Chapter 53: Complications and Follow-Up After Hematopoietic Cell Transplantation

Michael M. Boyiadzis; Juan C. Gea-Banacloche; Michael R. Bishop

INTRODUCTION

Multifactorial etiology of posttransplant hematopoietic cell transplantation (HCT) complications

Chemotherapy and/or radiation therapy used as conditioning regimen
Immunodeficiency state following HCT
Immunosuppressive therapy and adverse events related to medications
Graft-versus-host disease (after allogeneic HCT)

INFECTIOUS COMPLICATIONS FOLLOWING AUTOLOGOUS AND ALLOGENEIC HCT

Infectious Complications Following Autologous and Allogeneic HCT

Freifeld AG et al. Clin Infect Dis 2011;52:e56–e93

Tomblyn M et al. Biol Blood Marrow Transplant 2009;15:1143–1238

Wingard JR. Transpl Infect Dis 1999;1:3–20

Preengraftment Period (Before Neutrophil Recovery)

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Preengraftment Period (Before Neutrophil Recovery)

Autologous and allogeneic transplant recipients are similar with respect to early infectious complications. The risk of infection during this period is related to neutropenia and mucositis resulting from the conditioning regimen

Bacterial

Principal causes of sepsis

Gram-negative bacilli (eg, Pseudomonas aeruginosa, Enterobacteriaceae)
Gram-positive bacteria (eg, viridans group Streptococcus, coagulase-negative staphylococci)
Common sources include gastrointestinal tract and intravascular devices

Fungal

Fungal infections become more common with prolonged and profound neutropenia

Candida infections occur early and are often prevented with fluconazole (see table below for doses and duration of prophylaxis)

Aspergillus infections occur later (generally after 10–14 days of neutropenia)

There is no proven effective prophylaxis for Aspergillus infections after hematopoietic cell transplantation. The best evidence supports posaconazole; some experts recommend voriconazole, caspofungin, or micafungin

Viral

Herpes simplex virus (HSV) commonly reactivates during this period, and can worsen mucositis

Prophylaxis with acyclovir or valacyclovir reduces HSV reactivation (for dose and duration of prophylaxis see table below)

Early Postengraftment Period (30–100 Days After HCT)

The risk of infection is greater and different for allogeneic recipients than autologous recipients during this period

Autologous HCT

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Autologous HCT

There is some degree of immunodeficiency, but opportunistic infections are the exception rather than the rule

Bacterial

Related to an intravascular device

Fungal

Uncommon

Some centers continue prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii) for 6 months after transplantation

Viral

VZV reactivation and community respiratory virus infections

Allogeneic HCT

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Allogeneic HCT

The infection risk during this period is related to severely impaired cell-mediated immunity, acute GVHD and its treatment, and CMV reactivation. The latter two increase the risk of viral and fungal infections

Factors That Increase Risks

Factors That Lower Risks

Haplo-identical stem-cell transplantation

Transplants from an HLA-identical sibling

Unrelated donor

Cord blood

T-cell depletion (CD34 selection)

Bacterial

In the absence of acute GVHD and its treatment, the most common pathogens are related to use of an intravascular device and include:

Gram-positive organisms (eg, coagulase-negative staphylococci)
Nonfermentative Gram-negative bacilli (including Pseudomonas spp., Acinetobacter, and Stenotrophomonas)

Respiratory infections are also commonly seen, frequently following upper respiratory viral infections

In the presence of acute GVHD and its treatment, the most common pathogens are:
Enteric Gram-negative bacilli (eg, Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Serratia) and Pseudomonas

Fungal

Aspergillus is the most common mold, but prophylaxis with voriconazole increases the risk of infection with other molds, including Fusarium and the agents of mucormycosis (Mucor, Rhizopus)

Risk factors

CMV disease
Steroid use (≥1 mg/kg of prednisone equivalent for ≥1 week)

Non-albicans Candida infections, which may be resistant to fluconazole, are increasing

Viral

CMV reactivation occurs in up to 70% of recipients at risk

The risk of CMV varies depending on recipient/donor serostatus: R+/D− > R+/D+ > R−/D+ >> R−/D−. If both recipient and donor are CMV seronegative (R−/D−) the incidence is <5%

VZV and HSV can be prevented with acyclovir, which may be administered safely long-term

HHV6 commonly reactivates following allogeneic hematopoietic transplantation. In most cases, reactivation is asymptomatic. However, in some cases it has been associated with fever, rash, pneumonitis, and limbic encephalitis

Respiratory viruses: Adenovirus, RSV, and parainfluenza cause significant morbidity and mortality

Coinfections (particularly Aspergillus) have been documented with parainfluenza and other respiratory viruses

Bowden RA. Am J Med 1997;102(3 Suppl 1):27–30; discussion 42–43

Fukuda T et al. Blood 2003;102:827–833

Hentrich M et al. Br J Haematol 2005;128:66–72

Kumar D, Humar A. Infect Dis Clin North Am 2010;24:395–412

Ljungman P et al. Bone Marrow Transplant 2008;42:227–240

Nichols WG et al. Blood 2001;98:573–578

Late Postengraftment Period (>100 Days After HCT)

The risk of infection is higher for allogeneic recipients than autologous recipients

Allogeneic HCT

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Allogeneic HCT

Risk of sepsis from bacterial pathogens after an allogeneic hematopoietic transplantation persists, particularly in patients with chronic graft-versus-host disease, which induces a state of functional hyposplenism. The treatment of chronic GVHD consists of immunosuppressive agents that increase the risk of infection. There is also persistent humoral immunodeficiency

Bacterial

Encapsulated bacteria, particularly Streptococcus pneumoniae, are significant pathogens

Fungal

Fungal infections are uncommon except in the presence of active immunosuppression

Viral

CMV reactivation is an ever-present risk, higher if the patient received ganciclovir prophylaxis or treatment

Up to 25% of patients will have a VZV reactivation in the first few months after discontinuing acyclovir prophylaxis
Respiratory virus infections continue to be a problem for months. Influenza vaccination should be restarted 6 months after transplantation

Boeckh M et al. Blood 2003;101:407–414

Kulkarni S et al. Blood 2000;95:3683–3686

Prophylactic Agents Commonly Used to Reduce the Rates of Infections and Virus Reactivation Posttransplantation

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Prophylactic Agents Commonly Used to Reduce the Rates of Infections and Virus Reactivation Posttransplantation

Tomblyn M et al. Biol Blood Marrow Transplant 2009;15:1143–1238

FLUCONAZOLE

Indication:

To prevent invasive disease with Candida species
Administration of fluconazole should commence at the time of transplant and should continue for at least 75 days following HCT

Dose: Fluconazole 400 mg; administer orally or intravenously daily for at least 75 days following HCT

ACYCLOVIR

Indication:

Acyclovir prophylaxis reduces HSV reactivation by 75%
Acyclovir prophylaxis in adults can also be administered in HSV-negative patients
Administration of acyclovir or valacyclovir should commence at the time of transplant
Acyclovir prophylaxis can be continued safely for at least 1 year and reduces the incidence of HSV and VZV

Doses:

Acyclovir 800 mg; administer orally every 12 hours, or

Acyclovir 250 mg/m² per dose; administer intravenously every 12 hours, or

Valacyclovir 500 mg; administer orally once daily

COTRIMOXAZOLE (TRIMETHOPRIM + SULFAMETHOXAZOLE IN A 1:5 RATIO)

Indication:

Cotrimoxazole (trimethoprim + sulfamethoxazole; TMP + SMZ) is the agent of choice for prophylaxis against Pneumocystis jirovecii and confers some degree of protection against toxoplasmosis
Pneumocystis jirovecii prophylaxis is recommended from the time of engraftment until 6 months after HCT and after 6 months if the patient has GVHD or is receiving immunosuppressive therapy

Prophylaxis:

Cotrimoxazole (TMP 160 mg + SMZ 800 mg); administer orally, daily, or

Cotrimoxazole (TMP 80 mg + SMZ 400 mg); administer orally, daily, or

Cotrimoxazole (TMP 160 mg + SMZ 800 mg); administer orally, 3 days per week

Alternatively:

Dapsone 50 mg; administer orally, twice daily, or

Dapsone 100 mg; administer orally, once daily

Aerosolized pentamidine 300 mg; administer by inhalation every 3–4 weeks

Rule out G6PD deficiency before starting dapsone. Methemoglobinemia may develop in up to 5% of patients on dapsone prophylaxis

VARICELLA-ZOSTER IMMUNOGLOBULIN (VariZIG)

Indication:

Prevention of varicella-zoster viral disease after exposure of HCT recipients (<24 months after HCT, or >24 months after HCT if patient is receiving immunosuppressives, or has chronic GVHD) to a person with chickenpox or shingles

Dose: VariZIG is supplied in 125-IU vials and should be administered intramuscularly. The recommended dose is 125 IU/10 kg of body weight, up to a maximum of 625 IU (five vials). The minimum dose is 62.5 IU (0.5 vial) for patients weighing ≤2.0 kg and 125 IU (one vial) for patients weighing 2.1–10.0 kg

IMMUNE GLOBULIN INTRAVENOUS (IVIG)

Indication: IgG levels <400 mg/dL and severe infections

Dose: IVIG 400–500 mg/kg; administer intravenously, every 2–4 weeks until the patient is able to maintain a level of IgG ≥400 mg/dL on his or her own

Cytomegalovirus Surveillance and Treatment During the Posttransplantation Period

Tomblyn M et al. Biol Blood Marrow Transplant 2009;15:1143–1238

Ganciclovir prophylaxis (the systematic administration of ganciclovir to all patients at risk for CMV reactivation) reduces the incidence of CMV disease to 2–4%, but does not improve outcome and is associated with late CMV reactivation. The preferred approach is “preemptive,” based on monitoring CMV reactivation by measuring pp65 antigenemia or CMV DNA by PCR, and intervening with ganciclovir or foscarnet only when reactivation is detected, before active disease occurs

Indications for monitoring:

HCT recipients who are CMV IgG-positive or received a graft from a donor who is CMV IgG-positive

Monitoring (the choice of CMV PCR or antigenemia is based on laboratory test availability):

Weekly CMV antigenemia, or

Weekly CMV PCR (CMV PCR should be performed in patients with ANC <500/mm³)

Duration of monitoring:

Continue beyond posttransplantation day +100 if immune suppression continues (excluding immune suppression produced by cyclosporine or tacrolimus) or there is a history of late CMV reactivation (after day +75)

Treatment indications:

A patient with positive CMV antigenemia or 2 consecutive PCR assays positive for CMV

Treatment:

Ganciclovir 5 mg/kg per dose; administer intravenously, every 12 hours for 7 days, followed by:
Ganciclovir 5 mg/kg per dose; administer intravenously, once daily, 5 days per week

Alternative:

Foscarnet 60 mg/kg per dose; administer intravenously, every 12 hours for 7 days, followed by:
Foscarnet 60 mg/kg per dose; administer intravenously, once daily, 5 days per week

Alternative:

Valganciclovir 900 mg; administer orally, every 12 hours, followed by:
Valganciclovir 900 mg; administer orally, once daily, 5 days per week

Discontinue acyclovir when either ganciclovir or foscarnet is used

Ganciclovir and foscarnet are equally effective; the choice is usually made based on the risk of toxicity (myelosuppression with ganciclovir, nephrotoxicity and electrolyte disturbances with foscarnet. Valganciclovir, the prodrug of ganciclovir, has the advantage of oral administration. However, the difficulty of properly adjusting the dose may result in higher rate of myelotoxicity

Duration of treatment:

Continue treatment until 2 consecutive weekly CMV antigenemia tests or PCR for CMV are negative

Boeckh M et al. Blood 2003;101:407–414

Recommended Vaccinations for Adult Hematopoietic Stem-Cell Transplantation Recipients, Including Both Autologous and Allogeneic Recipients

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Recommended Vaccinations for Adult Hematopoietic Stem-Cell Transplantation Recipients, Including Both Autologous and Allogeneic Recipients

Type (Dose and Administration Route)

3–6 Months

12^‡‡ Months

14–18 Months

24 Months

Influenza virus

Lifelong, annually (seasonal), starting before HCT and resuming after 6 months

Pneumococcal 13-valent conjugate (0.5 mL, intramuscularly)

X (18 months)

Pneumococcal 23-valent

Vaccine (0.5 mL subcutaneously or intramuscularly)

X^††

DTaP^✫ (0.5 mL intramuscularly)

Hib^† conjugate (0.5 mL intramuscularly)

IPV^‡ (0.5 mL subcutaneously or intramuscularly)

Hepatitis A (1 mL intramuscularly)

Hepatitis B (1 mL intramuscularly)

Meningococcal^§ (0.5 mL subcutaneously)

MMR (0.5 mL subcutaneously)

VZV^✫✫ (0.5 mL subcutaneously)

^✫Diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine, absorbed (DTaP, Tdap)

^†Haemophilus b conjugate vaccine

^‡Poliovirus vaccine, inactivated (IPV). Consult product labeling for specific recommendations about revaccinating previously unvaccinated, incompletely vaccinated, and completely vaccinated subjects

^§Meningococcal polysaccharide-protein conjugate vaccine (Menactra) is recommended for patients in appropriate high-risk groups (ages 11–18 years, college students living in dormitories, other age groups with functional or anatomic asplenia or complement component deficiency. Refer to the CDC website for further guidance)

Measles, mumps, and rubella vaccine, live, attenuated; only given if patient is immunocompetent at 24 months; that is, NOT on immune suppression AND NO GVHD for 6 months

^✫✫Varivax is the only varicella virus vaccine that should be used in post-HCT recipients because of the higher plaque-forming unit content in Zostavax and a lack of safety data with Zostavax. HCT recipients who have not had chicken pox (including those who have previously received a varicella vaccine) should receive post-HCT vaccination. For patients with a history of chicken pox, varicella vaccination may be considered but it should be noted that efficacy in preventing zoster has not been established

^††For patients with chronic GVHD who are likely to respond poorly to the 23-valent pneumococcal vaccine, a fourth dose of the 7-valent conjugate should be considered

^‡‡Initiation of nonlive vaccination series can begin as early as 6 months postallogeneic transplantation if patients are off immunosuppression and do not have active GVHD. If early vaccination is given, consider monitoring for response. At any time point, if vaccination is initiated in a patient who remains on immunosuppression, consider monitoring for response

Hilgendorf I et al. Vaccine 2011;29:2825–2833

Tomblyn M et al. Biol Blood Marrow Transplant 2009;15:1143–1238

NONINFECTIOUS COMPLICATIONS FOLLOWING ALLOGENEIC HCT

Noninfectious Complications Following Allogeneic HCT

Antin JH. N Engl J Med 2002;347:36–42

Ferrara JLM et al. Lancet 2009;373:1550–1561

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Savani BN et al. Blood 2011;17:3002–3009

Socié G et al. Blood 2003;101:3373–3385

Wingard JR et al. Hematology 2002:422–444

ACUTE GRAFT-VERSUS-HOST DISEASE FOLLOWING ALLOGENEIC HCT

Ferrara JLM et al. Lancet 2009;373:1550–1561

Glucksberg H et al. Transplantation 1974;18:295–304

Jagasia M et al. Blood 2012;119:296–307

Martin PJ et al. Biol Blood Marrow Transplant 2012;18:1150–1163

Thomas ED et al. NEJM 1975;292:895–902

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Incidence at 100 Days^✫

HLA identical sibling donors

Grades B–D: 39%

Grades C–D: 16%

Unrelated donors

Grades B–D: 59%

Grades C–D: 32%

Risk Factors

HLA mismatch

Female donor to male recipient

Disease status other than early

Ineffective GVHD prophylaxis

Organ Involvement

Organ Involved

Percent of Patients

Skin

81%

Gastrointestinal

54%

Liver

50%

^✫Incidence of acute GVHD from a study of adults receiving allogeneic HCT from HLA-identical sibling donors (n = 3191) and unrelated donors (n = 2370) using the International Bone Marrow Transplant Registry (IBMTR) grating system (A–D)

Jagasia M et al. Blood 2012;119:296–307

Staging of Acute GVHD

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Staging of Acute GVHD

Skin, liver, and gastrointestinal tract are staged independently and these are combined for an overall grade

Stage

Skin^✫

Liver

Gastrointestinal Tract^†

Stage I

Rash on <25% of skin

Total bilirubin 2–3 mg/dL (34.2–51.3 μmol/L)

Diarrhea >500 mL/day

Stage II

Rash on 25–50% of skin

Total bilirubin 3.1–6 mg/dL (53–102.6 μmol/L)

Diarrhea >1000 mL/day

Stage III

Generalized erythroderma

Total bilirubin 6.1–15 mg/dL (104.3–256.5 μmol/L)

Diarrhea >1500 mL/day

Stage IV

Bullae

Total bilirubin >15 mg/dL (>256.5 μmol/L)

Severe abdominal pain, bleeding, ± ileus

^✫A maculopapular rash initially involving the face, ears, palms, soles, and upper trunk. If GVHD advances, rash spreads to the rest of the body, generally sparing the scalp. Histologic examination is needed to establish diagnosis

^†A pan-intestinal process that can present with nausea, vomiting, anorexia, diarrhea, and/or abdominal pain

The diagnosis of gastrointestinal GVHD must be made by mucosal biopsy

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Staging of Acute GVHD

Grading for Acute GVHD

Grade

Skin

Liver

Gut

1–2

1–3

and/or

III

2–3

2–4

and/or

2–3

2–4

and/or

2–4

Glucksberg H et al. Transplantation 1974;18:295–304

Przepiorka D et al. Bone Marrow Transplant 1995;15:825–828

Thomas ED et al. NEJM 1975;292:895–902

International Bone Marrow Transplant Registry Severity Index for grading acute GVHD

A–Stage 1 skin involvement; no liver or gut involvement

B–Stage 2 skin involvement; Stage 1 to 2 gut or liver involvement

C–Stage 3 skin, liver, or gut involvement

D–Stage 4 skin, liver, or gut involvement

Rowlings PA et al. Br J Haematol 1997;97:855–864

REGIMEN FOR PROPHYLAXIS: CYCLOSPORINE + METHOTREXATE AND TACROLIMUS + METHOTREXATE

Regimen for Prophylaxis: Cyclosporine + Methotrexate and Tacrolimus + Methotrexate

Storb R et al. Blood 1989;73:1729–1734

Storb R et al. Blood 1992;80:560–561

Storb R et al. N Engl J Med 1986;314:729–735

Cyclosporine + Methotrexate

Cyclosporine 2–5 mg/kg per dose; administer intravenously or orally twice daily (every 12 hours) starting 1–2 days prior to graft infusion, and continuing for a total of 6 months

Methotrexate 15 mg/m²; administer intravenously on day +1 after transplantation, (total dosage: 15 mg/m²), followed by:

Methotrexate 10 mg/m² per dose; administer intravenously for 3 doses, on days 3, 6, and 11, after transplantation (total dosage = 30 mg/m²)

Treatment Modifications

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Treatment Modifications

General guidance:

Cyclosporine dose modifications may be guided by pharmacokinetics when these are available. Often, however, therapeutic targets can be effectively achieved by making small, incremental changes of 10–25%
If levels are high, or in the presence of toxicity, withhold cyclosporine and resume a lower dose after:
- Demonstrating a concentration within the targeted range
- Adverse events have diminished or resolved

Adverse Event

Dose Modification

Baseline serum creatinine within normal limits and serum creatinine increases to 1.5–2 mg/dL (133–177 μmol/L)

Reduce cyclosporine dose by 50%

Baseline serum creatinine within normal limits and serum creatinine increases to >2 mg/dL (>177 μmol/L)

Hold cyclosporine and check daily creatinine and cyclosporine levels. Restart cyclosporine at 50% of the initial dose after creatinine is <2 mg/dL (<177 μmol/L)

Hypertension develops while on cyclosporine

Consider calcium channel blockers or β-adrenergic blockers as first-line therapy

Voriconazole therapy in a patient with therapeutic cyclosporine levels

Reduce cyclosporine dose by ≈50%

Notes

Begin with intravenous administration, convert to oral administration, and then continue
Oral cyclosporine is incompletely absorbed. Changing from intravenous to oral administration (or the reverse) requires a conversion
Table Graphic Jump Location
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Notes

Approximate IV-to-Oral Dose Ratio (mg:mg)

Cyclosporine (Sandimmune) Cyclosporine, Modified (Neoral)

1:2–3 1:1–2
Cyclosporine may also be given once daily; however, an intermittent 12-hour dose interval increases trough concentrations and decreases peak concentrations

Toxicity

Cyclosporine

Common

Headache

Hirsutism, hypertrichosis

Nausea, vomiting, diarrhea

Tremor

Hypertension

Nephrotoxicity

Hyperlipidemia

Serious

Reversible posterior leukoencephalopathy syndrome (RPLS): a neurologic syndrome defined by clinical and radiologic features. The typical clinical syndrome includes headache, confusion, visual symptoms, and seizures. Typical MRI findings are consistent with vasogenic edema and are predominantly localized to the posterior cerebral hemispheres. Although RPLS is most often reported with cyclosporine use, it has also been associated with other agents, including tacrolimus and sirolimus

Gingival hyperplasia

Hepatotoxicity

Hypomagnesemia

Anaphylaxis with intravenously administered products (rare)

Hyperkalemia (rare)

Pancreatitis (rare)

Paresthesia (rare)

Methotrexate

Common

Alopecia, photosensitivity, rash

Anorexia, diarrhea

Nausea, vomiting

Stomatitis

Serious

Cirrhosis

Elevated liver function test

Hepatic fibrosis, atrophy, necrosis, and failure

Gastrointestinal bleeding

Mucositis, ulceration

Hyperuricemia

Nephropathy, renal failure

Interstitial pneumonitis (acute, chronic)

Methotrexate-induced lung disease

Myelosuppression

Efficacy

Storb R et al. N Engl J Med 1986;314:729–735

In a seminal randomized trial comparing the effect of a methotrexate and cyclosporine combination to cyclosporine alone, there was a significant reduction in the cumulative incidence of grades II–IV acute GVHD in patients who received the combination regimen (33%) compared with those who received cyclosporine alone (54%) (p = 0.014)

Therapy Monitoring

Daily cyclosporine concentration measurements:
- When clinical toxicity is encountered
- When potentially interacting agents are added or withdrawn
Check cyclosporine concentrations 24–72 hours after changes in:
- Dose/dosage
- Administration schedule
- Route of administration
- Product formulation
Weekly to every 2 weeks:
- Check BUN and serum creatinine

Notes:

Be wary when comparing cyclosporine concentration results performed by different laboratory facilities. Cyclosporine assay methodologies vary among clinical laboratories
Therapeutic target concentrations also vary with:
- Type of sample assayed (if specimen other than whole blood is analyzed)
- Dosing interval
- Temperature
- Clinician preferences
Therapeutic monitoring strategies also vary. Sample collection times may be expressed in any of the following ways:
- For a sample collected before a cyclosporine dose is given: “predose,” “trough,” or “C0”
- For a sample collected 2 hours after a cyclosporine dose is given: “2-hour postdose,” “C2,” or “absorption profiling”
Verify whether aberrant cyclosporine measurements are correct before altering a cyclosporine regimen, particularly when they occur unexpectedly. Factors that perturb cyclosporine levels include:
- Noncompliance with an oral regimen
- The introduction, modification, and discontinuation of drugs that potentially interfere with cyclosporine absorption (after oral administration), metabolism, and elimination
- Incorrect sampling time
- Blood drawn through an intravenous catheter lumen previously used to administer cyclosporine
- Drawing specimens while administering cyclosporine intravenously
Cyclosporine is extensively metabolized by cytochrome P450 (CYP) CYP3A subfamily enzymes; its metabolism and elimination may be markedly perturbed by drugs that induce or inhibit CYP3A enzymes

Tacrolimus + Methotrexate

Nash RA et al. Blood 2000;96:2062–2068

Ratanatharathorn V et al. Blood 1998;92:2303–2314

Tacrolimus 0.03 mg/kg per day; administer by continuous IV infusion over 24 hours starting on the day before transplantation

Tacrolimus dosage is altered to achieve a concentration measurement within a targeted range of concentrations
Treatment is continued for 8 weeks (2 months after transplantation), after which the dose rate is slowly decreased (tapered) by 20% per month and discontinued 6 months after transplantation

Methotrexate 15 mg/m²; administer intravenously on day 1 after marrow transplantation, followed by:

Methotrexate 10 mg/m² per dose; administer intravenously for 3 doses on days 3, 6, and 11

Notes: Tacrolimus was converted from IV to oral administration at the ratio of 1 mg (IV) to 4 mg (orally). The total daily dose was given orally in 2 divided doses per day when the patients were able to tolerate oral intake. Tacrolimus dose was reduced by 25% when a serum creatinine measurement was increased 2-times greater than baseline, and decreased by 50% for patients whose creatinine increased to 3-times greater than baseline. Tacrolimus concentrations were maintained within the range 10–30 ng/mL (10–30 mcg/L)

Tacrolimus Adverse Effects

Common: Constipation, diarrhea, nausea, vomiting, headache, insomnia, tremor

Serious: Hyperglycemia (frequent), hyperkalemia, hypomagnesemia, hypertension, myocardial, hypertrophy, cardiac QT interval prolongation, torsades de pointes, nephrotoxicity

In comparison with cyclosporine and methotrexate, the combination of tacrolimus and methotrexate is associated with a greater reduction of acute GVHD and severe acute GVHD; however, there is no difference in all-cause mortality between the 2 approaches

Ram R et al. Bone Marrow Transplant 2009;43:643–653

REGIMEN FOR TREATMENT OF ACUTE GVHD

Regimen for Treatment of Acute GVHD

Martin PJ et al. Biol Blood Marrow Transplant 2012;18:1150–1163

Martin PJ et al. Blood 1990;76:1464–1472

Weisdorf D et al. Blood 1990;75:1024–1030

Whenever possible, a clinical diagnosis of acute GVHD (aGVHD) should be confirmed by biopsy of an affected end organ

First-line treatment:

Methylprednisolone 2 mg/kg per day; administer intravenously, or

Prednisone 2–2.5 mg/kg per day; administer orally

(aGVHD of the upper GI tract, a distinct clinical entity of anorexia, nausea, vomiting, and dyspepsia is responsive to low-dose systemic and topical steroid therapy; initial approach to treatment of aGVHD of the upper GI tract is methylprednisolone or prednisone at 1 mg/kg per day)

Efficacy: ~50% of patients who develop acute GVHD show durable improvement after initial steroid treatment
Decisions to begin systemic treatment depend not only on the severity of GVHD manifestations but also on their rate of progression
The survival and response data from studies combining the use of other immunosuppressive agents together with glucocorticoid treatment do not support this approach as the standard of care
Tapering steroid doses should begin as soon as GVHD manifestations show major improvement. Inappropriately rapid taper rates carry a risk of GVHD exacerbation or recurrence, whereas inappropriately slow taper rates increase the risk of steroid-related complications. Taper rates should be slowed after the daily prednisone dose has been decreased to <20–30 mg

Second-line therapy for acute graft-versus-host disease:

Criteria and indications for secondary systemic therapy of aGVHD have not been systematically defined. Both the severity and duration of manifestations should be taken into account in deciding that initial glucocorticoid treatment has not adequately controlled GVHD. In general, decisions to initiate secondary therapy should be made sooner for patients with more severe GVHD. For example, secondary therapy may be indicated after 3 days with progressive manifestations of GVHD, after 1 week with persistent, nonimproving grade III GVHD or after 2 weeks with persistent, nonimproving grade II GVHD

Because comparative data demonstrating superior efficacy for particular agents are not available, the choice of a second-line regimen should be guided by the effects of any previous treatment and by considerations of potential toxicity and interactions with other agents, including those used for prophylaxis, convenience, expense, the familiarity of the physician with the agent, and the prior experience of the physician

Agents used for second-line therapy include: methotrexate, basiliximab, daclizumab, denileukin diftitox, etanercept, infliximab, antithymocyte globulin, sirolimus

CHRONIC GRAFT-VERSUS-HOST DISEASE FOLLOWING ALLOGENEIC HCT

Ferrara JLM et al. Lancet 2009;373:1550–1561

Filipovich AH et al. Biol Blood Marrow Transplant 2005;11:945–956

Savani BN et al. Blood 2011;17:3002–3009

Wolff D et al. Biol Blood Marrow Transplant 2010;16:1611–1628

Wolff D et al. Biol Blood Marrow Transplant 2011;17:1–17

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CHRONIC GRAFT-VERSUS-HOST DISEASE FOLLOWING ALLOGENEIC HCT

Incidence

HLA-identical sibling donor

~40%

HLA-matched unrelated donor

~70%

Risk Factors

Higher degree of HLA mismatching

Older age of donor and/or recipient

Donor and recipient gender disparity

Prior acute GVHD

Cytomegalovirus seropositivity (donor and recipient)

The use of peripheral blood precursor cells rather than bone marrow

Timing of Onset of Chronic GVHD

HCT Source

Median Time to Diagnosis

HLA-identical sibling donor

201 days

HLA-non-identical related donor

159 days

Unrelated donor

133 days

Organ Involvement

Organ Involved

Percent of Patients

Skin

65–80%

Mouth

48–72%

Liver

40–73%

Eye

18–47%

Gastrointestinal

16–26%

Lung

10–15%

Joints

2–12%

The diagnosis of chronic GVHD requires the following:
1. Distinction from acute GVHD
2. Presence of at least one diagnostic clinical sign of chronic GVHD or presence of at least one distinctive manifestation confirmed by pertinent biopsy or relevant tests
3. Exclusion of other possible diagnoses
Scoring of organ manifestations requires careful assessment of signs, symptoms, laboratory values, and other study results

Categories of Chronic GVHD

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Categories of Chronic GVHD

Time of Symptoms after HCT or DLI

Presence of Acute GVHD Features

Presence of Chronic GVHD Features

Classic chronic GVHD

No time limit

Yes

Overlap syndrome

No time limit

Yes

Signs and Symptoms of Chronic GVHD

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Signs and Symptoms of Chronic GVHD

Organ or Site

Diagnostic

Sufficient to Establish the Diagnosis of Chronic GVHD

Distinctive

Seen in Chronic GVHD, but Insufficient Alone to Establish a Diagnosis of Chronic GVHD

Skin

Poikiloderma

Lichen-type features

Sclerotic features

Morphea-like features

Lichen-sclerosis

Depigmentation

Nails

Dystrophy

Longitudinal ridging, splitting, or brittle

Onycholysis

Pterygium unguis

Nail loss (usually symmetric, affects most nails)

Scalp and body hair

New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy)

Alopecia; scaling, papulosquamous lesions

Mouth

Lichen-type features

Hyperkeratotic plaques

Restriction of mouth opening from sclerosis

Xerostomia

Mucocele

Mucosal Atrophy

Eyes

New onset dry, gritty, or painful eyes

Cicatricial conjunctivitis

Keratoconjunctivitis sicca

Confluent areas of punctuate keratopathy

Genitalia

Lichen-type features

Vaginal stricture or stenosis

Erosions

Fissures

Ulcers

GI tract

Esophageal web

Strictures or stenosis in the upper to mid-third of the esophagus

Pancreatic insufficiency

Lung

Bronchiolitis obliterans diagnosed with lung biopsy

Bronchiolitis obliterans diagnosed with PFTs and radiology

Muscles, fascia, joints

Fasciitis

Joint stiffness or contractures secondary to sclerosis

Myositis or polymyositis

Treatment of Chronic GVHD

Mild chronic GVHD may be treated either with topical immunosuppressive agents or with systemic steroids alone. With respect to treatment limited to topical immunosuppression, close follow-up and screening for potential manifestations of chronic GVHD is crucial to detect systemic progression of chronic GVHD during topical treatment. Mild manifestations of chronic GVHD that cannot be sufficiently treated by topical treatment such as hepatic manifestations or fasciitis may be treated with systemic corticosteroids alone

Treatment of moderate chronic GVHD requires systemic immunosuppression. Standard treatment is prednisone 1 mg/kg per day, or a glucocorticoid equivalent dose of methylprednisolone (0.8 mg/kg per day). Dose intensity should be maintained for 2 weeks, then decreased (tapered) to 1 mg/kg every other day over a period of 6–8 weeks if symptoms are stable or improving, and then either maintain this dose for 2–3 months or continue to taper by dose decrements of 10–20% per month. Patients with complete responses (CRs) should have doses decreased further by 10–20% monthly, whereas persons without a CR who are still responding should stay on 1 mg/kg for about another 3 months after achieving maximum response, and then doses should be slowly tapered. If symptoms flare during tapering, increasing the steroid dose may again induce a favorable response

Treatment of severe chronic GVHD (cGVHD) follows the same rules as treatment of moderate chronic GVHD. Severe cGVHD has been associated with an increased mortality and may require prolonged immunosuppression

Refractory chronic GVHD: Generally, accepted criteria for steroid-refractory chronic GVHD, include:

Progression despite immunosuppressive treatment using prednisone 1 mg/kg per day for 2 weeks,
Stable disease after 4–8 weeks of prednisone ≥0.5 mg/kg per day, and
Inability to taper prednisone to <0.5 mg/kg per day

Although different treatment options are available for salvage therapy of steroid refractory cGVHD, the “trial-and-error system” remains, to date, the only way to identify the drug or drug combination effective in an individual patient. In principle, initial secondary treatment should include agents with an adequate safety profile and well-documented activity. Patients should be treated for an adequate length of time (at least 4 weeks) before concluding treatment failure

Treatment modalities are the use of steroids and calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalidomide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil, methotrexate, cyclophosphamide, pentostatin), rituximab, alemtuzumab, and etanercept

Antimicrobial Prophylaxis for Patients with Chronic GVHD

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Antimicrobial Prophylaxis for Patients with Chronic GVHD

Infections are a common cause of death in chronic GVHD. Recommendations regarding prophylaxis are based on expert opinion rather than controlled trials (Couriel D et al. Biol Blood Marrow Transplant 2006;12:375–396; Vogelsang GB. Blood 2001;97:1196–1201). A common practice is to start antimicrobial prophylaxis once the diagnosis of chronic GVHD is made, or at least once active immunosuppression for the treatment of chronic GVHD is started

First Choice

Alternative

Antibiotic Prophylaxis

Penicillin V potassium 500 mg; administer orally, twice daily

Penicillin allergy:

Cotrimoxazole (trimethoprim 80 mg + sulfamethoxazole 400 mg); administer orally, once daily

Penicillin and sulfonamide allergy:

Clarithromycin 500 mg; administer orally, daily

Be wary of potential interactions with CYP3A subfamily substrates

Antiviral Prophylaxis

Valacyclovir 500 mg; administer orally, once daily

Acyclovir 200 mg; administer orally every 12 hours

Most experience is with acyclovir; valacyclovir is more convenient and is an acceptable alternative

Antifungal Prophylaxis

It is unknown if administering antifungal prophylaxis during GVHD is efficacious in terms of decreasing the incidence of invasive fungal infections or improving outcome. Some experts, concerned with the risk of invasive aspergillosis advocate the use of voriconazole in this setting, but the approach is off-label and must be considered experimental. Emerging data regarding long-term toxicities of voriconazole (osteopathy-fluorosis and carcinogenesis) make this approach questionable

Pneumocystis Jirovecii Prophylaxis

Prophylaxis for Pneumocystis jirovecii should be administered to all patients undergoing treatment of chronic GVHD and for 6 months after immunosuppressive medications are discontinued

Cotrimoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg) per day; administer orally, 3 days/week

Aerosolized pentamidine 300 mg; administer by inhalation, every 4 weeks

ORAL COMPLICATIONS

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ORAL COMPLICATIONS

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Sicca Syndrome Caries

Risk factors: GVHD, TBI/radiation exposure to head and neck

Follow-up: Clinical oral evaluations should be performed at 6 months and 1 year and yearly thereafter. More frequent evaluations may be needed in patients at high risk of oral complications (eg, chronic GVHD, exposure to TBI)

All HCT recipients should receive a thorough evaluation by a dentist or oral medicine specialist at 1 year after HCT and yearly thereafter. More frequent dental consultations may be considered in patients with oral GVHD

Notes: The mouth is one of the most frequently affected organs in chronic GVHD. Changes involving the oral mucosa, salivary glands, oral and lingual muscles, taste buds, and gingiva may completely regress, but some long-term sequelae may continue despite the resolution of chronic GVHD

Salivary gland dysfunction and xerostomia increase the risk of dental caries, periodontal disease, and oral cancer. Particular attention to oral malignancies should be paid to patients with previous severe chronic GVHD of the oral and pharyngeal mucosa

Even in patients who have never had GVHD, some degree of salivary gland hypofunction may persist for prolonged periods of time after receiving chemotherapy, and especially after local irradiation

Patients with GVHD can be treated with topical oral steroids, systemic treatments for GVHD, and supportive care for xerostomia symptoms

Among HCT recipients who require dental procedures antimicrobial prophylaxis against endocarditis should be followed

OCULAR COMPLICATIONS

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OCULAR COMPLICATIONS

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Keratoconjunctivitis sicca syndrome

Cataract

Retinopathy

Optic disc edema

Infectious retinitis

Risk factors: TBI/radiation exposure to head and neck, corticosteroids, GVHD

Follow-up: Routine clinical evaluation of visual history and symptoms, with attention to sicca syndrome, is recommended at 6 months, 1 year, and yearly thereafter for all HCT recipients

Measurement of visual acuity and fundus examination at 1 year after transplantation is recommended for all HCT recipients. Patients with cGVHD may be referred for an ophthalmologic exam sooner than 1 year after transplantation. Subsequent frequency of routine screening should be individualized according to recognized defects, ocular symptoms, or the presence of cGVHD

Notes:

Ocular sicca syndrome: reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects, and corneal ulceration. The incidence is approximately 40–60% in patients with cGVHD. Artificial tears can provide symptomatic treatment of dry eyes. Temporary or permanent occlusion of the tear duct puncta for drainage control may provide benefit. Corticosteroids or calcineurin inhibitors may improve symptoms but can cause sight-threatening complications when inappropriately used in herpes simplex virus or bacterial keratitis

Cataract: After myeloablative single-dose TBI, almost all patients develop cataracts within 3–4 years. Fractionation of TBI delays the onset and reduces the incidence of cataract to 40–70% at 10 years after transplantation. In patients who receive conditioning without TBI, the probability of cataract formation at 10 years is 5–20%. Cataracts are effectively treated surgically

Ischemic microvascular retinopathy presents with cotton wool spots and optic disc edema. Retinopathy is observed almost exclusively after allogeneic transplantation, particularly in patients conditioned with TBI and in patients receiving cyclosporine for GVHD prophylaxis. In most cases, retinal lesions resolve with withdrawal or reduction of immunosuppressive therapy, even in cases where visual acuity is decreased

ENDOCRINE COMPLICATIONS

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ENDOCRINE COMPLICATIONS

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Hypothyroidism

Gonadal dysfunction

Adrenal failure

Risk factors: TBI/radiation exposure, corticosteroids, young age at time of HCT, chemotherapy exposure

Follow-up:

Thyroid function tests (TSH, T₃, and free T₄) should be performed at 1 year after HCT and yearly thereafter in all transplantation recipients and additionally if relevant symptoms develop

Clinical and endocrinologic gonadal assessment at 1 year after HCT is recommended for all women who were postpubertal at the time of transplantation. Frequency of subsequent assessments should be guided by clinical need (eg, menopausal status). Women should have annual gynecologic evaluations as part of general health screening, at which time, hormone replacement therapy should be addressed for those who are postmenopausal

Gonadal function in men, particularly FSH, LH, and testosterone, should be assessed if symptoms warrant (lack of libido or erectile dysfunction). Consider referral to an endocrinologist for men who may need testosterone replacement therapy

Notes:

Subclinical, compensated hypothyroidism: elevated TSH and normal serum-free T₄ levels, occurs in 7–15% of patients in the first year after transplantation. Single-dose ablative TBI is associated with a 50% incidence of overt hypothyroidism, whereas fractionated TBI is associated with an incidence of approximately 15%. The incidence reported after busulfan and cyclophosphamide conditioning is 11%. The median time to diagnosis of hypothyroidism is nearly 4 years after HCT or TBI exposure

Gonadal dysfunction is highly prevalent in HCT recipients, with rates as high as 92% for males and 99% for females. Although the risk of gonadal failure is high in all individuals, women generally experience higher rates of failure than do men. Hypogonadism is nearly universal after high-dose irradiation or busulfan. Fractionation of radiation reduces the risk compared with unfractionated radiation. The risk is lower with cyclophosphamide alone. In general, ovarian endocrine failure is irreversible in adult women

Adult women should be evaluated by a gynecologist and may require hormone replacement therapy to maintain libido, sexual function, and bone density. Vaginal GVHD may result in strictures and synechiae

Most men have normal testosterone levels after transplantation, although germ cell damage (infertility) is a near-universal finding in men exposed to high doses of radiation or chemotherapy

Adrenal failure: Greater durations and intensity of exposure generally are associated with longer persistence of adrenal suppression. Patients with prolonged exposure to corticosteroids after HCT should have adrenal axis testing when withdrawing corticosteroids, particularly if symptoms of adrenal insufficiency develop

PULMONARY COMPLICATIONS

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PULMONARY COMPLICATIONS

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Idiopathic pneumonia syndrome

Bronchiolitis obliterans syndrome

Cryptogenic organizing pneumonia

Sinopulmonary infections

Diffuse alveolar hemorrhage

Pulmonary thromboembolism

Pulmonary venoocclusive disease

Pleural effusions

Risk factors: TBI/radiation exposure to chest, GVHD, infectious agents, allogeneic HCT, exposure to busulfan or carmustine (BCNU)

Follow-up: clinical assessment by history and physical exam for pulmonary complications at 6 months, 1 year, and yearly thereafter

In patients with symptoms or signs of lung compromise, PFTs and focused radiologic assessment should be performed as clinically indicated. Follow-up evaluations should be guided by clinical circumstances for patients with recognized defects

Notes:

Bronchiolitis obliterans syndrome (BOS): Occurs with an incidence of 2–14% among allogeneic HCT recipients and is almost exclusively seen among patients with cGVHD. Treatment of BOS includes immunosuppressive agents such as corticosteroids, calcineurin inhibitors, sirolimus, and antithymocyte globulin. The prognosis of BOS is poor, and 5-year survival rates are <20% if patients do not respond to initial treatment

Cryptogenic organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia): Presents typically in the first 6–12 months posttransplantation. Pulmonary function tests typically show a restrictive pattern. Corticosteroids are the mainstay of treatment and 80% of patients can be expected to recover, but relapses are common if steroids are rapidly tapered

Sinopulmonary infections can occur in patients with delayed immune reconstitution and cGVHD. Appropriate vaccinations are recommended, and in patients with ongoing immune deficiency and infections, immune globulin levels should be monitored and replacement should be considered

CARDIAC AND VASCULAR ABNORMALITIES

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CARDIAC AND VASCULAR ABNORMALITIES

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Cardiomyopathy

Congestive heart failure

Arrhythmias

Valvular anomaly

Coronary artery disease

Cerebrovascular disease

Peripheral arterial disease

Risk factors: Anthracycline exposure, TBI/radiation exposure to neck or chest, older age at HCT, allogeneic HCT, cardiovascular risk factors before/after HCT, chronic kidney disease, metabolic syndrome

Follow-up: Routine clinical assessment and cardiovascular risk factor evaluation for all HCT recipients at 1 year and yearly thereafter. More frequent assessments and if clinically appropriate, extended cardiac evaluations (eg, electrocardiogram, echocardiogram) may be indicated in patients at high risk for cardiac complications (eg, patients with Hodgkin lymphoma who have received mediastinal radiation therapy, patients with amyloidosis, and patients with preexisting cardiac and vascular abnormalities)

LIVER COMPLICATIONS

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LIVER COMPLICATIONS

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GVHD

Hepatitis B

Hepatitis C

Iron overload

Venoocclusive disease

Risk factors: Cumulative transfusion exposure, risk factors for viral hepatitis transmission

Follow-up: LFTs (serum total bilirubin, alkaline phosphatase, and transaminases) should be performed every 3–6 months for the first year, and then at least yearly thereafter. More frequent assessments may be needed based on an individual patient's medical status (eg, patients with GVHD) and particularly in allogeneic transplantation survivors

Serum ferritin should be measured at 1 year after transplantation in patients who received RBC infusions pre- or posttransplantation. Subsequent monitoring with serum ferritin should be considered among patients with elevated levels, especially in the presence of abnormal LTFs, continued RBC transfusions, or HCV infection. Additional diagnostic testing (eg, liver biopsy, MRI, or superconducting quantum interference device [SQUID]) may be indicated if therapy is contemplated for suspected iron overload

Notes:

Chronic GVHD is a major cause of liver dysfunction after transplantation and can manifest with elevations of serum alanine transaminase, alkaline phosphatase, and gamma-glutamyl transferase. Evaluation should exclude other causes of liver dysfunction (eg, viral infections, drug-related injury). Liver biopsy should be performed to confirm the diagnosis when liver dysfunction occurs as the only manifestation of cGVHD and systemic immunosuppression is being considered

The cumulative incidence of HCV progressing to cirrhosis is 11% at 15 years and 24% at 20 years, being more rapid in transplantation than in nontransplantation patients (18 vs. 40 years). In patients with known HCV infection, liver biopsy can be considered at 8–10 years after transplantation to assess for the presence of cirrhosis

When iron overload is suspected, the hepatic iron content should be estimated by appropriate imaging (specialized magnetic resonance imaging [MRI] protocols or superconducting quantum interference device [SQUID]) or liver biopsy. Patients with significant iron overload (eg, >7 mg/g dry weight liver iron) and liver dysfunction are candidates for phlebotomy or iron-chelation therapy

Hepatic sinusoidal obstruction syndrome (hepatic SOS, previously called hepatic veno-occlusive disease) is associated with hepatomegaly, right upper quadrant pain, jaundice, and ascites, and usually begins within 6 weeks after HCT. Not all features may be present, and the severity of signs and symptoms can vary. The incidence following high-dose chemotherapy and TBI is 20–50%

For patients suspected to have hepatic SOS, perform ultrasound and Doppler studies to determine whether there is attenuation or reversal of venous flow or portal vein thrombosis. Prophylaxis with ursodiol (ursodeoxycholic acid) is recommended in HCT recipients to reduce hepatic complications:

Ursodiol 600 mg/day (eg, 300 mg twice daily); administer orally, from transplantation day −1 to day +80 after transplantation

RENAL COMPLICATIONS

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RENAL COMPLICATIONS

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Chronic Kidney Disease

Risk factors: older age at HCT, diagnosis (eg, myeloma) and pretransplantation renal function and therapy exposures (eg, platinum compounds), acute GVHD and cGVHD, use of TBI in conditioning regimen, exposure to medications to prevent or treat GVHD (eg, calcineurin inhibitors), and certain antimicrobials (eg, acyclovir, amphotericin, aminoglycosides)

Blood pressure should be checked at every clinic visit, and hypertension should be investigated and managed appropriately in all HCT recipients

Renal function should be evaluated at 6 months, 1 year, and at least yearly thereafter for all HCT recipients. Screening should include assessment of BUN, serum creatinine, and urine protein. Further work-up (eg, renal ultrasound, renal biopsy), as clinically indicated should be pursued in patients with late-onset acute renal failure or chronic kidney disease posttransplantation

Notes: The incidence of chronic kidney disease defined as sustained decrease in glomerular filtration rate <60 mL/min per 1.73 m², has been reported to range from 5–65%. The majority of patients have an idiopathic form of chronic kidney disease which is not associated with thrombotic microangiopathy or nephrotic syndrome and has a multifactorial etiology

MUSCULOSKELETAL COMPLICATIONS

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MUSCULOSKELETAL COMPLICATIONS

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Avascular necrosis

Osteoporosis

Osteopenia

Myopathy

Fasciitis/scleroderma

Polymyositis

Risk factors: inactivity, TBI, corticosteroids, GVHD, hypogonadism, allogeneic HCT

Follow-up: A screening dual-photon densitometry should be performed 1 year after transplantation in adult women, all allogeneic HCT recipients, and patients who are at high risk for bone loss after transplantation (eg, prolonged treatment with corticosteroids or calcineurin inhibitors). Repeat densitometry should be performed in those with recognized defects, ongoing risk factors, or to follow-up response to therapy. Physicians should evaluate gonadal and other related endocrine abnormalities in patients with a decline in bone density

Notes:

Rapid loss of bone usually takes place within 6–12 months after transplantation with incidence rates as high as 25% for osteoporosis and 50% for osteopenia. Treatment choices for patients with established osteopenia and osteoporosis include active exercise, calcium and vitamin D supplementation, use of estrogen replacement in women, and minimizing the total exposure and duration of steroid and other immune-suppressive therapies. Bisphosphonate therapy should be considered for treatment of patients with established osteopenia and osteoporosis, patients with evidence of progressive bone density loss, and patients at high risk for bone loss (eg, patients with GVHD on extended steroid therapy). Osteonecrosis of the jaw has been reported in patients who receive bisphosphonates for osteoporosis, especially among those undergoing oral procedures while on these agents. If appropriate, dental evaluation should be performed before starting bisphosphonates in order to detect and correct dental problems

Avascular necrosis (AVN) has been described in 4–19% of HCT survivors. Although the hip is the most frequently affected joint (>80% of cases; bilateral in >60%), other joints can be affected, including the knees, wrists, and ankles. Most adult patients with advanced AVN will require surgical intervention

Myopathy after HCT is one of the most frequent complications of long-term steroid therapy for cGVHD. Myopathy progresses insidiously in most cases. Proximal lower extremity muscles are commonly involved, with quadriceps muscles affected most severely

Myositis or polymyositis is a rare distinctive feature of cGVHD as defined by National Institutes of Health consensus criteria. Chronic GVHD-associated polymyositis or myopathy usually occurs 2–5 years after HCT. The common presenting symptoms are moderate to severe proximal muscle weakness and/or myalgia; lower extremities are commonly involved. This syndrome may be hard to distinguish from steroid-induced myopathy. The majority of patients have increased serum creatine kinase (creatine phosphokinase, CK) levels, a myopathic pattern on electromyography, a largely perifascicular lymphocytic infiltration on muscle biopsy, and a very favorable response to immunosuppressive therapy

Sclerosis can affect the skin and subcutaneous tissues including fasciae, joints, and the musculoskeletal system with varying degrees of severity and is a diagnostic feature of cGVHD. Aggressive and prolonged immunosuppressive therapy is necessary to prevent progression of contractures, but is usually ineffective at reversing established contractures. Early intervention and rehabilitation become essential to restore range of motion and strength

For patients on corticosteroids, frequent clinical evaluation is recommended for steroid-induced myopathy by manual muscle tests or by assessing patients' ability to rise from a seated to a standing position

MUCOCUTANEOUS COMPLICATIONS

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MUCOCUTANEOUS COMPLICATIONS

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Cutaneous sclerosis

GVHD

Risk factors: GVHD, TBI/radiation exposure to pelvis

Follow-up: All women recipients of allogeneic HCT should undergo clinical screening for symptoms of genital GVHD. Women who have established chronic GVHD should have gynecologic examination to screen for genital involvement

Late complications involving skin and appendages are frequent after HCT. Nearly 70% of patients with chronic GVHD experience skin involvement. Early changes of lichen planus-like or papulosquamous lesions may progress to sclerosis or poikiloderma and can be associated with skin ulcers and subsequent infections

Severe genital GVHD may develop in ~12% of women with or without associated systemic GVHD

Patients may present with excoriated or ulcerated mucosa, fissures, narrowing of introitus, or vaginal scarring and obliteration that may lead to hematocolpos. Treatment of vaginal GVHD includes topical steroids, topical cyclosporine and vaginal dilators. Surgical intervention can be used to treat severe cases. Genital involvement with GVHD is less common in men

NEUROPSYCHOLOGICAL DEFICITS

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NEUROPSYCHOLOGICAL DEFICITS

Majhail NS et al. Biol Blood Marrow Transplant 2012;18:348–371

Leukoencephalopathy

Late infections

Neuropsychological and cognitive deficits

Calcineurin neurotoxicity

Peripheral neuropathy

Depression

Anxiety

Fatigue

Risk factors: TBI/radiation fields that include the head, GVHD, exposure to fludarabine, intrathecal chemotherapy, hypogonadism, long-term corticosteroid administration

Follow-up: All HCT recipients should undergo clinical assessment for symptoms or signs of neurologic dysfunction 1 year after HCT, and at least yearly thereafter. Earlier and more frequent evaluations may be considered in high-risk patients, which includes allogeneic HCT recipients; patients who receive prolonged immune suppression with calcineurin inhibitors, TBI, cranial radiation, or intrathecal chemotherapy; and patients with chronic GVHD

Clinical assessment is recommended throughout the recovery period, at 6 months, at 1 year, and at least yearly thereafter, with assessment by a mental health professional for those with recognized deficits

Notes:

Neuropsychological deficits have been described in nearly 20% of recipients and cognitive deficits in ~10% of HCT recipients

Neurocognitive function generally improves over time, but long-term deficits may persist in more than 40% of survivors

SECONDARY MALIGNANCIES

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SECONDARY MALIGNANCIES

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Patients who receive allogeneic HCT have a 2- to 3-fold increased risk of developing solid tumors, compared with an age-, gender-, and region-adjusted population. Risk of secondary leukemia or myelodysplasia after autologous HCT is also greater than anticipated, with an overall incidence of approximately 4% 7 years after transplantation, with a median onset of 2.5 years (range: 3 months to 7 years) posttransplantation

Risk factors: GVHD, TBI/radiation exposure, T-cell depletion, exposure to alkylating agents or etoposide

Follow-up: All patients should at least receive country-specific general population recommendations for cancer screening. Screening for breast cancer is recommended at an earlier age (25 years or 8 years after radiation, whichever occurs later) but no later than age 40 years among recipients of TBI or chest irradiation

Notes:

Nearly all cancer types are described after allogeneic and autologous transplantation

Posttransplantation lymphoproliferative disorder (PTLD) is a rare complication of allogeneic HCT that is associated with donor–recipient HLA disparity, T-cell depletion, and GVHD. Overall incidence is 1% at 10 years after HCT. Although PTLD usually occurs early (within 6 months after transplantation), it is reported as late as 8 years after HCT. The majority of PTLDs are associated with Epstein-Barr virus infection

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Chapter 53: Complications and Follow-Up After Hematopoietic Cell Transplantation

Citation

Jump to a Section

Updated chapter to come.

INTRODUCTION

INFECTIOUS COMPLICATIONS FOLLOWING AUTOLOGOUS AND ALLOGENEIC HCT

NONINFECTIOUS COMPLICATIONS FOLLOWING ALLOGENEIC HCT

REGIMEN FOR PROPHYLAXIS: CYCLOSPORINE + METHOTREXATE AND TACROLIMUS + METHOTREXATE

REGIMEN FOR TREATMENT OF ACUTE GVHD

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