Early Patient Monitoring

Both myeloablative and reduced-intensity conditioning regimens used prior to hematopoietic cell transplantation (HCT) will cause some degree of post-transplant immunodeficiency in recipients. In addition, both chemotherapy- and radiation-based conditioning regimens can cause organ and tissue damage. Transplant recipients therefore require careful monitoring in the early post-transplant period.

The most common complications that may occur in the early post-transplant period are listed on this page, along with their brief description. Basic treatments are described, and more detailed information can be found in the references cited. Because it can appear later in the recovery period, chronic graft-versus-host disease (GVHD) is discussed separately in Long-term and GVHD screening.

For a comprehensive discussion on the prevention of post-transplant infectious complications, the NMDP recommends an international consensus report published in Biology of Blood and Marrow Transplantation. [1] 

Acute graft-versus-host disease (GVHD)

Acute graft-versus-host disease (GVHD) is a common complication of allogeneic HCT in which activated donor T cells attack the tissues of the transplant recipient after recognizing host tissues as antigenically foreign. The resulting inflammatory cytokines can cause tissue damage; commonly involved organs include the liver, skin, mucosa, and the gastrointestinal tract.

The severity of GVHD can range from mild to life-threatening, and is graded from Stage I (mild) to Stage IV (severe). By classical definition, GVHD appearing before day 100 post-transplant is acute GVHD, and GVHD appearing after day 100 is chronic GVHD.

However, acute GVHD may still occur later than 100 days post transplant (e.g., during tapering of immunosupressive drugs or following a donor lymphocyte infusion). Some patients may also develop an overlap syndrome, where features of both acute and chronic GVHD are present.

GVHD prophylaxis begins during the pre-transplant conditioning period, where calcineurin inhibitors (e.g., cyclosporine, tacrolimus) and methotrexate may be administered. Other agents used for GVHD prophylaxis include corticosteroids, antithymocyte globulin and ex-vivo T-cell depletion.

If acute GVHD occurs, first-line treatment is systemic glucocorticoids such as prednisone. No consensus exists on the preferred second-line treatment for steroid-refractory acute GVHD, and successful outcomes (partial or complete response) in these patients are typically below 50%. [2] 

More information:

• ASBMT recommendations on first- and second-line treatment of acute GVHD [2] 
• Acute GVHD biomarkers [3] 
• Risk factors for acute and chronic GVHD [4] 

Stem cell graft failure

Graft failure is a rare, but life-threatening complication following allogeneic HCT. The most common cause of graft failure is an immunological rejection of the graft mediated by recipient T cells, natural killer cells, and/or antibodies. Other causes are infection, recurrent disease, or an insufficient number of stem cells in the donated graft. Graft failure occurs in approximately 5% of allogeneic transplants. [5,6] 

The rate of failure can vary by graft source, and is increased in HLA-mismatched grafts, unrelated-donor grafts, T cell-depleted grafts, and umbilical cord blood grafts. Patients allo-sensitized through prior blood transfusions or pregnancy, and those receiving reduced-intensity conditioning are also at a higher risk of experiencing graft failure.

If graft failure occurs, treatment is a second HCT, using cells from the same donor or from a different donor. Patients experiencing graft failure after a cord blood transplant cannot get backup cells from the same cord blood unit. However, it may be possible to use a different cord blood unit or a backup adult donor instead.

More information:

• Graft failure after allogeneic HCT [5] 
• Risk factors for graft failure [6] 
• Second HCT in myeloid malignancies [7] 

Organ injury/toxicity

Organ injury and toxicity following HCT can include thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (now also commonly called sinusoidal obstruction syndrome), renal failure, and pulmonary toxicity.

Thrombotic microangiopathy

Transplant-associated TMA is more common after allogeneic HCT, but it can also be a significant complication of autologous transplantation. Risk factors for TMA include pre-transplant conditioning with busulfan, fludarabine, platinum-based chemotherapy, and total body irradiation (TBI). [8] TMA is also associated with the use of the calcineurin inhibitors, tacrolimus and cyclosporine.

Transplant-associated TMA syndromes present as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). Treatment includes cessation of the calcineurin inhibitor and, if necessary, substitution with other immune suppressants. Patients with transplant-associated TMA require careful management of hypertension and renal damage – by dialysis, if necessary.

Liver complications

Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. Risk factors include the use of busulfan (especially before pharmacokinetic dosing), TBI, infection, acute GVHD, and pre-existing liver dysfunction due to iron overload or hepatitis.

Supportive care is standard therapy for SOS/VOD, but defibrotide, an oligonucleotide mixture that modulates endothelial cell injury, has been shown to decrease mortality in the treatment of severe VOD. [9]

Renal complications

Approximately 15% of patients undergoing HCT will develop chronic kidney disease (CKD). [10] CKD is associated with the use of TBI in the transplant conditioning regimen, although many cases are idiopathic. TBI-associated CKD has a typical latency of 3-6 months from irradiation to injury.

CKD after HCT may not be recognized early due to competing clinical priorities such as the treatment of GVHD, and monitoring for infections and disease recurrence.

Pulmonary complications

In the early post-transplant neutropenic period, there is an increased risk of various bacterial, fungal, and viral infections of the lung, and pneumonia develops in 40% to 60% of HCT recipients. [11] The pneumonias that can occur include herpes simplex pneumonitis, cytomegalovirus pneumonitis, and Pneumocystis carinii pneumonia.

Bronchiolitis obliterans syndrome and bronchiolitis obliterans organizing pneumonia can appear later (post day 100) in the transplant recovery period. Bronchiolitis obliterans is closely associated with chronic GVHD and may result from alloimmunologic injury to host bronchiolar epithelial cells. [12]

More information:

• Review: Transplant-related TMA [8]
• BMT CTN consensus report on transplant-related TMA [13]
• Defibrotide and other investigational SOS/VOD therapies [9]
• Chronic kidney disease following HCT [10]
• Pulmonary complications following HCT [11,12]

Oral mucositis

Oral mucositis is inflammation of oral mucosa that typically manifests as erythema or ulcerations. It can result from the cytotoxic effects of chemotherapy- and radiation-based pre-transplant conditioning regimens.

Mouth sores associated with acute GVHD may also develop 2-4 weeks post-transplant, and it can be difficult to tell whether the sores are from the conditioning regimen or from GVHD.

Treatments focusing on easing the symptoms of oral mucositis include coating agents (e.g., amphogel), saline and/or sodium bicarbonate rinses, topical painkillers (e.g., lidocaine, benzocaine), and cryotherapy (ice chips), which is indicated for patients receiving melphalan.

Palifermin (keratinocyte growth factor-1) stimulates cell growth and repair and is approved for use in stem cell transplant recipients to decrease the incidence and duration of severe mucositis.

More information:

• Oral complications of chemo/radiotherapy [14]
• Guidelines for the prevention and treatment of mucositis [15]

Infections

All transplant recipients are susceptible to infections and require careful monitoring, which allows for timely administration of antibacterial, antiviral, and/or antifungal agents.

Practices vary among transplant centers, with some administering agents pre-emptively as soon as symptoms are observed, while others may wait until an infection diagnosis is confirmed via laboratory analysis.

The relative times of immune recovery are:

• Neutrophils and phagocytes: 1 month
• T cells: 6-12 months
• B cells: 12-24 months

Table 1 outlines possible complications and common infections in each of three post-transplant time periods.

Table 1. Post-transplant complications: 0-3 months, 3-12 months and >12 months.
 

More information:

• Guidelines for preventing post-HCT infectious complications [1]

References

1. 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. 2009; 15(10): 1143-1238.
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2. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: Recommendations of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012; 18(8): 1150-1163.
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3. Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. Blood. 2013; 121(4): 585-594.
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4. Flowers MED, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011; 117(11): 3214-3219.
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5. Mattsson J, Ringdén O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008; 14(1; suppl.): 165-170.
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6. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013; 48(4): 537-543.
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7. Arfons LM, Tomblyn M, Rocha V, Lazarus H. Second hematopoietic stem cell transplantation in myeloid malignancies. Curr Opin Hematol. 2009; 16(2): 112-123.
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8. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011; 118(6): 1452-1462.
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9. Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant. 2008; 41(3): 229-237.
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10. Cohen EP, Pais P, Moulder JE. Chronic kidney disease after hematopoietic stem cell transplantation. Semin Nephrol. 2010; 30(6): 627-634.
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11. Yen KT, Lee AS, Krowka MJ, Burger CD. Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment. Clin Chest Med. 2004; 25(1): 189-201.
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12. Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13(7): 749-759.
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13. Ho VY, 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. 2005; 11(8): 571-575.
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14. Oral Complications of Chemotherapy and Head/Neck Radiation: Oral Mucositis. National Cancer Institute (PDQ database).
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15. Keefe DM, Schubert MM, Elting LS, et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007; 109(5): 820-831.
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