Antigen-specific T and B cell responses are profoundly deficient early after HSCT and gradual reconstitution occurs over 1-2 years. However recovery can take significantly longer due to ongoing immunosuppressive therapy, CGVHD, in HLA-mismatched transplants and with T-cell depleted grafts. Some physicians follow CD4 counts and CD4/8 ratios as a way to asses need for prophylactic antimicrobial therapy. Concurrent hypogamaglobulinaemia also increases the risk of infections in this group of patients.
Infections by capsulated bacteria (S. pneumoniae, H. influenza, and N. meningitides) remain a significant problem along with recurrent sino-pulmonary infections related to hypogamaglobulinaemia. The most common fungal infections are caused by Aspergillus species (lung/sinuses). However infections by Candida and Mucor species can also be seen. In terms of viral infections herpes viruses including VZV (particularly in the first year) and CMV (late reactivations and disease can occur in the presence of significant immunocompromise if early reactivations/disease have been an issue) infections can be problematic. Pneumocystis jirovicii (PCP) and Toxoplasma gondii infections are seen even several months post transplant and prophylaxis ideally with Co-trimoxazole should be continued until the patient is off all immunosuppression.
Penicillin V 300mg bid should be commenced in all non-allergic patients on therapy for CGVHD.
Fungal prophylaxis with an azole should be considered whilst patients are on systemic corticosteroid therapy
Pneumocystis prophylaxis (with Septra DS one tablet bid twice weekly in non-allergic patients) should be continued for as long as patients are on immunosuppressive therapy
Valaciclovir prophylaxis should be continued for at least one year post-transplant and continued on in patients on ongoing immunosuppressive therapy for CGVHD.
Immunoglobulin assays should be done at yearly intervals in patients on corticosteroids or in the presence of recurrent infections and replacement therapy (IVIg 0.4g/kg monthly) commenced in patients with IgG < 4g/L.
Please follow AHA guidelines for dental procedures (Dajani et al.)
Post transplant vaccination with inactivated vaccines should be commenced at 1 year post-transplant or when a patient is considered to be able to respond to the same i.e., off most immunosuppressive therapy (vaccination schedule in L/BMT Manual). Live attenuated vaccines should be avoided for the first 2 years and in those with CGVHD.
Oral & Ocular
CGVHD and prior radiotherapy both contribute to the sicca syndrome seen commonly post HSCT. This sicca syndrome increases the risk of caries development in these patients. Ongoing symptomatic CGVHD can be a significant issue. Surveillance for oral malignancy should be done as ongoing GVHD increases the risk in this patient population.
Hygiene measures, fluoride treatment and artificial saliva (if appropriate) should be recommended.
Dental evaluation should be done at 3 months and then subsequently at least annually. Earlier or more frequent assessments may be required based on symptoms.
Kerato conjunctivitis sicca occurs as part of a generalized sicca syndrome including xerostomia, vaginitis, and dry skin and occurs with greater frequency in patients with CGVHD (40% vs. 20%). The decreased tear flow also increases the risk of sterile conjunctivitis, corneal epithelial defects and epithelial ulceration. Topical management includes the use of lubricating eye drops, lachrymal duct occlusion, autologous serum drops and possibly sclera lens. In the context of CGVHD topical cyclosporine and topical retinoic acid have been found to be useful. Topical steroids may be associated with sight threatening bacterial and viral keratitis and therefore should be used with caution.
Posterior sub-capsular cataracts occur in the majority (80% at 6-10 yrs) of patients who have received TBI as part of conditioning for transplant. The other risk factors include older age at transplant and corticosteroid therapy longer than 3 months. Cataract surgery offers a simple and excellent solution to this complication.
Posterior chamber complications include ischaemic microvascular retinopathy, hemorrhage, bilateral optic disc edema and infectious retinitis. Risk factors for ischemic micro vascular retinopathy (incidence: 10% post allo-HSCT) include TBI based conditioning, use of cyclosporine for immunosupression and is manifested as disc edema and cotton wool spots. Withdrawal of cyclosporin is often associated with improvement in vision. Infectious retinitis can be due to fungi, herpes viruses (including CMV) and T.gondii.
Routine ophthalmological evaluation (including Schrimer’s test) at 3 months and subsequently yearly should be performed particularly in patients with CGVHD. Earlier more frequent assessments will be required in patients with ongoing symptoms.
New onset of visual symptoms/deterioration in vision should be prompt urgent ophthalmology review. (Please note the patient diagnosis, conditioning therapy and current medications in the consult request).
Significant numbers of patients (15-40%) develop late respiratory complications post allogeneic HSCT. These include infectious complications of the immunocompromised host (not discussed here) and noninfectious complications of the lung. The most common obstructive noninfectious complications include bronchiolitis obliterans (BO), bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pneumonia syndrome (IPS). The risk factors for developing respiratory compromise include abnormal pulmonary function pre-transplant, chemotherapy received during the course of the disease, chemo/radiotherapy used in pre-transplant conditioning, immune mediated lung injury (CGVHD), infections and smoking.
The most common sub-type of chronic obstructive pulmonary disease (with reduction of FEV1/FVC) seen in this patient group is Bronchiolitis obliterans (BO) which occurs in up to 14% of this population and is associated with significant morbidity and mortality (up to 50%). BO is characterized by a nonspecific inflammatory injury affecting mainly the small airways. In the early stages it is an obstructive respiratory disease but in the advanced stages has both restrictive and obstructive functional changes. Risk factors include CGVHD, recurrent infections, reduced serum immunoglobulin levels, older age of donor/recipient, busulphan in pre-transplant conditioning and GVHD prophylaxis with Methotrexate. The median onset of symptoms is 1 year post-HSCT. Symptoms include a non-productive cough, wheeze, dysnoea and recurrent respiratory tract infections. Patients may be asymptomatic with abnormal PFTs in 20% of cases. The progress is associated with a gradual decline in respiratory function. CXR is often normal in the early stages and in the later stages reveals changes of hyperinflation. High resolution CT (HRCT) scan in the expiratory phase reveals air-trapping (characteristic mosaic image). Small airways thickening and bronchiectasis may also be seen. The diagnosis of BO can be made when the following diagnostic criteria are met: (1) FEV1/FVC ratio <0.7 and FEV1<75% of predicted value; (2) evidence of air trapping or small airway thickening or bronchiectasis on HRCT; (3) absence of infection in the respiratory tract. Management is based on treatment of CGVHD with immunosuppressive therapy including with corticosteroids (1-1.5 mg/day for 2- 6 weeks) followed by a slow taper over 6-12 months and CSA/FK. The addition of a third immunosuppressive agent such as azathioprine, MMF, thalidomide, infliximab, ATG or the use of Azithromycin (250 mg three times/week has been associated with improvement of pulmonary function in some cases. Prompt treatment of infections and replacement of immunoglobulins (with IVIg when IgG levels <4g/L) may help delay progress of the respiratory compromise. Bronchodilators and inhaled corticosteroids can be used. ECP has been found to be useful in small studies.
BOOP occurs earlier in the course of HSCT, between 1-12 months post transplant with an incidence of <2%. Patients present acutely with fever cough, dysnoea. The CXR reveals patchy peripheral consolidation, ground glass attenuation and nodular opacities PFTs reveal a restrictive pattern with reduced TLC and DLCO. Bronchoscopy and biopsy helps to rule out infection and confirm diagnosis. Despite the lack of evidence systemic or inhaled corticosteroids are considered first line therapy and can result in improvement of the condition.
An idiopathic pneumonia syndrome can be seen within 3 months post transplant. The etiologies include infections (bacterial and viral), radiotherapy, chemotherapy (e.g. Busulfan, bleomycin, BCNU) and CGVHD.
Restrictive defects (with reduction of TLC and possibly DLCO) occur in the early (3-6/12 post-transplant) and are often stable and can improve in the subsequent years post-transplant.
Recurrent sino-pulmonary infections can occur. Replacement of immunoglobulins and smoking cessation can help in the management of these infections.
Regular clinical evaluations at least 6 monthly or more frequently in the presence of CGVHD should be performed.
Smoking cessation should be advocated.
Pulmonary function testing at 3 months and subsequently yearly post transplant in the presence of CGVHD or symptoms.
Radiology (CXR, HRCT) to be done based on symptoms or abnormal PFT.
Referral to respirology is recommended in the presence of abnormal PFT and/or symptoms for management and consideration of BAL and biopsy.
Compared to the general population the risk of late death due to cardiac complications is 2-3 fold higher after allo-HSCT and 4 fold higher in females even after auto-HSCT. There are few studies looking at cardiac late effects in adults. In children the use of TBI and anthracyclines pre-transplant is associated with a 5 year cumulative incidence of cardiac impairment of 26% ( majority asymptomatic). It is highly likely therefore that similar changes would be observed in adults and the true magnitude of these defects will become apparent with longer term studies.
A retrospective EBMT study found a cumulative incidence of arterial event (cerebrovascular/cardiovascular/peripheral arterial) of 6% at 15 years. The CI of an arterial event for patients with a high cardiovascular score (defined as presence of ≥50% of the risk factors including arterial hypertension, diabetes, dyslipidaemia, increased body-mass index, physical inactivity and smoking) was 17%, as compared with 4% in those with a low risk score. The increased incidence has been postulated to be secondary due to endothelial damage provoked by CGVHD and possibly decrease in microvessels. Also, there is an increase in the incidence of cardiovascular risk factors in this patient population.
History of cardiac and cardiovascular risk factors since previous visit should be assessed and clinical examinations conducted.
Life style modification (smoking, weight loss etc) should be recommended.
Cardiovascular risk factors (HT, DM, Lipids) should be assessed yearly and therapy optimized
Consider ECHO/ECG at 1year for patients who have received TBI/anthracyclines and base subsequent follow-up on results/symptoms
Liver & Renal
A number of factors can cause derangement of liver function including but not limited to medication, CGVHD, viral hepatitis and iron overload. The management of CGVHD is available in the relevant guideline.
Monitor liver function tests at least yearly
Ferritin assessment should be done at 1year post-transplant. Monitoring should continue in patients with ongoing RBC transfusions, Hepatitis C infection or elevated LFTs. Spontaneous reductions in ferritin do occur over several years post transplant. Iron overload should be confirmed with Trasferrin saturation. Iron overload can be managed with venesections. The role of chelation is unclear at present. No formal guidelines are available on level at which venesection should be commenced.
HBsAg, HBcAg, anti-HBsAb, Hepatitis C PCR should be done at 100 days and 1 year post-transplant. In patients with known Hepatitis B or C monitoring should continue with viral load assays and therapy as recommended by hepatologist should be instituted. Patients with a history of Hepatitis B infection should commence Lamivudine 100mg/day at commencement of chemotherapy and continue for 6 months post or until they are off all immunosuppression.
Liver biopsy at 8-10 years post SCT should be considered in Hepatitis C positive patients due to the increased risk of cirrhosis.
Chronic renal dysfunction post transplant is seen quite frequently (27% at 10 years, 3% with severe renal disease i.e., GFR< 30 mls/min/1.73 m2) several years post transplant and can be related to the disease process, nephrotoxins (prior chemotherapy/medication e.g. platinum compounds, carmustine, ifosfamide, anti-infectious agents, immunosuppressive drugs), sepsis, age at transplant, female gender, reduced GFR pre-transplant and hypertension. Management includes discontinuation of the offending nephrotoxic agent, hydration, treatment of sepsis, management of HT and referral to a nephrologist. Nephrotic syndrome can be seen as a manifestation of CGVHD usually responding within 12 weeks to treatment with corticosteroids and cyclosporine (the exception being that seen after NMAs which are quite refractory to therapy). Radiation induced nephritis can be seen up to 6 months post transplant. Substantial hemorrhagic cystitis can subsequently lead to bladder wall scarring and contraction.
Regular assessments of renal function should be performed (6-12 monthly BUN, creatinine).
Yearly 24 hour urine protein estimations should be considered in patients with CGVHD. Yearly GFR estimated in patients with abnormal renal function.
Renal dysfunction should be appropriately investigated (medications, ultrasound, biopsy) and nephrology consult considered.
Subclinical compensated hypothyroidism with elevated TSH and normal serum free T4 occurs in 7-15% of patients in the 1st year following allo-HSCT. Replacement therapy at this point is not mandated but a close follow-up (3 monthly TFT) is warranted. Median time to development of overt hypothyroidism is 4 years in up to 11-15% of patients, particularly in those who have received TBI or head and neck radiation. These patients should be commenced on therapy. Radiation induced and auto-immune thyroiditis can occur.
Radiation to the head and neck results in a dose related increase in malignancy risk. The relative risk of thyroid cancer is increased 3 fold compared to an age and sex matched population. The other factors increasing malignancy risk include female sex, age at HSCT and CGVHD.
Yearly TSH, free T4 assessments and management based on results. Referral to endocrinology for abnormal results is advisable.
High index of suspicion to be maintained to diagnose thyroid malignancy
Gonadal dysfunction is very common post transplant. The risk of hypogonadism is related to age at transplant (older age associated with greater risk), gender (females >males) and pre-transplant conditioning therapy (TBI, busulfan>single agent melphalan, cyclophosphamide). Men appear to mostly retain normal testosterone levels although infertility is almost universal (recovery seen in 10-15% over several years). In women the risk of hypergonadotrophic hypogonadism is very high and almost universal with TBI or Busulfan conditioning with recovery of ovarian tissue occurring in 5-10% of women years later. The chances of recovery are greater (50%) in patients receiving BEAM chemotherapy. Prepubertal girls have a significantly higher chance of recovery. However if puberty is not achieved by 12-13 years then referral to a specialist is warranted.
Testosterone assessments should be done in men with symptoms of erectile dysfunction or loss of libido. Alternatively it could be routinely assessed at 3 months, 1 year.
In terms of fertility pre-chemotherapy sperm banking with subsequent assisted fertility techniques should be considered.
Women should undergo yearly clinical and endocrinological assessments (FSH, LH, estrogen assays). Patients should be referred to endocrinology for HRT to help maintain libido, sexual function, retain bone density and reduce the risk of cardiovascular and lipid disorders.
Yearly gynaecological assessments should be done in women with ongoing GVHD as vaginitis, strictures and synechiae formation can be ongoing issues.
In terms of fertility embryo cryopreservation prior to receipt of chemotherapy is the only technique proven to be beneficial. However, as this requires a delay in treatment of several weeks and a willing partner, it may not be suitable in a number of patients.
Chronic steroid use can lead to reversible suppression of pituitary/adrenal axis. Slow terminal tapering of corticosteroids is recommended with formal assessment of adrenal function if patients develop symptoms of adrenal insufficiency on steroid withdrawal. Stress dose steroids should be given in times of acute illness.
Secondary hyperglycaemia is often seen due to steroid therapy of GVHD and patients should be investigated and managed appropriately, ideally with referral to endocrinology.
Osteopenia is a systemic condition characterized by reduced bone mass and increased susceptibility to bone fracture. Osteoporosis is associated with a more significant reduction in bone mass and a greater tendency to bone fracture. The risk of developing either can be related to dose and duration of steroid, cyclosporine/FK 506 use, TBI, inactivity and in women who are hypoestrogenic. As per WHO criteria nearly 50% of all patients have reduced bone density with 10% having osteoporosis 12-18 months post transplant. Nontraumatic stress fractures occur in 10% of patients.
Yearly dual photon densimetry in the presence of abnormalities or if the patient is on steroid therapy is recommended.
Therapy with Calcium, Vitamin D, HRT in women, exercise, and judicious use of corticosteroids can be useful.
Bisphosphonate therapy (Fosamax 70mg weekly) in osteoporosis can lead to improvement in bone density in the lumbar spine but the benefit to the femoral neck and hence fracture reduction is less clear. Please also assess thyroid hormone function in patients with reduced bone density.
Avascular Necrosis of Bone
The risk of developing avascular necrosis is between 4-10% at median time of 18 months post-transplant. The risk factors include corticosteroid therapy, fractionated TBI>12GY. Patients receiving transplants for ALL and SAA appear to be at a greater risk than those with other disease sub-types. Pain is often the presenting feature with 80% of AVNs occurring at the hip joint and 10% at the knees. AVN of the wrist and ankle bones can also occur. X-ray changes usually occur late. MRI of the relevant joint is the investigation of choice. Joint replacement is warranted in the majority (80%) of patients. Long term follow up of the prostheses is needed in younger patients.
Muscles and Fascia
Corticosteroid induced muscle weakness is often seen in patients on therapy for GVHD. This preferentially affects the proximal muscles resulting in myalgia and weakness which is often slow to resolve on cessation of steroid therapy. Alternate day dosing can result in reduction in the incidence of myopathy.
CGVHD can also be associated with polymyositis with severe proximal muscle weakness, myalgia, arthralgia and results in elevated CK, aldolase. The diagnosis can be confirmed with a muscle biopsy and treated with steroid therapy. CGVHD can also cause fasciitis and disabling sclerodermatous changes.
Regular clinical evaluation at clinic visits.
Physiotherapy offered for patients on long term corticosteroid therapy, fasciitis, sclerodermatous changes.
The incidence of secondary malignancy is increased 2-3 fold post transplant compared to gender, age and region matched population. The cumulative risk is 2.5% at 10 years and 8.8% at 20 years. The transplant related risk factors include radiotherapy, length and severity of immunosuppression and CGVHD. The risk increases with time after transplant especially for radiation induced malignancies.
The incidence of PTLDs is 1% at 10 years with the majority being EBV related and occurring within 6 months post transplant. The risk is increased with greater recipient-donor HLA disparity, T-depletion and GVHD.
The risk factors for Squamous cell carcinoma (SCC) include male sex, CGVHD and immunosupression. There is a 5 fold increase in SCC in patients with CGVHD at 1-4 years post-transplant with the risk remaining high for several years. The risk of cutaneous malignancy risk is increased by exposure to radiotherapy and photosensitive effects of medication.
Non-SCC (breast, thyroid, brain, bone, CNS, connective tissue, melanoma) risk is linked to radiotherapy, age at which radiotherapy was received and risk increases with increasing time from transplant. Patients who have been irradiated have a 10 fold higher risk compared to non-irradiated patients for up to 30 years post transplant. There is a 6 fold increase in breast malignancy in patients receiving local radiotherapy/TBI prior to transplant. The risk particularly increased after 10 years post-transplant. The risk is significantly increased when the radiotherapy was received prior to 18 years of age. The relative risk of developing thyroid malignancy is 6 times for patients post transplant. The risk increase with younger age, radiation exposure, female sex and CGVHD. The risk factors for developing CNS malignancy (RR almost 6) is younger age at transplant, radiotherapy and receipt of anthracyclines and alkylators. Risk for developing Melanomas (RR3.5) is radiation exposure, T-cell depletion and short (<1 year) latency period. High index of suspicion needs to be maintained for the diagnosis of all of the above as routine screening is not available for most.
Patients should be reminded to perform regular self breast and skin examinations.
Patients should be advised to stop smoking.
Patients should be advised to avoid excessive UV exposure and use sun-screen regularly.
Mammography should commence at 40 years (for patients without a family history or who have not received mantle radiotherapy). In patients with Hodgkins Lymphoma or who have received local radiotherapy it should commence at 10 years post therapy or at 40 years whichever is earlier.
Pap smears should be done every 1-2 years as per protocol.
Yearly dental exam for oral malignancy should be done.
Yearly gynaecological exam is recommended.
Colorectal cancer screening in the form of yearly stool FOB should begin at 50 years as per BCCA protocol.
Digital rectal examination (DRE) either routinely or in men with urinary symptoms should be considered in patients between 50-70 years. If DRE is abnormal perform PSA and refer to urologist if PSA >4.
Michelle L. Griffith et al. Dyslipidaemia after allogeneic hematopoietic stem cell transplantation: evaluation and management. Blood 2010; 116:1197-1204.
J. Douglas Rizzo et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009; 113; 1175-1183.
Andre Tichelli et al. Late Pulmonary, Cardiovascular, and Renal Complications after Hematopoietic Stem Cell Transplantation and Recommended Screening Practices. Hematology (ASH education book) 2008: 125-133.
Andre Tichelli et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93(8): 1203-1210.
JD Rizzo et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow transplant research, and the American society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplantation 2006; 37:249-261.
Gerard Socie et al. Nonmalignant late effects after stem cell transplantation. Blood 2003; 101: 3373-85.