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. [PMC free article: PMC1895304] [PubMed: 15994282]
2. ElSawy M, Storer BE, Pulsipher MA, et al.: Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 170 (4): 574-83, 2015. [PMC free article: PMC4526353] [PubMed: 25945807]
3. 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. [PMC free article: PMC2200822] [PubMed: 17916744]
4. 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: 17724349]
5. 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: 18311781]
6. 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. [PMC free article: PMC4093684] [PubMed: 24797298]
7. 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: 21228326]
8. 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: 21384538]
9. Sorror ML, Logan BR, Zhu X, et al.: Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 21 (8): 1479-87, 2015. [PMC free article: PMC4512746] [PubMed: 25862591]

Infectious Risks and Immune Recovery After Transplant

Defective immune reconstitution is a major barrier to successful HSCT, regardless of graft source.[1,2] Serious infections have accounted for a significant percentage (4%–20%) of late deaths after HSCT.[3]

Factors that can significantly slow immune recovery include the following:[4]

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

Figure 1 illustrates the immune defects, contributing transplant-related factors, and types and timing of infections that occur after allogeneic transplant.[5]

Figure 1. Phases of predictable immune suppression with their opportunistic infections among allogeneic hematopoietic stem cell transplant 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 research into the role of prophylactic antibacterial medications during the neutropenic phase.[6]

A joint effort between the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Transplantation and Cellular Therapy established guidelines for the prevention of infections after HSCT.[7] Approaches include preventive or prophylactic antivirals, antifungals, and antibiotics; escalation to heightened empiric therapy for signs of infection; and continued careful monitoring through the full duration of the immunocompromised period after HSCT.

Prophylaxis against fungal infections is standard during the first several months after transplant 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 infections can occur in all patients after bone marrow transplants, and prophylaxis is mandatory.[6]; [8][Level of evidence C1]

After HSCT, 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 today, effective drugs to treat CMV are available. In addition, preventive strategies, including quantitative polymerase chain reaction (PCR) monitoring followed by preemptive therapy with ganciclovir, have been developed. In addition, the U.S. Food and Drug Administration (FDA) approved letermovir for CMV prophylaxis in adults. There is solid experience using letermovir in children aged 12 years and older and emerging experience in children younger than 12 years.[9,10]
• Epstein-Barr virus (EBV). EBV rarely causes lymphoproliferative disease and is generally associated with intensive, multidrug GVHD therapy or T-cell–depleted HSCT.
• Adenovirus. Adenovirus infection is a major issue in T-cell–depleted transplant, 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.[11]
• Other. Other viruses have been implicated in hemorrhagic cystitis (BK virus), encephalitis and poor count recovery (human herpes virus 6), and other clinical issues.[6] One study suggested that high BK viral loads early after transplant (4–7 weeks) may be associated with long-term decreases in glomerular filtration rate.[12]

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 HSCT patients can become functionally asplenic, and antibiotic prophylaxis is recommended. Patients should remain on infection prophylaxis (e.g., Pneumocystis jirovecii pneumonia prophylaxis) until immune recovery. Time to immune recovery varies but ranges from 3 months to 9 months after autologous HSCT, and 9 months to 24 months after allogeneic HSCT without GVHD. Patients with active chronic GVHD may have persistent immunosuppression for years. Many centers monitor T-cell subset recovery after bone marrow transplants as a guide to infection risk.[6]

Sinusoidal Obstruction Syndrome/Veno-occlusive Disease (SOS/VOD)

Pathologically, SOS/VOD of the liver 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 patients who undergo myeloablative transplants.[18,19]

Risk factors for SOS/VOD include the following:[18,19]

• Use of busulfan (especially before therapeutic pharmacokinetic monitoring).
• Total-body irradiation.
• Serious infection.
• GVHD.
• Preexisting liver dysfunction caused by 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 transplant and is characterized by multiorgan system failure.[20] Milder, reversible forms can occur, with full recovery expected. Pediatric patients who have severe SOS/VOD without increased bilirubin have been reported.[21] Therefore, it is important to be vigilant about monitoring patients who have other symptoms without increased bilirubin.

Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Although TA-TMA 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.[41] TA-TMA has most frequently been associated with the use of the calcineurin inhibitors tacrolimus and cyclosporine, and it has been noted to occur more frequently when either of these medications is used in combination with sirolimus.[42]

Diagnostic criteria for this syndrome have been updated based on expert consensus opinion and are a modification of criteria published in 2014 (see Table 3).[43,44]

Evidence (impact of TA-TMA on HSCT outcomes):

1. A multicenter study of TA-TMA in pediatric patients used the following definition of TA-TMA:[46]

   1. Histological evidence of TA-TMA, or
   2. Presence of at least four of the following laboratory and clinical markers diagnostic for TA-TMA:

      • Lactate dehydrogenase (LDH) levels above reference value for age.
      • Schistocytes on peripheral blood smear.
      • De novo thrombocytopenia or requirement for platelet transfusions.
      • De novo anemia or requirement for red blood cell transfusions.
      • Hypertension greater than 99% for age (aged <18 years) or 140/90 mm Hg (aged ≥18 years) requiring ≥2 antihypertensive agents.
      • Proteinuria ≥30 mg/dL on random urine analysis twice or random urine protein to creatinine ratio >1 mg/mg.
      • Terminal complement activation: Elevated plasma sC5b-9 above normal limit (≥244 ng/mL).
   3. This study demonstrated the following results:

      • In 614 sequential patients who underwent allogeneic or autologous HSCT, 19% of allogeneic recipients and 10% of autologous recipients developed TA-TMA.
      • Patients who developed TA-TMA had increased rates of acute GVHD and steroid-refractory GVHD, intensive care unit admission, invasive ventilation, pericardial effusions, pulmonary hypertension, dialysis or continuous renal replacement therapy, acute kidney injury, and VOD.
      • In patients who underwent allogeneic HSCT, treatment-related mortality during the first 6 months was significantly higher in patients with TA-TMA than in those without TA-TMA (20% vs. 3%; P ≤ .0001).
      • In patients who underwent autologous HSCT, the overall survival (OS) rate during the first 6 months was significantly lower in patients with TA-TMA than in those without TA-TMA (79% vs. 98%; P = .001).

Idiopathic Pneumonia Syndrome (IPS)

IPS is characterized by diffuse, noninfectious lung injury that occurs between 14 and 90 days after the infusion of donor cells. Possible etiologies include direct toxic effects of conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli.[52]

The incidence of IPS 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.[52] 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:[53]

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

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

Autoimmune Cytopenias (AIC)

AIC after allogeneic HSCT can be restricted to one cell lineage (e.g., autoimmune hemolytic anemia), two cell lineages, or three cell lineages. Most data about AIC in pediatric patients after HSCT are reported from single-center experiences, with the number of cases ranging from 20 to 30 over a 10- to 20-year period.[56-58] The incidence of AIC is about 5% after allogeneic HSCT. Risk factors for developing AIC seem to be age younger than 10 years and having a nonmalignant disease as an HSCT indication. At least one study has identified use of serotherapy, use of cord blood as the donor source, and severe GVHD as risk factors, but this finding has not been confirmed in other studies. One study demonstrated that patients who develop AIC have inferior outcomes compared with patients who did not develop AIC.[58] However, other studies did not demonstrate an inferior outcome.[56,57]

The National Institutes of Health task force on chronic GVHD has recognized AIC as a possible atypical feature of chronic GVHD (although they may be distinct pathologically).[59] This group has created standardized diagnostic criteria and a proposed prospective study of this complication.

Epstein-Barr Virus (EBV)–Associated Lymphoproliferative Disorder

After HSCT, 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 HSCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin [ATG] or alemtuzumab, and, to a lesser degree, use of cord blood).[62-64]

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).

Acute GVHD

GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities in the tissues of a recipient.[71] Acute GVHD usually occurs within the first 3 months posttransplant, although delayed acute GVHD has been noted with 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:

• 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 (see Tables 4 and 5).[72] 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.

Because the outcomes of patients with different grades of acute GVHD vary, investigators have sought to more precisely define acute GVHD risk based on serum biomarkers. A study that included both adults and children used a score calculated based on the levels of a combination of three biomarkers (tumor necrosis factor receptor 1 [TNFR1], suppression of tumorigenicity 2 [ST2], and regenerating islet-derived 3-alpha [REG3-alpha]), measured at the onset of acute GVHD. Investigators were able to define patients with low (8%), intermediate (27%), and high (46%, P < .0001) risk of 6-month mortality. The biomarker score was more sensitive and specific for predicting survival than clinical staging.[74] Additional refining of the prediction algorithm showed that measurement of only two biomarkers (ST2 and REG3-alpha) reliably predicted outcome. In addition, after 4 weeks of therapy, changes in the biomarker score were able to further refine prediction of survival outcomes.[75] These findings have led to several studies targeting biomarker high-risk or low-risk subsets of patients with acute GVHD and are influencing clinicians regarding the timing and intensity of acute GVHD therapies.

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65. 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. [PMC free article: PMC4113553] [PubMed: 19835968]
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67. 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: 23771985]
68. 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: 11785836]
69. Bollard CM, Heslop HE: T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127 (26): 3331-40, 2016. [PMC free article: PMC4929925] [PubMed: 27207801]
70. Keller MD, Hanley PJ, Chi YY, et al.: Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment. Nat Commun 15 (1): 3258, 2024. [PMC free article: PMC11026387] [PubMed: 38637498]
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72. Przepiorka D, Weisdorf D, Martin P, et al.: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15 (6): 825-8, 1995. [PubMed: 7581076]
73. Harris AC, Young R, Devine S, et al.: International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 22 (1): 4-10, 2016. [PMC free article: PMC4706482] [PubMed: 26386318]
74. Levine JE, Braun TM, Harris AC, et al.: A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2 (1): e21-9, 2015. [PMC free article: PMC4340092] [PubMed: 26687425]
75. Srinagesh HK, Özbek U, Kapoor U, et al.: The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease. Blood Adv 3 (23): 4034-4042, 2019. [PMC free article: PMC6963240] [PubMed: 31816061]
76. Luznik L, O'Donnell PV, Fuchs EJ: Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 39 (6): 683-93, 2012. [PMC free article: PMC3808078] [PubMed: 23206845]
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78. Watkins B, Williams KM: Controversies and expectations for the prevention of GVHD: A biological and clinical perspective. Front Immunol 13: 1057694, 2022. [PMC free article: PMC9726707] [PubMed: 36505500]
79. Locatelli F, Zecca M, Rondelli R, et al.: Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 95 (5): 1572-9, 2000. [PubMed: 10688810]
80. Storb R, Deeg HJ, Pepe M, et al.: Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 73 (6): 1729-34, 1989. [PubMed: 2653461]
81. Pulsipher MA, Langholz B, Wall DA, et al.: The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 123 (13): 2017-25, 2014. [PMC free article: PMC3968388] [PubMed: 24497539]
82. Ueda Oshima M, Storer BE, Qiu H, et al.: Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis. Transplant Cell Ther 27 (2): 163.e1-163.e7, 2021. [PMC free article: PMC8035484] [PubMed: 33830025]
83. Mehta RS, Saliba RM, Rondon G, et al.: Post-Transplantation Cyclophosphamide Versus Tacrolimus and Methotrexate Graft-Versus-Host Disease Prophylaxis for HLA-Matched Donor Transplantation. Transplant Cell Ther 28 (10): 695.e1-695.e10, 2022. [PubMed: 35902049]
84. Borovkova AS, Paina OV, Semenova EV, et al.: Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia. Clin Transplant 38 (1): e15181, 2024. [PubMed: 37922213]
85. Fierro-Pineda JC, Tsai HL, Blackford A, et al.: Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias. Blood Adv 7 (18): 5639-5648, 2023. [PMC free article: PMC10546347] [PubMed: 37257193]
86. McCurdy SR, Kanakry CG, Tsai HL, et al.: Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide. Biol Blood Marrow Transplant 25 (6): 1128-1135, 2019. [PMC free article: PMC6559825] [PubMed: 30599208]
87. 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. [PMC free article: PMC4209101] [PubMed: 25267759]
88. Soiffer RJ, Kim HT, McGuirk J, et al.: Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation. J Clin Oncol 35 (36): 4003-4011, 2017. [PMC free article: PMC8462523] [PubMed: 29040031]
89. Socié G, Schmoor C, Bethge WA, et al.: Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 117 (23): 6375-82, 2011. [PubMed: 21467544]
90. Kröger N, Solano C, Wolschke C, et al.: Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med 374 (1): 43-53, 2016. [PubMed: 26735993]
91. Admiraal R, Nierkens S, Bierings MB, et al.: Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial. Lancet Haematol 9 (2): e111-e120, 2022. [PubMed: 35114150]
92. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al.: Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2 (5): e194-203, 2015. [PubMed: 26688094]
93. Watkins B, Qayed M, McCracken C, et al.: Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD. J Clin Oncol 39 (17): 1865-1877, 2021. [PMC free article: PMC8260909] [PubMed: 33449816]
94. Peters C, Schrappe M, von Stackelberg A, et al.: Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol 33 (11): 1265-74, 2015. [PubMed: 25753432]
95. Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al.: National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide. J Clin Oncol 39 (18): 1971-1982, 2021. [PMC free article: PMC8260905] [PubMed: 33905264]
96. Wagner JE, Eapen M, Carter S, et al.: One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med 371 (18): 1685-94, 2014. [PMC free article: PMC4257059] [PubMed: 25354103]
97. Eapen M, Kurtzberg J, Zhang MJ, et al.: Umbilical Cord Blood Transplantation in Children with Acute Leukemia: Impact of Conditioning on Transplantation Outcomes. Biol Blood Marrow Transplant 23 (10): 1714-1721, 2017. [PMC free article: PMC5605440] [PubMed: 28684372]
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99. Admiraal R, Lindemans CA, van Kesteren C, et al.: Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood 128 (23): 2734-2741, 2016. [PubMed: 27702800]
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101. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PMC free article: PMC9918850] [PubMed: 35776909]
102. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PubMed: 30348653]
103. Merli P, Algeri M, Galaverna F, et al.: TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood 143 (3): 279-289, 2024. [PubMed: 37738655]
104. Mehta PA, Davies SM, Leemhuis T, et al.: Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 129 (16): 2308-2315, 2017. [PMC free article: PMC5766838] [PubMed: 28179273]
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109. Jagasia M, Perales MA, Schroeder MA, et al.: Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood 135 (20): 1739-1749, 2020. [PMC free article: PMC7229262] [PubMed: 32160294]
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Organ Manifestations of Chronic GVHD

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).[3]

Commonly involved tissues include the skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may also be involved. Tables 6 to 10 list organ manifestations of chronic GVHD, including 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.[4]

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.

Risk Factors for Chronic GVHD

Chronic GVHD occurs in approximately 15% to 30% of children after sibling-donor HSCT [5] and in 20% to 45% of children after unrelated-donor HSCT. There is a higher risk of chronic GVHD with peripheral blood stem cells (PBSCs) and a lower risk with cord blood and selected approaches to haploidentical HSCT.[6-8]

Risk factors for the development of chronic GVHD include the following:[5,9,10]

• Patient’s age (older than 10 years).
• Type of donor (unrelated and mismatched donors).
• Use of PBSCs.
• History of acute GVHD.
• Conditioning regimen (myeloablative and total-body irradiation (TBI)–based regimens).

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.

The nonrelapse mortality rates were 17% at 1 year, 22% at 3 years, and 24% at 5 years after diagnosis of 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.[11]

Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 broadened the description of chronic GVHD to three categories to better predict long-term outcomes.[12] The three NIH grading categories are as follows:[3]

• 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/kg of prednisone 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 was 4% for children with mild chronic GVHD, 11% for children with moderate chronic GVHD, and 36% for children with severe chronic GVHD.[13] In another large prospective trial with central review that used the NIH consensus criteria, about 28% of patients were misclassified as having chronic GVHD when they actually had late-acute GVHD. Additionally, there were significant challenges when using the NIH consensus criteria for bronchiolitis obliterans in children.[14]

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.[15] Topical therapy to affected areas is preferred for patients with limited disease.[16] The following agents have been tested with some success:

• Mycophenolate mofetil.[17]
• Pentostatin.[18]
• Sirolimus.[19]
• Rituximab.[20]
• Ibrutinib.[21]
• Ruxolitinib.[22]
• Belumosudil.[23]

Other approaches, including extracorporeal photopheresis, have been evaluated and show some efficacy in some patients.[24]

A series of drugs have been approved for the treatment of chronic GVHD in children.

Evidence (treatment of chronic GVHD in children):

1. Ibrutinib is indicated for pediatric patients aged 1 year or older with chronic GVHD after failure of one or more lines of systemic therapy. Efficacy of ibrutinib was evaluated in an open-label multicenter trial of pediatric and young adult patients with moderate or severe chronic GVHD. The study included 47 patients who had one or more lines of therapy fail. The median age was 13 years (range, 1–19 years).[25]

   • The overall response rate was 60% (95% confidence interval [CI], 44%–74%) by week 25.
   • The median duration of response was 5.3 months (95% CI, 2.8–8.8).
   • The median time from first response to death or new systemic therapies for chronic GVHD was 14.8 months.
2. The U.S. Food and Drug Administration (FDA) approved ruxolitinib for the treatment of chronic GVHD in adults and children older than 12 years after failure of one or two lines of systemic therapy. The approval was based on one study that randomly assigned 329 patients to receive either ruxolitinib or best available therapy.[22]

   • The overall response rate was 70% (95% CI, 63%–77%) for patients in the ruxolitinib arm and 57% (95% CI, 49%–65%) for patients in the best available therapy arm.
3. Belumosudil, a kinase inhibitor, was approved to treat chronic GVHD in adult and pediatric patients aged 12 years and older after failure of at least two prior lines of systemic therapy. The approval was based on a study of 65 patients with chronic GVHD that was refractory to multiple lines of therapy.[23]

   • The overall response rate was 74% (95%, 62%–84%) for patients who received 200 mg of belumosudil once per day and 77% (95% CI, 65%–87%) for patients who received 200 mg of belumosudil twice per day. High response rates were observed in all subgroups of patients.
   • All affected organs demonstrated complete responses.

No comparative studies have been performed with these three agents. Therefore, the best drug for specific types of chronic GVHD in children has yet to be determined.

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.

Transplant-related complications account for 70% of the deaths in patients with chronic GVHD.[5] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[16,26]

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References

1. Schechter T, Pole JD, Darmawikarta D, et al.: Late mortality after hematopoietic SCT for a childhood malignancy. Bone Marrow Transplant 48 (10): 1291-5, 2013. [PubMed: 23665822]
2. Duncan CN, Majhail NS, Brazauskas R, et al.: Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 21 (1): 151-8, 2015. [PMC free article: PMC4272862] [PubMed: 25316109]
3. Holmqvist AS, Chen Y, Wu J, et al.: Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report. Blood 131 (24): 2720-2729, 2018. [PMC free article: PMC6032893] [PubMed: 29661789]

Methodological Challenges in the Study of Late Effects After HSCT

Although the main cause of death in patients who have undergone HSCT is from relapse of the primary disease, many of these patients die from infections related to graft-versus-host disease (GVHD), second malignancies, or cardiac or pulmonary issues.[2,4-6] In addition, other studies have revealed that up to 40% of HSCT survivors experience severe, disabling, and/or life-threatening events or die because of an adverse event associated with primary or previous cancer treatment.[7,8]

Before studies aimed at decreasing the incidence and 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-HSCT therapy are not included in many studies.[9]
• 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.
• Extended exposure to nonchemotherapeutic agents: Patients who undergo transplants may receive immunosuppressants that have significant toxicity for an extended period of time (e.g., cyclosporine or tacrolimus, which can cause hypertension and kidney damage). In addition, it is routine for patients to receive extended courses of supportive medications or antimicrobials that can be associated with organ damage (e.g., liposomal amphotericin B). These medications should be considered when assessing the risk of late effects.

Individuals differ in their susceptibility to specific organ damage from chemotherapy or in their risk of GVHD based on genetic differences in both the donor and recipient.[9-11]

Cardiovascular System Late Effects

Although cardiac dysfunction has been studied extensively in non-HSCT settings, less is known about the incidence and predictors of congestive heart failure following HSCT in childhood. Potentially cardiotoxic exposures unique to HSCT include the following:[12]

• Conditioning with high-dose chemotherapy, especially cyclophosphamide.
• TBI.

HSCT 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 HSCT or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[8,12] In a study of 661 pediatric patients who survived at least 2 years after allogeneic HSCT, 52% of patients had obesity or were overweight at their most recent examination, 18% of patients had dyslipidemia (associated with pre-HSCT anthracycline or cranial or chest irradiation), and 7% of patients were diagnosed with diabetes.[13]

Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) who were treated in Seattle from 1985 to 2006. The survivors and a population-based comparison group were matched by age, year, and sex.[14] 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]). Survivors also 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 increased their risk of developing more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).[14]

In addition, cardiac function and pre-HSCT exposures to chemotherapy and radiation therapy have been shown to significantly impact post-HSCT cardiac function. In evaluating post-HSCT patients for long-term issues, it is important to consider levels of pre-HSCT anthracycline and chest irradiation.[15] Although more specific studies are needed to verify this approach, current evidence suggests that the risk of late-occurring cardiovascular complications after HSCT may largely result from pre-HSCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[16,17]

For more information, see the Late Effects of the Cardiovascular System section in Late Effects of Treatment for Childhood Cancer.

Neurocognitive Late Effects

Many studies report normal neurodevelopment after HSCT, with no evidence of decline.[18-25]

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.[21-23] This research group reported poorer outcomes in patients who underwent unrelated-donor transplant when the patients received TBI and when they experienced GVHD. But these effects on outcomes were small compared with the much larger effects of socioeconomic status on cognitive function.[22] 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-HSCT.[25] Stable cognitive function was also noted in a large cohort monitored from pretransplant to 2 years post-HSCT.[20] A smaller study reported similar normal functioning and the absence of declines over time in HSCT survivors.[18] HSCT 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.[19] Based on findings to date, it appears that HSCT poses low-to-minimal risk of late cognitive and academic deficits in survivors.

Several studies, however, have reported some decline in cognitive function after HSCT.[26-32] 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-HSCT, deficits that were maintained at 3 years post-HSCT.[27,28] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who underwent transplant with TBI.[30,31] 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. Patients who received TBI had a significantly lower IQ at 5 years (P = .05) than did those who did not receive TBI.[32]

For more information, see the Hematopoietic stem cell transplant (HSCT) section in Late Effects of Treatment for Childhood Cancer.

Digestive System Late Effects

Endocrine System Late Effects

Musculoskeletal System Late Effects

Reproductive System Late Effects

Respiratory System Late Effects

Urinary System Late Effects

Quality of Life

Published Guidelines for Long-Term Follow-Up

Several organizations have published consensus guidelines for follow-up for late effects after HSCT. 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 HSCT.[179]

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). The COG has also published more specific recommendations for late effects surveillance after HSCT.[180] To address the lack of detailed, pediatric-specific, late-effects data and guidelines for long-term follow-up after HSCT, the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) 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.[9,34,64,181-183]

Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are under way, the PTCTC summary and guideline recommendations provide a consensus outline for monitoring children for late effects after HSCT.[64]

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the complications, graft-versus-host disease, and late effects after hematopoietic stem cell transplant for the treatment of pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

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PDQ® Pediatric Treatment Editorial Board. PDQ Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/hp-stem-cell-transplant/gvhd. Accessed <MM/DD/YYYY>. [PMID: 35133768]

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