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Childhood Hematopoietic Cell Transplantation (PDQ®)

Complications After HCT

Pre-HCT Comorbidities that Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Charlson Comorbidity Index

Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, functional status, etc.) is associated with risk of transplant-related mortality. The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index. Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the Charlson Comorbidity Index elements were correlated with transplant-related mortality in adult and pediatric patients. They also determined several additional comorbidities that have predictive power specific to transplant patients. Successful validation defined what is now termed the HCT-Charlson Comorbidity Index (HCT-CCI).[1] Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (refer to Table 4).

Table 4. Definitions of Comorbidities Included in the Hematopoietic Cell Transplantation-Charlson Comorbidity Index (HCT-CCI)a
AST/ALT = aspartate aminotransferase/alanine aminotransferase; DLCO = diffusion capacity of carbon monoxide; FEV1 = forced expiratory volume in one second; ULN = upper limit of normal.
aAdapted from Sorror et al.[1]
bOne or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass graft.
1 2 3
Arrhythmia: Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmiasModerate pulmonary: DLCO and/or FEV1 66%–80% or dyspnea on slight activityHeart valve disease: Excluding mitral valve prolapse
Cardiac: Coronary artery disease,b congestive heart failure, myocardial infarction, or ejection fraction ≤50%Moderate/severe renal: Serum creatinine >2 mg/dL, on dialysis, or prior renal transplantationModerate/severe hepatic: Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN
Cerebrovascular disease: Transient ischemic attack or cerebrovascular accidentPeptic ulcer: Requiring treatmentPrior solid tumor: Treated at any time in the patient’s history, excluding nonmelanoma skin cancer
Diabetes: Requiring treatment with insulin or oral hypoglycemic agents but not diet aloneRheumatologic: Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, mixed connective tissue disease, or polymyalgia rheumaticaSevere pulmonary: DLCO and/or FEV1 <65% or dyspnea at rest or requiring oxygen
Hepatic, mild: Chronic hepatitis, bilirubin > ULN or AST/ALT > ULN to 2.5 × ULN  
Infection: Requiring continuation of antimicrobial treatment after day 0  
Inflammatory bowel disease: Crohn disease or ulcerative colitis  
Obesity: Body mass index >35 kg/m2  
Psychiatric disturbance: Depression or anxiety requiring psychiatric consult or treatment  

The predictive power of this index for both transplant-related mortality and overall survival (OS) is strong, with a hazard ratio of 3.54 (95% confidence interval [CI], 2.0–6.3) for nonrelapse mortality (NRM) and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or more compared with those who have a score of 0. Although the original studies were performed with patients receiving intense, myeloablative approaches, the HCT-CCI has been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens as well.[2] It has also been combined with disease status [3] and Karnofsky score,[4] leading to even better prediction of survival outcomes. In addition, high HCT-CCI scores (>3) have been associated with a higher risk of grades 3 to 4 acute graft-versus-host disease (GVHD).[5]

Most patients assessed in the HCT-CCI studies have been adults, and the comorbidities listed are skewed toward adult diseases. The relevance of this scale for pediatric and young adult recipients of HCT has been explored in two studies. A retrospective cohort study was conducted at four large centers of pediatric patients with a median age of 6 years and a wide variety of both malignant and nonmalignant disorders.[6] The HCT-CCI was predictive of both NRM and survival, with 1-year NRM of 10%, 14%, and 28% and 1-year OS of 88%, 67%, and 62% for patients with scores of 0, 1 to 2, and 3 or higher, respectively. A second study included young adults (aged 16–39 years) and demonstrated similar increases in mortality with higher HCT-CCI scores (NRM of 24% and 38% and OS of 46% and 28% for patients with scores of 0–2 and 3+, respectively).[7] In both studies, more than three-quarters of the reported comorbidities were associated with respiratory or hepatic conditions and infection.[6,7] Patients with pre-HCT pulmonary dysfunction were at particularly high risk for comorbidity, with a 2-year OS of 29% compared with 61% in those with normal lung function before HCT.[7]

Selected HCT-Related Acute Complications

Sinusoidal obstruction syndrome/veno-occlusive disease

Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is defined clinically by right upper quadrant pain with hepatomegaly, fluid retention (weight gain and ascites), and hyperbilirubinemia. Pathologically, the disease is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of myeloablative transplantations in children, and risk factors include the use of busulfan (especially before therapeutic pharmacokinetic monitoring), total-body irradiation, serious infection, GVHD, and pre-existing liver dysfunction due to hepatitis or iron overload.[8,9] Life-threatening SOS/VOD generally occurs early after transplantation and is characterized by multiorgan system failure.[10] Milder, reversible forms can occur with full recovery expected.

Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied with mixed results, but recent studies have suggested prophylactic ursodiol may have an effect on SOS/VOD.[11] One small, retrospective, single-center study showed a benefit from corticosteroid therapy; this requires further validation.[12] Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has been shown to decrease mortality in the treatment of severe VOD [13-15] and seems to show efficacy in decreasing VOD incidence when used prophylactically.[16][Level of evidence: 1iiA] Defibrotide is not FDA approved but is routinely used by U.S. centers through a pre-approval protocol.

The British Society for Blood and Marrow Transplantation published evidence-guided recommendations on the diagnosis and management of VOD.[17] They recommend that biopsy be reserved for difficult cases and performed using the transjugular approach. They suggest that plasminogen activator inhibitor 1 levels should not be used routinely for the diagnosis of SOS/VOD. They recommend the prophylactic use of defibrotide or ursodeoxycholic acid for patients at high-risk of developing SOS/VOD, but concluded there was insufficient data to support the use of prostaglandin E1, pentoxifylline, or antithrombin. For treatment of VOD, they recommend aggressive fluid balance management, early involvement of critical care and gastroenterology specialists, and the use of defibrotide and perhaps methylprednisolone, but found insufficient evidence to support the use of tissue plasminogen activator and N-acetylcysteine.[17,18]

Transplant-associated microangiopathy

Although transplant-associated microangiopathy clinically mirrors hemolytic uremic syndrome, its causes and clinical course are different from other hemolytic uremic syndrome–like syndromes. Studies have linked this syndrome with disruption of alternative complement pathways.[19] Transplant-associated microangiopathy has most frequently been associated with the use of the calcineurin inhibitors, tacrolimus and cyclosporine, and has been noted to occur more frequently when either of these two medications are used in combination with sirolimus.[20] Diagnostic criteria for this syndrome have been standardized and include the presence of schistocytes on a peripheral smear and increased lactic dehydrogenase, decreased haptoglobin, and thrombocytopenia with or without anemia.[21] Suggestive symptoms consistent but not necessary for the diagnosis include a sudden worsening of renal function and neurologic symptoms. Treatment for transplant-associated microangiopathy includes cessation of the calcineurin inhibitor and substitution with other immune suppressants if necessary. In addition, careful management of hypertension and renal damage by dialysis, if necessary, is vital. Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most transplant-associated microangiopathy associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after stopping sirolimus, and in some cases, both medications.[20]

Idiopathic pneumonia syndrome

Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs within the first few months after transplantation. Diagnostic criteria include signs and symptoms of pneumonia, evidence of nonlobar radiographic infiltrates, and abnormal pulmonary function, all in the absence of documented infectious organisms.[22] With this in mind, early assessment by bronchioalveolar lavage to rule out infection is important. Time of onset ranges from 14 days to 90 days after the infusion of donor cells. Mortality rates of 50% to 70% have been reported,[23] although these estimates are from the mid-1990s and outcomes may have improved. Possible etiologies include direct toxic effects of the conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli. Traditional therapy has been high-dose methylprednisolone and pulmonary support. The addition of etanercept, a soluble interleukin-2 receptor, to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies,[24] but multicenter studies showing improved long-term survival are lacking. In recent years, the incidence of this complication appears to be decreasing, possibly due to less-intensive preparative regimens, better HLA matching, and better definition of occult infections through polymerase chain reaction (PCR) testing of blood and bronchioalveolar specimens.

Epstein-Barr virus–lymphoproliferative disorder

Epstein-Barr virus (EBV) infection increases through childhood from approximately 40% in 4-year olds to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk for reactivation of EBV when undergoing HCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin or alemtuzumab, and to a lesser degree, use of cord blood).[25-27] Patients experiencing EBV reactivation can vary from isolated increase in EBV titers in the bloodstream as measured by PCR to an aggressive monoclonal disease with marked lymphadenopathy presenting as lymphoma (lymphoproliferative disorder). Isolated bloodstream reactivation can improve in some cases without therapy as immune function improves; however, lymphoproliferative disorder may require more aggressive therapy. Treatment of EBV-lymphoproliferative disorder in the past has relied on decreasing immune suppression and treatment with chemotherapy such as cyclophosphamide. Recently, CD20-positive EBV-lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy, rituximab.[28-30] In addition, some centers have found efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[31] Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.

Acute graft-versus-host disease (GVHD)

GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities present in the tissues of a recipient.[32] Acute GVHD usually occurs within the first 3 months of transplantation, although delayed acute GVHD has been noted in reduced-intensity conditioning and nonmyeloablative approaches, where achieving a high level of full donor chimerism is sometimes delayed. Typically, acute GVHD presents with at least one of three manifestations: skin rash, hyperbilirubinemia, and secretory diarrhea. Acute GVHD is classified by grading the severity of skin, gastrointestinal, and liver involvement and further combining the individual grading of these three areas into an overall stage that is prognostically significant (refer to Tables 5 and 6).[33] Patients with grade III or IV acute GVHD are at higher risk for mortality, generally due to organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Table 5. Grading and Staging of Acute Graft-Versus-Host Disease (GVHD)a
StageSkinLiver (bilirubin)bGI/Gut (stool output/day)c
BSA = body surface area; GI = gastrointestinal.
aChildren's Oncology Group/Pediatric Blood and Marrow Transplant Consortium consensus, adapted from the modified Glucksberg system.
bThere is no modification of liver staging for other causes of hyperbilirubinemia.
cFor GI staging: The “adult” stool output values should be used for patients weighing >50 kg. Use 3-day averages for GI staging based on stool output. If stool and urine are mixed, stool output is presumed to be 50% of total stool/urine mix.
dIf colon or rectal biopsy is positive, but stool output is <500 mL/day (<10 mL/kg/day), then consider as GI stage 0.
eFor stage 4 GI: the term “severe abdominal pain” will be defined as having both (a) pain control requiring treatment with opioids or an increased dose in ongoing opioid use; and (b) pain that significantly impacts performance status, as determined by the treating physician.
0No GVHD rash<2 mg/dLChild: <10 mL/kg/d; Adult: <500 mL/d
1Maculopapular rash <25% BSA2–3 mg/dLAdult: 500–999 mL/dd; Child: 10–19.9 mL/kg/d; Persistent nausea, vomiting, or anorexia, with a positive upper GI biopsy
2Maculopapular rash 25%–50% BSA3.1–6 mg/dLChild: 20–30 mL/kg/d; Adult: 1000–1500 mL/d
3Maculopapular rash >50% BSA6.1–15 mg/dLChild: >30 mL/kg/d; Adult: >1500 mL/d
4Generalized erythroderma plus bullous formation and desquamation >5% BSA>15 mg/dLSevere abdominal paine with or without ileus, or grossly bloody stool (regardless of stool volume)
Table 6. Overall Clinical Grade (Based on the Highest Stage Obtained)
GI = gastrointestinal.
Grade 0:No stage 1–4 of any organ
Grade I:Stage 1–2 skin and no liver or gut involvement
Grade II:Stage 3 skin or Stage 1 liver involvement or Stage 1 GI
Grade III:Stage 0–3 skin, with Stage 2–3 liver or Stage 2–3 GI
Grade IV:Stage 4 skin, liver, or GI involvement
Prevention and treatment of acute GVHD

Morbidity and mortality from acute GVHD can be reduced through immune suppressive medications given prophylactically or T-cell depletion of grafts, either ex vivo by actual removal of cells from a graft or in vivo with anti-lymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]). Approaches to GVHD prevention in non-T-cell–depleted grafts have included intermittent methotrexate, a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics), or various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil. When significant acute GVHD occurs, first-line therapy is generally methylprednisolone.[34] Patients with acute GVHD resistant to this therapy have a poor prognosis but a good percentage of cases respond to second-line agents (e.g., mycophenolate mofetil, infliximab, pentostatin, sirolimus, or extracorporeal photopheresis).[35] Complete elimination of acute GVHD with intense T-cell depletion approaches has generally resulted in increased relapse, more infectious morbidity, and increased EBV-lymphoproliferative disorder. Because of this, most HCT GVHD prophylaxis is given in an attempt to balance risk by giving sufficient immune suppression to prevent most severe acute GVHD but not completely removing GVHD risk.

Chronic Graft-versus-Host Disease

Chronic GVHD is a syndrome that may involve a single or several organ systems, with clinical features resembling autoimmune diseases.[36,37] Chronic GVHD is usually first noted 2 to 12 months after HCT. Traditionally, symptoms occurring more than 100 days after HCT were considered to be chronic GVHD, and symptoms occurring earlier than 100 days post-HCT were considered to be acute GVHD. Because some approaches to HCT can lead to late-onset acute GVHD, and manifestations that are diagnostic for chronic GVHD can occur earlier than 100 days, the following three distinct types of chronic GVHD have been described:

  • Classic chronic GVHD—occurs with diagnostic and/or distinct features of chronic GVHD (Tables 7–11) after a previous history of resolved acute GVHD.
  • Overlap syndrome—an ongoing GVHD process when manifestations diagnostic for chronic GVHD occur while symptoms of acute GVHD persist.
  • De novo chronic GVHD—new-onset GVHD generally occurring at least 2 months after transplant, with diagnostic and/or distinct features of chronic GVHD and no history of or features of acute GVHD.

Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT [38] and in 20% to 45% of children after unrelated donor HCT, with higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk with cord blood.[39,40] The tissues that are commonly involved include skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may be involved.

Risk factors for the development of chronic GVHD include the following:[38,41,42]

  • Patient’s age.
  • Type of donor.
  • Use of PBSCs.
  • History of acute GVHD.
  • Conditioning regimen.

The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive Schirmer test).[43] Tables 7 to 11 list organ manifestations of chronic GVHD with a specific listing of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsy of affected sites may be needed to confirm the diagnosis.[44]

Table 7. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Skin, Nails, Scalp, and Body Haira
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
aReprinted from Biology of Blood and Marrow Transplantation, Volume 11 (Issue 12), Alexandra H. Filipovich, Daniel Weisdorf, Steven Pavletic, Gerard Socie, John R. Wingard, Stephanie J. Lee, Paul Martin, Jason Chien, Donna Przepiorka, Daniel Couriel, Edward W. Cowen, Patricia Dinndorf, Ann Farrell, Robert Hartzman, Jean Henslee-Downey, David Jacobsohn, George McDonald, Barbara Mittleman, J. Douglas Rizzo, Michael Robinson, Mark Schubert, Kirk Schultz, Howard Shulman, Maria Turner, Georgia Vogelsang, Mary E.D. Flowers, National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report, Pages 945-956, Copyright 2005, with permission from American Society for Blood and Marrow Transplantation and Elsevier.[43]
bSufficient to establish the diagnosis of chronic GVHD.
cSeen in chronic GVHD, but insufficient alone to establish a diagnosis of chronic GVHD.
dCan be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed.
eIn all cases, infection, drug effects, malignancy, or other causes must be excluded.
fDiagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
SkinPoikilodermaDepigmentationSweat impairmentPruritus
Lichen planus-like features IchthyosisErythema
Sclerotic features Keratosis pilarisMaculopapular rash
Morphea-like features Hypopigmentation 
Lichen sclerosus-like features Hyperpigmentation 
Nails Dystrophy  
Longitudinal ridging, splitting, or brittle features
Pterygium unguis
Nail loss (usually symmetric; affects most nails)e
Scalp and body hair New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy)Thinning scalp hair, typically patchy, coarse, or dull (not explained by endocrine or other causes) 
Scaling, papulosquamous lesionsPremature gray hair
Table 8. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Mouth and GI Tracta
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ULN = upper limit of normal.
Refer to Table 7 footers for definitions of a through e.
MouthLichen-type featuresXerostomia Gingivitis
Hyperkeratotic plaquesMucoceleMucositis
Restriction of mouth opening from sclerosisPseudomembraneseErythema
 Mucosal atrophyPain
GI TractEsophageal web Exocrine pancreatic insufficiencyAnorexia
Strictures or stenosis in the upper to mid third of the esophaguseNausea
 Weight loss
 Failure to thrive (infants and children)
 Total bilirubin, alkaline phosphatase >2 × ULNe
 ALT or AST >2 × ULNe
Table 9. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Eyesa
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
Refer to Table 7 footers for definitions of a through f.
Eyes New onset dry, gritty, or painful eyesfBlepharitis (erythema of the eyelids with edema) 
Cicatricial conjunctivitis
Keratoconjunctivitis siccafPhotophobia
Confluent areas of punctate keratopathyPeriorbital hyperpigmentation
Table 10. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Genitaliaa
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
Refer to Table 7 footers for definitions of a through e.
GenitaliaLichen planus–like featuresErosionse  
Vaginal scarring or stenosisUlcerse
Table 11. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Lung, Muscles, Fascia, Joints, Hematopoietic and Immune Systems, and Other Symptomsa
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
AIHA = autoimmune hemolytic anemia; BOOP = bronchiolitis obliterans–organizing pneumonia; ITP = idiopathic thrombocytopenic purpura; PFTs = pulmonary function tests.
Refer to Table 7 footers for definitions of a through f.
LungBronchiolitis obliterans diagnosed with lung biopsyBronchiolitis obliterans diagnosed with PFTs and radiologyf  BOOP
Muscles, fascia, jointsFasciitisMyositis or polymyositisfEdema 
Muscle cramps
Arthralgia or arthritis
Hematopoietic and immune  Thrombocytopenia 
Hypo- or hypergammaglobulinemia
Autoantibodies (AIHA and ITP)
Other  Pericardial or pleural effusions 
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction abnormality or cardiomyopathy

Common skin manifestations include alterations in pigmentation, texture, elasticity, and thickness, with papules, plaques, or follicular changes. Patient-reported symptoms include dry skin, itching, limited mobility, rash, sores, or changes in coloring or texture. Generalized scleroderma may lead to severe joint contractures and debility. Associated hair loss and nail changes are common. Other important symptoms that should be assessed include dry eyes and oral changes such as atrophy, ulcers, and lichen planus. In addition, joint stiffness along with restricted range of motion, weight loss, nausea, difficulty swallowing, and diarrhea should be noted.

Several factors have been associated with increased risk of nonrelapse mortality (NRM) in children who develop significant chronic GVHD. Children who received HLA mismatched grafts, PBSCs, who were older than 10 years, or who had platelet counts of less than 100,000/µL at diagnosis of chronic GVHD have an increased risk of NRM. NRM was 17%, 22%, and 24% at 1, 3, and 5 years after diagnosis with chronic GVHD. Many of these children require long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died either of relapse or NRM, a third were off immune suppression, and a third still required some form of immune suppressive therapy.[45]

Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 proposed broadening the description of chronic GVHD to three categories in order to better predict long-term outcomes.[46] The three current NIH grading categories are as follows:[43]

  • Mild disease—involving only one or two sites with no significant functional impairment (maximum severity score of 1 in a 0-to-3–point scale).
  • Moderate disease—involving either more sites (>2) or is associated with higher severity score (maximum score of 2 in any site).
  • Severe disease—indicating major disability (a score of 3 in any site or a lung score of 2).

Thus, high-risk patients include those with severe disease of any site or extensive involvement of multiple sites, especially those with symptomatic lung involvement, greater than 50% skin involvement, platelet count of less than 100,000/µl, poor performance score (<60%), weight loss greater than 15%, chronic diarrhea, progressive onset chronic GVHD, or a history of steroid treatment with greater than 0.5 mg/kg/day of prednisone for acute GVHD.

Treatment of chronic GVHD

Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including use of calcineurin inhibitors.[47] Topical therapy to affected areas is preferred for patients with limited disease.[48] A number of agents such as mycophenolate mofetil,[49] pentostatin,[50] sirolimus,[51] and rituximab,[52] have been tested with some success. Other approaches including extracorporeal photopheresis have been evaluated and show some efficacy in a percentage of patients.[53]

Besides significantly affecting organ function, quality of life, and functional status, infection is the major cause of chronic GVHD-related death. Therefore, all patients with chronic GVHD should receive prophylaxis against Pneumocystis jirovecii pneumonia, common encapsulated organisms, and varicella by using agents such as trimethoprim/sulfamethoxazole, penicillin, and acyclovir. While disease progression is the primary cause of death in long-term follow-up of hematopoietic stem cell transplantation patients with no chronic GVHD, transplant-related complications account for 70% of the deaths in patients with chronic GVHD.[38] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[48]


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  • Updated: December 12, 2014