Childhood Hematopoietic Cell Transplantation (PDQ®) 3/5 —Health Professional Version - National Cancer Institute

Childhood Hematopoietic Cell Transplantation (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Hematopoietic Cell Transplantation (PDQ®)–Health Professional Version

Complications After HCT

In This Section

• Pre-HCT Comorbidities That Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Specific Comorbidity Index
• Selected HCT-Related Acute Complications
  • Infectious risks and immune recovery after transplantation
  • Sinusoidal obstruction syndrome/veno-occlusive disease
  • Transplant-associated microangiopathy
  • Idiopathic pneumonia syndrome
  • Epstein-Barr virus (EBV)–associated lymphoproliferative disorder
  • Acute graft-versus-host disease (GVHD)
• Chronic GVHD
  • Treatment of chronic GVHD
• Late Mortality After HCT

Pre-HCT Comorbidities That Affect the Risk of Transplant-Related Mortality: Predictive Power of the HCT-Specific 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, and functional status) is associated with a 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 (CCI). Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the CCI 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 hematopoietic cell transplantation–specific comorbidity index (HCT-CI).[1,2] 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–Specific Comorbidity Index (HCT-CI)a

HCT-CI Score
1	2	3
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.
Arrhythmia: Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias	Moderate pulmonary:DLCO and/or FEV1 66%–80% or dyspnea on slight activity	Heart 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 transplantation	Moderate/severe hepatic:Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN
Cerebrovascular disease:Transient ischemic attack or cerebrovascular accident	Peptic ulcer: Requiring treatment	Prior 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 alone	Rheumatologic: Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, mixed connective tissue disease, or polymyalgia rheumatica	Severe 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 and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or higher, compared with those who have a score of 0. Although the original studies were performed with patients receiving intense myeloablative approaches, the HCT-CI has also been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens.[3] It has also been combined with disease status [4] and Karnofsky score,[5] leading to even better prediction of survival outcomes. In addition, high HCT-CI scores (>3) have been associated with a higher risk of grades 3 to 4 acute graft-versus-host disease (GVHD).[6]

Most patients assessed in the HCT-CI 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 the following studies:

• A retrospective cohort study was conducted at four large centers of pediatric patients (median age, 6 years) with a wide variety of both malignant and nonmalignant disorders.[7] The HCT-CI was predictive of both nonrelapse mortality and survival, with 1-year nonrelapse mortality 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-CI scores (nonrelapse mortality of 24% and 38% and OS of 46% and 28% for patients with scores of 0–2 and 3+, respectively).[8]
• As part of a prospective validation of the HCT-CI through the Center for International Blood and Marrow Transplant Research, 23,876 patients—including 1,755 children—who underwent transplant between 2007 and 2009 were scored and outcomes were tracked. Although adults treated with myeloablative regimens had increased mortality with scores of 1 or 2, pediatric patients did not have increased mortality until a score of 3 or higher was noted.[9]

Most of the reported comorbidities in these studies were with respiratory or hepatic conditions and infection.[7,8] In the adolescent and young adult study, patients with pre-HCT pulmonary dysfunction were at particularly high risk of comorbidity, with a 2-year OS of 29%, compared with 61% in those with normal lung function before HCT.[8]

Selected HCT-Related Acute Complications

Infectious risks and immune recovery after transplantation

Defective immune reconstitution is a major barrier to successful HCT, regardless of graft source.[10,11] Serious infections have been shown to account for a significant percentage (4%–20%) of late deaths after HCT.[12]

Factors that can significantly slow immune recovery include the following:[13]

• Graft manipulation (removal of T cells).
• Stem cell source (slow recovery with cord blood).
• Chronic GVHD.

Figure 5 illustrates the immune defects, contributing transplant-related factors, and types and timing of infections that occur after allogeneic transplantation.[14]

ENLARGE

Figure 5. Phases of predictable immune suppression with their opportunistic infections among allogeneic hematopoietic stem cell transplantation recipients. Adapted from Burik and Freifeld. This figure was published in Clinical Oncology, 3rd edition, Abeloff et al., Chapter: Infection in the severely immunocompromised patient, Pages 941–956, Copyright Elsevier (2004).

Bacterial infections tend to occur in the first few weeks after transplant during the neutropenic phase, when mucosal barriers are damaged from the conditioning regimen; there is significant ongoing study about the role of prophylactic antibacterial medications during the neutropenic phase.[15]

Prophylaxis against fungal infections is standard during the first several months after transplantation and may be considered for patients with chronic GVHD who are at high risk of fungal infection. Antifungal prophylaxis must be tailored to the patient's underlying immune status. Pneumocystis infection can occur in all patients post–bone marrow transplant, and prophylaxis is mandatory.[15]; [16][Level of evidence: 3iiiB]

After HCT, viral infections can be a major source of mortality, especially after T-cell–depleted or cord blood procedures. Types of viral infections include the following:

• Cytomegalovirus (CMV). CMV infection has been a major cause of mortality in the past, but effective drugs to treat CMV are available, and preventive strategies, including quantitative polymerase chain reaction (PCR) monitoring followed by preemptive therapy with ganciclovir, have been developed.
• Epstein-Barr virus (EBV). EBV rarely causes lymphoproliferative disease and is generally associated with intensive, multidrug GVHD therapy or T-cell–depleted HCT.
• Adenovirus. Adenovirus infection is a major issue in T-cell–depleted transplantation, and monitoring by quantitative blood PCR followed by therapy with cidofovir or brincidofovir (available through a compassionate-use protocol) has led to a major decrease in morbidity.[17]
• Other. Other viruses have been implicated in hemorrhagic cystitis (BK virus), encephalitis and poor count recovery (human herpes virus 6), and other clinical issues.[15]

Careful viral monitoring is essential during high-risk allogeneic procedures.

Late bacterial infections can occur in patients who have central lines or patients with significant chronic GVHD. These patients are susceptible to infection with encapsulated organisms, particularly pneumococcus. Despite reimmunization, these patients can sometimes develop significant infections, and continued prophylaxis is recommended until a serological response to immunizations has been documented. Occasionally, postallogeneic HCT patients can become functionally asplenic, and antibiotic prophylaxis is recommended. Patients should remain on infection prophylaxis (e.g., Pneumocystis jiroveciipneumonia prophylaxis) until immune recovery. Time to immune recovery varies, but ranges from 3 months to 9 months after autologous HCT and 9 months to 24 months after allogeneic HCT without GVHD. Patients with active chronic GVHD may have persistent immunosuppression for years. Many centers monitor T-cell subset recovery post–bone marrow transplant as a guide to infection risk.[15]

Vaccination after transplantation

Specific guidelines have been developed by international transplant and infectious disease groups for administration of vaccinations after autologous and allogeneic transplantation.[15] Comparative studies aimed at defining ideal timing of vaccination after transplantation have not been performed, but the vaccine guidelines outlined in Table 5result in protective titers in most patients who receive vaccinations. These guidelines recommend that autologous transplant recipients receive immunizations beginning at 6 months after stem cell infusion and receive live vaccines 24 months after the transplant. Patients undergoing allogeneic procedures can begin immunizations as soon as 6 months after transplant. However, many groups prefer to wait either until 12 months after the procedure for patients remaining on immune suppression or until patients are off immune suppression.

Vaccination recommendations should be reconsidered at times of local endemic or epidemic disease outbreaks. In those settings, earlier vaccination with killed vaccines may be implemented, acknowledging limited host responses.

Table 5. Vaccination Schedule for Hematopoietic Stem Cell Transplantation (HSCT) Recipientsa

Autologous HSCT	6 Mob	8 Mob	12 Mob	24 Mob
Allogeneic HSCT (if not immunized before 12 mo post-HSCT; start regardless of GVHD status or immunosuppression)	12 mob (sooner if off immunosuppression)	14 mob(or 2 mo after first dose)	18 mob(or 6 mo after first dose)	24 mob
GVHD = graft-versus-host disease; IM = intramuscular; PO = orally.
aAdapted from Tomblyn et al.,[15] Centers for Disease Control and Prevention,[18] and Kumar et al.[19]
bTimes indicated are times posttransplant (day 0).
cUse of Tdap is acceptable if DTap is not available.
dTiters may be considered for pediatric patients and patients with GVHD who received immunizations while on immune suppression (minimum 6–8 weeks after last vaccination).
eMay start as soon as 4 months post-HSCT or sooner for patients with CD4 counts >200/mcL or at any time during an epidemic. If given <6 months after HSCT, may require second dose. Children younger than 9 years require second dose, separated by 1 month.
fConsider pre- or postvaccine (at least 6–8 weeks after) titers.
gPCV 7 at 24 months only for patients with GVHD; all other patients can get PPV 23.
hPediatric patients should receive two doses at least 1 month apart.
Inactivated Vaccines
Diphtheria, tetanus, acellular pertussis (DTap)	Xc	Xc	Xc,d
Haemophilus influenzae (Hib)	X	X	Xd
Hepatitis B (HepB)	X	X	Xd
Inactive polio (IPV)	X	X	Xd
Influenza—seasonal injection (IM)	Xe
Pneumococcal conjugate (PCV 7, PCV 13)	Xf	X	Xd,f,g
Pneumococcal polysaccharide (PPV 23)			Xd,f,g
Live Attenuated Vaccines (contraindicated in patients with active GVHD or on immunosuppression)
Measles, mumps, rubella				Xd,h
Optional Inactivated Vaccines
Hepatitis A			Optional
Meningococcal			Xd (for high-risk patients)
Optional Live Vaccines (contraindicated in patients with active GVHD or on immunosuppression)
Chicken pox (varicella vaccine)				Optional
Rabies			May be considered at 12–24 mo if exposed
Yellow fever, tick-borne encephalitis (TBE), Japanese B encephalitis				For travel in endemic areas
Contraindicated Vaccines
Intranasal influenza (trivalent live-attenuated influenza vaccine)—household contacts and caregivers should not receive within 2 weeks before contact with HSCT recipient; shingles; bacillus Calmette-Guerin (BCG); oral polio vaccine (OPV); cholera; typhoid vaccine (PO, IM); rotavirus.

Sinusoidal obstruction syndrome/veno-occlusive disease

Pathologically, sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) 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 pediatric myeloablative transplantation patients.[20,21]

Risk factors include the following:[20,21]

• Use of busulfan (especially before therapeutic pharmacokinetic monitoring).
• Total-body irradiation.
• Serious infection.
• GVHD.
• Pre-existing liver dysfunction due to hepatitis or iron overload.

SOS/VOD is defined clinically by the following:

• Right upper quadrant pain with hepatomegaly.
• Fluid retention (weight gain and ascites).
• Hyperbilirubinemia.

Life-threatening SOS/VOD generally occurs soon after transplantation and is characterized by multiorgan system failure.[22] Milder, reversible forms can occur, with full recovery expected. Pediatric patients who have severe SOS/VOD without increased bilirubin have been reported;[23] therefore, it is important to be vigilant about monitoring patients who have other symptoms without increased bilirubin.

Prevention and treatment of SOS/VOD

Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied, with mixed results.[24] One small, retrospective, single-center study showed a benefit from corticosteroid therapy, but further validation is needed.[25] Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has demonstrated the following:

• Decreased mortality in the treatment of severe SOS/VOD.[26-29]; [30][Level of evidence: 3iiiA]
• Decreased SOS/VOD mortality associated with the early initiation of defibrotide treatment soon after diagnostic criteria for SOS/VOD were met.[31][Level of evidence: 2A]
• Efficacy in decreasing SOS/VOD incidence when used prophylactically.[32][Level of evidence: 1iiA]

Defibrotide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients who have hepatic SOS/VOD with renal or pulmonary dysfunction after HSCT.

The British Society for Blood and Marrow Transplantation (BSBMT) published evidence-guided recommendations for the diagnosis and management of SOS/VOD.[29] They recommend that biopsy be reserved for difficult cases and be performed using the transjugular approach. The BSBMT supports the use of defibrotide for the prevention of SOS/VOD (defibrotide prophylaxis is not currently part of the FDA indication), but concluded there is insufficient data to support the use of prostaglandin E1, pentoxifylline, or antithrombin. For treatment of SOS/VOD, they recommend aggressive fluid balance management, early involvement of critical care and gastroenterology specialists, and the use of defibrotide and possibly methylprednisolone, but concluded there is insufficient evidence to support the use of tissue plasminogen activator or N-acetylcysteine.[29,33] More detailed consensus recommendations for the diagnosis and management of SOS/VOD in children after HCT have been published by the Pediatric Blood and Marrow Transplant Consortium (PBMTC), who worked with the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI).[34-36]

Transplant-associated microangiopathy

Although transplant-associated microangiopathy clinically mirrors hemolytic uremic syndrome, its causes and clinical course differ from those of other hemolytic uremic syndrome–like diseases. Studies have linked this syndrome with dysregulation of complement pathways.[37] 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 medications are used in combination with sirolimus.[38]

Diagnostic criteria for this syndrome have been standardized and include the following:[39]

• Presence of schistocytes on a peripheral smear.
• Increased lactic dehydrogenase.
• Decreased haptoglobin.
• Thrombocytopenia with or without anemia.

Suggestive symptoms consistent with but not necessary for the diagnosis include a sudden worsening of renal function or neurologic symptoms.

Treatment of transplant-associated microangiopathy

Treatment for transplant-associated microangiopathy includes the following:

• Cessation of the calcineurin inhibitor and substitution with other immune suppressants, if necessary.
• 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 sirolimus is stopped, and in some cases, after both medications are stopped.[38]

Some evidence suggests a role for complement modulation (c5, eculizumab therapy) in preserving renal function; further assessment of the role of this medication in treating this complication is ongoing.[40,41]

Idiopathic pneumonia syndrome

Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs from 14 to 90 days after the infusion of donor cells. 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.[42]

The incidence of this complication appears to be decreasing, possibly because of less intensive preparative regimens, better HLA matching, and better definition of occult infections through PCR testing of blood and bronchioalveolar specimens. Mortality rates of 50% to 70% have been reported;[42] however, these estimates are from the mid-1990s, and outcomes may have improved.

Diagnostic criteria include the following signs and symptoms in the absence of documented infectious organisms:[43]

• Pneumonia.
• Evidence of nonlobar radiographic infiltrates.
• Abnormal pulmonary function.

Early assessment by bronchioalveolar lavage to rule out infection is important.

Treatment of idiopathic pneumonia syndrome

Traditional therapy has been high-dose methylprednisolone and pulmonary support.

Etanercept is a soluble fusion protein that joins the extracellular ligand-binding domain of the tumor necrosis factor (TNF)–alpha receptor to the Fc region of the immunoglobulin G1 antibody. It acts by blocking TNF-alpha signaling. The addition of etanercept to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies.[44] A large phase II trial of this approach in pediatrics showed promising results, with overall survival rates of 89% at 1 month and 63% at 12 months.[45]

Epstein-Barr virus (EBV)–associated lymphoproliferative disorder

After HCT, EBV infection incidence increases through childhood, from approximately 40% in children aged 4 years to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk of EBV reactivation 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).[46-48]

Features of EBV reactivation can vary from an 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 requires more aggressive therapy. Treatment of EBV–associated lymphoproliferative disorder has relied on decreasing immune suppression and treatment with chemotherapy agents such as cyclophosphamide. CD20-positive EBV–associated lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy rituximab.[49-51] In addition, some centers have shown efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[52,53]

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.[54] Acute GVHD usually occurs within the first 3 months posttransplantation, 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 the following three manifestations:

• Skin rash.
• Hyperbilirubinemia.
• Secretory diarrhea.

Acute GVHD is classified by staging the severity of skin, liver, and gastrointestinal involvement and further combining the individual staging of these three areas into an overall grade that is prognostically significant (refer to Tables 6 and 7).[55] Patients with grade III or grade IV acute GVHD are at higher risk of mortality, generally resulting from organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Table 6. Staging of Acute Graft-Versus-Host Disease (GVHD)a

Stage	Skin	Liver (bilirubin)b	GI/Gut (stool output per day)c
			Adult	Child
BSA = body surface area; GI = gastrointestinal.
aAdapted from Harris et al.[56]
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 results of colon or rectal biopsy are 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.
0	No GVHD rash	<2 mg/dL	<500 mL or <3 episodes/day	<10 mL/kg or <4 episodes/day
1	Maculopapular rash <25% BSA	2–3 mg/dL	500–999 mLd or 3–4 episodes/day	10–19.9 mL/kg or 4–6 episodes/day; persistent nausea, vomiting, or anorexia, with a positive result from upper GI biopsy
2	Maculopapular rash 25%–50% BSA	3.1–6 mg/dL	1,000–1,500 mL or 5–7 episodes/day	20–30 mL/kg or 7–10 episodes/day
3	Maculopapular rash >50% BSA	6.1–15 mg/dL	>1,500 mL or >7 episodes/day	>30 mL/kg or >10 episodes/day
4	Generalized erythroderma plus bullous formation and desquamation >5% BSA	>15 mg/dL	Severe abdominal painewith or without ileus, or grossly bloody stool (regardless of stool volume)	Severe abdominal paine with or without ileus, or grossly bloody stool (regardless of stool volume)

Table 7. 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 and/or stage 1 liver involvement and/or stage 1 GI
Grade III:	Stage 0–3 skin, with stage 2–3 liver and/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 antilymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]).

Approaches to GVHD prevention in non–T-cell-depleted grafts have included the following:[57,58]; [59][Level of evidence: 3iiiA]

• Intermittent methotrexate.
• Calcineurin inhibitor (e.g., cyclosporine or tacrolimus).
• Combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics).
• Various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil.
• Non–calcineurin inhibitor (intensive T-cell depletion, posttransplant cyclophosphamide, etc.). Non–calcineurin inhibitor approaches have been developed and are becoming more widely used.

When significant acute GVHD occurs, first-line therapy is generally methylprednisolone.[60] 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).[61]

Complete elimination of acute GVHD with intense T-cell depletion has generally resulted in increased relapse, more infectious morbidity, and increased EBV-associated lymphoproliferative disorder. Because of this, most HCT GVHD prophylaxis is given in an attempt to balance risk by giving sufficient immune suppression to prevent severe acute GVHD but not completely remove GVHD risk.

Chronic GVHD

Chronic GVHD is a syndrome that may involve a single organ system or several organ systems, with clinical features resembling an autoimmune disease.[62,63] 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 sooner 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 sooner than 100 days post-HCT, the following three distinct types of chronic GVHD have been described:

• Classic chronic GVHD: Occurs with diagnostic and/or distinct features of chronic GVHD (refer to Tables 8–12) 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 or features of acute GVHD.

Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT [64] and in 20% to 45% of children after unrelated-donor HCT, with a higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk associated with cord blood.[65,66] 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:[64,67,68]

• 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 results of a Schirmer test).[69] Tables 8 to 12 list organ manifestations of chronic GVHD with a description of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsies of affected sites may be needed to confirm the diagnosis.[70]

Table 8. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Skin, Nails, Scalp, and Body Haira

ENLARGE

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen with Both Acute and Chronic GVHD)
aReprinted from Biology of Blood and Marrow TransplantationExit Disclaimer, 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.[69]
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).
Skin	Poikiloderma	Depigmentation	Sweat impairment	Pruritus
	Lichen planus–like features		Ichthyosis	Erythema
	Sclerotic features		Keratosis pilaris	Maculopapular rash
	Morphea-like features		Hypopigmentation
	Lichen sclerosus–like features		Hyperpigmentation
Nails		Dystrophy
		Longitudinal ridging, splitting, or brittle features
		Onycholysis
		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 lesions	Premature gray hair

Table 9. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Mouth and GI Tracta

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen with Both Acute and Chronic GVHD)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ULN = upper limit of normal.
Refer to Table 8 footers for definitions of a through e.
Mouth	Lichen-type features	Xerostomia		Gingivitis
	Hyperkeratotic plaques	Mucocele		Mucositis
	Restriction of mouth opening from sclerosis	Pseudomembranese		Erythema
		Mucosal atrophy		Pain
		Ulcerse
GI Tract	Esophageal web		Exocrine pancreatic insufficiency	Anorexia
	Strictures or stenosis in the upper to mid third of the esophaguse			Nausea
				Vomiting
				Diarrhea
				Weight loss
				Failure to thrive (infants and children)
				Total bilirubin, alkaline phosphatase >2 × ULNe
				ALT or AST >2 × ULNe

Table 10. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Eyesa

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen with Both Acute and Chronic GVHD)
Refer to Table 8 footers for definitions of a through f.
Eyes		New onset dry, gritty, or painful eyesf	Blepharitis (erythema of the eyelids with edema)
		Cicatricial conjunctivitis
		Keratoconjunctivitis siccaf	Photophobia
		Confluent areas of punctate keratopathy	Periorbital hyperpigmentation

Table 11. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Genitaliaa

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen with Both Acute and Chronic GVHD)
Refer to Table 8 footers for definitions of a through e.
Genitalia	Lichen planus–like features	Erosionse
		Fissurese
	Vaginal scarring or stenosis	Ulcerse

Table 12. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Lung, Muscles, Fascia, Joints, Hematopoietic and Immune Systems, and Other Symptomsa

ENLARGE

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (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 8 footers for definitions of a through f.
Lung	Bronchiolitis obliterans diagnosed with lung biopsy	Bronchiolitis obliterans diagnosed with PFTs and radiologyf		BOOP
Muscles, fascia, joints	Fasciitis	Myositis or polymyositisf	Edema
			Muscle cramps
			Arthralgia or arthritis
Hematopoietic and immune			Thrombocytopenia
			Eosinophilia
			Lymphopenia
			Hypo- or hypergammaglobulinemia
			Autoantibodies (AIHA and ITP)
Other			Pericardial or pleural effusions
			Ascites
			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 in children who develop significant chronic GVHD. Children who received HLA-mismatched grafts, received PBSCs, were older than 10 years, or had platelet counts lower than 100,000/µL at diagnosis of chronic GVHD have an increased risk of nonrelapse mortality. Nonrelapse mortality was 17% at 1 year, 22% at 3 years, and 24% at 5 years after diagnosis with chronic GVHD. Many of these children required long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died of either relapse or nonrelapse mortality, a third were off immune suppression, and a third still required some form of immune suppressive therapy.[71]

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 to better predict long-term outcomes.[72] The three NIH grading categories are as follows:[69]

• Mild disease: Involving only one or two sites, with no significant functional impairment (maximum severity score of 1 on a scale of 0 to 3).
• Moderate disease: Either involving more sites (>2) or 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 the following:

• Symptomatic lung involvement.
• Skin involvement greater than 50%.
• Platelet count lower than 100,000/µL.
• Poor performance score (<60%).
• Weight loss of more than 15%.
• Chronic diarrhea.
• Progressive-onset chronic GVHD.
• History of steroid treatment with more than 0.5 mg of prednisone per kilogram per day for acute GVHD.

One study demonstrated a much higher chance of long-term GVHD-free survival and lower treatment-related mortality in children with mild and moderate chronic GVHD than in children with severe chronic GVHD. At 8 years, the probability of continued chronic GVHD in children with mild, moderate, and severe chronic GVHD was 4%, 11%, and 36%, respectively.[73]

Treatment of chronic GVHD

Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including the use of calcineurin inhibitors.[74] Topical therapy to affected areas is preferred for patients with limited disease.[75] The following agents have been tested with some success:

• Mycophenolate mofetil.[76]
• Pentostatin.[77]
• Sirolimus.[78]
• Rituximab.[79]
• Ibrutinib.[80]

Other approaches, including extracorporeal photopheresis, have been evaluated and show some efficacy in a percentage of patients.[81]

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 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 seen 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.[64] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[75]

Late Mortality After HCT

The highest incidence of mortality after HCT occurs in the first 2 years, mostly caused by relapse. A study of late mortality (≥2 years) after HCT showed that about 20% of the 479 patients who were alive at 2 years suffered a late death. Late mortality in the allogeneic group was 15% (median follow-up, 10.0 years; range, 2.0–25.6 years), mainly caused by relapse (65%). A total of 26% of patients suffered a late death after autologous HCT (median follow-up, 6.7 years; range, 2.0–22.2 years),[82] and recurrence of the primary malignancy accounted for 88% of these deaths. In contrast to studies of adult patients, nonrelapse mortality is less common in children, and death caused by chronic GVHD and secondary malignancies is less common. Another study reviewed the causes of late mortality after second allogeneic transplantation.[83] Of the children who were alive and relapse free 1 year after second HCT, 55% remained alive at 10 years. The most common cause of mortality at 10 years in this group was relapse (77% of deaths), generally occurring in the first 3 years after transplantation. The cumulative incidence of nonrelapse mortality for this cohort at 10 years was 10%. Chronic GVHD occurred in 43% of children in this study and was the leading cause of nonrelapse mortality.

A study focused on late mortality after autologous HCT in children showed that mortality rates remained elevated from those of the general population more than 10 years after the procedure, but approached the rates of the general population at 15 years. The study also showed a decrease in late mortality in the more current treatment eras (before 1990: 35.1%; 1990–1999: 25.6%; 2000–2010: 21.8%; P = .05).[84]

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