martes, 16 de abril de 2019

Childhood Hematopoietic Cell Transplantation (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

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

National Cancer Institute

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

Complications 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
123
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 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 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]
ENLARGEChart showing phases of predictable immune suppression and associated opportunistic infections among allogeneic hematopoietic stem cell transplantation recipients.
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 HSCT6 Mob8 Mob12 Mob24 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)XcXcXc,d 
Haemophilus influenzae (Hib)XXXd 
Hepatitis B (HepB)XXXd 
Inactive polio (IPV)XXXd 
Influenza—seasonal injection (IM)Xe
Pneumococcal conjugate (PCV 7, PCV 13)XfXXd,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:
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
StageSkinLiver (bilirubin)bGI/Gut (stool output per day)c
   AdultChild
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.
0No GVHD rash<2 mg/dL<500 mL or <3 episodes/day<10 mL/kg or <4 episodes/day
1Maculopapular rash <25% BSA2–3 mg/dL500–999 mLd or 3–4 episodes/day10–19.9 mL/kg or 4–6 episodes/day; persistent nausea, vomiting, or anorexia, with a positive result from upper GI biopsy
2Maculopapular rash 25%–50% BSA3.1–6 mg/dL1,000–1,500 mL or 5–7 episodes/day20–30 mL/kg or 7–10 episodes/day
3Maculopapular rash >50% BSA6.1–15 mg/dL>1,500 mL or >7 episodes/day>30 mL/kg or >10 episodes/day
4Generalized erythroderma plus bullous formation and desquamation >5% BSA>15 mg/dLSevere 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 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.[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).
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
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 lesionsPremature gray hair
Table 9. 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 8 footers for definitions of a through e.
MouthLichen-type featuresXerostomia Gingivitis
Hyperkeratotic plaquesMucoceleMucositis
Restriction of mouth opening from sclerosisPseudomembraneseErythema
 Mucosal atrophyPain
 Ulcerse 
 
GI TractEsophageal web Exocrine pancreatic insufficiencyAnorexia
Strictures or stenosis in the upper to mid third of the esophaguseNausea
 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 SiteDiagnosticbDistinctivecOther FeaturesdCommon (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 eyesfBlepharitis (erythema of the eyelids with edema) 
Cicatricial conjunctivitis
Keratoconjunctivitis siccafPhotophobia
Confluent areas of punctate keratopathyPeriorbital hyperpigmentation
Table 11. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Genitaliaa
Organ or SiteDiagnosticbDistinctivecOther FeaturesdCommon (Seen with Both Acute and Chronic GVHD)
Refer to Table 8 footers for definitions of a through e.
GenitaliaLichen planus–like featuresErosionse  
Fissurese
Vaginal scarring or stenosisUlcerse
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 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 8 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 
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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Late Effects After HCT in Children

Data from studies of child and adult survivors of hematopoietic cell transplantation (HCT) have shown a significant impact from treatment-related exposures on survival and quality of life.[1] Of patients alive at 2 years after HCT, a 9.9-fold increased risk of premature death has been noted.[2]

Methodological Challenges Specific to HCT

Although the main cause of death in this cohort is from relapse of the primary disease, a sizeable number of these patients die from graft-versus-host disease (GVHD)–related infections, second malignancies, or cardiac or pulmonary issues.[2-5] In addition, other studies have revealed that up to 40% of HCT survivors experience severe, disabling, and/or life-threatening events or die because of an adverse event associated with primary/previous cancer treatment.[6,7]
Before studies aimed at decreasing the incidence or severity of these effects are initiated, it is important to understand what leads to the development of these complications:
  • Pretransplant therapy: Pretransplant therapy plays an important role, but the details of significant exposures associated with pre-HCT therapy are not included in many studies.[8]
  • Preparative regimen: The transplant preparative regimen itself, including total-body irradiation (TBI) and high-dose chemotherapy, has often been studied, but this intense therapy is only a small part of a long course of therapy filled with potential causes of late effects.
  • Allogenicity: The effect of allogenicity—differences in major and minor HLA antigens that lead to GVHD, autoimmunity, chronic inflammation, and, sometimes, undetected organ damage—also contributes to these late effects.
Individuals differ in their susceptibility to specific organ damage from chemotherapy or in their risk of GVHD on the basis of genetic differences in both the donor and recipient.[8-10]

Cardiovascular System Late Effects

Although cardiac dysfunction has been studied extensively in non-HCT settings, less is known about the incidence and predictors of congestive heart failure following HCT in childhood. Potentially cardiotoxic exposures unique to HCT include the following:[11]
  • Conditioning with high-dose chemotherapy, especially cyclophosphamide.
  • TBI.
HCT survivors are at increased risk of developing cardiovascular risk factors such as hypertension and diabetes, partly as a result of exposure to TBI and prolonged immunosuppressive therapy after allogeneic HCT, or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[7,11] A study of 661 pediatric patients surviving at least 2 years after allogeneic HCT showed that 52% of patients were obese or overweight at their most recent examination, 18% of patients had dyslipidemia (associated with pre-HCT anthracycline or cranial or chest irradiation), and 7% of patients were diagnosed with diabetes.[12]
Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) treated in Seattle from 1985 to 2006. The survivors and a population-based comparison group were matched by age, year, and sex.[13] Survivors experienced increased rates of cardiovascular death (adjusted incidence rate difference, 3.6 per 1,000 person-years [95% confidence interval, 1.7–5.5]) and had an increased cumulative incidence of the following:
  • Ischemic heart disease.
  • Cardiomyopathy/heart failure.
  • Stroke.
  • Vascular diseases.
  • Rhythm disorders.
Survivors also had an increased cumulative incidence of related conditions that predispose towards more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).[13]
In addition, cardiac function and pre-HCT exposures to chemotherapy and radiation therapy have been shown to have significant impact on post-HCT cardiac function. In evaluating post-HCT patients for long-term issues, it is important to consider levels of pre-HCT anthracycline and chest irradiation.[14] Although more specific work needs to be done to verify this, current evidence suggests that the risk of late-occurring cardiovascular complications after HCT may largely result from pre-HCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[15,16]
(Refer to the Late Effects of the Cardiovascular System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Central Nervous System Late Effects

Neurocognitive outcomes

A preponderance of studies report normal neurodevelopment after HCT, with no evidence of decline.[17-24]
Researchers from St. Jude Children’s Research Hospital have reported on the largest longitudinal cohort to date, describing remarkable stability in global cognitive function and academic achievement during 5 years of posttransplant follow-up.[20-22] This group reported poorer outcomes in patients undergoing unrelated-donor transplant when the patients received TBI and when they experienced GVHD, but these effects were small compared with the much larger effects seen on the basis of differences in socioeconomic status.[21] Most published studies report similar outcomes. Normal cognitive function and academic achievement were reported in a cohort of 47 patients monitored prospectively through 2 years post-HCT.[24] Stable cognitive function was also noted in a large cohort monitored from pretransplant to 2 years post-HCT.[19] A smaller study reported similar normal functioning and the absence of declines over time in HCT survivors.[17] HCT survivors did not differ from their siblings in cognitive and academic function, with the exception that survivors performed better than siblings on measures of perceptual organization.[18] On the basis of the findings to date, it appears that HCT poses low to minimal risk of late cognitive and academic deficits in survivors.
A number of studies, however, have reported some decline in cognitive function after HCT.[25-31] These studies tended to include samples with a high percentage of very young children. One study reported a significant decline in IQ in their cohort at 1 year post-HCT, and these deficits were maintained at 3 years post-HCT.[26,27] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who underwent transplant with TBI.[29,30] Another study from St. Jude Children's Research Hospital reported that while all children younger than 3 years had a decline in IQ at 1 year after transplant, patients who did not receive TBI during conditioning recovered later. However, patients who received TBI had a significantly lower IQ at 5 years (P = .05) than did those who did not receive TBI.[31]
(Refer to the Stem cell transplantation section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Digestive System Late Effects

Gastrointestinal, biliary, and pancreatic dysfunction

Most gastrointestinal late effects are related to protracted acute GVHD and chronic GVHD (refer to Table 13). (Refer to the Hepatobiliary Complications section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
As GVHD is controlled and tolerance is developed, most symptoms resolve. Major hepatobiliary concerns include the consequences of viral hepatitis acquired before or during the transplant, biliary stone disease, and focal liver lesions.[32] Viral serology and polymerase chain reaction should be performed to differentiate these from GVHD presenting with hepatocellular injury.[33]
Table 13. Causes of Gastrointestinal (GI), Hepatobiliary, and Pancreatic Problems in Long-Term Transplant Survivorsa
Problem AreasCommon CausesLess Common Causes
ALT = alanine transaminase; AP = alkaline phosphatase; CMV = cytomegalovirus; GGT = gamma glutamyl transpeptidase; GVHD = graft-versus-host disease; HSV = herpes simplex virus; Mg++ = magnesium; VZV = varicella zoster virus.
aReprinted from Biology of Blood and Marrow Transplantation, Volume 17 (Issue 11), Michael L. Nieder, George B. McDonald, Aiko Kida, Sangeeta Hingorani, Saro H. Armenian, Kenneth R. Cooke, Michael A. Pulsipher , K. Scott Baker, National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction, Pages 1573–1584, Copyright 2011, with permission from American Society for Blood and Marrow Transplantation and Elsevier.[33]
Esophageal symptoms: heartburn, dysphagia, painful swallowing [34-39]Oral chronic GVHD (mucosal changes, poor dentition, xerostomia)Chronic GVHD of the esophagus (webs, rings, submucosal fibrosis and strictures, aperistalsis)
Reflux of gastric fluidHypopharyngeal dysmotility (myasthenia gravis, cricopharyngeal incoordination)
 Squamous > adenocarcinoma
 Pill esophagitis
 Infection (fungal, viral)
 
Upper gut symptoms: anorexia, nausea, vomiting [40-44]Protracted acute GI GVHDSecondary adrenal insufficiency
Activation of latent infection (CMV, HSV, VZV)Acquisition of infection (enteric viruses, Giardia, cryptosporidia, Haemophilus pylori)
Medication adverse effectsGut dysmotility
 
Mid gut and colonic symptoms: diarrhea and abdominal pain [45,46]Protracted acute GI GVHDAcquisition of infection (enteric viruses, bacteria, parasites)
Activation of latent CMV, VZVPancreatic insufficiency
Drugs (mycophenolate mofetil, Mg++, antibiotics)Clostridium difficile colitis
 Collagen-encased bowel (GVHD)
 Rare: inflammatory bowel disease, sprue;[46] bile salt malabsorption; disaccharide malabsorption
 
Liver problems [32,47-56]Cholestatic GVHDHepatitic GVHD
Chronic viral hepatitis (B and C)VZV or HSV hepatitis
CirrhosisFungal abscess
Focal nodular hyperplasiaNodular regenerative hyperplasia
Nonspecific elevation of liver enzymes in serum (AP, ALT, GGT)Biliary obstruction
 Drug-induced liver injury
 
Biliary and pancreatic problems [57-60]CholecystitisPancreatic atrophy/insufficiency
Common duct stones/sludgePancreatitis/edema, stone or sludge related
Gall bladder sludge (calcium bilirubinate)Pancreatitis, tacrolimus related
Gallstones 

Iron overload

Iron overload occurs in almost all patients who undergo HCT, especially if the procedure is for a condition associated with transfusion dependence before HCT (e.g., thalassemia, bone marrow failure syndromes) or pre-HCT treatments requiring transfusions after myelotoxic chemotherapy (e.g., acute leukemias). Inflammatory conditions such as GVHD also increase gastrointestinal iron absorption. The effects of iron overload on morbidity post-HCT have not been well studied; however, reducing iron levels after HCT for thalassemia has been shown to improve cardiac function.[61] Non-HCT conditions leading to iron overload can lead to cardiac dysfunction, endocrine disorders (e.g., pituitary insufficiency, hypothyroidism), diabetes, neurocognitive effects, and second malignancies.[33]
Although data supporting iron reduction therapies such as phlebotomy or chelation after HCT have not identified specific levels at which iron reduction should be performed, higher levels of ferritin and/or evidence of significant iron overload by liver biopsy or T2-weighted magnetic resonance imaging (MRI) [62] should be addressed by iron reduction therapy.[63]

Endocrine System Late Effects

Thyroid dysfunction

Studies show that rates of thyroid dysfunction in children after myeloablative HCT vary, with larger series reporting an average incidence of about 30%.[64-73] A lower incidence in adults (on average, 15%) and a notable increase in incidence in children younger than 10 years undergoing HCT suggest that a developing thyroid gland may be more susceptible to damage.[64,66,70]
Pretransplant local thyroid radiation contributes to high rates of thyroid dysfunction in patients with Hodgkin lymphoma.[64] Early studies showed very high rates of thyroid dysfunction after high single-dose fractions of TBI,[74] but traditional fractionated TBI/cyclophosphamide compared with busulfan/cyclophosphamide showed similar rates of thyroid dysfunction, suggesting a role for high-dose chemotherapy in thyroid damage.[67-69] Rates of thyroid dysfunction associated with newer combinations of busulfan/fludarabine or reduced-intensity regimens have yet to be reported. (Refer to the Posttransplant thyroid dysfunction section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Higher rates of thyroid dysfunction occur with single-drug versus three-drug GVHD prophylaxis,[75] along with increased rates of thyroid dysfunction after unrelated-donor versus related-donor HCT (36% vs. 9%),[65] suggesting a role for alloimmune damage in causing thyroid dysfunction.[69,76]

Growth impairment

Growth impairment is generally multifactorial. Factors that play a role in failure to achieve expected adult height in young children who have undergone HCT include the following:
  • Diminished growth hormone level.
  • Thyroid dysfunction.
  • Disruption of pubertal sex hormone production.
  • Steroid therapy.
  • Poor nutritional status.
The incidence of growth impairment varies from 20% to 80%, depending on age, risk factors, and the definition of growth impairment used by reporting groups.[71,72,77-80] Risk factors include the following:[67,68,78,81]
  • TBI.
  • Cranial irradiation.
  • Younger age.
  • Undergoing HCT for acute lymphoblastic leukemia.
  • HCT occurring during a pubertal growth spurt.[82]
Patients younger than 10 years at the time of HCT are at the highest risk of growth impairment, but also respond best to growth hormone replacement therapy. Early screening and referral of patients with signs of growth impairment to endocrinology specialists can result in significant restoration of height in younger children.[80]
(Refer to the Growth hormone deficiency section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Abnormal body composition/metabolic syndrome

After HCT, adult survivors have a risk of premature cardiovascular-related death that is increased 2.3-fold compared with the general population.[83,84] The exact etiology of cardiovascular risk and subsequent death is largely unknown, although the development of metabolic syndrome (a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), especially insulin resistance, as a consequence of HCT has been suggested.[85-87]
In studies of conventionally treated leukemia survivors compared with those who underwent HCT, transplant survivors are significantly more likely to manifest metabolic syndrome or multiple adverse cardiac risk factors, including central adiposity, hypertension, insulin resistance, and dyslipidemia.[33,88,89] The concern over time is that survivors who develop metabolic syndrome after HCT will be at higher risk of experiencing significant cardiovascular-related events and/or premature death from cardiovascular-related causes.
(Refer to the Metabolic Syndrome section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Sarcopenic obesity

The association of obesity with diabetes and cardiovascular disease risk in the general population is well established, but obesity as determined by body mass index (BMI) is uncommon in long-term survivors after HCT.[89] However, despite having a normal BMI, HCT survivors develop significantly altered body composition that results in both an increase in total percent fat mass and a reduction in lean body mass. This finding is termed sarcopenic obesity and results in a loss of myocyte insulin receptors and an increase in adipocyte insulin receptors; the latter are less efficient in binding insulin and clearing glucose, ultimately contributing to insulin resistance.[90-92]
Preliminary data from 119 children and young adults and 81 healthy sibling controls found that HCT survivors had significantly lower weight but no differences in BMI or waist circumference when compared with siblings.[93] HCT survivors had a significantly higher percent fat mass and lower lean body mass than did controls. HCT survivors were significantly more insulin resistant than were controls, and they also had a higher incidence of other cardiovascular risk factors such as elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides; these differences were found only in patients who had received TBI as part of their transplant conditioning regimen.

Musculoskeletal System Late Effects

Low bone mineral density

A limited number of studies have addressed low bone mineral density after HCT in children.[94-100] A significant portion of children experienced reduction in total-body bone mineral density or lumbar Z-scores showing osteopenia (18%–33%) or osteoporosis (6%–21%). Although general risk factors have been described (female sex, inactivity, poor nutritional status, white or Asian ethnicity, family history, TBI, craniospinal irradiation, corticosteroid therapy, GVHD, cyclosporine, and endocrine deficiencies [e.g., growth hormone deficiency, hypogonadism]), most reported populations have been too small to perform multivariate analysis to test the relative importance of each of these factors.[101-111]
Some studies in adults have shown improvement over time in low bone mineral density after HCT;[99,112,113] however, this has yet to be shown in children.
Treatment for children has generally included a multifactorial approach, with vitamin D and calcium supplementation, minimization of corticosteroid therapy, participation in weight-bearing exercise, and resolution of other endocrine problems. The role of bisphosphonate therapy in children with this condition is unclear.
(Refer to the Osteoporosis/fractures section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Osteonecrosis

Reported incidence of osteonecrosis in children after HCT has been 1% to 14%; however, these studies were retrospective and underestimated actual incidence because patients may be asymptomatic early in the course.[114-116] Two prospective studies showed an incidence of 30% and 44% with routine MRI screening of possible target joints.[98,117] Osteonecrosis generally occurs within 3 years after HCT, with a median onset of about 1 year. The most common locations include knees (30%–40%), hips (19%–24%), and shoulders (9%). Most patients experience osteonecrosis in two or more joints.[74,114,118,119]
In one prospective report, risk factors by multivariate analysis included age (markedly increased in children older than 10 years; odds ratio, 7.4) and presence of osteonecrosis at the time of transplant. It is important to note that pre-HCT factors such as corticosteroid exposure are very important in determining patient risk. In this study, 14 of 44 children who developed osteonecrosis had the disease before HCT.[117] A Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective nested control study of 160 cases and 478 control children suggested older age (>5 years), female sex, and the presence of chronic GVHD as risk factors for developing osteonecrosis.[120]
Treatment has generally consisted of minimization of corticosteroid therapy and surgical joint replacement. Most patients are not diagnosed until they present with symptoms. In one study of 44 patients with osteonecrosis lesions in whom routine yearly MRI was performed, 4 resolved completely, and 2 had resolution of one of multiply involved joints.[117] The observation that some lesions can heal over time suggests caution in the surgical management of asymptomatic lesions.
(Refer to the Osteonecrosis section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Reproductive System Late Effects

Pubertal development

Delayed, absent, or incomplete pubertal development occurs commonly after HCT. Two studies showed pubertal delay or failure in 16% of female children who received cyclophosphamide alone, 72% of those who received busulfan/cyclophosphamide, and 57% of those who underwent fractionated TBI. In males, incomplete pubertal development or failure was noted in 14% of those who received cyclophosphamide alone, 48% of those who received busulfan/cyclophosphamide, and 58% of those who underwent TBI.[73,121] Boys receiving more than 24 Gy of radiation to the testicles developed azoospermia and also experienced failure of testosterone production, requiring supplementation to develop secondary sexual characteristics.[122]

Fertility

Women
Pretransplant and transplant cyclophosphamide exposure is the best-studied agent affecting fertility. Postpubertal women younger than 30 years can tolerate up to 20 g/m2 of cyclophosphamide and have preserved ovarian function; prepubertal females can tolerate as much as 25 g/m2 to 30 g/m2. Although the additional effect added by pretransplant exposures to cyclophosphamide and other agents has not been specifically quantitated in studies, these exposures plus transplant-related chemotherapy and radiation therapy lead to ovarian failure in 65% to 84% of females undergoing myeloablative HCT.[123-126] The use of cyclophosphamide, busulfan, and TBI as part of the preparative regimen are associated with worse ovarian function. Younger age at the time of HCT is associated with a higher chance of menarche and ovulation.[127,128] (Refer to the Ovarian function after HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Studies of pregnancy are challenging because data seldom indicate whether individuals are trying to conceive. Nonetheless, a large study of pregnancy in pediatric and adult survivors of myeloablative transplantation demonstrated conception in 32 of 708 patients (4.5%).[123] Of those trying to conceive, patients exposed to cyclophosphamide alone (total dose 6.7 g/m2 with no pretransplant exposure) had the best chance of conception (56 of 103, 54%), while those receiving myeloablative busulfan/cyclophosphamide (0 of 73, 0%) or TBI (7 of 532, 1.3%) had much lower rates of conception.
Men
The ability of men to produce functional sperm decreases with exposure to higher doses and specific types of chemotherapy. Most men will become azoospermic at a cyclophosphamide dose of 300 mg/kg.[129] After HCT, 48% to 85% will experience gonadal failure.[123,129,130] One study showed that men who received cyclophosphamide conceived only 24% of the time, compared with 6.5% of men who received busulfan/cyclophosphamide and 1.3% of those who underwent TBI.[123] (Refer to the Testicular function after HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Effect of reduced-toxicity/reduced-intensity/nonmyeloablative regimens
On the basis of clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, the use of reduced-intensity/toxicity and nonmyeloablative regimens will likely lead to a higher chance of preserved fertility after HCT. Because the use of these regimens is relatively new and mostly confined to older or sicker patients, most reports have consisted of single cases. Registry reports are beginning to describe pregnancies after these procedures.[126] In addition, a single-center study compared myeloablative busulfan/cyclophosphamide with reduced-intensity fludarabine/melphalan.[131][Level of evidence: 3iiiC] Spontaneous puberty occurred in 56% of girls and 89% of boys after busulfan/cyclophosphamide, whereas 90% of girls and all of the boys in the fludarabine/melphalan group entered puberty spontaneously (P = .012). Significantly more girls (61%) conditioned with busulfan/cyclophosphamide required hormone replacement than did girls in the fludarabine/melphalan group (10.5%; P = .012). In boys, no difference was noted between the two conditioning groups in time to follicle-stimulating hormone elevation (median, 4 years in the fludarabine/melphalan group vs. 6 years in the busulfan/cyclophosphamide group). While the two regimens have similar effects on testicular function, ovarian function seems to be better preserved in girls undergoing stem cell transplantation with reduced-intensity conditioning approaches.

Respiratory System Late Effects

Chronic pulmonary dysfunction

The following two forms of chronic pulmonary dysfunction are observed after HCT:[132-137]
  • Obstructive lung disease.
  • Restrictive lung disease.
The incidence of both forms of lung toxicity can range from 10% to 40%, depending on donor source, the time interval after HCT, definition applied, and presence of chronic GVHD. In both conditions, collagen deposition and the development of fibrosis in either the interstitial space (restrictive lung disease) or the peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.[138]
Obstructive lung disease
The most common form of obstructive lung disease post–allogeneic HCT is bronchiolitis obliterans.[134,137,139,140] This condition is an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive obstructive lung disease.[132]
Historically, the term bronchiolitis obliterans has been used to describe chronic GVHD of the lung and begins 6 to 20 months after HCT. Pulmonary function tests show obstructive lung disease with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in 1 second (FEV1), and associated decreases in the FEV1/FVC ratio with or without significant declines in the diffusion capacity of the lung for carbon monoxide (DLCO).
Risk factors for bronchiolitis obliterans include the following:[132,139]
  • Lower pretransplant FEV1/FVC values.
  • Concomitant pulmonary infections.
  • Chronic aspiration.
  • Acute and chronic GVHD.
  • Older recipient age.
  • Use of mismatched donors.
  • High-dose (vs. reduced-intensity) conditioning.
The clinical course of bronchiolitis obliterans is variable, but patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression.
Standard treatment for obstructive lung disease combines enhanced immunosuppression with supportive care, including antimicrobial prophylaxis, bronchodilator therapy, and supplemental oxygen, when indicated.[141] The potential role for tumor necrosis factor-alpha in the pathogenesis of obstructive lung disease suggests that neutralizing agents such as etanercept may have promise.[142]
Restrictive lung disease
Restrictive lung disease is defined by reductions in FVC, total lung capacity (TLC), and DLCO. In contrast to obstructive lung disease, the FEV1/FVC ratio is maintained near 100%. Restrictive lung disease is common after HCT and has been reported in 25% to 45% of patients by day 100.[132] Importantly, declines in TLC or FVC occurring at 100 days and 1 year after HCT are associated with an increase in nonrelapse mortality. Early reports suggested that the incidence of restrictive lung disease increases with advancing recipient age, but subsequent studies have revealed significant restrictive lung disease in children receiving HCT.[143]
The most recognizable form of restrictive lung disease is bronchiolitis obliterans organizing pneumonia. Clinical features include dry cough, shortness of breath, and fever. Radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in fewer than 10% of HCT recipients, the development of bronchiolitis obliterans organizing pneumonia is strongly associated with previous acute and chronic GVHD.[138]
The response in patients with restrictive lung disease to multiple agents such as corticosteroids, cyclosporine, tacrolimus, and azathioprine is limited.[141] The potential role for tumor necrosis factor-alpha in the pathogenesis of restrictive lung disease suggests that neutralizing agents such as etanercept may have promise.[142]
(Refer to the Respiratory complications associated with HSCT section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Urinary System Late Effects

Renal disease

Chronic kidney disease is frequently diagnosed after transplant. There are many clinical forms of chronic kidney disease, but the most commonly described ones include thrombotic microangiopathy, nephrotic syndrome, calcineurin inhibitor toxicity, acute kidney injury, and GVHD-related chronic kidney disease. Various risk factors associated with the development of chronic kidney disease have been described; however, recent studies suggest that acute and chronic GVHD may be a proximal cause of renal injury.[33]
In a systematic review of 9,317 adults and children from 28 cohorts who underwent HCT, approximately 16.6% of patients (range, 3.6% to 89%) developed chronic kidney disease, defined as a decrease in estimated glomerular filtration rate of at least 24.5 mL/min/1.73 m2 within the first year after transplant.[144] The cumulative incidence of chronic kidney disease developing approximately 5 years after transplant ranges from 4.4% to 44.3%, depending on the type of transplant and stage of chronic kidney disease.[145,146] Mortality rates among patients with chronic kidney disease in this setting are higher than those in transplant recipients who retain normal renal function, even when studies have controlled for comorbidities.[147]
It is important to aggressively treat hypertension in patients post-HCT, especially in those treated with prolonged courses of calcineurin inhibitors. Whether post-HCT patients with albuminuria and hypertension benefit from treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers requires further study, but careful control of hypertension with captopril, an ACE inhibitor, did show a benefit in a small study.[148]

Quality of Life

Health-related quality of life (HRQL)

HRQL is a multidimensional construct, incorporating a subjective appraisal of one’s functioning and well-being, with reference to the impact of health issues on overall quality of life.[149,150]. Many studies have shown that HRQL varies according to the following:[151]
  • Time after HCT: HRQL is worse with more recent HCT.
  • Transplant type: Unrelated-donor HCT has worse HRQL than does autologous or allogeneic related-donor HCT.
  • Presence or absence of HCT-related sequelae: HRQL is worse with chronic GVHD.
Pre-HCT factors, such as family cohesion and a child’s adaptive functioning, have been shown to affect HRQL.[152] Several groups have also identified the importance of pre-HCT parenting stress on parental ratings of children’s HRQL post-HCT.[152-156] A report of the trajectories of HRQL over the 12 months after HCT noted that the poorest HRQL was seen at 3 months post-HCT, with steady improvement thereafter. Recipients of unrelated-donor transplants had the steepest declines in HRQL from baseline to 3 months. Another study reported that compromised emotional functioning, high levels of worry, and reduced communication during the acute recovery period had a negative impact on HRQL at 1-year post-HCT.[157] Longitudinal studies identified an association of the following additional baseline risk factors with the trajectory of HRQL after HCT:
  • Child's age (older children, worse HRQL).[152,158,159]
  • Child's sex (females, worse HRQL).[159]
  • Rater (mothers report lower HRQL than do fathers; parents report lower HRQL than do children).[160,161]
  • Concordance by primary language or by sex of the raters (concordant pairs, higher HRQL).[162]
  • Parental emotional distress (greater parental distress, worse HRQL).[158]
  • Child's race (African American children, better HRQL).[159]
A report on the impact of specific HCT complications on children’s HRQL indicated that HRQL was worse among children with severe end-organ toxicity, systemic infection, or GVHD.[153] Cross-sectional studies report that the HRQL among pediatric HCT survivors of 5 years or longer is reasonably good, although psychological, cognitive, or physical problems appear to negatively influence HRQL. Female sex, causal diagnosis for HCT (acute myelogenous leukemia, worse HRQL), and intensity of pre-HCT therapy were all identified as affecting HRQL post-HCT.[163,164] Finally, another cross-sectional study of children 5 to 10 years post-HCT cautioned that parental concerns about the child’s vulnerability may induce overprotective parenting.[156]

Functional outcomes

Physician-reported physical performance
Clinician reports of long-term disability among childhood HCT survivors suggest that the prevalence and severity of functional loss is low.
  • A study from the European Society for Blood and Marrow Transplantation used the Karnofsky performance scale to report outcomes among 647 HCT survivors (surviving ≥5 years).[165] In this cohort, 40% of survivors were younger than 18 years when they underwent transplant; only 19% had Karnofsky scores lower than 100. Seven percent had scores lower than 80, defined as the inability to work. Similar low rates of clinician-graded poor functional outcome were reported by two other groups.[163,166]
  • Among 50 survivors of childhood allogeneic HCT treated at the City of Hope National Medical Center and Stanford University Hospital, all had Karnofsky scores of 90 or 100.[166]
  • Among 73 young adults (mean age, 26 years) treated at the Karolinska University Hospital, the median Karnofsky score at 10 years post-HCT was 90.[163]
Self-reported physical performance
Self-reported and proxy data among survivors of childhood HCT indicated similar low rates of functional loss in the following studies:
  • One study evaluated 22 survivors of childhood allogeneic HCT (mean age at HCT, 11 years; mean age at questionnaire, 25 years) and reported no differences between survivors’ scores and population-expected values on standardized physical performance scales.[167]
  • Another study compared a group of survivors who underwent transplant for childhood leukemia (n = 142) with a group of childhood leukemia survivors treated with chemotherapy alone (n = 288).[168] There were no differences between the groups on the physical function and leisure scales using multiple standardized measures.
Other studies that have reported functional limitations include the following:
  • In the Bone Marrow Transplant Survivors Study (BMTSS), among 235 survivors of childhood HCT, 17% reported long-term physical performance limitations, compared with 8.7% of a sibling comparison group.[169]
  • A Seattle study evaluated physical function in 214 young adults (median age at questionnaire, 28.7 years; 118 males) who underwent transplant at a median age of 11.9 years. When compared with age- and sex-matched controls, the HCT survivors in this cohort scored one-half standard deviation lower on the physical component score of the SF-36 and the physical function and role physical subscales, quality-of-life measures.[164]
  • A Swedish study also identified lower self-reported physical health among 73 young adult (median age, 26 years) HCT survivors who were a median of 10 years from transplant. HCT survivors scored significantly below population normative values on physical functioning (90.2 for HCT survivors vs. 95.3 for population), satisfaction with physical health (66.0 for HCT survivors vs. 78.7 for population), and role limitation because of physical health (72.7 for HCT survivors vs. 84.9 for population).[163]
Measured physical performance
Objective measurements of function in the pediatric HCT patient and survivor population hints that loss of physical capacity may be a bigger problem than revealed in studies that rely on either clinician or self-report data. Studies measuring cardiopulmonary fitness have observed the following:
  • One study used exercise capacity with cycle ergometry in a group of 20 children and young adults before HCT, 31 patients at 1 year post-HCT, and 70 healthy controls.[170] The average peak oxygen consumption was 21 mL/kg/min in the pre-HCT group, 24 mL/kg/min in the post-HCT group, and 34 mL/kg/min in the healthy controls. Among the HCT survivors, 62% of those with cancer diagnoses scored in the lowest fifth percentile for peak oxygen consumption, compared with healthy controls.
  • Another study examined exercise capacity with a Bruce treadmill protocol in 31 survivors of pediatric HCT. In this cohort, 25.8% of HCT survivors had exercise capacities in the 70% to 79% of predicted category, and 41.9% had exercise capacities in the lower than 70% of predicted category.[171]
  • In a third study of exercise capacity among 33 HCT survivors who underwent transplant at a mean age of 11.3 years, at the 5-year post-HCT time point, only 4 of 33 survivors scored above the 75th percentile on a serial cycle ergometry test.[172]
Predictors of poor physical performance
In the BMTSS, associations were found between chronic GVHD, cardiac conditions, immune suppression, or treatment for a second malignant neoplasm and poor physical performance outcomes.[173] In a study from the Fred Hutchison Cancer Research Center, poor performance was associated with myeloid disease.[164]

Published Guidelines for Long-term Follow-up

A number of organizations have put forward consensus guidelines for follow-up for late effects after HCT. The CIBMTR, along with the American Society of Blood and Marrow Transplant (ASBMT) and in cooperation with five other international transplant groups, published consensus recommendations for screening and preventive practices for long-term survivors of HCT.[174]
Although some pediatric-specific challenges are addressed in these guidelines, many important pediatric issues are not. Some of these issues have been partially covered by general guidelines published by the Children's Oncology Group (COG) and other children’s cancer groups (United Kingdom, Scotland, and Netherlands). The COG has also published more specific recommendations for late effects surveillance after HCT.[175] To address the lack of detailed pediatric-specific late effects data and guidelines for long-term follow-up after HCT, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) published six detailed papers outlining existing data and summarizing recommendations from key groups (CIBMTR/ASBMT, COG, and the United Kingdom), along with expert recommendations for pediatric-specific issues.[8,33,63,176-178]
Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are under way, the PBMTC summary and guideline recommendations provide the most current outline for monitoring children for late effects after HCT.[63]
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  136. Cerveri I, Zoia MC, Fulgoni P, et al.: Late pulmonary sequelae after childhood bone marrow transplantation. Thorax 54 (2): 131-5, 1999. [PUBMED Abstract]
  137. Uhlving HH, Bang CL, Christensen IJ, et al.: Lung function after allogeneic hematopoietic stem cell transplantation in children: a longitudinal study in a population-based cohort. Biol Blood Marrow Transplant 19 (9): 1348-54, 2013. [PUBMED Abstract]
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  139. Chien JW, Zhao LP, Hansen JA, et al.: Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation. Blood 107 (5): 2200-7, 2006. [PUBMED Abstract]
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  142. Yanik GA, Mineishi S, Levine JE, et al.: Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 18 (7): 1044-54, 2012. [PUBMED Abstract]
  143. Norman BC, Jacobsohn DA, Williams KM, et al.: Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 46 (10): 1369-73, 2011. [PUBMED Abstract]
  144. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008. [PUBMED Abstract]
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  153. Parsons SK, Shih MC, Duhamel KN, et al.: Maternal perspectives on children's health-related quality of life during the first year after pediatric hematopoietic stem cell transplant. J Pediatr Psychol 31 (10): 1100-15, 2006 Nov-Dec. [PUBMED Abstract]
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Changes to This Summary (04/10/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Allogeneic Hematopoietic Cell Transplantation (HCT)
Added Bertaina et al. as reference 62.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hematopoietic cell transplantation in treating childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Hematopoietic Cell Transplantation are:
  • Thomas G. Gross, MD, PhD (National Cancer Institute)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hematopoietic Cell Transplantation. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/child-hct-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389503]
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  • Updated: April 10, 2019
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