MODULE: II BMT COMPLICATIONS AND SIDE EFFECTS

LEARNING OBJECTIVES:

At completion of this module, the learners will be able to

• distinguish between early and late complications of BMT
• identify and manage common side effects and complications of BMT

BMT COMPLICATIONS AND SIDE EEFECTS:

Patients who undergo a Blood and Marrow Transplant  are subject to many complications during and post-transplant. These can occur in the short-term and for many years following transplant.

BMT can lead to increased morbidity and mortality, significantly affecting quality of life for patients.

EARLY COMPLICATIONS

Complications typically occur from the time after starting the conditioning regimen and up to 12 months post-transplant.

Pre-engraftment Complications:

Pre-engraftment complications (up to approximately Day+30)complications typically associated with conditioning therapy include:

💢 Cytopenia

💢Oral mucositis

💢Febrile neutropenia

💢Sinusoidal obstruction syndrome/Veno-occlusive disease.

Post-engraftment complications: 

Post-engraftment complications (after Day +30) may include acute GVHD and infections with less common complications such as transplant-associated microangiopathy (TAM) and reactivation of cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV).

Many of these complications can be minimized, and the multidisciplinary team play an important role in educating the patient and identifying complications as they arise.

Risk of infection:

Infection is the leading cause of morbidity and mortality following BMT, and patients are at an increased risk of infection for up to a year post-transplant or while on immunosuppressant medication. Many factors influence the risk of infection and are often interrelated, with some listed below:

Patient Factors:

Transplant related Factors:

Degree of exposure of microorganisms:

Implementation of infection control measures are important to reduce the risk of infection.

Graft Failure

INFECTIONS

Blood and marrow transplant recipients are at an increased risk of infections at different phases after their transplant.

Immediate management of neutropenic fever:

Definition:

Temperature of 38.3°C or greater (or a temperature of 38.0°C or greater sustained over a one-hour period) and neutrophil count of less than 0.5 x 109 cells/L, or less than 1.0 x 109 cells/L and predicted to fall to lower than 0.5 x 109 cells/L.

Symptoms and signs:

Patients with a temperature of 38.0°C or higher and neutrophil count of less than 0.5 x 109 cells/L, or less than 1.0 x 109 cells/L and predicted to fall to lower than 0.5 x 109 cells/L.

Other symptoms and signs may include:

💡Tachycardia

💡 Tachypnoea 

💡 Hypotension

💡 Rigors

💡 Diaphoresis

💡 Altered mental status

💡 Decreased capillary refill, cyanosis or mottling

💡Dysuria, decreased or increased urine output

Signs and symptoms specific to an infectious source (e.g. pain or purulent exudate from wound or catheter site, or cough, dyspnea, hypoxia)

Risk assessment:

MASCC index score:

Multinational Association for Supportive Care in Cancer risk index as the preferred risk assessment tool for patients experiencing medical complications from neutropenic fever which has been validated in patients with solid tumours and patients with haematological malignancy.

• The maximum value in this system is 26. A score of > 21 predicts a < 6% risk for severe complications and a very low mortality (< 1%) in neutropenic febrile patients.
• Previous fungal infection: means demonstrated fungal infection or empirically treated suspected fungal infection
• Outpatient status: means onset of fever as an outpatient.

 Initial Management:

Management:

All patients presenting with fever following anticancer therapy should be managed as neutropenic, and receive empiric antibiotics . Management may be subsequently modified if neutrophil count and function are found to be adequate.

• patients with features of systemic compromise such as hypotension, hypoxia, confusion, major organ dysfunction should receive antibiotics within 30 minutes of presentation.
• clinically stable patients should receive antibiotics within 1 hour of presentation after appropriate cultures have been taken.
• administration of antibiotics should not be delayed by the conduct of laboratory or radiological investigation.

Step 1: Perform septic workup

Step 2: Commence empiric antibiotic therapy 

For further reading:

https://www.eviq.org.au/clinical-resources/oncological-emergencies/123-immediate-management-of-neutropenic-fever.

Risk factors for opportunistic infections during each phase following allogeneic BMT:

Autologous BMT recipients are susceptible to similar infections during the pre and post-engraftment periods while awaiting full count recovery.

Typical timing of infections among autologous haematopoietic cell recipients receiving antimicrobial prophylaxis.

Several infections, namely viral infections (herpes simplex virus (HSV), varicella zoster virus (VZV) or cytomegalovirus (CMV)) and EBV can present due to reactivation of asymptomatic latent infections. The risk for CMV and EBV reactivation/infection is influenced by both the donor and recipient CMV serostatus.

INFECTION PROPHYLAXIS:

Patients at high risk of infection should receive pneumocystis jiroveci pneumonia (PJP), antiviral and antifungal prophylaxis medication to help reduce the risk of developing these infections.

Pneumocystis Jirovecii (carinii) pneumonia Prophylaxis 

Pneumocystis jirovecii pneumonia  is a potentially life-threatening infection that occurs in severely immunocompromised patients such as haematopoietic cell transplant patients, solid-organ transplant patients, or patients on chronic immunosuppressive therapy.

👉It is associated with high morbidity and mortality rates in patients (30-60%) following treatment for haematological malignancies or after haematopoietic stem cell transplant.

👉In allogeneic  recipients without adequate prophylaxis, PJP has been noted to occur with an incidence of approximately 5-16% and occurred at a median of 9 weeks after transplant.

👉Appropriate and adequate prophylaxis for all moderate- to high-risk patients is a key strategy for improving outcomes as most cases of PJP occur in patients either not receiving adequate prophylaxis or not complying with their prescribed prophylaxis.

This implies both the early recognition of patients at risk as well as using the drug of choice, including adequate dose, route of administration and duration of prophylaxis.

Risk factors:

There are well-defined patients who are at risk of PJP due to several factors including

💿Underlying diseases (including relapsed disease) and  associated specific treatments

💿Heavily pre-treated patients e.g. multiple lines of chemotherapy or patients with lymphoproliferative disorders including chronic lymphocytic leukaemia,  non-Hodgkin lymphoma  and multiple myeloma.

💿Presence of T-cell defects or low lymphocyte count

💿Pre-existing respiratory diseases such as chronic obstructive pulmonary disease and asthma

💿Use of specific therapies such as corticosteroids, chemotherapy agents and monoclonal antibodies.

PJP prophylaxis recommendations:

High risk prophylaxis is recommended for Allogeneic haematopoietic stem cell transplant (HSCT) From engraftment, for at least 6 months post-transplant and while immunosuppressive treatment is ongoing.

Intermediate risk - consider prophylaxis  for engraftment patients , for 3 to 6 months post-transplant.

Herpes simplex virus  and Varicella zoster virus Prophylaxis 

⌛Morbidity and mortality in patients with malignancies are increased by viral infections.

⌛Most viral infections in patients with haematologic malignancies, solid tumours or undergoing BMT result from reactivation of asymptomatic latent infections, predominantly of herpes viruses, such as herpes simplex virus (HSV) and varicella zoster virus (VZV).

Risk factors:

⇰ The risk of viral reactivation is determined by baseline serostatus, commonly occurs in the setting of mucositis and neutropenia, whereas VZV is common in therapies that are T cell depleting. 

⇰ Patients at highest risk of reactivation of both HSV and VZV are allogeneic stem cell transplant recipients who have received T cell depleting conditioning regimens and who remain on long term immunosuppression for graft versus host disease. 

⇰ For allogeneic transplant recipients, the pre-engraftment period during which mucositis occurs is the time of heightened disease risk. 

⇰ HSV prophylaxis may be extended beyond this time in patients who experience frequent HSV recurrences

Herpes simplex virus (HSV):

👤 Reactivation and infections with HSV occur in 60 to 80% of BMT recipients and in acute leukaemia patients with no primary HSV prophylaxis undergoing induction or re-induction therapy who are seropositive for HSV. 

👤Once a patient has had a HSV reactivation infection requiring treatment, it is recommended that HSV prophylaxis be administered during all future active antineoplastic treatment and episodes of neutropenia induced by treatment.

Varicella zoster virus (VZV):

💮The principle risk factor for VZV is impaired cellular immunity. In allogeneic BMT recipients with a history of VZV infection, about 30% without antiviral prophylaxis have VZV disease reactivation. 

💮 VZV seropositive patients pre transplant should receive prophylaxis for at least 12 months post allogeneic transplant, as this has been shown to significantly decrease the incidence of VZV disease.

💮Continuation of prophylaxis beyond this time is recommended in patients with chronic graft versus host disease (cGvHD) who continue on immunosuppression. 

💮Prophylaxis may be discontinued when CD4 counts are greater than 200 cells/microL and immunosuppressive therapy ceased.

Management:

Allogeneic BMT(High risk category):

HSV prophylaxis: during active therapy including periods of neutropenia and/or mucositis for at least 30 days after BMT.

VZV prophylaxis: consider for at least 1 year after BMT.Continue HSV and VZV prophylaxis for longer if there is ongoing immunosuppression. 

GvHD requiring steroid treatment:

HSV and/or VZV prophylaxis: during periods of neutropenia and possibly longer.

Autologous BMT:

HSV prophylaxis: during active therapy and at least 30 days after transplant.

VZV prophylaxis: consider for at least 6 to 12 months post transplant.

Antifungal prophylaxis

Antifungal prophylaxis should not be used routinely in all patients with neutropenia. The rationale for antifungal prophylaxis is to prevent fungal infections in a targeted group of high risk patients, especially those with AML, longer durations of neutropenia or with graft versus host disease (GVHD) post allogeneic blood or marrow transplant.

Allogeneic HSCT with expected neutropenia > 14 days:

• High risk
• Mould-active prophylaxis

Allogeneic HSCT with expected neutropenia< 14 days & Selected autologous HSCT :

• Low risk
• Anti-Candida prophylaxis

SINUSOIDAL OBSTRUCTION SYNDROME

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease is a potentially fatal complication that can occur following BMT.

📌Typically occurs within the first 30 days post-BMT, although it can occur later. 

📌SOS/VOD is caused by toxic injury to the veins and blood vessels inside the liver from the conditioning therapy for BMT.

📌It manifests as hepatomegaly (enlarged liver) and/or right upper quadrant pain, jaundice and fluid retention.

📌This toxic injury causes a cascade of events which, if left untreated can lead to hepatocellular necrosis, liver failure, multi-organ dysfunction and death. 

Risk factors:

High-risk patients can be given prophylaxis medications to reduce the risk of developing SOS.

Signs and symptoms :

📜Early diagnosis of SOS/VOD is important so that treatment can be initiated. 

📜Nursing assessments and interventions play a crucial role in identifying patients as high risk and detecting the symptoms of SOS/VOD. 

📜Assessment should be conducted and documented at baseline and then throughout treatment in order to identify any changes.

Nursing assessment should include:

💊 Risk assessment for SOS/VOD prior to commencing therapy

💊 Baseline and then twice daily weight

💊 Strict fluid balance monitoring including input, output and balance.

💊 Baseline measurement of abdominal girth followed by daily measurements if any suspicion of SOS/VOD, to detect fluid retention and ascites. Ensure the same area is measured and the area is marked. 

💊 Daily urinalysis

💊 Skin integrity for signs of breakdown and jaundice

💊 Abdomen for right upper quadrant pain and distension signs of bleeding

💊 Baseline blood tests and then daily or as clinically indicated: EUC, LFT, bilirubin, FBC, coagulation profile and drug levels for hepatotoxic and nephrotoxic drugs

💊 Respiratory assessment to detect pulmonary oedema regular vital signs, including blood pressure.

Diagnosis of SOS 

Several clinical criteria guidelines which are primarily based on clinical factors of jaundice, weight gain, hepatomegaly and ascites. Guidelines include Seattle, modified Seattle, Baltimore and the EBMT criteria.

New EBMT criteria for severity grading of suspected SOS/VOD in adults:

Mild stage:

• Meets diagnostic criteria
• Requires no specific intervention
• Self limiting.

Moderate stage:

• Evidence of liver injury
• Requires active treatment for excess fluid and pain management
• Resolves in most patients.

Severe stage:

• Persistent hepatic dysfunction with severe hyperbilirubinemia
• Does not resolve within 100 days post BMT
• Associated with multi organ failure
• Can lead to:renal insufficiency, confusion or disorientation,cardiac failure, bleeding requiring transfusion support.
• untreated SOS/VOD may be associated with a mortality rate of over 80% 

Management:

Prevention:

Preventive measures for SOS/VOD include:

1. Pre-BMT risk assessment
2. Reversal of SOS/VOD risk factors where possible
3. Pharmacoprophylaxis

Risk assessment:

Most low-risk patients do not require specific prophylaxis for SOS/VOD.

Patients at high risk of SOS/VOD include those who are receiving an allogeneic stem cell transplant & have at least one of the following additional risk factors for SOS/VOD.

📌Pre-existing liver disease 

📌Prior autologous or allogeneic transplant

📌Allogeneic transplant for leukaemia beyond second relapse

📌Prior treatment with gemtuzumab ozogamicin

📌Primary hemophagocytic, lymphohistiocytosis adrenoleukodystrophy or osteopetrosis

📌Haemoglobinopathy 

📌Prior abdominal irradiation

📌Hepatitis B or C positive (not Ab positive),

📌Pre-existing hepatic fibrosis or iron overload

📌GVHD prophylaxis with sirolimus and tacrolimus

Treatment:

Supportive care:

It is vitally important to provide adequate supportive care for patients with SOS/VOD. This includes:

💉adequate analgesia,

💉maintenance of intravascular volume

💉avoidance of nephrotoxins

💉diuretics and salt restriction

💉dialysis

💉respiratory support, and

💉drainage of ascites and pleural effusions.

Pharmacoprophylaxis:

Ursodeoxycholic acid prophylaxis: recommended dosage of 12 mg per kg per day orally given in 2 to 4 divided doses

Heparin: low molecular weight heparins may be useful for prevention of venous thromboembolic events no evidence that heparin have role in preventing SOS.

Defibrotide   is a sodium salt of complex single-stranded oligodeoxyribonucleotides  for the treatment of severe hepatic SOS/VOD in HSCT therapy. Recommended dose is 6.25 mg/kg intravenously four times a day.

ORAL MUCOSITIS

🔅Describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation

🔅 Typically manifests as erythema or ulcerations.

🔅 May be exacerbated by local factors.

🔅 Lead to reduced nutritional intake, significant weight loss and impact a patient’s quality of life. 

🔅 Due to the mucosal injury, oral mucositis is the perfect environment for infections to develop, especially in immunocompromised patients.

Risk factors:

Oral mucositis is commonly graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)

Signs and symptoms :

Management:

💉Treatment of mucositis is aimed at symptom control and reducing infection risk. 

💉It may include analgesia for pain relief, good mouth and dental hygiene with regular mouthwashes.

💉Modification of diet with softer foods or liquids and avoiding acidic, salty, spicy or dry foods may also assist with symptoms. 

💉The patient may have their medications switched to intravenous or liquid formulations if they have difficulty swallowing. 

💉Mucositis puts the patient at a high risk of developing an infection so, antibacterial, antiviral and antifungal prophylaxis should be started.

 Nursing Management

💊 Frequent Oral assessments

💊 Continuous Intake and output monitoring

💊 Pain and Symptoms management as appropriate 

💊 Frequent mouth care

💊 Health education 

For Further reading : Symptom management course; Oral mucositis 

                      GRAFT VERSUS HOST DISEASE

Graft versus host disease (GVHD) is a common complication of allogeneic BMT and can cause significant morbidity and mortality in transplant recipients.

GVHD occurs when immune cells transplanted from a donor (the graft) recognise the recipient (the host) as foreign and initiate an immune response against healthy host tissue.

GVHD may be classified as:

1. Acute GVHD
2. Chronic GVHD

Acute GVHD:

Typically occurring within the first 100 days post allogeneic transplant primarily affecting the skin, gastrointestinal tract (GIT) and liver. May also occur beyond the first 100 days.

Incidence:

•  20 to 50% of allogeneic HSCT recipients and is dependent on a number of factors.
•  Pre-transplant co-morbidities appear to increase the incidence and severity of acute GVHD. 

Risk factors:

📛 Degree of HLA disparity

📛Donor and recipient gender disparity (particularly a multiparous female donor with a male recipient)  

📛 Intensity of pre-transplant conditioning regimen

📛Source of graft (peripheral blood is higher risk than bone marrow, while umbilical cord blood is the lowest risk)

📛 Type and status of underlying disease

📛 Increasing age of the recipient

Magic Staging Chart to grade GVHD:

• An overall grade is assigned based on the individual stages of the organs involved (skin disease plus liver and/or gastrointestinal). 
• The skin is usually the first organ involved in acute GVHD and the most commonly affected organ

Overall clinical grade (based upon most severe target organ involvement):

Management:

💉Treatment of acute GVHD should be based on clinical symptoms and depends on the grade of symptoms.

💉Standard treatment involves restarting or continuing the prophylaxis immunosuppressive treatment, supportive care and systemic corticosteroids if symptoms are Grade 2 or above for aGVHD.

💉 Acute GVHD can cause significant morbidity and mortality especially if it is untreated or not adequately controlled.

LATE COMPLICATIONS:

Late complications normally occur beyond a year post-transplant and can affect a single organ or several. They include:

These can cause a reduction in quality of life (QOL) as well as resulting in significant morbidity and mortality. QOL is important for BMT patients and includes the patient’s perception of function and independence, financial capacity, psychological wellbeing and social and sexual fulfilment.

Chronic graft versus host disease:

Chronic GVHD is the leading cause of non-relapse mortality after allogeneic BMT and can have a significant impact on the recipient's QOL.

Chronic GVHD affects multiple organ systems and may have clinical symptoms like autoimmune disorders.

Incidence:

The incidence of cGVHD is approximately 40% of allogeneic HSCT recipients and is dependent on a number of factor.

Risk factors:

Common risk factors for the development of cGVHD include 

💢 Higher degree of HLA mismatching

💢 Donor and recipient gender disparity (particularly a multiparous female donor with a male recipient)  

💢 Intensity of pre-transplant conditioning regimen

💢 Source of graft (peripheral blood is higher risk than bone marrow, while umbilical cord blood is the lowest risk)

💢 Prior aGVHD

💢 Increasing age of the donor or recipient

💢 Cytomegalovirus serostatus of donor or recipient

💢 Epstein-Barr virus seropositivity of donor 

💢 Previous splenectomy

The presence of more than one risk factor increases the risk of developing cGVHD.

Management:

👉Mild chronic GVHD may respond well to topical therapies, systemic treatment is usually indicated in moderate to severe chronic GVHD.

👉Corticosteroids remain the mainstay of first-line treatment, either alone or in combination with other agents

👉Appropriate antimicrobial prophylaxis

👉Protection from viral and fungal infections.

👉Patients should be educated as to the risk of sepsis and advised to seek medical attention at an early stage 

Nursing management for GVHD patients:

💉Nursing care of patients with skin GVHD should be determined by the degree of severity and percentage of body surface area of the rash with specific considerations made regarding hygiene, topical and systemic treatment, infection prevention and relief of symptoms. 

💉Nursing care of patients with GI GVHD should include accurate recording of intake and output, obtaining cultures, monitoring for fluid and electrolyte imbalances, nutrition assessments, and managing side effects of treatments. 

💉Management of complications of GVHD treatments, namely the effects of prolonged exposure to corticosteroids, requires experts from many disciplines to provide comprehensive care.

REFERENCES:

1. Worth LJ, Lingaratnam S, Taylor A et al. 2011. "Use of risk stratification to guide ambulatory management of neutropenic fever". Intern Med J. Jan;41(1b):82
2. https://www.eviq.org.au/clinical-resources/side-effect-and-toxicity-management/prophylaxis-and-treatment/220-pneumocystis-jirovecii-pneumonia-pjp
3. http://www.bccancer.bc.ca/healthprofessionals/clinical-resources/nursing/symptom-management
4. https://my.clevelandclinic.org/health/diseases/10255-graft-vs-host-disease-an-overview-in-bone-marrow-transplant
5. https://education.nccn.org/node/87857#group-tabs-node-course-default