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Childhood Hematopoietic Cell Transplantation (PDQ®)

Complications After HCT

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

Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, and functional status) is associated with risk of transplant-related mortality. The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index (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 HCT-CCI.[1] Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (refer to Table 4).

Table 4. Definitions of Comorbidities Included in the Hematopoietic Cell Transplantation-Charlson Comorbidity Index (HCT-CCI)a
HCT-CCI Score
AST/ALT = aspartate aminotransferase/alanine aminotransferase; DLCO = diffusion capacity of carbon monoxide; FEV1 = forced expiratory volume in one second; ULN = upper limit of normal.
aAdapted from Sorror et al.[1]
bOne-or-more–vessel coronary artery stenosis requiring medical treatment, stent, or bypass graft.
1 2 3
Arrhythmia: Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 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 (NRM) 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-CCI has also been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens.[2] It has also been combined with disease status [3] and Karnofsky score,[4] leading to even better prediction of survival outcomes. In addition, high HCT-CCI scores (>3) have been associated with a higher risk of grades 3 to 4 acute graft-versus-host disease (GVHD).[5]

Most patients assessed in the HCT-CCI studies have been adults, and the comorbidities listed are skewed toward adult diseases. The relevance of this scale for pediatric and young adult recipients of HCT has been explored in the following two studies:

  • A retrospective cohort study was conducted at four large centers of pediatric patients (median age of 6 years) with a wide variety of both malignant and nonmalignant disorders.[6] The HCT-CCI was predictive of both NRM and survival, with 1-year NRM of 10%, 14%, and 28% and 1-year OS of 88%, 67%, and 62% for patients with scores of 0, 1 to 2, and 3 or higher, respectively.
  • A second study included young adults (aged 16–39 years) and demonstrated similar increases in mortality with higher HCT-CCI scores (NRM of 24% and 38% and OS of 46% and 28% for patients with scores of 0–2 and 3+, respectively).[7]

In both studies, more than three-quarters of the reported comorbidities were associated with respiratory or hepatic conditions and infection.[6,7] Patients with pre-HCT pulmonary dysfunction were at particularly high risk of comorbidity, with a 2-year OS of 29%, compared with 61% in those with normal lung function before HCT.[7]

Selected HCT-Related Acute Complications

Infectious risks and immune recovery after transplantation

Defective immune reconstitution is a major barrier to successful HCT, regardless of graft source.[8,9] Serious infections have been shown to account for a significant percentage (4%–20%) of late deaths after HCT.[10] Factors that can significantly slow immune recovery include graft manipulation (removal of T cells), stem cell source (slow recovery with cord blood), and chronic graft-versus-host disease (GVHD).[11]

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.[12] 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.[12]

After HCT, viral infections can be a major source of mortality, especially after T-cell–depleted or cord blood procedures. Cytomegalovirus (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 PCR monitoring followed by preemptive therapy with ganciclovir, have been developed. EBV rarely causes lymphoproliferative disease and is generally associated with intensive, multidrug GVHD therapy or T-cell–depleted HCT. Adenovirus infection is a major issue in T-cell–depleted transplantation, and monitoring by quantitative blood PCR followed by cidofovir therapy has led to a major decrease in morbidity. Other viruses have been implicated in hemorrhagic cystitis (BK virus), encephalitis and poor count recovery (human herpes virus 6), and other clinical issues. Careful viral monitoring is essential during high-risk allogeneic procedures.[12]

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., PCP 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.[12]

Vaccination after transplantation

Specific guidelines have been developed by international transplant and infectious disease groups for administration of vaccinations after autologous and allogeneic transplantation (refer to Table 5).[12] Autologous transplant recipients should receive immunizations beginning at 6 months after stem cell infusion and should 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. Comparative studies aimed at defining ideal timing of vaccination after transplantation have not been performed, but the vaccine guidelines outlined in Table 5 result in protective titers in most patients who receive vaccinations.

Table 5. Vaccination Schedule for Hematopoietic Stem Cell Transplantation (HSCT) Recipientsa
Autologous HSCT 6 Mob 8 Mob 12 Mob 24 Mob
GVHD = graft-versus-host disease; IM = intramuscular; PO = orally.
aAdapted from Tomblyn et al.,[12] Centers for Disease Control and Prevention,[13] and Kumar et al.[14]
bTimes indicated are times posttransplant (day 0).
cOk to use Tdap 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.
Allogeneic HSCT (if not immunized prior to 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 mo b
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 prior to 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

Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is defined clinically by the following:

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

Pathologically, the disease is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of pediatric myeloablative transplantation patients; risk factors include the use of busulfan (especially before therapeutic pharmacokinetic monitoring), total-body irradiation, serious infection, GVHD, and pre-existing liver dysfunction due to hepatitis or iron overload.[15,16] Life-threatening SOS/VOD generally occurs soon after transplantation and is characterized by multiorgan system failure.[17] Milder, reversible forms can occur, with full recovery expected.

Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied, with mixed results.[18] One small, retrospective, single-center study showed a benefit from corticosteroid therapy, but further validation is needed.[19] Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has been shown to decrease mortality in the treatment of severe VOD [20-23] and has also shown efficacy in decreasing VOD incidence when used prophylactically.[24][Level of evidence: 1iiA] Defibrotide is not FDA approved but is routinely used by U.S. centers through a pre-approval protocol.

The British Society for Blood and Marrow Transplantation published evidence-guided recommendations on the diagnosis and management of VOD.[23] They recommend that biopsy be reserved for difficult cases and performed using the transjugular approach. They support the use of defibrotide for prevention of SOS/VOD (defibrotide prophylaxis is not currently allowed on the U.S. pre-approval protocol), but concluded there is insufficient data to support the use of prostaglandin E1, pentoxifylline, or antithrombin. For treatment of VOD, they recommend aggressive fluid balance management, early involvement of critical care and gastroenterology specialists, and the use of defibrotide and possibly methylprednisolone, but concluded there is insufficient evidence to support the use of tissue plasminogen activator or N-acetylcysteine.[23,25]

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 disruption of alternative complement pathways.[26] 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.[27]

Diagnostic criteria for this syndrome have been standardized and include the presence of schistocytes on a peripheral smear and increased lactic dehydrogenase, decreased haptoglobin, and thrombocytopenia with or without anemia.[28] Suggestive symptoms consistent with but not necessary for the diagnosis include a sudden worsening of renal function and neurologic symptoms.

Treatment for transplant-associated microangiopathy includes cessation of the calcineurin inhibitor and substitution with other immune suppressants if necessary. In addition, careful management of hypertension and renal damage by dialysis, if necessary, is vital. Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most transplant-associated microangiopathy associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after sirolimus is stopped, and in some cases, both medications.[27] 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.[29]

Idiopathic pneumonia syndrome

Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs from 14 days 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. Mortality rates of 50% to 70% have been reported;[30] however, these estimates are from the mid-1990s, and outcomes may have improved. 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 polymerase chain reaction (PCR) testing of blood and bronchioalveolar specimens.

Diagnostic criteria include signs and symptoms of pneumonia, evidence of nonlobar radiographic infiltrates, and abnormal pulmonary function, all in the absence of documented infectious organisms.[31] Early assessment by bronchioalveolar lavage to rule out infection is important.

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 TNF-alpha receptor to the Fc region of the IgG1 antibody and that 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.[32] A large phase II trial of this approach showed promising results, with overall survival rates of 89% at 1 month and 63% at 12 months.[33]

Epstein-Barr virus (EBV)–lymphoproliferative disorder

(EBV infection 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).[34-36]

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 may require more aggressive therapy. Treatment of EBV–lymphoproliferative disorder has relied on decreasing immune suppression and treatment with chemotherapy agents such as cyclophosphamide. CD20-positive EBV–lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy rituximab.[37-39] In addition, some centers have found efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[40] 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.[41] 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 three manifestations: skin rash, hyperbilirubinemia, and secretory diarrhea. Acute GVHD is classified by grading the severity of skin, liver, and gastrointestinal involvement and further combining the individual grading of these three areas into an overall stage that is prognostically significant (refer to Tables 6 and 7).[42] Patients with grade III or grade IV acute GVHD are at higher risk of mortality, generally due to organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Table 6. Grading and Staging of Acute Graft-Versus-Host Disease (GVHD)a
Stage Skin Liver (bilirubin)b GI/Gut (stool output per day)c
BSA = body surface area; GI = gastrointestinal.
aChildren's Oncology Group/Pediatric Blood and Marrow Transplant Consortium consensus, adapted from the modified Glucksberg system.
bThere is no modification of liver staging for other causes of hyperbilirubinemia.
cFor GI staging: The adult stool output values should be used for patients weighing >50 kg. Use 3-day averages for GI staging based on stool output. If stool and urine are mixed, stool output is presumed to be 50% of total stool/urine mix.
dIf colon or rectal biopsy is positive, but stool output is <500 mL/day (<10 mL/kg/day), then consider as GI stage 0.
eFor stage 4 GI: the term severe abdominal pain will be defined as having both (a) pain control requiring treatment with opioids or an increased dose in ongoing opioid use; and (b) pain that significantly impacts performance status, as determined by the treating physician.
0 No GVHD rash <2 mg/dL Child: <10 mL/kg; adult: <500 mL
1 Maculopapular rash <25% BSA 2–3 mg/dL Adult: 500–999 mLd; child: 10–19.9 mL/kg; persistent nausea, vomiting, or anorexia, with a positive upper GI biopsy
2 Maculopapular rash 25%–50% BSA 3.1–6 mg/dL Child: 20–30 mL/kg; adult: 1000–1500 mL
3 Maculopapular rash >50% BSA 6.1–15 mg/dL Child: >30 mL/kg; adult: >1500 mL
4 Generalized erythroderma plus bullous formation and desquamation >5% BSA >15 mg/dL 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 anti-lymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]). Approaches to GVHD prevention in non-T-cell–depleted grafts have included intermittent methotrexate, a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), a combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics), or various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil. Non–calcineurin inhibitor approaches (intensive T-cell depletion, posttransplant cyclophosphamide, etc.) have been developed and are becoming more widely used.[43,44]

When significant acute GVHD occurs, first-line therapy is generally methylprednisolone.[45] 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).[46]

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

Chronic GVHD

Chronic GVHD is a syndrome that may involve a single organ system or several organ systems, with clinical features resembling autoimmune diseases.[47,48] 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 (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 of or features of acute GVHD.

Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT [49] and in 20% to 45% of children after unrelated donor HCT, with higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk with cord blood.[50,51] 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:[49,52,53]

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

The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive Schirmer test).[54] 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. Biopsy of affected sites may be needed to confirm the diagnosis.[55]

Table 8. Chronic Graft-versus-Host Disease (GVHD) Symptoms in the Skin, Nails, Scalp, and Body Haira
Organ or Site Diagnosticb Distinctivec Other Featuresd Common (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.[54]
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
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 (NRM) in children who develop significant chronic GVHD. Children who received HLA mismatched grafts, PBSCs, who were older than 10 years, or who had platelet counts lower than 100,000/µL at diagnosis of chronic GVHD have an increased risk of NRM. NRM was 17%, 22%, and 24% at 1, 3, and 5 years, respectively, after diagnosis with chronic GVHD. Many of these children require long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died of either relapse or NRM, a third were off immune suppression, and a third still required some form of immune suppressive therapy.[56]

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.[57] The three NIH grading categories are as follows:[54]

  • 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: Involving either 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 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, or a history of steroid treatment with more than 0.5 mg of prednisone per kilogram per day for acute GVHD.

Treatment of chronic GVHD

Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including use of calcineurin inhibitors.[58] Topical therapy to affected areas is preferred for patients with limited disease.[59] The following agents have been tested with some success:

  • Mycophenolate mofetil.[60]
  • Pentostatin.[61]
  • Sirolimus.[62]
  • Rituximab.[63]

Other approaches, including extracorporeal photopheresis, have been evaluated and show some efficacy in a percentage of patients.[64]

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.[49] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[59]

References

  1. Sorror ML, Maris MB, Storb R, et al.: Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106 (8): 2912-9, 2005. [PUBMED Abstract]
  2. Sorror ML, Storer BE, Maloney DG, et al.: Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111 (1): 446-52, 2008. [PUBMED Abstract]
  3. Sorror ML, Sandmaier BM, Storer BE, et al.: Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25 (27): 4246-54, 2007. [PUBMED Abstract]
  4. Sorror M, Storer B, Sandmaier BM, et al.: Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112 (9): 1992-2001, 2008. [PUBMED Abstract]
  5. Sorror ML, Martin PJ, Storb RF, et al.: Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 124 (2): 287-95, 2014. [PUBMED Abstract]
  6. Smith AR, Majhail NS, MacMillan ML, et al.: Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 117 (9): 2728-34, 2011. [PUBMED Abstract]
  7. Wood W, Deal A, Whitley J, et al.: Usefulness of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in predicting outcomes for adolescents and young adults with hematologic malignancies undergoing allogeneic stem cell transplant. Pediatr Blood Cancer 57 (3): 499-505, 2011. [PUBMED Abstract]
  8. Antin JH: Immune reconstitution: the major barrier to successful stem cell transplantation. Biol Blood Marrow Transplant 11 (2 Suppl 2): 43-5, 2005. [PUBMED Abstract]
  9. Fry TJ, Mackall CL: Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant 35 (Suppl 1): S53-7, 2005. [PUBMED Abstract]
  10. Wingard JR, Majhail NS, Brazauskas R, et al.: Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29 (16): 2230-9, 2011. [PUBMED Abstract]
  11. Bunin N, Small T, Szabolcs P, et al.: NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: persistent immune deficiency in pediatric transplant survivors. Biol Blood Marrow Transplant 18 (1): 6-15, 2012. [PUBMED Abstract]
  12. Tomblyn M, Chiller T, Einsele H, et al.: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15 (10): 1143-238, 2009. [PUBMED Abstract]
  13. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation: Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49 (RR-10): 1-125, CE1-7, 2000. [PUBMED Abstract]
  14. Kumar D, Chen MH, Welsh B, et al.: A randomized, double-blind trial of pneumococcal vaccination in adult allogeneic stem cell transplant donors and recipients. Clin Infect Dis 45 (12): 1576-82, 2007. [PUBMED Abstract]
  15. Reiss U, Cowan M, McMillan A, et al.: Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol 24 (9): 746-50, 2002. [PUBMED Abstract]
  16. Cesaro S, Pillon M, Talenti E, et al.: A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 90 (10): 1396-404, 2005. [PUBMED Abstract]
  17. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85 (11): 3005-20, 1995. [PUBMED Abstract]
  18. Ruutu T, Eriksson B, Remes K, et al.: Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 100 (6): 1977-83, 2002. [PUBMED Abstract]
  19. Myers KC, Lawrence J, Marsh RA, et al.: High-dose methylprednisolone for veno-occlusive disease of the liver in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant 19 (3): 500-3, 2013. [PUBMED Abstract]
  20. Richardson PG, Murakami C, Jin Z, et al.: Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 100 (13): 4337-43, 2002. [PUBMED Abstract]
  21. Corbacioglu S, Kernan N, Lehmann L, et al.: Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol 5 (3): 291-302, 2012. [PUBMED Abstract]
  22. Richardson PG, Soiffer RJ, Antin JH, et al.: Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant 16 (7): 1005-17, 2010. [PUBMED Abstract]
  23. Dignan FL, Wynn RF, Hadzic N, et al.: BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol 163 (4): 444-57, 2013. [PUBMED Abstract]
  24. Corbacioglu S, Cesaro S, Faraci M, et al.: Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 379 (9823): 1301-9, 2012. [PUBMED Abstract]
  25. Ruutu T, Juvonen E, Remberger M, et al.: Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study. Biol Blood Marrow Transplant 20 (1): 135-8, 2014. [PUBMED Abstract]
  26. Jodele S, Licht C, Goebel J, et al.: Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood 122 (12): 2003-7, 2013. [PUBMED Abstract]
  27. Cutler C, Henry NL, Magee C, et al.: Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (7): 551-7, 2005. [PUBMED Abstract]
  28. Ho VT, Cutler C, Carter S, et al.: Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (8): 571-5, 2005. [PUBMED Abstract]
  29. Jodele S, Fukuda T, Vinks A, et al.: Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant 20 (4): 518-25, 2014. [PUBMED Abstract]
  30. Kantrow SP, Hackman RC, Boeckh M, et al.: Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63 (8): 1079-86, 1997. [PUBMED Abstract]
  31. Clark JG, Hansen JA, Hertz MI, et al.: NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147 (6 Pt 1): 1601-6, 1993. [PUBMED Abstract]
  32. Yanik GA, Ho VT, Levine JE, et al.: The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112 (8): 3073-81, 2008. [PUBMED Abstract]
  33. Yanik GA, Grupp SA, Pulsipher MA, et al.: TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521). Biol Blood Marrow Transplant 21 (1): 67-73, 2015. [PUBMED Abstract]
  34. Gerritsen EJ, Stam ED, Hermans J, et al.: Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant 18 (2): 377-82, 1996. [PUBMED Abstract]
  35. Shapiro RS, McClain K, Frizzera G, et al.: Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71 (5): 1234-43, 1988. [PUBMED Abstract]
  36. Brunstein CG, Weisdorf DJ, DeFor T, et al.: Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 108 (8): 2874-80, 2006. [PUBMED Abstract]
  37. Blaes AH, Cao Q, Wagner JE, et al.: Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant 16 (2): 287-91, 2010. [PUBMED Abstract]
  38. Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000. [PUBMED Abstract]
  39. Styczynski J, Gil L, Tridello G, et al.: Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 57 (6): 794-802, 2013. [PUBMED Abstract]
  40. Liu Z, Savoldo B, Huls H, et al.: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent Results Cancer Res 159: 123-33, 2002. [PUBMED Abstract]
  41. Ferrara JL, Levine JE, Reddy P, et al.: Graft-versus-host disease. Lancet 373 (9674): 1550-61, 2009. [PUBMED Abstract]
  42. Przepiorka D, Weisdorf D, Martin P, et al.: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15 (6): 825-8, 1995. [PUBMED Abstract]
  43. Kanakry CG, O'Donnell PV, Furlong T, et al.: Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 32 (31): 3497-505, 2014. [PUBMED Abstract]
  44. Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014. [PUBMED Abstract]
  45. Jacobsohn DA: Acute graft-versus-host disease in children. Bone Marrow Transplant 41 (2): 215-21, 2008. [PUBMED Abstract]
  46. Deeg HJ: How I treat refractory acute GVHD. Blood 109 (10): 4119-26, 2007. [PUBMED Abstract]
  47. Shlomchik WD, Lee SJ, Couriel D, et al.: Transplantation's greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (1 Suppl 1): 2-10, 2007. [PUBMED Abstract]
  48. Bolaños-Meade J, Vogelsang GB: Chronic graft-versus-host disease. Curr Pharm Des 14 (20): 1974-86, 2008. [PUBMED Abstract]
  49. Zecca M, Prete A, Rondelli R, et al.: Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood 100 (4): 1192-200, 2002. [PUBMED Abstract]
  50. Eapen M, Logan BR, Confer DL, et al.: Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant 13 (12): 1461-8, 2007. [PUBMED Abstract]
  51. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007. [PUBMED Abstract]
  52. Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007. [PUBMED Abstract]
  53. Arora M, Klein JP, Weisdorf DJ, et al.: Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood 117 (24): 6714-20, 2011. [PUBMED Abstract]
  54. Filipovich AH, Weisdorf D, Pavletic S, et al.: 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. Biol Blood Marrow Transplant 11 (12): 945-56, 2005. [PUBMED Abstract]
  55. Shulman HM, Kleiner D, Lee SJ, et al.: Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 12 (1): 31-47, 2006. [PUBMED Abstract]
  56. Jacobsohn DA, Arora M, Klein JP, et al.: Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease. Blood 118 (16): 4472-9, 2011. [PUBMED Abstract]
  57. Pavletic SZ, Martin P, Lee SJ, et al.: Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 12 (3): 252-66, 2006. [PUBMED Abstract]
  58. Koc S, Leisenring W, Flowers ME, et al.: Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100 (1): 48-51, 2002. [PUBMED Abstract]
  59. Couriel D, Carpenter PA, Cutler C, et al.: Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 12 (4): 375-96, 2006. [PUBMED Abstract]
  60. Martin PJ, Storer BE, Rowley SD, et al.: Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood 113 (21): 5074-82, 2009. [PUBMED Abstract]
  61. Jacobsohn DA, Gilman AL, Rademaker A, et al.: Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood 114 (20): 4354-60, 2009. [PUBMED Abstract]
  62. Jurado M, Vallejo C, Pérez-Simón JA, et al.: Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 701-6, 2007. [PUBMED Abstract]
  63. Cutler C, Miklos D, Kim HT, et al.: Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108 (2): 756-62, 2006. [PUBMED Abstract]
  64. González Vicent M, Ramirez M, Sevilla J, et al.: Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol 32 (8): 589-93, 2010. [PUBMED Abstract]
  • Updated: April 9, 2015