estimates of annual numbers of HCT are 45,000 to50,000 worldwide. During 2006, 16,000 transplants were reg-istered with the Center for International Blood and MarrowTransplant Research (CIBMTR), of which one-half were al-logeneic. Allogeneic HCT is most commonly performed inadults using PBSC grafts. In contrast, children now predom-inantly receive cord blood or marrow grafts (NMDP Web site:http://www.marrow.org/). PBSC is less used in children becauseof the difficulties harvesting PBSC from young children and be-cause of the increased risk of chronic GVHD.

Risk Factors for Transplant-RelatedMorbidity and Mortality

The likelihood of developing transplant-related complicationsdepends on patients age, the intensity of the preparative reg-imen, the type and stage of the underlying disease, and thepresence of comorbidities. Prognosis is most heavily influencedby the underlying disorder. Patients with chronic malignanciesand nonmalignant disorders, such as aplastic anemia, have ahigher likelihood of survival compared to those with aggres-sive malignancies, who have a greater tendency to relapse fol-lowing HCT. Mortality caused by the transplant procedure,and not from disease relapse, termed transplant-related mor-tality, ranges from 15% to 40% for allogeneic HCT recipi-ents compared to 5% to 10% for autologous HCT recipients.HLA disparity between donor and recipient increases the riskof transplant-related mortality owing to the greater likelihoodof developing GVHD and graft rejection. The risk for mor-tality increases significantly with age, although improvementsin supportive care and donor selection and the introductionof nonmyeloablative preparative regimens have increased theproportion of patients older than 60 years who benefit from al-logeneic HCT. Recent studies have demonstrated that pretrans-plant assessment of comorbidities using simple but transplant-specific comorbidity scoring systems has improved the abilityto predict subsequent transplant-related mortality and survival[14,17].

TRANSPLANT-RELATEDCOMPLICATIONS

Transplanted-related complications include infections, regi-men-related toxicity (RRT), and complications associated withalloreactivity. More intense conditioning regimens and higherdegrees of donor-recipient HLA disparity are associated withgreater risk for infection. Regimen-related toxicities includeprofound cytopenias and organ damage that follow myeloabla-tive conditioning. The complications seen after allogeneic HCTthat may occur irrespective of the intensity of the conditioningregimen include rejection, GVHD, and hemolysis.

Regimen-Related Pancytopenia

Reconstitution of hematopoiesis after HCT occurs in an or-derly pattern; in general, neutrophil recovery occurs first, fol-lowed by recovery of platelets and red blood cells. The tempoof hematopoietic reconstitution varies according to the type




of HSC product, being earlier after PBSC grafts and later af-ter UCB grafts, compared with marrow grafts. Transfusionsof platelets and red blood cells often are needed until thereis marrow recovery. Transfusion of red blood cells should bedetermined by the clinical condition of the patient, includ-ing hemodynamic stability and presence of active hemorrhage.Red blood cell transfusions generally are indicated when thehemoglobin falls below 8 g per dL. Platelet transfusions are in-dicated when the platelet count falls below 10,000 cells per Lto minimize the risk for spontaneous bleeding [18,19]. Trans-fusions thresholds should be increased before invasive proce-dures or in patients with bleeding to a level appropriate for anyother intensive care unit (ICU) patient [18]. Platelet consump-tion may be increased in patients with fever, disseminated in-travascular coagulation (DIC), or splenomegaly. Patients whohave become alloimmunized to platelet antigens demonstratepoor response to platelet transfusions and may achieve higherplatelet counts by limiting the number of donor exposures,controlling fever or DIC, using platelet products that are lessthan 48 hours old, or use of nonpooled (single-donor) or HLA-matched platelets [20,21].

Precautions should be taken in preparation of blood prod-ucts for transfusion into HCT patients because passenger lym-phocytes pose a risk for generating GVHD and latent virusesmay be transferred through leukocytes. Except for the stem cellgraft, all other components should be irradiated at a dose of1,500 to 3,000 cGy to inactivate or eliminate contaminatinglymphocytes. Depletion of leukocytes or use of blood compo-nents that test seronegative for cytomegalovirus (CMV) is effec-tive for prevention of CMV transmission to CMV-seronegativerecipients [21]. Removal of white blood cells from platelet andred blood cell products also decreases the risk for alloimmu-nization of the patient [22].

Regimen-Related Toxicity

High-dose cytotoxic chemotherapy with or without doses ofTBI exceeding 6 Gy may severely disrupt mucosal integrity andhas the potential to cause RRT in the skin, GI tract, liver, blad-der, lung, heart, kidney, and nervous system. RRT occurs pre-dominantly within the first 3 to 4 weeks after conditioning [23]and is more common after myeloablative than nonmyeloabla-tive conditioning. RRT increases the risk for opportunistic in-fection, which is already high because of concomitant profoundimmunosuppression and regimen-related cytopenias. This sec-tion will focus on the noninfectious complications of individualorgans specifically attributable to conditioning toxicity. Oppor-tunistic infection or, after allografting, GVHD must strongly beconsidered as etiologies for organ dysfunction in the differen-tial diagnosis of RRT. These alternative diagnoses are coveredelsewhere under the appropriate subsection.

Skin

Generalized skin erythema is common after doses of TBI ex-ceeding 12 Gy but is self-limiting and rarely associated withskin breakdown. Regimens that contain cytosine arabinoside(Ara-C), thiotepa, busulfan, etoposide, and carmustine mayalso cause erythema. Hyperpigmentation typically follows theinflammatory dermatitis, with skin folds often being particu-larly noticeable. Skin biopsies during the first 3 weeks aftertransplant often show nonspecific inflammatory changes irre-spective of cause, making them frequently unhelpful in distin-guishing between RRT, drug allergies, or acute GVHD [24].

Gastrointestinal Tract

Mucositis. Most patients who receive high-dose conditioningregimens develop mucositis. Symptoms include inflammation,

desquamation, and edema of the oral and pharyngeal epithe-lial tissue that typically presents within the first several daysafter HCT and usually resolves by the third week. Anorexia,nausea, or other intestinal symptoms that persist after day21 are more likely to be caused by GVHD or infection. Severemucositis places patients at risk for aspiration and occasion-ally airway compromise, indicating the need for endotrachealintubation. Damage to the mucosa of the lower GI tract resultsin secretory diarrhea, cramping abdominal pain, and anorexia,and it facilitates translocation of intestinal bacteria with sepsis[23,25].

Mucositis is treated supportively with total parenteral nu-trition, administration of intravenous fluids, and intravenousnarcotics for pain control. It is important to recognize an ia-trogenic narcotic bowel syndrome, characterized by abdominalpain and bowel dilatation, which occasionally may be a sideeffect of efforts to control painful symptoms of mucositis orsinusoidal-obstruction syndrome [26].

Acute Upper Esophageal Bleeding. The combination of mu-cositis, thrombocytopenia, and severe retching may result ina MalloryWeiss tear, or esophageal hematoma [27]. The lat-ter condition may have associated symptoms of dysphagia andretrosternal pain, and can be diagnosed by computed tomog-raphy (CT) scan. These conditions are treated supportivelywith transfusions to maintain platelet counts of greater than50,000 per L and optimal management of nausea and vom-iting.

Liver

Sinusoidal Obstruction Syndrome. Sinusoidal obstruction syn-drome (SOS; formerly referred to as veno-occlusive disease) de-velops in 10% to 60% of patients and is a clinical diagnosisbased on the triad of tender hepatomegaly, jaundice, and un-explained weight gain usually within 30 days after HCT and inthe absence of other explanations for these symptoms and signs[28,29]. It is more likely to be severe in patients with cirrhosis orfibrosis of the liver, or those with a history of hepatitis or liver ir-radiation (greater than 12 Gy), or chemotherapy-induced SOS[29,30].

Elevations of total serum bilirubin and serum transaminasesare sensitive but nonspecific markers for SOS, and urinarysodium levels are typically low. A hepatobiliary ultrasound mayshow hepatomegaly, ascites, and dilatation of the hepatic veinor biliary system [31]. Doppler ultrasonography may show at-tenuation, or diagnostic, reversal of hepatic venous flow, butabsence of this pattern does not exclude SOS [32]. If the diag-nosis remains unclear, a transvenous liver biopsy may be help-ful, and simultaneous measurement of hepatic venous pressureshowing a gradient of greater than 10 mm Hg is highly specificfor SOS [33].

Other causes of jaundice after HCT seldom lead to re-nal sodium avidity, rapid weight gain, or hepatomegaly. Cy-closporine, methotrexate, and total parenteral nutrition are ia-trogenic causes of hyperbilirubinemia, although rarely causelevels greater than 4 mg per dL [34]. Combinations of illnessesthat may mimic SOS are cholangitis lenta (cholestatic effects ofendotoxin [35], especially when combined with renal insuffi-ciency); cholestatic liver disease with hemolysis and congestiveheart failure; GVHD and sepsis syndrome.

Once SOS is established, mathematical models can be usedto predict prognosis, based on rates of increase in serum biliru-bin and weight according to the elapsed time after transplan-tation [29,36]. The treatment for the 70% to 85% of patientswho are predicted to have a mild or moderate course is largelysupportive, with attention to management of sodium and waterbalance to avoid fluid overload [29]. Diuretics must be used ju-diciously to avoid depletion of intravascular volume and renal




hypoperfusion. Paracentesis is indicated if the degree of ascitesthreatens respiratory function. There is no universally effectivetherapy for severe SOS. However, multiple studies, includinga recent large international multicenter phase II clinical trial,have demonstrated 30% to 60% complete remission rates withdefibrotide, even among patients with severe SOS [37]. There isno support for insertion of peritoneovenous shunts and limitedsupport for use of portosystemic shunts to reduce ascites [38].Liver transplantation has been successful in a small number ofpatients [39].

Lung

Pulmonary complications occur in 40% to 60% of patients af-ter HCT [40,41]. Noninfectious pulmonary problems that mayoccur within 30 days from the transplant include idiopathicpneumonia syndrome (IPS), diffuse alveolar hemorrhage, pul-monary edema [42] due to excessive sodium and fluid ad-ministration or associated with SOS, or acute cardiomyopathyinduced by cyclophosphamide, and sepsis with adult respira-tory distress syndrome (ARDS) [43]. These complications oc-cur more frequently in older patients, those who receive higher-dose conditioning regimens, and those with allogeneic donors,particularly HLA-disparate donors [44]. Although the inci-dence of life-threatening pulmonary infections has decreasedover the past decade due to the introduction of routine antimi-crobial prophylaxis, pulmonary complications continue to bea leading cause of death.

Idiopathic Pneumonia Syndrome. IPS is defined as a noninfec-tious inflammatory lung process that may be triggered by TBIand chemotherapies such as carmustine or busulfan. IPS hasbeen reported in 5% to 10% of patients and occurs with a me-dian onset of 2 to 3 weeks after myeloablative HCT [44,45].Contributing factors to IPS lung injury may be release of inflam-matory cytokines due to alloreactivity or sepsis. The clinicalsymptoms cannot be distinguished from infection, and may in-clude fever, nonproductive cough, and tachypnea. Hemoptysisis infrequent and more likely related to indicate invasive fungaldisease or diffuse alveolar hemorrhage. Radiographic imagingshows diffuse interstitial or multifocal intra-alveolar infiltrates.Arterial blood gases show hypoxemia and the alveolararterialoxygen gradient is increased. In the occasional patient who isnot too ill to attempt lung function studies, a new restrictivepattern or a reduced diffusing capacity is characteristic. Mea-surements of pulmonary artery occlusion pressure or echocar-diography may be useful to rule out cardiogenic pulmonaryedema. Bronchoalveolar lavage or lung biopsy is necessaryto exclude bacterial, fungal, or viral infection because IPSis a diagnosis of exclusion. Multifocal bronchiolitis obliter-ans with organizing pneumonia (BOOP) may mimic late-onsetIPS and has been more commonly associated with chronicGVHD.

Management of IPS is mainly supportive, including judi-cious diuresis to decrease pulmonary edema, transfusions ofblood components to reverse bleeding diathesis, support ofoxygenation, and administration of antibiotics to prevent su-perinfection with mold and bacteria, particularly in patientsreceiving high-dose glucocorticoids. Effective therapy for idio-pathic pneumonia has not been demonstrated. High-dose glu-cocorticoids (1 to 2 mg per kg) have been reported to havean adjunctive role in treatment of diffuse alveolar hemorrhageor idiopathic pneumonia, but their efficacy has not been vali-dated in controlled studies [46]. In a recent study of 15 patientswho had IPS after allogeneic HCT, combination treatment withsoluble tumor necrosis factor receptor (etanercept) and glu-cocorticoids resulted in an encouraging day-28 survival rateof 73% [47]. More than half of the patients included in thisstudy had required mechanical ventilation at therapy onset.

Long-term survival, however, did not appear to be superiorcompared with historic controls.

The mortality associated with IPS after myeloablative HCTis 50% to 70% [45,48]. Aggressive management, includinginitiation of mechanical ventilation to identify and treat re-versible causes of respiratory failure, is a reasonable approachfor most HCT recipients with diffuse or multifocal pulmonaryinfiltrates. When hemodynamic instability or sustained hepaticand renal failure develop, survival is extremely unlikely. With-drawal of mechanical ventilation may be appropriate in specificsituations.

Acute Respiratory Distress Syndrome. An ARDS-like syn-drome also has been described as a presenting feature of acuteGVHD, typically early-onset (hyperacute) GVHD. ARDS hasan extremely high mortality rate in the transplant population;recovery depends on aggressive treatment of associated infec-tions and support of respiratory and cardiac function [49,50].The diagnosis of ARDS often is complicated by presence ofother illnesses, such as SOS, hemorrhage, or disseminated in-travascular hemolysis, which can cause difficulties in fluid man-agement and indicate the need for pulmonary artery catheteri-zation.

Diffuse Alveolar Hemorrhage. Diffuse alveolar hemorrhagemay be a manifestation of diffuse alveolar damage. However,the erosion of blood vessels by fungal organisms always needsto be considered [51]. Hemorrhage occurs more frequently inolder patients and those with malignancy, severe mucositis, orrenal failure [52]. Bloody bronchoalveolar lavage (BAL) fluidwith hemosiderin-laden macrophages is characteristic of dif-fuse alveolar hemorrhage.

Heart

Cardiac complications occur in 5% to 10% of patients afterHCT, but death from cardiac failure is uncommon [53,54].Cardiac injury with hemorrhagic myocardial necrosis is a rarebut known adverse effect of high-dose cyclophosphamide, oneof the most commonly used chemotherapy agents in condition-ing regimens. Acute cardiac failure due to cyclophosphamidehas a case mortality rate exceeding 50%. Risk factors for cy-clophosphamide cardiotoxicity include use of doses equal to orgreater than 120 mg per kg, an underlying diagnosis of lym-phoma, prior radiation to the mediastinum or left chest wall,older age, and prior abnormal cardiac ejection fraction [54,55].Patients who had prior cumulative anthracycline exposures of550 mg per m2 doxorubicin equivalents are at an increased riskfor developing heart failure. Signs and symptoms of conges-tive heart failure may occur within a few days of receiving cy-clophosphamide, while anthracycline-related cardiomyopathymay have a delayed onset. The electrocardiogram (ECG) mayshow voltage loss or arrhythmia, and echocardiography mayreveal systolic dysfunction, pericardial effusion or tamponade[56]. Older age and a history of abnormal ejection fraction areother factors that predispose to cardiac toxicity [54]. Manage-ment includes attention to fluid and sodium balance, afterloadreduction, and inotropes.

Kidney and Bladder

Acute Renal Failure. Acute renal failure (ARF), defined by dou-bling of baseline serum creatinine, occurs in 30% to 50% ofall patients during the first 100 days after HCT, and most oftenduring the first 10 to 30 days [57,58]. Occasionally, ARF devel-ops during conditioning or infusion of HSC, as a consequenceof tumor or red-cell lysis. ARF occurs most frequently in the set-ting of SOS and is characterized by low urinary sodium concen-tration and high blood urea nitrogen to creatinine ratio, similarto the hepatorenal syndrome. Renal hypoperfusion, caused by




acute hemorrhage, sepsis, or high-volume diarrhea, may resultin ARF. Nephrotoxic drugs like cyclosporine, tacrolimus, allamphotericin products, and aminoglycosides frequently causerenal insufficiency.

Thrombotic microangiopathy (TMA), endothelial dam-age caused by chemoradiotherapy, cyclosporine, tacrolimus,or sirolimus, occurs in 5% to 20% of patients, morefrequently in allograft recipients [59]. The hallmark of throm-botic microangiopathy is red blood cell (RBC) fragmenta-tion (schistocytes) associated with increased RBC turnover(increased reticulocytes; elevations of serum lactate dehydro-genase and indirect bilirubin) without evidence for immune-mediated hemolysis or disseminated intravascular coagulation.The syndrome ranges from subclinical hemolysis to a life-threatening hemolytic syndrome, the latter being seen more fre-quently when sirolimus therapy is combined with cyclosporineor tacrolimus (calcineurin inhibitors, CNIs) and immediatelyfollowing conditioning with busulfan and cyclophosphamide.High-therapeutic or supratherapeutic serum levels of CNIs orsirolimus are more prone to be associated with TMA [60].Management involves careful assessment of volume status anddiscontinuation or adjustment of the drug levels of the offend-ing agent(s). The use of plasma exchange has been associatedwith high mortality rates in most series [61] with recent excep-tions [62], and may be skewed by selection bias because onlythe sickest patients are likely to receive the treatment. For thisreason, determination of any survival benefit attributable toplasma exchange in the absence of a controlled study is impos-sible.

Hypertension. Hypertension develops in approximately 60%of patients after HCT, more often in patients given CNIsfor GVHD prophylaxis. Glucocorticoid therapy also con-tributes to the development of hypertension. Uncontrolledhypertension may lead to fatal intracerebral bleeding inthrombocytopenic patients. Therefore, hypertension should beanticipated and controlled medically. Most patients respondto conventional antihypertensive therapy, such as a calciumchannel blocker, angiotensin-converting enzyme inhibitor, orbeta-blocker. Correction of hypomagnesemia, which often con-founds CNI therapy, may improve control of hypertension [63].

Hemorrhagic Cystitis. High-dose cyclophosphamide is com-monly used for conditioning, and one of its toxic metabolites,acrolein, accumulates in the urine and may cause a hemorrhagicchemical cystitis during the conditioning regimen or later afterHCT [64,65]. Measures to prevent hemorrhagic cystitis includeaggressive fluid hydration to increase urine volume that dilutesand minimizes contact of acrolein with the mucosa, and admin-istration of the drug mesna, which provides free thiol groupsto detoxify acrolein. Viral infections, particularly adenovirusand BK virus, also have been implicated in the developmentof hemorrhagic cystitis [66] and the diagnosis is established byviral culture or polymerase chain reaction (PCR) test of a urinesample [66]. Unless there is evidence of disseminated infection,viral cystitis is managed with supportive therapy, includingaggressive hydration and platelet transfusions. Intravesicularinfusions of -aminocaproic acid or prostaglandins have beenreported to improve outcome of severe hemorrhagic cystitis[67]. Severe hemorrhagic cystitis caused by BK virus that provesrefractory to supportive therapy may respond to therapy withcidofovir [68].

Central Nervous System

Noninfectious complications include cerebrovascular eventsand encephalopathies due to metabolic, toxic, and immune-mediated causes. Focal symptoms are more indicative of infec-tious or cerebrovascular mechanisms, while diffuse symptomssuch as delirium or coma may have metabolic causes. Fever is

not necessarily associated with central nervous system (CNS)infections. Infection should be considered as the cause of anyneurologic symptom and should prompt evaluation, includingobtaining CT or magnetic resonance imaging (MRI) scans ofthe head and a sample of cerebrospinal fluid for appropriatecultures, cytochemistry stains, and PCR tests should be under-taken.

Cerebrovascular Events. Thrombocytopenia poses a risk forintracranial hemorrhage, which usually presents as abrupt on-set of focal neurologic deficit or mental status changes [69].Patients with sickle cell disease have a predisposition to CNShemorrhage after HCT and should be managed carefully byensuring sufficient platelet and magnesium levels and strict con-trol of hypertension [70]. Ischemic stroke is an unusual com-plication after HCT but has been reported in patients with As-pergillus infections, hypercoagulable states, or TMA [59,71].

Toxic Encephalopathies. Conditioning with high-dose busul-fan or carmustine may cause encephalopathy and seizure pro-phylaxis with phenytoin is usual. High-dose cytarabine maycause cerebellar dysfunction, encephalopathy, and seizures.High-dose cyclophosphamide can be associated with the syn-drome of inappropriate antidiuretic hormone (SIADH), rarelycausing acute decline in the serum sodium that may promptseizures. Fludarabine, used frequently in nonmyeloablativeconditioning, may cause an encephalopathy.

A rare syndrome of encephalopathy and hyperammone-mia without other chemical evidence of liver failure has beenreported after HCT [72]. Contributing factors may includehypercatabolism induced by conditioning, glucocorticoids, orsepsis, and high nitrogen loads associated with parenteral nu-trition or intestinal hemorrhage. The syndrome is difficultto reverse and has a high mortality rate. Treatment involveshemodialysis and administration of ammonia-trapping agents,such as sodium benzoate or sodium phenylacetate.

Related to a tendency to accumulate in nervous tissues dueto their lipophilic characteristics, CNIs can cause a range ofneurologic toxicities [73]. Tremor develops in most patients.Seizures have been reported in up to 6% of patients and maypresent in association with headaches, tremor, or visual distur-bances [74]. Seizures should be managed with anticonvulsanttherapy and cessation of the drug. When CNIs are essentialfor management of GVHD, substitution of one agent for theother, or reinstitution of the offending agent at a lower dose,may be feasible [75]. A unique and usually reversible syndromeof cortical blindness has been reported as a complication of cy-closporine treatment; hypertension and hypomagnesemia arethought to be predisposing factors [76]. Toxicity due to cal-cineurin inhibitor therapy may occur with therapeutic druglevels, and clinical suspicion is often confirmed by MRI scansthat show multifocal areas of signal hyperintensity on T2 (timefor 63% of transverse relaxation) and fluid-attenuated inver-sion recovery (FLAIR) sequences, most often in the occipitallobe white matter.

Glucocorticoid therapy may be associated with psychosis,mania, or delirium in a dose-dependent fashion. Seizures oraltered sensorium may be associated with the use of sedative-hypnotic drugs and have been reported as adverse side ef-fects of many of the commonly used antibiotics and antivi-ral agents. Metabolic encephalopathy may be associated withGram-negative sepsis, hypoxic encephalopathy with IPS, andhepatic encephalopathy due to SOS or GVHD.

Treatment of metabolic encephalopathies should be directedat the underlying problem, and offending drugs have to be dis-continued. In patients with CNI neurotoxicity, temporary dis-continuation of the CNI and the restarting at a lower dose isusually successful. Short-term phenytoin for seizure prophy-laxis may be indicated.




Infection

Conditioning regimens and GVHD severely impair host de-fense mechanisms, and the process of immune reconstitutionnecessarily requires many months for completion. Togetherthese factors place patients at high risk for acquisition of severeinfections. Proper medical care of patients after HCT includesmeasures to monitor and prevent infection, as it is a leadingcause of death.

Prevention of infection is of vital importance to the successof HCT procedures. Hospitalized patients should be housedin single rooms that have positive-pressure airflow and ven-tilation systems with rapid air exchange and high-efficiencyparticulate air filtration [77]. Strict visitation, hand washing,and isolation policies should be instituted to prevent introduc-tion or spread of communicable disease. A daily program ofskin and oral care should include bathing all skin surfaces with

mild soap, brushing teeth with a soft brush, frequent rinsingof the oral cavity with saline, and good perineal hygiene. Thediet should exclude foods known to contain bacteria or fungi,and patients should avoid exposure to dried or fresh plants orflowers. Caregivers should be trained in the proper handling ofcentral venous catheters.

Immunologic reconstitution after HCT can broadly be cat-egorized into three phases, which are characterized by a spec-trum of opportunistic infections. Advances in management ofantimicrobial prevention of opportunistic infections after HCTare outlined in Table 188.2.

Before Engraftment Period

The period before engraftment (less than 30 days posttrans-plant) is characterized by neutropenia and oral and gastroin-testinal mucosal damage. The most common infections are bac-terial and fungal. The use of indwelling central venous catheters

TA B L E 1 8 8 . 2

ADVANCES IN PREVENTION OF OPPORTUNISTIC INFECTIONS AFTER ALLOGENEIC HEMATOPOIETIC CELLTRANSPLANTATION

Recommendations for prophylaxis (strength of recommendation)a

Infection All patients Patients with chronic GVHD

Bacteria Broad-spectrum antibiotic(s) during period ofneutropenia (ANC




heightens the risk of blood infections with organisms that colo-nize the skin, such as coagulase negative staphylococci or Can-dida spp., and gastrointestinal mucosal damage increases therisk of infections with enteric organisms, such as Escherichiacoli. Clostridium difficile toxic colitis can be a common infec-tion in transplant patients, particularly those patients in inten-sive care units. Patients with a history of prolonged neutropeniaprior to HCT are at risk for developing fungal infections in-volving the skin, lung, sinuses, which typically are a mold suchas Aspergillus, or the liver and spleen, typically Candida spp.The most likely viral infection in this period is herpes simplexvirus. Fever of unknown origin also occurs commonly duringthe neutropenic period. Prophylactic systemic antibiotics con-ventionally are administered to reduce the risk of bacteremiaduring the neutropenic period, although improvement in sur-vival has not been demonstrated [77,78]. Administration ofgrowth factors, such as granulocyte colony-stimulating factor,shortens the duration of neutropenia, but there is little evidencefor improvement in outcome [79].

Following Engraftment Period

The period following engraftment (30 to 100 days post-transplant) is characterized by skin and mucosal damageand compromised cellular immunity related to GVHD andits treatment. Viral (CMV) and fungal (Aspergillus, Pneu-mocystis jiroveci) infections predominate during this period.Gram-negative bacteremias related to GVHD-associated mu-cosal damage and Gram-positive infections due to indwellingcatheters remain a risk. Other causes of fever of unknownorigin after engraftment include occult sinusitis, hepatospleniccandidiasis, and pulmonary or disseminated Aspergillus infec-tion.

Late Phase

The late phase (greater than 100 days posttransplant) is char-acterized by a persistently impaired cellular immunity in pa-tients with chronic GVHD. Patients with chronic GVHDare highly susceptible to recurrent bacterial infections, es-pecially from encapsulated bacteria, including Streptococcuspneumonia, Haemophilus influenzae, and Neisseria meningi-tides (functional asplenia). Bronchopulmonary infections, sep-ticemia, and ear, nose, and throat infections occur. Commonnonbacterial infections at this time include varicella zoster,CMV, P. jiroveci, and Aspergillus.

Evaluation and Treatment

Signs and symptoms of infection may be diminished in patientswho are neutropenic or receiving immunosuppressive drugs[80]. Thus, preemptive antibiotic therapy should be institutedpromptly for any fever during the neutropenic period, becauseinfections can progress rapidly to a fatal outcome [81]. Thefebrile patient should be examined thoroughly for source ofinfection, including the oral cavity, perianal tissue, and skinsurrounding the central venous catheter. Cultures should be ob-tained of blood, urine, and stool if diarrhea is present, and chestradiograph should be performed. Antibiotic therapy shouldprovide empiric coverage for the most common organisms,Gram-positive bacteria that colonize the skin and oral cavity, aswell as the less common but more virulent Gram-negative bac-teria that arise from the GI tract [78,80,81]. Broad-spectrumantibiotic therapy should be continued through the durationof neutropenia, even if fever resolves. If fever persists, the an-tibiotic regimen should be broadened after 4 days to provideempiric treatment of fungi. C. difficile infection should be con-sidered in patients with diarrhea and can be treated with oralmetronidazole.

Evaluation of persistent fevers after granulocyte recoveryshould consider occult sources of bacterial infection, such assinuses, perirectal tissue, or central venous lines, as well as vi-ral or fungal etiologies. Removal of the central venous catheteris occasionally required. Viral infections must be consideredin patients with GI symptoms and may involve the esophagus,upper and lower intestines, or liver [82]. The diagnosis is estab-lished by biopsy or brushings taken from the center of the le-sions so as to include infected endothelial cells and submucosaltissue. Host immunosuppression associated with GVHD andits treatment predisposes patients to a variety of opportunis-tic infections. Patients with active chronic GVHD should re-ceive prophylaxis for P. jiroveci pneumonia with trimethoprimsulfamethoxazole and for encapsulated organisms with dailytrimethoprimsulfamethoxazole, penicillin, or azithromycin.Infectious causes of pulmonary infiltrates must be differenti-ated from noninfectious causes to ensure prompt institution ofappropriate therapy [48,83].

BAL should be performed without delay to establish the eti-ology of diffuse infiltrates, unless clearly related to pulmonaryedema [84]. BAL specimens should be assayed for the pres-ence of common nosocomial bacteria as well as Legionella,Mycobacteria, and Nocardia; P. jiroveci; fungi other thanP. jiroveci pneumonia; respiratory viruses; and herpes groupviruses by cultures and immunocytochemical stains. Focal pul-monary infiltrates that occur after HCT are most frequentlycaused by infection, particularly fungal infection [85]. Evalua-tion of a focal infiltrate should include a CT scan to delineatethe number and extent of infiltrates. BAL should be performedas a first step because the procedure is minimally invasive andhistorically has produced a diagnosis in 50% of patients withfungal lesions using standard diagnostic approaches, althoughthe predictive value of negative results was poor [84]. At somecenters, the increasing use of more diagnostic approaches likegalactomannan antigen testing [86] or, ongoing development ofmolecular methods to detect fungi or viral pathogens (e.g., hu-man metapneumovirus [87,88]) continues to improve the yieldof BAL. As a result, the number of lung biopsies performedat these centers has declined. Transbronchial biopsy is not rec-ommended because it has not been shown to improve sensitiv-ity in these situations, and often thrombocytopenia precludesthe ability to perform the procedure safely. Percutaneous fine-needle aspiration is indicated for diagnosis of peripheral infil-trates that cannot be evaluated by BAL. Fine-needle aspirationhas a sensitivity of approximately 67% for diagnosis of fungalinfection, but it has a poor negative predictive value. If the di-agnosis is not ascertained after BAL or fine-needle aspiration,a biopsy is required [89]. Specimens should be evaluated histo-logically and undergo testing for bacteria, fungi, and viruses byappropriate cultures and immunocytochemical stains as notedpreviously. Surgical resection of a solitary fungal lesion mayimprove the chances for cure [90].

Opportunistic Infections

Pneumocystis jiroveci Pneumonia. Inadequate cell-mediatedimmunity poses a risk for development of P. jiroveci pneumoniainfection after HCT [91]. Recommendations for prevention ofPJP are found in Table 188.2 [77,92].

Fungal Infections

Factors that predispose to invasive yeast infections includeneutropenia, mucosal barrier disruption, and broad-spectrumantibiotics that promote colonization of the GI mucosa [93].Candidal infections generally occur within the first 3 weeks af-ter HCT, coinciding with the period of neutropenia, althougha second period of risk occurs during treatment for chronicGVHD. Invasive candidiasis may involve the liver and spleen,with potential for dissemination to kidneys or rarely, the CNS




[94,95]. The diagnosis of invasive candidiasis is difficult be-cause blood cultures are negative in approximately one half ofthe cases with organ involvement. Recommendations for pre-vention of candidiasis are found in Table 188.2. Fluconazoleis effective for treatment of the most common Candida spp,C. albicans and C. tropicalis [96,97] (see Table 188.2), but doesnot prevent or treat infection with C. glabrata, C. krusei, orC. parapsilosis. Removal of the central venous catheter shouldbe considered when Candida sp. is isolated from blood cultures.Fungal vegetations on heart valves are possible and echocar-diography is often considered. Lipid-complexed amphotericinproducts, echinocandins, or other azoles may be useful alter-natives [98].

Invasive mold infections develop in up to 20% of patients af-ter HCT [99]. The incidence of Aspergillus infections is highestwithin the first month after HCT, and there is a second peakincidence during chronic GVHD. Aspergillus infections havebeen difficult to diagnose by standard methods, and more than20% of the cases have been diagnosed only at autopsy. Cul-tures of BAL fluid are negative in 50% of pulmonary disease;therefore, the diagnosis frequently requires a biopsy of affectedtissues [85]. The Aspergillus Galactomannan Enzyme Im-munoassay detects a polysaccharide secreted from Aspergillushyphae and is a useful screening tool, with a sensitivity of 65%and specificity of 95% [100]. High-risk patients, those with se-vere GVHD treated with high-dose corticosteroids, should begiven prophylaxis with agents like voriconazole or posacona-zole which is active against aspergillosis and certain othermolds. Because invasive aspergillosis is associated with a highmortality rate, documented or suspected infections should betreated aggressively with voriconazole, lipid-complexed am-photericin products, or combination therapy [101,102]. Surgi-cal removal of infected tissue should be restricted to cases ofcircumscribed disease [103].

Viral Infections

Cytomegalovirus. Protection from exposure by use of seroneg-ative or leukocyte-reduced blood components has reduced theincidence of CMV infection among seronegative patients [21],whereas ganciclovir has been shown to be an effective agentfor prevention of CMV disease in seropositive patients [104106] (see Table 188.2). Ganciclovir should be initiated as pro-phylaxis after engraftment, with careful monitoring of the pa-tient for marrow suppression, a side effect that can lead tolife-threatening infection (Table 188.2) [107]. A reasonable al-ternative is to monitor for CMV reactivation with serum PCRassays, followed by prompt institution of ganciclovir when theCMV copy number reaches a positive threshold [108110].Generally, surveillance CMV PCR testing is performed weeklyfrom transplant day 0 through day 100; however, monitoringgenerally is continued for CMV positive patients on high-dosecorticosteroids.

Although prophylaxis greatly reduces the risk for CMVdisease, severe pneumonitis, gastroenteritis, hepatitis, or bonemarrow failure continue to occur in a small proportion of pa-tients [111]. The diagnosis of CMV pneumonitis can be estab-lished in most patients by PCR assay or rapid shell vial cultureof BAL fluid [112]. CMV enteritis is often indistinguishablefrom GVHD clinically, and the diagnosis relies on endoscopicevaluation [113]. CMV enteritis appears as ulcerations of theesophagus, stomach, or intestines. Viral cultures and histologicstains of the affected tissue are used to establish the diagnosis.Treatment of CMV infection includes ganciclovir (foscarnet orcidofovir are acceptable alternatives) in combination with im-mune globulin [114,115]. Foscarnet can be used in place ofganciclovir if significant marrow toxicity occurs or drug resis-tance is identified.

Herpes Simplex Virus. Herpes simplex virus (HSV) is the mostcommon cause of infectious mucositis after HCT and maycause life-threatening encephalitis, hepatitis, or pneumonia inimmunocompromised patients [116118]. HSV pneumonitisor hepatitis is associated with high mortality rates; althoughless serious, HSV mucositis produces severe local pain andswelling. Acyclovir prophylaxis has been shown to be very ef-fective for prevention of HSV reactivation in seropositive pa-tients and for treatment of established disease [119,120] (seeTable 188.2).

Varicella Zoster Virus. Varicella zoster virus (VZV) causeslife-threatening disease in immunocompromised patients, as aprimary infection or reactivation of endogenous virus [121].Exposed seronegative patients should receive VZV immuneglobulin within 96 hours if available, and acyclovir shouldbe administered from days 3 to 22 after exposure [122].Among seropositive patients, VZV reactivation occurs in ap-proximately 40%, with the highest incidence around 5 monthsafter HCT [121,123]. Prophylaxis with acyclovir is recom-mended for seropositive patients until 1 year after HCT or un-til complete discontinuation of immunosuppressive therapy forchronic GVHD immunity [124] (see Table 188.2). VZV infec-tion typically causes local skin involvement, but it can dissemi-nate in immunocompromised patients, resulting in pneumoni-tis, esophagitis, pancreatitis, hepatitis, or encephalitis [125128]. VZV hepatitis may present as a syndrome of fever, se-vere abdominal pain, and elevated aminotransferase levels, andbecause it is associated with a high mortality rate, should betreated presumptively with high-dose acyclovir [128]. For lo-calized infection, a short course of intravenous acyclovir for24 to 48 hours can be followed by oral valacyclovir for theduration of therapy.

Respiratory Viruses. Respiratory viruses may spread quicklywithin HCT patient populations, causing epidemics of life-threatening infection. Respiratory syncytial virus (RSV),influenza, and parainfluenza are the most frequently encoun-tered respiratory viruses in these situations [129]. Symptomsof upper respiratory infection should prompt cultures of na-sopharyngeal secretions, careful monitoring for progression ofdisease, and isolation to prevent spread to other patients. Pa-tients in the period before engraftment are at greatest risk forprogression to lower tract disease with RSV. Once lower-tractdisease occurs, however, mortality is high regardless of en-graftment status [130]. If lower-tract disease is suspected, BALshould be performed to obtain samples for viral fluorescenceantibody and PCR tests and viral cultures [131].

Adenovirus. Adenovirus and polyoma BK virus are commoncauses of hemorrhagic cystitis after HCT [66]. When dissem-inated, adenovirus can cause hemorrhagic enterocolitis, inter-stitial pneumonitis, myocarditis, nephritis, meningoencephali-tis, or severe hepatitis [132]. Adenoviral infections occur morecommonly in children and after allogeneic grafts [133]. Patientswith poor T-cell function, such as recipients of T celldepletedgrafts or those receiving intensive immune suppressing thera-pies, are at greatest risk for disseminated infection. Dissemi-nated infections are often difficult to detect by viral cultures,and PCR assays may be more useful [134]. The most promis-ing treatment results have been reported after administration ofcidofovir, although renal insufficiency is a potential side effect[135]. Polyoma BK virus should be considered in the differ-ential diagnosis of renal insufficiency in patients on chronicimmune suppression, and can be diagnosed by renal biopsy.

Epstein-Barr Virus. EpsteinBarr virus (EBV) seropositive im-munocompromised patients are at risk for development oflife-threatening lymphoproliferative disease (LPD) after HCT




[136]. The risk for EBVLPD is highest among patients who re-ceive T-celldepleted grafts or who are given intensive immunesuppression for treatment of GVHD [137]. The diagnosis ismade by biopsy of enlarged nodes or affected tissue. A pre-sumptive diagnosis can be made in high-risk patients who haveclinical symptoms and elevated plasma or cellular EBV DNAcopy number [138]. The mainstay of therapy is reduction orelimination of immunosuppressive therapy to allow reconsti-tution of EBV-specific T-cell immunity. However, it may notbe feasible to eliminate immunosuppression therapy withoutrisking a flare of life-threatening GVHD. Some studies haveshown encouraging results with mAb directed against CD20,which targets EBV-infected B cells [139]. EBVLPD that devel-ops in recipients of T celldepleted grafts may be amelioratedby infusion of donor T lymphocytes [140].

Graft Rejection

Graft rejection presents as failure to recover hematopoiesis af-ter transplantation, termed primary graft failure, or as the lossof an established donor graft, termed secondary graft failure.Persistence of neutropenia (an absolute neutrophil count ofmore than 100 cells per L) after day 26 is associated with in-creased risk of early mortality [141]. Although the molecularand cellular mechanisms are not completely understood, graftrejection appears to be mediated preferentially by recipientT cells [142]. Another described mechanism includes rejectionmediated by host natural killer cells which, to some extent,can be overcome by the preparative regimen. Finally, alloim-mune antibodies in sensitized recipients may cause rejection inmice but their role in humans is controversial. Donor HLA dis-parity stimulates strong alloreactive immune responses in theimmunocompetent recipient and increases the risk for graft re-jection. Donor T cells counteract the rejection responses of hostalloreactive cells that have survived the conditioning regimen[143]. Higher stem cell doses facilitate engraftment, particu-larly when T celldepleted grafts are used [144,145].

Quantitation of donor engraftment (donor chimerism), us-ing PCR-based techniques to detect donor-specific variablenucleotide tandem repeats (VNTR) sequences, may be help-ful in determining whether the graft has been rejected, inwhich case the peripheral blood T cells will be primarily ofhost origin, or whether the donor graft is not functioning, inwhich case the cells will be of donor origin. In the latter case,other causes of graft suppression should be considered, includ-ing relapse, medications such as ganciclovir or trimethoprimsulfamethoxazole, mycophenolate mofetil, or viral infectionssuch as CMV, human herpes virus 6, or parvovirus B19. Ineither case, graft failure after myeloablative conditioning is alife-threatening complication because autologous reconstitu-tion is uncommon and results in death from hemorrhage orinfection. A range of cellular therapies have been used to over-come rejection ranging from donor lymphocyte infusions in thecase of declining donor T-cell chimerism, possibly combinedwith immunosuppressive therapy. In fulminant rejection, re-transplantation is necessary, using the same or another donor.Conditioning should preferentially differ from that used at thefirst transplant to avoid unnecessary toxicity, and a high graftcell dose should be targeted [142].

Graft-Versus-Host Disease

The most significant immunologic barrier to successful HCTis the graft-versus-host reaction, which can result in life-threatening inflammation and tissue destruction. Donor T cellsthat recognize disparate recipient alloantigens are the centralmediators of GVHD. The most important alloantigens are

those encoded by the major histocompatibility complex, orHLA system, although non-HLA antigens may certainly be in-volved. Despite the significance of GVHD as a complicationof HCT, patients who develop GVHD have lower relapse ratesthan patients without GVHD, and this can also be explained byan immunologically mediated graft-versus-tumor (GVT) effectthat helps eradicate the underlying malignancy.

Acute Graft-Versus-Host Disease

The incidence and severity of acute GVHD are determined pri-marily by the degree of HLA disparity and influenced by thenature of GVHD prophylaxis [146148]. Severe acute GVHD(grades III to IV) develops in 15% of recipients transplantedfrom HLA-identical sibling donors, and in a greater proportionof those given unrelated or mismatched grafts. Acute GVHDtypically begins abruptly at 2 to 4 weeks after myeloablativeHCT and generally occurs before day 100, but the onset maybe delayed after nonmyeloablative HCT. The clinicopathologicsyndrome is consistent with various combinations of inflam-matory dermatitis, enteritis, and hepatitis, which reflect thepathophysiology of T-cell activation with generation of cyto-toxic lymphocytes and elaboration of inflammatory cytokinesthat cause tissue damage. The severity of acute GVHD in thethree main target organs (skin, liver, and GI tract) is staged1 through 4 based on accepted criteria that primarily includethe extent of rash, magnitude of hyperbilirubinemia, and vol-ume of diarrhea. The various combinations of skin, liver, andGI involvement can then be used to assign an overall grade ofGVHD: grade I being mild, and grade IV being life threatening[149,150] (Table 188.3). When cellular injury is severe, GVHDof the skin may manifest with bulla formation and skin ulcer-ation. In the GI tract, symptoms range from mild anorexia, tonausea and vomiting, or to severe bloody diarrhea with cramp-ing periumbilical pain.

Chronic Graft-Versus-Host Disease

Chronic GVHD (CGVHD) occurs in approximately 30% to60% of transplant recipients, more often when the donor is notan HLA-identical sibling and when there is a history of acuteGVHD [151]. There is a higher risk for developing CGVHDwith growth factormobilized PBSC grafts compared to mar-row grafts [152]. CGVHD also is more likely when the recipi-ent or donor is older or CMV seropositive, or in a male patientwho receives HSC from a multiparous female donor. Risk fac-tors for mortality at the time of diagnosis of CGVHD include:platelet counts less than 100 109 per L, greater than 0.5 mgper kg per day prednisone, serum total bilirubin greater than34 mol per L, older recipient, prior acute GVHD, older donor,and graft-versus-host HLA mismatching [153,154].

CGVHD is defined without reference to time after HCT,but by the presence of hallmark CGVHD features, which re-semble autoimmune diseases such as systemic sclerosis, Sjo-grens syndrome, primary biliary cirrhosis, wasting syndrome,bronchiolitis obliterans, immune cytopenias, and chronic im-munodeficiency [155] (Table 188.4). Simply stated, the distinc-tion of chronic from acute GVHD requires the presence of atleast one diagnostic clinical sign of CGVHD or presence ofat least one distinctive manifestation confirmed by pertinentbiopsy or other relevant tests. The overall severity of CGVHDis determined by a 0- to 3-point score (none, mild, moder-ate, severe) that reflects the clinical effect of CGVHD on thepatients functional status in any number of different organs.CGVHD frequently involves the skin, liver, eyes, mouth, upperrespiratory tract, lungs, and esophagus. Less frequently, serosalsurfaces, lower GI tract, female genitalia, or fascia are involved.Major causes of morbidity include scleroderma, contractures,ulceration, keratoconjunctivitis, strictures, obstructive pul-monary disease, and weight loss. Uncontrolled chronic GVHD




TA B L E 1 8 8 . 3

CLASSIFICATION OF GRAFT-VERSUS-HOST DISEASE

Acute GVHD organ staging

Organ Stage Scores Description

Skin 1 25% body surface area with maculopapular rash2 25%50% body surface area with maculopapular rash3 50% body surface area with maculopapular rash or

erythroderma4 Generalized erythroderma with bullae

Liver 1 Bilirubin 2.03.0 mg/dL2 Bilirubin 3.05.9 mg/dL3 Bilirubin 6.014.9 mg/dL4 Bilirubin rise to 15 mg/dL

GI tract Stage is assigned according to a total GI score basedon volume of diarrhea, presence of bloody stool,and abdominal pain or cramping

1 Total GI score of 12 Total GI score of 23 Total GI score of 344 Total GI score of 57

GI scoring Diarrhea volume averaged over 3 dAdult (mL/d), childa (mL/kg/d)

+1 >500999, >1020+2 1,0001,499, >2030+3 >1,500, >30+2 Score additional 2 points for presence of abdominal

pain or cramping+2 Score additional 2 points for presence of bloody stools

Acute GVHD overall grade Skin stage Liver stage GI stage

I 12 0 0II 3 or 1 or 1III 23 23IV 4 or 4 or 4

aChildren




TA B L E 1 8 8 . 4

CLASSIFICATION OF SYMPTOMS AND SIGNS OF CHRONIC GRAFT-VERSUS-HOST DISEASE

Organ or site Diagnostic Distinctivea Commonb

Skin Poikiloderma Depigmentation ErythemaLichen planus-like features Maculopapular rashSclerotic features PruritusMorphea-like featuresLichen-sclerosislike features

Nails DystrophyLongitudinal ridging, splitting, or

brittle featuresOnycholysisPterygium unguisNail lossc

Scalp and body hair New onset of scalp alopeciaScaling, papulosquamous lesions

Mouth Lichen-type features Xerostomia GingivitisHyperkeratotic plaques Mucocele MucositisRestriction of mouth opening Mucosal atrophy Erythema

Pseudomembranesc PainUlcersc

Eyes New onset dry, gritty, or painfuld

Cicatricial conjunctivitisKeratoconjunctivitis siccad

Confluent punctate keratopathy

Genitalia Lichen-planuslike features Erosionsc

Vaginal scarring or stenosis Fissuresc

Ulcersc

GI tract Esophageal web Anorexia, nauseavomiting, diarrhea,

Esophageal strictures or stenosis inupper to mid thirdc

Failure to thrive

Liver Bilirubin >2 ULNAlk Phosp >2 ULNAST/ALT >2 ULN

Lung Bronchiolitis obliterans based on lungbiopsy

Bronchiolitis obliterans based on PFTs+ radiologyd

BOOP

Muscles, fascia, joints Fasciitis Myositis or polymyositisJoint stiffness or contractures

secondary to sclerosis

Features acknowledged as part of chronic GVHD symptomatology if the diagnosis is already confirmed

Skin Sweat impairment, ichthyosis, keratosis pilaris, hypopigmentation, hyperpigmentationHair Thinning scalp hair, typically patchy, coarse, dull not explained by endocrine or other causes, premature

gray hairEyes Photophobia, periorbital hyperpigmentation, blepharitisGI tract Exocrine pancreatic insufficiencyMuscles/Joints Edema, muscle cramps, arthralgia, or arthritis.Hematology Thrombocytopenia, eosinophilia, lymphopeniaImmune Lymphopenia, hypo- or hypergammaglobulinemia, autoantibodies (AIHA, ITP)Other Pericardial/pleural effusions, ascites, peripheral neuropathy, nephrotic syndrome, myasthenia gravis,

cardiac conduction abnormality, or cardiomyopathy

aSeen in chronic GVHD but are insufficient alone to establish the diagnosis.bSeen in both acute and chronic GVHD alone to establish a diagnosis of chronic GVHD.cIn all cases must exclude infection, drug effects, malignancy, or other causes.dDiagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmers test for eyes).AIHA, autoimmune hemolytic anemia; ALT, alanine aminotransferase; AST aspartate aminotransferase; BOOP, bronchiolitis obliterans with organizingpneumonia; GI, gastrointestinal; ITP, idiopathic (immune) thrombocytopenic purpura; PFTs, pulmonary function tests; ULN, upper limit of normalrange for age.Modified from Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus development project on criteria for clinical trials inchronic graft-versus-host disease: I. Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 11(12):945956, 2005, withpermission.




TA B L E 1 8 8 . 5

DIFFERENTIAL DIAGNOSIS OF ACUTEGRAFT-VERSUS-HOST DISEASE (AGVHD)

AGVHD manifestation Differential diagnosis

Rash Drug reactionAllergic reactionInfectionRegimen-related toxicity

Diarrhea Infection (viral, fungal)Narcotic bowel syndrome (opiate

withdrawal)

Abdominal pain Acute pancreatitisAcute cholecystitis (biliary sludge,

stones, infection)Narcotic bowel syndrome (opiate

withdrawal)

Elevated liver enzymes Sinusoidal obstruction syndromeMedication toxicities (e.g.,

cyclosporine)Cholangitis lenta (sepsis)Biliary sludge syndromeViral infections (CMV, EBV,

hepatitis B)Hemolysis

CMV, cytomegalovirus; EBV, EpsteinBarr virus.

Postgrafting Immunosuppression. In the absence of T-cell de-pletion, posttransplant immune suppression must be admin-istered to control donor alloreactive T cells. Standard pro-phylaxis regimens deliver a 6-month course of cyclosporineor tacrolimus combined with a short course of methotrex-ate administered intravenously on the 1st, 3rd, 6th, and11th days after HCT [147]. After myeloablative conditioning,methotrexate toxicity may exacerbate RRT in high turnovercells such as in oral and intestinal mucosae and hepatocytes.Some patients, particularly those with the C677T polymor-phism in the methylenetetrahydrofolate reductase gene, havemore severe mucositis and slower platelet engraftment whengiven methotrexate [160]. Variations of CNI plus methotrex-ate include CNI plus mycophenolate mofetil [147,161]. or,tacrolimus and sirolimus, with or without methotrexate [162164]. Steady-state serum CNI and sirolimus levels requiremonitoring. Dose reductions should be made when toxicitiesemerge or when serum trough levels exceed the upper limit ofthe therapeutic range.

Treatment of Graft-Versus-Host Disease

Despite GVHD prophylaxis regimens, 30% to 80% of allo-geneic HCT recipients develop acute GVHD and require addi-tional therapy with glucocorticoids.

Acute Graft-Versus-Host Disease. Glucocorticoids have beenthe mainstay of primary therapy for acute GVHD. Initial start-ing doses have been recently calibrated to the severity andextent of organ involvement as demonstrated by one large ret-rospective study [165]. This approach requires further vali-dation, particularly for grades III and IV acute GVHD. Forthe one third of patients who develop GVHD without liverinvolvement, and whose GI symptoms are defined as stage 1(anorexia, nausea, or vomiting with peak stool volume lessthan 1,000 mL per day), with or without rash involving less

then 50% of the body surface, treatment may reasonably beginat 1 mg per kg per day methylprednisolone (or oral equivalent)combined with topical and minimally absorbed glucocorticoids(beclomethasone or budesonide). When there is liver involve-ment, or when intestinal and skin GVHD is greater than de-fined above, methylprednisolone is typically begun at a dose of2 mg per kg per day for 14 days, by which time rash, diarrhea,abdominal pain, and liver dysfunction usually remit and a glu-cocorticoid taper is considered appropriate. In patients with GIhemorrhage, surgery very rarely is indicated, and the mainstayof therapy is initiation of immune suppression, along with theinfusion of appropriate blood components [166,167]. Severalstudies, including a randomized trial, have shown no benefitfor administration of doses greater than 2 mg per kg per dayof methylprednisolone [168,169]. The results of a recent mul-ticenter randomized phase II trial suggested that response andearly survival after standard therapy with prednisone might beimproved by adding mycophenolate mofetil [170]. A follow-up phase III study to more definitively evaluate this finding isimminent.

Chronic Graft-Versus-Host Disease. In practice, systemic ther-apy is considered when chronic GVHD is present in more thantwo organs, or there are moderate to severe abnormalities of asingle organ with functional impairment (Table 188.6). In con-trast, systemic therapy is generally not warranted for patientswith mild abnormalities of one or two organs that do not causefunctional impairment. For example, jaundice, or marked ele-vations of liver enzymes or skin manifestations that are not ex-tensive. However, mild chronic GVHD does warrant systemictherapy when either thrombocytopenia or steroid treatment ispresent at diagnosis.

Standard primary therapy for clinical extensive CGVHDusually begins with glucocorticoids and extended administra-tion of a CNI. After newly diagnosed CGVHD manifestationshave been controlled by daily glucocorticoids, the judicious useof glucocorticoids at the lowest effective dose and alternate-day administration can minimize steroid-related side effects.The median duration of systemic immunosuppression for thetreatment of CGVHD approximates 2 to 3 years [153]. Longertherapy tends to be required for recipients of peripheral bloodstem cells, male patients with female donors, multiple organ

TA B L E 1 8 8 . 6

INDICATION FOR SYSTEMIC IMMUNOSUPPRESSIONAT DAY 80

Global severity of High-risk Systemicchronic GVHD featuresa therapy

None Yes Noneb

Mild (




TA B L E 1 8 8 . 7

THERAPY OPTIONS FOR STEROID-REFRACTORY ACUTE GRAFT-VERSUS-HOSTDISEASE

Therapy Comments

SystemicPolyclonal

Antithymocyte globulin (ATGAM,a

Thymoglobulinb)Monoclonal

Anti-CD3 (OKT3,c visilizumabd,e)Anti-IL2 (daclizumab,d basiliximab f )Anti-TNF (infliximab f )Anti-CD52 (alemtuzumabd)Anti-CD2 (alefaceptg)

Fusion proteinsAnti-IL2 (denileukin diftitox)Anti-TNF (etanercept)

Macrolides and antimetabolitesTacrolimusSirolimusMycophenolate mofetil

Extracorporeal photopheresis

Mesenchymal stem cells

TopicalGlucocorticoids

BudesonideBeclomethasonee

PUVA

Delayed use appears to be very ineffective. Skinresponds best.

Currently used infrequently.Depletes conventional and regulatory T cells.Consider early for refractory lower GI tract.Depletes T & B cells (lower risk EBV PTLD)Depletes memory T cells; needs further study.

Anti-T cell but also depletes regulatory T cells.

Inhibits conventional and regulatory T cellsInhibits conventional but not regulatory T cells.Enteric coated formulation may minimize toxicity

but liquid formulation not availableMechanism includes facilitation of regulatory

T cells Particularly effective in skin, infrequentlyassociated with opportunistic infections.

Mechanism poorly understood but thought tomodulate tissue repair.

Useful as steroid-sparing agent in lower GI tract.Useful as steroid-sparing agent in upper GI tractUseful for skin only involvement.

aEquine.bRabbit.cMurine.dHumanized.eNot commercially available.f Chimeric murinehuman.gHuman IgG1-fusion protein.

involvement at the onset of CGVHD, graft-versus-host HLAmismatching, and hyperbilirubinemia.

Within 3 years of primary therapy, just over one quarterof the patients have resolved CGVHD, 1 out of 10 patientswill continue primary therapy beyond 3 years and one-thirdrequire secondary treatment with a variety of other immuno-suppressive agents [171]. The remaining patients develop recur-rent malignancy or die from nonrelapse causes. Infection froma broad array of pathogens is the major cause of nonrelapsemortality, followed by progressive organ failure from CGVHDinvolvement. Therefore, antibiotic prophylaxis to prevent in-fection (Table 188.2) and supportive care to minimize morbid-ity and prevent disability are critically important componentsof CGVHD management [172].

Steroid-Refractory Graft-Versus-Host Disease. Glucocorti-coids often fail to control acute GVHD manifestations suchthat 40% to 60% of patients have steroid-refractory (SR) acuteGVHD. SR-GVHD has been defined operationally as the pro-gression of acute GVHD symptoms beyond 3 days after start-ing methylprednisolone. Persistence of GVHD beyond 7 to 14days also should be considered failure of response. The progno-sis of acute GVHD can be related to its overall severity (grade)

and response to glucocorticoids [173,174]. It is of no surprisethat grade III and IV SR acute GVHD, especially with visceralinvolvement, requires urgent initiation of effective secondarytherapy.

Unfortunately, there is no generally accepted therapy for SRacute GVHD. A full review of the various secondary GVHDtherapies is beyond the scope of this review but various ap-proaches are listed in Table 188.7 together with a summaryof outcomes (Table 188.8). Polyclonal antithymocyte globulins(ATG), and more recently monoclonal antibodies, are generallyused to treat life-threatening visceral manifestations where ur-gent control of GVHD is necessary. Unfortunately, longer termsurvival has been unusual when visceral manifestations are se-vere [175179]. However, early administration of ATG within14 days of primary therapy was reported in one study to beassociated with improved survival [180]. It has remained dif-ficult to improve the survival after SR-refractory acute GVHDbecause progressive organ dysfunction is often irreversible, andbecause second-line therapies constitute a second hit to animmune system that has already been impaired by cumulativeexposure to high-dose prednisone. In this regard, high dailyprednisone doses increase the risk for CMV viremia [181]. Sim-ilarly, invasive aspergillosis occurs more frequently in patients




TA B L E 1 8 8 . 8

ADVANCES IN THERAPY OPTIONS FOR STEROID-REFRACTORY ACUTE GRAFT-VERSUS-HOST DISEASE (AGVHD)

Treatment Study design/results Comments Reference

Antithymocyteglobulin (equineATG)

Single-arm Phase II studies (N = 2979)from 1980 to 1999. CR/PR 30% overall(59%72% for skin), OS 5%32%.

Responses considerably better in skin thanvisceral organs. OS worse in visceral ormore severe GVHD. One study foundOS better if ATGAM given within 14 dof primary therapy (46% vs. 19%,p = 0.05).

[175,180,190,191]

Antithymocyteglobulin (rabbitATG)

Single-arm Phase II (N = 36). 89% hadmostly three-system Grade III/IV GVHD.CR/PR 59% overall (96% skin, 46% GI,36% liver. OS 6%.

Very poor survival.Infections, including 25% EBV PTLD rate,

were major problems.

[176]

Daclizumab Single center Phase I/II (N = 1357) from1990s to 2006. CR/PR 51%92%overall. OS 25%46%.

Well tolerated. Responses better inchildren and in skin GVHD. Significantmorbidity and mortality due toinfections. Patient selection andaggressive antiviral and fungalprophylaxis advised.

[179,192,193]

DenileukinDiftitox

Single center Phase I/II (N = 32).CR/PR 71% overall. OS 30%.

Reversible transaminitis in 22% at MTD.OS 58% (7/12) if achieved CR.

[178]

Infliximab Single center retrospective (N = 2132)from 1998 to 2004. CR/PR 59%82%overall. CR 19%62%. OS 38%46%at 1 year.

Well tolerated and active, particularly forGI tract. Better response if age




who develop CMV disease and in patients receiving higherdoses of prednisone [182]. After nonmyeloablative HCT, highdose prednisone therapy at the time of diagnosis of mold in-fection has been associated with an increased risk for moldinfection-related death [183].

When CGVHD becomes refractory to steroids, in contrastto SR acute GVHD, secondary therapy generally avoids potentantibody therapies unless the manifestations overlap with thedisease features typically associated with severe acute GVHD.The time to complete resolution of classical CGVHD manifes-tations is in the order of weeks to months, and total duration oftherapy spans months to years. Therefore, secondary therapiesfor SR-CGVHD must try to avoid profound T-cell depletionand must generally be more easily delivered chronically in theoutpatient setting. Ideally, second-line agents should promotetransplantation tolerance so that the morbidity associated withprolonged use of glucocorticoids and other immunosuppressiveagents can be minimized.

Promising new agents or strategies that warrant furthercontrolled clinical trials include sirolimus, extracorporeal pho-tophoresis, rituximab, and the platelet-derived growth factorreceptor, imatinib, which is of particular interest for the treat-ment of sclerotic GVHD. A number of ancillary measures thatare used with topical intent are often used to target specificorgan involvement [172].

Hemolysis

RBC hemolysis may be encountered after HCT and may in-clude more than one etiology. Thrombotic microangiopathymay present as mild hemolysis with RBC fragmentation (schis-tocytes) or as a more severe form, with thrombocytopenia, re-nal insufficiency, fever, and altered mental status, similar tohemolytic uremic syndrome (HUS) or thrombotic thrombocy-topenic purpura (TTP) [59,184]. Predisposing factors include:endothelial cell injury triggered by chemotherapy, radiation, orimmunosuppressive therapy (e.g., CNIs) [59,185]. Drugs suchas fludarabine, antithymocyte globulin, or infections with my-coplasma also may produce hemolysis. Unlike the precedingetiologies, hemolysis mediated by major or minor blood groupincompatibilities is only seen in recipients of allografts.

Major ABO incompatibility occurs in 30% of allograft re-cipients and is defined by the presence of isohemagglutininswithin recipient plasma that are directed against donor A or Bantigens. Minor ABO incompatibility also occurs in 30% of re-cipients and is defined by presence of isohemagglutinins within

the donor plasma directed against recipient A or B. Bidirec-tional ABO incompatibility may be present as in the case of atype A recipient and type B donor or vice versa. After successfuldonor engraftment, the conversion of recipient to donor bloodtype may take weeks to months because of the relatively longhalf-life of red blood cells.

Major ABO incompatibility poses a serious risk of severehemolytic reactions at the time of infusion of the HSC productif preventative steps are not taken. Immediate hemolytic reac-tions are more likely in the presence of high-level isoagglutinintiters. Therefore, red blood cells are most commonly removedfrom the graft before infusion to avoid life-threatening hemol-ysis. Delayed recovery of donor hematopoiesis or hemolysismay occur because recipient plasma cells continue to produceisohemagglutinins for up to several months after HCT [186].In this case, the diagnosis relies on detection of a positive di-rect antiglobulin test and the presence of isohemagglutininsdirected against donor-type red blood cells. Management ofmajor ABO incompatibility includes the transfusion of groupO red blood cells, donor-type platelets, and donor-type plasmauntil isohemagglutinins against donor-type red blood cells dis-appear. In the rare cases of ongoing hemolysis due to persistenceof donor-directed isohemagglutinins, additional therapy withimmunosuppressive agents, erythropoietin, plasma exchange,anti-B-cell antibodies (rituximab), or plasma exchange may beconsidered [187].

Minor ABO incompatibility poses a risk for mild and self-limited hemolysis at the time of infusion. Delayed hemolysis,seen more commonly after PBSC transplantation, is mediatedby clonally expanded donor passenger lymphocytes and canpresent as an abrupt and potentially fatal hemolytic transfu-sion reaction typically at 1 to 2 weeks after HCT [188,189].In contrast to major ABO incompatibility, pretransplant donorisohemagglutinin titers do not predict the severity of hemolysisfollowing minor ABO-mismatched HCT. The diagnosis reliesagain on the detection of a positive direct antiglobulin test andthe presence of isohemagglutinins directed against recipient-type red blood cells. To prevent hemolysis, plasma should beremoved from the donor HSC product if donor hemagglu-tinin titers are high. Emergence of donor-derived RBC and iso-hemagglutinin titers should be monitored after allogeneic HCT.Management of minor ABO incompatibility after HCT in-cludes supportive care with judicious fluid management aimedat preventing acute renal failure, and the transfusion of groupO red blood cells and recipient type platelets and plasma.There is no convincing evidence to support the use of plasmaexchange.

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