# **<IP_ADDRESS> Initial Treatment of Acute GvHD**

Despite all of the recent advances in the understanding and treatment of GvHD, steroids remain the best and frst-line therapy. The mechanism of action of steroids for aGvHD is unclear but most likely relates to the suppression of cytokines such as prevention of synthesis of interleukin-1 by antigen-presenting cells and lymphocyte activities (Greinix 2008).

Steroids are effective treatment in approximately 40% of people, with 30% having a longlasting response and a probability of survival at 1 year of 53%, with the skin being the most responsive at 40% with a response rate of 15–35% for those with liver involvement and 45% in GI. The lower the grade of aGvHD and the fewer organs affected, the better the response to steroids (Greinix 2008). Mohty et al. (2020) suggest that corticosteroid refractoriness occurs after 3 days of treatment with 2 mg/kg of methylprednisolone or no improvement after 7 days or progression to a new organ or recurrence during or after a taper.

# **12.4.6 Second-Line Therapies for aGvHD**

Once frst-line therapy has failed, there are multiple options such as the following:

**Further second- and third-line therapies are discussed below.**

Often, at least two second-line therapies will be used before moving on to a third-line treatment

# **12.4.7 Nursing Care Considerations for aGvHD**

In addition to systemic treatments, there are often topical management techniques as well as general care that nurses can offer to patients that will lead to relief from frequently troublesome symptoms of aGvHD. Below are a few pointers for consideration when caring for patients with aGvHD affecting their skin or gastrointestinal system.

# **12.4.8 Cutaneous**

Basic Skin Care

The key issue with patients who have cutaneous aGvHD is to maintain the integrity of the skin, and the following suggestions are key factors in doing this: Regular application of preferred emollients (e.g. QV, Hydromol, Diprobase). Advise application of a thin layer (enough to make the skin appear 'shiny'), in the direction of hair growth. Try not to 'rub' as this will increase any pain or itch. As guidance for amounts, it would be suggested that an adult would use on average 500 g/week and a child, 250 g/week. Use of bath/shower preparations (e.g. Dermol, QV, Hydromol) rather than soap, use of high SPF sunscreen (e.g. SunSense SPF 50+) and localised use of topical antipruritic agents (e.g. Dermacool 0.5–1%) if required. If the skin is still faky, the patient can be advised to apply lipids (e.g. coconut oil) in addition to the emollients. Equally good-quality creams containing aloe vera gel are often very soothing (note: do not use aloe vera gel alone as this will dry the skin).Topical immunomodulation (e.g. steroid/ tacrolimus cream) should be prescribed as per local protocol; however, there are a few general rules about the use of topical steroids: think about the potency/duration of the product used in relation to the age of the patient and the area of the body it is being applied to. Always apply thinly – once daily is usually enough. Think about whether the skin is weepy, when a cream/lotion is appropriate or dry/scaly, in which case, an ointment may be preferable. Steroids should be applied at a different time to emollients (at least a 30-min gap between) to ensure effective absorption, and remember that broken skin is a contraindication to use.

Topical Management of Specifc Stages of Cutaneous aGvHD/Maculopapular Rash (Pruritic/Painful).

Emollients are key to management at all stages. With sensitive, irritated skin, an emollient that is too thick will just not be used, whereas one that is too 'thin' will be perceived as ineffective.

*Topical steroids*: each hospital will have its own protocol for prescription of topical steroids, and this should be adhered to.

*Menthol cream* (0.5–1%, e.g. Dermacool) can be useful for management of painful and pruritic skin but must be used with care as they can make the patient feel very cold with widespread use and so are better used only on focal areas with extreme itchiness/pain.

*Medical-grade silk clothing* (e.g. Dermasilk, Espere Healthcare): it is important to explore the holistic care of the patient. Many clothing materials can cause irritation – even natural materials such as cotton. If there are widespread areas of the torso affected, it is worth suggesting the use of medical-grade silk as this is manufactured to cause minimal irritation and, in some countries, can be prescribed. If this is not available, clothing made from bamboo can be suggested as an alternative.

Your hospital may have a protocol specifcally for patients with bullous desquamation, and treatment would be similar to those people who suffer severe burns. An example would be to irrigate with sterile water, apply an antibacterial cream (e.g. Flamazine) and protect the area from the air to minimise pain and risk of infection. The cream can be applied directly to sterile theatre gauze and wrapped around the patient to prevent trauma.

# **12.4.9 Gastrointestinal**

Patients who develop GI symptoms affecting upper, lower GI as well as their liver may have multiple problems: reduced appetite, bloating and early satiety with nausea and frequent retching or vomiting and abdominal discomfort related to liver pain or as a consequence of increased bowel activity. Nurses should ensure that stool samples are sent to exclude infective components. Once ruled out and treatment started, nursing care may aid in a more rapid recovery and maintenance of weight. Ensuring an adequate oral input with high-calorie supplements and strict fuid balance are of primary importance. Options for enteral feeding or intravenous total parental nutrition in the short term to rest the bowel need to be kept in mind if the above actions are not suffcient, with procedures such as a radiologically inserted gastrostomy (RIG) used for long-term issues. Those with upper GI disturbance, nausea and vomiting need advice on small and frequent meals as well as supplements. For itch associated with jaundice, topical or oral antihistamines can be used. Patients who develop grade IV GI aGvHD will beneft from use of fexi-seal faecal collection devices if they have high faecal output.

# **12.5 Chronic Graft-Versus-Host Disease**

Chronic GvHD is a serious and life-threatening condition and is a major cause of late morbidity and mortality after allogeneic haematopoietic cell transplantation occurring in 30–70% of patients (Miklos et al. 2017). Chronic GvHD prevalence and severity has increased with the increasing use of HSCT for treatment of olderage patients, the widespread use of mobilised blood cells instead of marrow for grafting and improvements in survival during the frst several months after allograft. Preventing cGvHD remains challenging (Inamoto et al. 2021). Typically occurring in the frst 12 months, it can be seen as early as 2 months and as late at 7 years at onset, although onset at >1 year from transplant occurs in <10% of cases (Flowers and Martin 2015). The risk of infection due to the delay in immune reconstitution and use of immunosuppressive therapies to treat cGvHD remains, however, the leading cause for death in this group of patients (Couriel et al. 2006). Supportive care advances have decreased the morbidity, but survival has not changed signifcantly since the 1980s. Patients with cGvHD have a 5-year survival of 40–70%, with only 50% being able to stop immunosuppression at 5 years, with 10% needing treatment beyond this time point. The other 40% either die or develop a further malignancy before cGvHD resolves (Martin et al. 2006).

# **12.6 Chronic GvHD Grading**

Historically if patients developed signs and symptoms of GvHD after day 100, this was labelled as chronic, even if clinically the patient appeared to have acute features. The criteria for the diagnosis of cGvHD are based on pathological changes occurring in the skin, lung, mucous membranes, gastrointestinal tract and musculoskeletal system (Greinix 2008).

Chronic GvHD includes classic cGvHD, presenting with manifestations that can be ascribed only to cGvHD; however, it also includes an overlap syndrome, which has diagnostic or distinctive cGvHD manifestations together with features typical of aGvHD (Vigorito et al. 2009).

The National Institute of Health (NIH) described a reliable and reproducible scoring scheme to evaluate the individual organ severity of four grades with scores 0–3:

The clinical score describes how affected the patient is by their inability to perform activities of daily living. This evaluation covers the involvement of individual organs and sites. For example, if they are unable to work due to ocular loss, they would be scored as 3, severe (Carpenter 2011). The scoring should be undertaken initially at 3 months post-transplant and at 3 monthly intervals and more frequently if new signs or symptoms are found or there is a change in treatment.

The NIH in 2014 provided a Diagnosis and Staging Working Group Report. A revision was made to the diagnostic criteria for involvement of the mouth, eyes, genitalia and lungs. Schirmer's test was removed, and an ophthalmology review is recommended. Also, if an unequivocal explanation can be made for a specifc abnormality that is not GvHD, then that organ should be regarded as not affected by GvHD (Jagasia et al. 2015). Earlier recognition is important, and the NIH published a series of papers in 2021 (Inamoto et al. 2021) to describe features that did not yet meet the NIH 2014 criteria. This was to enable less experienced practitioners the ability to recognise and make appropriate referrals. There were also descriptions of the use of electronic tools such as the eGvHD app to aid in earlier diagnosis (Kitko et al. 2021).

Chronic GvHD commonly occurs in patients who have previously had aGvHD although it is not simply a case of evolution from one to another. Chronic GvHD usually occurs within 3 years of allograft and is a disease of deregulated immunity with protean manifestations that mimic autoimmune disorders such as Sjogren syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis obliterans, immune cytopenias and chronic immunodefciency (Jagasia et al. 2015).

Single organs alone may be affected and can progress to other organs; however, cGvHD nearly always affects multiple sites, having major impact upon a patient's quality of life. There is a wide range in severity and how this relates to compromise in patients' QoL, with some manifestations being more problematic to treat (Flowers and Martin 2015).

# **12.6.1 Diagnosis of cGvHD**

For a diagnosis of cGvHD to be made, the NIH 2014 working group suggest that at least one diagnostic manifestation of cGvHD or at least one distinctive manifestation, with the latter confrmed by pertinent biopsy, laboratory tests, evaluation by a specialist or radiology in the same or other organ be present, unless stated otherwise. It is important with any organ considered for a diagnosis of cGvHD that other causes for the symptoms are excluded such as infection or recurrent or new malignancy (Jagasia et al. 2015). The features should also differ from the typical dermatitis, enteritis and cholestatic liver manifestations of aGvHD (see Appendix 12.A.2 for the full tables of assessment).

# **12.6.2 Chronic GvHD of the Skin**

For a clinical diagnosis of skin cGvHD, features of poikiloderma, lichen planus-like eruption, deep sclerotic features, morphea-like superfcial sclerotic features or lichen sclerosus-like lesions are needed (Jagasia et al. 2015). Assessment of the skin is performed to look at the four anatomic levels of involvement, and the score is based on the percentage of area involved and the differentiation between non-sclerotic and sclerotic features:

Points 1–3 are assessed using the 'rule of 9s' body surface area score. Local skin involvement below 20% body surface and the absence of sclerotic features are classifed as 'mild'. Skin involvement between 20% and 50% is 'moderate', with more than 50% becoming 'severe' (Greinix 2008). This scoring system is effective in adults but less so in children; however, it is still used in children over the age of 1 year. Ulceration is recorded by measuring the diameter of the largest ulcer (Pavletic et al. 2006). The skin is often very fragile and becomes damaged easily with poor healing of any wound. Distinctive features of cGvHD that are not seen in aGvHD are depigmentation, although this occurs gradually and may only be perceptible over long time periods, and papulosquamous lesions, although this alone is not enough for a diagnosis. It must be made in combination with other signs or confrmed with biopsy. Common features of both acute and chronic GvHD are erythema, maculopapular rash and pruritis (Jagasia et al. 2015). Itching is common and, therefore, should be recorded using a scale of 1–10 for severity, with the patient asked what was the highest score this week (Pavletic et al. 2006).

Distinctive signs of nail cGvHD are longitudinal ridging, splitting or brittleness, onycholysis and loss of nails that is usually symmetric and affects most nails (Jagasia et al. 2015).

Loss of hair can be a devastating effect of cGvHD for patients, and in this context, it is considered a distinctive feature alone. Hair has often returned following chemotherapy or radiotherapy, and the loss is often patchy and happens across the whole body. Patients may suffer with premature greying, thinning or brittleness of their hair (Jagasia et al. 2015).

# **12.6.3 Chronic GvHD of the Oral Cavity**

Patients with oral cGvHD complain of a sore mouth that is not dissimilar to the pain suffered with oral mucositis post-chemotherapy/radiotherapy. Tolerance of spicy food stuff is poor, toothpaste burns are common and hot drinks such as tea and coffee are almost impossible to take. It is important to rule out infection as this will cause pain to be worse. Frequent swabs for virus, bacterial and fungal infection should be taken and acted upon promptly. To aid with oral pain management, Caphosol, Gelclair, lidocaine, paracetamol mist and Diffam mouthwash can be used.

Advise patients to frequently swill the mouth after eating to remove any debris using plain water. This is refreshing and ph7 so comfortable to do. Encourage the use of products to aid in production of saliva as the mucosa is usually very dry. Artifcial saliva or sugar-free gum and, in some centres, pilocarpine may be used.

Many medications have side effects of dry mouth. Look to see if there are any alternatives that could be prescribed for your patient.

Early referral to the dentist is vital, as the risk of dental caries and secondary oral cancers is higher in patients with oral GvHD. Advice to perform regular oral exercises to reduce the risk of contractures.

For patients who have received stem cells derived from the bone marrow (BM), oral cGvHD is the most common site of involvement, and the oral cavity is the second most common site with PBSC (Meier et al. 2011). There are three components to mouth and oral mucosa assessment:

Within the oral cavity, clinical diagnostic features include lichen planus-like changes. These are described as white lines and lacyappearing lesions or plaque-like changes. This can occur on any oral surface including the tongue and lips. The mouth will be dry (xerostomia) and have mucoceles, mucosal atrophy, ulcers and pseudomembranes. Common features of both acute and chronic GvHD are gingivitis, mucositis, erythema and pain (Jagasia et al. 2015). If new lesions occur >3 years posttransplant, secondary malignancy should be excluded with biopsy. The lesion often starts as leukoplakia and can be confused with cGvHD but may be a squamous cell carcinoma (SCC) (Couriel et al. 2006).

Chronic GvHD of the mouth is scored as 3 areas using the standard 0–3 scale with a percentage of area involved:

Oral sensitivity is measured on a self-score system from 1 to 10, with the worst and therefore highest score it has been for the past week recorded (Pavletic et al. 2006). The consequences of oral cGvHD in cases of hypo-salivation and xerostomia are in relation to the function of saliva and lack thereof. Poor protection against oral infections and mechanical and chemical epithelial injuries can occur. Remineralisation is impaired that can lead to dental caries, speech may be altered and eating becomes problematic (Meier et al. 2011; Treister et al. 2013).

# **12.6.4 Chronic GvHD of the Eyes**

New onset of dry, gritty or painful eye with cicatricial conjunctivitis, keratoconjunctivitis sicca and confuent areas of punctate keratopathy are distinctive features and may occur in isolation with no other active cGvHD (Couriel et al. 2006). Lacrimal dysfunction or destruction is responsible for dry eye symptoms (Pavletic et al. 2006). Infection should be excluded and treated if apparent. Patients may describe photophobia, burning, irritation, pain, a foreign body sensation, blurred vision and paradoxically excessive tearing.

Scoring of eyes is based on frequency of use of eye drops and the occurrence of keratoconjunctivitis sicca. Asymptomatic keratoconjunctivitis sicca or need for eye drops less than three times per day is classed as 'mild', whilst symptomatic and the need for more than three times daily eye drops +/− punctual plugs is 'moderate'. Those with 'severe' ocular cGvHD are unable to work because of ocular symptoms or require special eyewear such as dark glasses to relieve pain or have loss of vision due to keratoconjunctivitis sicca (Greinix 2008).

# **12.6.5 Chronic GvHD of the Genitalia**

Patients who suffer from oral or skin cGvHD are also very likely to have some degree of genital cGvHD. This affects both men and women and is signifcantly under-reported. Some basic nursing input can help with symptoms of pain and discomfort experienced. Asking patients if this is a problem for them is the frst step as patients are often reticent about mentioning genital problems to the medical team. In women, vaginal scarring and clitoral/labial agglutination occur, and in men, phimosis and urethral/meatus scarring are features. In both sexes, lichen planus-like and lichen sclerosis features are diagnostic. It is essential due to the under-reporting of symptoms that patients are examined for early signs especially if oral features are present. Studies suggest that 3–15% of women have vulvar or vaginal cGvHD (Couriel et al. 2006). The diagnosis relies heavily on sign and symptom reporting. Symptoms in women may include dryness, burning, pruritis, pain to touch, dysuria and dyspareunia. Signs include patchy or generalised erythema, mucosal erosions or fssures, labial resorption, circumferential fbrous vaginal banding, vaginal shortening and complete vaginal stenosis. Female genital tract involvement is scored as 'mild' if any erythema on vulvar mucosal surfaces, vulvar lichen planus or vulvar lichen sclerosis exists. Those with any erosive infammatory changes of the vulvar mucosa or fssures in the vulvar folds are scored as 'moderate'. Severe scores are when there is labial fusion, clitoral hood agglutination, fbrinous vaginal adhesions, circumferential fbrosis vaginal banding, vaginal shortening, synechia, dense sclerotic changes and complete vaginal stenosis (Couriel et al. 2006).

In the absence of diagnostic manifestations of cGvHD in other organs, histological evidence is strongly recommended and ruling out of oestrogen defciency or infection with yeast, HPV or bacteria (Couriel et al. 2006). A referral pathway to the gynaecologist and if possible one with an interest in assessing these patients should be implemented.

There are a variety of treatments that may offer some symptomatic beneft. With female patients, application of an emollient to the vulval region and use of dilators with a lubricant such as olive oil or coconut oil will help minimise the risk of contractures. Vaginal moisturisers may make women feel more comfortable. Referral through to endocrinology for discussions about hormone replacement therapy (HRT) with oestrogen can be initiated by nursing staff. Mechanical and chemical irritants should be avoided. Washing with warm water, using products from such ranges as Oilatum or Dermol if required (rather than soap), cleaning in a front-to-back direction and then air-drying are to be advised. Bacteriostatic gels such as Replens may be used in the vagina for comfort as this adheres to the vaginal wall and has a long-lasting effect. Vulval and vaginal topical management can include steroid/immunosuppressant cream. In extreme cases, surgical interventions may be required to release strictures and adhesion formation. In all cases, particularly if the woman is not sexually active, dilators lubricated with, for example, a lipid, such as coconut oil, should be thought about as a way of maintaining vaginal patency and capacity. Men may have painful intercourse and a burning sensation on micturition. Signs include non-infectious balanoposthitis, lichen sclerosis-like or lichen planus-like features, phimosis or urethra or meatus scarring or stenosis (Jagasia et al. 2015). Signs of lichen planus-like features are classed as 'mild', lichen sclerosis-like features or moderate erythema is 'moderate' and 'severe' signs are phimosis or urethral or meatal scarring. Application of emollient is suggested alongside good hygiene to help reduce tightening of the foreskin.

Body image and sexual dysfunction are signifcant problems for both men and women posttransplant and are especially problematic upon development of cGvHD. Counselling and early involvement with psych-oncology services are important to aid in maintaining normality in an abnormal situation.

In a frst case series describing vvGvHD in a paediatric and young adult population, 42% of patients were asymptomatic at the time of diagnosis. This may be due to a misunderstanding and under-reporting of genital symptoms in paediatric patients. It may indicate that paediatric patients are at greater risk than adult women for delayed or missed diagnosis. Larger, prospective studies are needed to evaluate treatment regimens and establish clinical care guidelines for paediatric vvGvHD (Cizek et al. 2019).

# **12.6.6 Chronic GvHD of the Gastrointestinal (GI) Tract**

Gastrointestinal tract symptoms occur frequently, and oesophageal web, stricture or concentric rings demonstrated on endoscopy or imaging are diagnostic features for GI cGvHD. Patients may have dysphagia, odynophagia, heartburn, anorexia, nausea, vomiting, abdominal pain, cramping, diarrhoea, weight loss and malnutrition, and these are all common features present in both acute and chronic GvHD as well as other aetiologies. It is important to make a frm diagnosis before commencing treatment. Diarrhoea should be investigated with stool culture and virology examination to exclude *C. diff* and CMV in particular (Couriel et al. 2006). Patients may also suffer from pancreatic atrophy and exocrine insuffciency that causes malabsorption and can respond to pancreatic enzyme supplementation (Jagasia et al. 2015). For upper GI, early satiety, anorexia and nausea and vomiting are scored on occasional symptoms with little reduction in oral intake during the past week being 'mild'; a 'moderate' score of cGvHD as intermittent symptoms with some reduction in oral intake during the past week; and 'severe' if the patient has persistent symptoms throughout the day with a marked reduction in oral intake on almost every day of the past week. Lower GI disturbance with diarrhoea will score 'mild' if the patient has occasional loose or liquid stool on some days throughout the week. If the patient is having intermittent loose or liquid stool throughout the day, on almost every day of the last week, without requiring intervention to prevent or correct volume depletion, it is scored as 'moderate'. Those with 'severe' disease have voluminous diarrhoea on almost every day of the past week, requiring intervention to prevent or correct volume depletion.

# **12.6.7 Chronic GvHD of the Liver**

The liver has no frm diagnostic features of cGvHD, and all other causes need to be excluded, e.g. viral infections, biliary obstruction and drug toxicity. A biopsy, if possible, can help carry a high risk of bleeding and is therefore not frequently performed; imaging may be useful to exclude liver abscess, infltration or gall bladder disease (Couriel et al. 2006). Patients may present in two ways, with a liver function test showing a steep rise in serum ALT, with or without jaundice or transaminitis, or as a progressive cholestatic picture with elevation of serum alkaline phosphatase and GGT followed by jaundice (Jagasia et al. 2015). Any elevation of liver enzymes greater than twice normal may be regarded as 'mild', 2.5 times upper limit of normal as 'moderate' and 'severe' if fve times.

# **12.6.8 Chronic GvHD Pulmonary System**

Historically, for a frm diagnosis of pulmonary cGvHD, a biopsy was essential to prove bronchiolitis obliterans (BO); however, as there was a high risk of bleeding, it is now accepted that a diagnosis of bronchiolitis obliterans syndrome (BOS) can be made following pulmonary function testing (PFT). Pre-transplant screening is essential to obtain a baseline PFT with posttransplant PFT at 3 months and 1 year or more frequently if the patient develops signs as patients remain asymptomatic with an insidious onset of symptoms (Flowers and Martin 2015). A new onset of an obstructive lung defect is indicative of BOS. Clinically, the patient may be short of breath on exertion and have a cough or wheeze, but these may be later effects. There are strict criteria for BOS, and all need to be met for a diagnosis:

Air trapping by expiratory chest high-resolution CT or small airway thickening or bronchiectasis or trapping on PFT where there is a residual volume of >120% or residual volume/total lung capacity >120% predicted is supporting evidence for BOS (Jagasia et al. 2015).

Chronic lung GvHD may be treated with bronchodilators, inhaled corticosteroids, systemic steroids, montelukast and referral to a physical rehabilitation programme (Couriel et al. 2006). Lung GvHD has a somewhat dismal outcome as it is not very responsive to any modality. Nurses and physiotherapists can help patients manage distress and possible panic situations the patient may feel due to increasing breathlessness by teaching complementary self-management skills such as breathing techniques, focused relaxation and stress management.

# **12.6.9 Chronic GvHD of the Musculoskeletal System**

Diagnostic features of the musculoskeletal system include fascial involvement usually of the forearms or legs, but frequently affecting the abdomen and chest wall with sclerosis of the overlying skin and subcutaneous tissue and joint stiffness or contractures that can develop and severely impact on quality of life (Jagasia et al. 2015). The degree of functional impairment is scored as 'mild' if there is mild tightness of arms or legs, normal or mild decreased range of movement (ROM) and does not affect activities of daily living (ADL). Where there is tightness of arms or legs or joint contractures or erythema thought due to fasciitis, a moderate decrease of ROM and mild-to-moderate limitation of ADL, it is scored as 'moderate'. For 'severe' then, the patient will have contractures with signifcant decrease of ROM and signifcant limitation of ADL, e.g. unable to tie shoelaces, button a shirt or dress self.

# **12.6.10 Scoring of Chronic GvHD**

The global scoring system of NIH 2014 was developed to be suitable for clinical trial assessments and refects the clinical impact of cGvHD on the patient's functional status and organ impairment and is defned by Jagasia et al. (2015) in Table 12.1.

Jagasia et al. (2015) with permission.

# **12.7 Assessment of Response**

Pavletic et al. (2006) proposed a set of measures for assessing the response to treatment of cGvHD patients. These should be performed at three monthly intervals or whenever a major change occurs. Organ-specifc measures should be recorded from clinical signs and symptoms and a global rating of mild/moderate/severe made. Assessment with non-specifc ancillary measures such as grip strength, 2-min walk test (or Activity Scale for Kids (ASK)) and Karnofsky score with a quality of life (QoL) score is recommended. Quality of life assessment tools such as SF-36 or FACT-BMT in adults or CHRIs (Child Health Ratings Inventories) in children can be used.

# **12.8 Treatment of Chronic GvHD**

The long-term aim of cGvHD therapy is for the patient to develop immune tolerance and reduce morbidity. This is recognised by the ability to withdraw immunosuppression without a fare of symptoms. Most therapeutic options focus on the development of immunosuppressive agents and the ex vivo removal of the unfractionated donor T-cell population from the stem cell graft (Greinix 2008). The mainstay of treatment has for more than 30 years been the use of systemic steroids, usually with a starting dose of 1 mg/kg per day with or without calcineurin inhibitor (CNI). Steroids have a multitude of side effects such as toxicities, diabetes, weight gain, bone loss, myopathy, hypertension, mood swings, cataracts, avascular necrosis and an increase in infections (Flowers and Martin 2015).

Treatment for cGvHD is far from satisfactory with only approximately 50% of patients responding to systemic steroids with or without calcineurin inhibitors and less than 20% of patients alive without disability at 4 years. Combinations of steroids with azathioprine, thalidomide, mycophenolate mofetil or hydroxychloroquine in randomised trials have not yielded any beneft over steroids alone for survival or duration of therapy (Flowers and Martin 2015). However, the recent REACH 3 trial results found that ruxolitinib signifcantly improved outcomes across a range of effcacy measures when compared to best available therapy in steroid-refractory/steroid-dependent patients (Zeiser et al. 2021). Steroids still offer the best frst-line treatment choice for those with cGvHD and should be started as soon as a diagnosis is made.

The ROCKstar study looked at belumosudil in steroid-refractory cGvHD and found promising effcacy and favourable safety profle in patients with fbrotic manifestations who had previously received at least three prior therapies. This has the potential to improve the outlook for patients with diffcult lung and skin symptoms (Cutler et al. 2021).

# **12.8.1 Second-Line, Third-Line and Other Therapies for Chronic GvHD**

Below is a brief list of second- and third-line therapies for cGvHD; it is not exhaustive by any means, and many treatments are used following limited evidence from small non-randomised trials. The choice for further therapies is in most part governed by the features of cGvHD and the toxicities that may be inficted as well as the availability of the drug locally. The lack of consistently effective treatment in this setting underscores the need for high-quality clinical trials. Please refer to local policies and guidance with respect to second-line and subsequent therapies.

*Ruxolitinib* is an oral JAK 1 and 2 tyrosine kinase inhibitor originally used for polycythemia or myelofbrosis patients. It is widely used as a second-line therapy following the REACH 3 trial (Zeiser et al. 2021).

*Ibrutinib*, a Bruton's tyrosine kinase and interleukin-2-inducible T-cell kinase inhibitor, targets B- and T-cells. It can interfere with platelet function, leading to bleeding problems (Wolff et al. 2021). In pre-clinical models, it delayed progression and improved clinical manifestations (Miklos et al. 2017).

*Extracorporeal photopheresis* (ECP) is widely used in mucocutaneous cGvHD as a second-line therapy in steroid-refractory patients and has been shown to be effective in up to 80% of patients (Couriel et al. 2006). A UK consensus paper supported the fndings and recommended ECP use in this group, with paired sessions every 2 weeks with reassessment at 3 months (Scarisbrick et al. 2008).

*Imatinib*, a tyrosine kinase inhibitor licenced for use in chronic myeloid leukaemia (CML), has gained popularity over the past few years. Experiments have shown reduction in fbrosis possibly from a dual inhibition process of transforming growth factor beta and platelet-derived growth factor pathways (Dignan et al. 2012).

*Sirolimus*, an mTOR inhibitor, may be used in combination with other agents but with caution in CNI due to increased risk of thrombotic microangiopathy and hyperlipidaemia.

*Rituximab* is commonly used in haematology for B-cell malignancy and is a potent anti-CD20 monoclonal antibody, and there is some limited evidence of its use in cGvHD for musculoskeletal and cutaneous manifestations (Dignan et al. 2012).

*Mesenchymal stem cells* (MSC) (Ringden and Keating 2011) have generated considerable interest in treatment of aGvHD following initial studies from the group at the Karolinska Institute. There was some evidence from early experiments that MSC worked in autoimmune disorders, and given the fact that cGvHD may resemble this in some ways, MSC have been used for cGvHD treatment but remain mainly within clinical trials.

*Belumosudil* (REZUROCK™), a selective ROCK2 inhibitor (Rho-associated coiled-coilcontaining protein kinase), is important in tissue response to injury. It has gained frst approval in the USA for use in patients ≥12 years with cGvHD after failure of at least two prior lines of systemic therapy as it has shown to be able to restore immune homeostasis and reduce fbrosis (Zanin-Zhorov and Blazar 2021).

# **12.8.2 Topical Treatments for cGvHD of the Eyes**

The aim of treatment is to give symptomatic relief of dry eye, and care should be coordinated with an experienced ophthalmologist. Focus is placed upon increasing ocular surface moisture via lubrication and decreasing tear evaporation and tear drainage from the eye and decreasing ocular surface infammation. Preservative-free drops coat the eye surface, minimising dry spots on the cornea, decreasing ocular symptoms and improving vision. It may take several different trials of drops to fnd one that works, as patients may be more sensitive to one solution. Temporary (with punctual plugs) or permanent (with cauterisation) occlusion of the tear duct may offer a solution to those with severe dry eye. Where there is infammation of the ocular surface, direct application of steroid eye drops may be benefcial especially if the patient is on a taper of systemic immunosuppression and eye fare symptoms (Couriel et al. 2006). If available, autologous or allogeneic serum eye drops may decrease surface infammation.

Dark glasses will reduce irritants such as wind and block any debris that may blow into the patient's eyes. There are a variety of graded dark glasses that may be obtained through an optician that can block up to 90% of light and reduce photophobia signifcantly. It is often useful to wear glasses inside the house to reduce discomfort. Cold compress with ice packs and chamomile tea bags are useful in some instances.

Ciclosporin eye drops appear to offer a solution, but they cause irritation in most patients, and thus compliance is often poor. Specialist ophthalmology clinics may have access to scleral lens replacement in severe cases.

# **12.8.3 Topical Treatments for Oral cGvHD**

Management of oral cGvHD aims to alleviate symptoms of dry mouth, sensitivity and pain whilst maintaining oral function and restoring mucosal integrity (Meier et al. 2011). It may appear obvious, but the single most important action for patients is to maintain good oral hygiene (daily care and regular dental visits). Children's toothpaste causes less irritation and should be used with a soft toothbrush, with the addition of lip salve if appropriate. Avoidance of potential triggers for fares of cGvHD such as spicy or hot food or sharp foodstuffs that can cause damage is also suggested. Sip water and chew sugar-free gum to improve xerostomia.

Often, patients require systemic therapy as multiple sites are involved. However, the oral cavity can be refractory to systemic therapy; thus, complementary topical treatment is needed. There are a variety of topical steroid mouthwashes that are the frst line of therapy, including prednisolone, budesonide or betamethasone. Tacrolimus 0.1% mouthwash is well tolerated and has shown to be an effective option and may be used alongside steroid mouthwashes as second-line therapy. It is important to describe adequately how to use these preparations as in many cases, this is not their usual route of administration.

To relieve oral pain, topical application of local anaesthetics such as lidocaine can be applied, either as a gel, mouthwash or spray. These should be used with caution as the gag refex may be compromised and lead to choking and aspiration.

# **12.8.4 Ancillary and Supportive Care for cGvHD of the Skin**

The skin remains the most affected organ for chronic GvHD, which is often debilitating when in extremis. Topical treatments are a vital therapy in addressing the manifestations of itch, rash, pain and dyspigmentation, whilst the use of physical therapy helps patients with limited range of movement maintain some degree of functionality. Other healthcare providers such as tissue viability and infection control teams can offer help, guidance and support when the skin becomes friable and breaks down, leaving ulcers, erosions and superadded infections. The patient with cutaneous cGvHD is at an increased risk of skin cancer, and regular monitoring and assessment are advised. Any suspicion should be followed up with biopsy. Advice with respect to UV exposure should be given regularly: avoiding direct sun exposure and using sunblocks and sunscreens and loose-ftting clothing with hat and glasses.

One of the major challenges for topical management of cutaneous cGvHD is the often severe sclerotic features—characterised by thickened, tight and fragile skin. This is frequently associated with poor wound healing, inadequate lymphatic drainage and skin ulcers from minor trauma or idiopathic origin. The following are important points to be given and regularly reinforced to all patients:

# **12.8.5 Connective Tissue Involvement in cGvHD**

Patients with cGvHD affecting skin, joints and connective tissue will beneft from inclusion in an exercise rehabilitation programme along with occupational therapy. Functional losses associated with muscle loss, weakness, contractures and limb swelling lead to fatigue and a decreased ability to perform activities of daily living and often preclude patients from being able to return to work. Rehabilitation should aim to improve strength and mobility of joints and muscles and ideally should occur before permanent and lasting damage has set in (Couriel et al. 2006). Such programmes should include family members where possible, as exercises need to be carried out on a regular basis to be effective, with the patient often needing support to do this. It can also be psychologically helpful to any family/ carers involved as it allows them to feel confdent to be part of the care of their loved one.

In addition to exercise, regular massage can help maintain fexibility and function of affected limbs. If there is fascial involvement, any massage provided will need to access these tissue layers to be effective. It is therefore important that the therapist providing this treatment has been trained in using such techniques. Again, it is possible to teach family members appropriate massage skills, which will improve the effcacy of therapy provided.

# **12.8.6 Quality of Life**

QoL is severely compromised in cGvHD, with reports of fatigue, pain and GI upset. FACT-BMT QoL questionnaire studies have revealed that physical, sexual and social functioning is also lower with higher rates of depression and anxiety and adverse effects on social and family interactions. Depressive symptoms are more severe and last longer and often manifest when patients complain of loss of memory or poor concentration. Fatigue may be considered as a separate entity but is often mixed with QoL, anxiety and depression. It may be described as a persistent and subjective state of tiredness that interferes with usual functioning and can continue for several years after transplant (Couriel et al. 2006). Using questionnaires to assess these issues with individual patients is something which nurses can instigate to identify the impact of psychological morbidity in specifc cases. These can be used as a framework to enable patients to express their concerns and structure a support programme to help manage specifc issues—including onward referrals to appropriate professionals. de Vere et al. (2021) carried out a qualitative exploration of quality of life issues in patients with GvHD. They found that there was signifcant variation in symptoms and the extent that the symptoms affected each patient, a key point that nurses should note to be able to individualise care.

# **12.9 The Future**

HSCT numbers continue to increase annually, and the morbidity and mortality associated with GvHD remains a signifcant problem. There is emerging understanding of the pathophysiology, and several new therapies have emerged in the past 2 years that have signifcantly improved the outlook for patients. Success in prophylaxis and treatment of GvHD will depend on whether GvHD can be prevented without losing the antitumour effect. Risk stratifcation and the emergence of a bedside GvHD test based on proteomics may be on the horizon and will ultimately then improve the outlook for this diffcult-to-treat group of patients (Greinix 2008).

# **12.10 GvHD in Children**

Data and research on GvHD in the paediatric population are limited with only a few studies specifcally focused on children. Most studies are small, and children are often grouped into larger adult series (Baird et al. 2010; Gatza et al. 2020). In this short review, we will emphasise on the specifc aspects of paediatric GvHD, primarily focusing on cGvHD.

In a recent publication, the Paediatric Diseases Working Party of the EBMT surveyed centres performing paediatric HSCT, looking at real-life approaches of prevention and treatment strategies in aGvHD. The fndings highlight the need for standardised paediatric approaches towards aGvHD prophylaxis/treatment differentiated for malignant and non-malignant diseases (Lawitschka et al. 2020). Adolescents and young adults have increased rates of aGvHD when compared to children, and it is multifactorial, related to both biological and psychosocial factors. This likely contributes to a substantially greater risk of TRM (Friend and Schiller 2021). MacMillan et al. (2020) report a single-centre large paediatric series of 370 patients, examining the clinical phenotype of aGvHD at diagnosis and response to upfront steroid therapy. They conclude that aGvHD is different in children, with a higher incidence of isolated skin involvement, less liver involvement and less multi-organ involvement than adults. Children respond to steroids as upfront GVHD therapy to a similar extent as adults.

Most of the literature on cGvHD has focused on adults. Although the clinical manifestation of cGvHD in children is similar to that in adults, the consequences of treatment and non-responses are remarkably different in a growing organism (Lawitschka et al. 2012). Children with cGvHD are of particular interest, given their longer life expectancy and developmental issues following the complications of cGvHD and its therapy (Jacobsohn 2010; Jacobsohn et al. 2011). Compared with childhood cancer survivors who did not undergo transplantation, HSCT survivors have a substantially increased burden of serious chronic conditions and impairments involving every organ. A history of GvHD or presence of cGvHD contributes to increased rate of longterm complications in the paediatric transplant survivors (Chow et al. 2016). Chronic GvHD has negative effects on an individual's physical and mental health and can lead to the development of functional impairments and activity limitations over their lifetime (Baird et al. 2010) as well as reduced quality of life (Inagaki et al. 2015). However, paediatric cGvHD remains an understudied area of research (Jacobsohn et al. 2011; (Cuvelier et al. 2019)); therefore, large paediatric multicentre studies are needed (Watkins et al. 2016).

# **12.10.1 Incidence and Risk Factors**

Overall the rates of cGvHD are lower in children than adults (Champlin et al. 2000; Rocha et al. 2000). However, the incidence of cGvHD in the paediatric population is still substantial and has increased recently in association with the expanded use of peripheral blood stem cells and unrelated donors (Baird et al. 2010). Zecca et al. (2002) in a large paediatric study reported a cumulative probability of cGvHD of 27%; this probability is nearly half of the estimated probability of 40–50% described in adults. Flowers et al. (2011) published a large single-centre study of risk factors for aGvHD and cGvHD. The sample included both adult and paediatric patients; cGvHD was defned according to the NIH cGvHD criteria (Filipovich et al. 2005). The incidence of moderate-to-severe cGvHD in the paediatric patient was 28% (Watkins et al. 2016).

The risk factors for cGvHD in childhood are still poorly defned. Zecca et al. (2002) reported the risk factors associated with cGvHD in children: male patients transplanted from a female donor experience more cGvHD. Children with non-malignant disorders had a reduced risk of developing cGvHD. This might be due to the fact that children with these diseases do not beneft from GvHD since they do not need any graftversus-malignancy effect, and therefore the most effective pharmacologic strategies for both prevention and treatment of aGvHD were used in these patients. The condition of mixed donor chimerism is associated with reduced susceptibility to GvHD. Some of the children with nonmalignant disorders (those with aplastic anaemia or with congenital immunodefciencies) are given less intensive preparative regimens, and it has been hypothesised that the cytokine storm, which is dependent on the intensity of the conditioning regimen, triggers development of GvHD. Malignant diseases and the use of myeloablative protocol as well as TBI as part of the preparative regimen offer an increased risk of classic aGvHD (Faraci et al. 2012). Older recipient and donor ages are another risk factors for cGvHD (Watkins et al. 2016).

# **12.10.2 Treatment**

The major emphasis in GvHD has been on prevention, as results with treatment have been disappointing. Currently, most centres use a combination of a calcineurin inhibitor (cyclosporine or tacrolimus) with short-course methotrexate (Jacobsohn 2008), with differences between malignant and non-malignant diseases and myeloablative and reduced-intensity conditioning (Lawitschka et al. 2020).

The treatment of cGvHD in paediatrics is highly variable and mostly extrapolated from the experience in adults. Although there is no proven standard therapy, prednisolone and cyclosporine are commonly used as front-line therapy. As steroids remain the basis of cGvHD therapy, the consequences of long-term steroid use in children are well described, and long-term harmful effects on growth and bone density persist even after discontinuation of therapy.

Other potential treatment strategies include extracorporeal photopheresis (as discussed earlier in this chapter) and the infusion of allogeneic human mesenchymal stem cells (MSC) for the treatment of aGvHD and cGvHD. Multiple MSC infusions are safe and effective for children with steroid-refractory aGvHD, especially when employed early in the disease course. Early treatment may be associated with reduced treatmentrelated mortality and better overall survival (Ball et al. 2013). MSC offer new potential modalities of treatments for paediatric cGvHD refractory to standard treatments (Lawitschka et al. 2012). The treatment in paediatric patients must take into consideration the potential effect on growth, nutrition, organ function, bone metabolism, hormonal balance, psychosocial aspects and immune reconstitution (Baird et al. 2010; Lawitschka et al. 2012).

Recently, the FDA has approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and paediatric patients 12 years and older (Przepiorka et al. 2020). Ruxolitinib is a promising treatment in SR-GvHD. There are a few studies in children that demonstrated it is an effective option in acute and chronic SR-GVHD (Moiseev et al. 2020) with moderate-toxicity profle (Mozo et al. 2021) and with high overall response for acute and chronic GvHD, with a high ORR of 77% and 89%, respectively (González Vicent et al. 2019).

Ibrutinib is another novel medication indicated for the treatment of adult patients with cGvHD after failure of one or more lines of systemic therapy. A small study of 22 paediatric patients concluded that administration of ibrutinib shows promising responses in cGvHD as salvage and second-line therapy, but further studies are needed (Teusink-Cross et al. 2020).

The nursing management and care of children with GvHD are complex and require expert skills and knowledge as well as adjustment to the child's/adolescent's developmental need. Patients and families, who initially felt great relief to be cured from their primary disease, now face the challenge of a chronic devastating disease, for which preventative and treatment strategies are suboptimal (Baird et al. 2010). The treatment and support of the children and their families require a multidisciplinary team care that will be able to provide a comprehensive response to all their needs.

# **Appendix 1: Classifcation of Patients with Acute GVHD**

# **Hyperlink to MAGIC Paper and Acute GvHD Assessment**

# https://www.astctjournal.org/article/S1083- 8791(15)00602-3/fulltext

Glucksberg et al. (1974) modifed criteria taken from the EBMT 2008 revised edition of handbook with permission.

# **Appendix 2: Scoring of Chronic GvHD**

https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4329079/

Jagasia et al. (2015) with permission.

# **References**

Janssen JJWM, Petersen E, Socie G, Nagler A, Rocha V, Mohty M. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the acute leukemia working Party of the European group for blood and marrow transplantation. Leukemia. 2012;26:2462–8.

Bladon J, Taylor P. The down regulation of IL1 and IL6, in monocytes exposed to ECP treated lymphocytes, is not dependent on lymphocyte phosphatidylserine externalisation. Transpl Int. 2006;19(4): 319–24.

Blood and Marrow Transplantation. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012;158(1):30–45.

working group report. Biol Blood Marrow Transplant. 2006;12:252–66.

from the chronic GVHD consortium. Bone Marrow Transplant. 2013;48:1123–8.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Mairéad NíChonghaile

#### **Abstract**

The treatment of relapsed disease remains challenging, and it is well accepted that concept of allogeneic HSCT relies upon both the conditioning or preparative regimen used for the recipient and the graft versus malignancy (GvM) or leukaemia (GvL) effect provided by the donor T cells and NK cells. Strategies which involve harnessing this effect are crucial to success and need to be exploited and refned to improve outcome. Further research is required to identify new strategies and therapies to improve the outlook for patients who relapse post-HSCT.

The nursing challenges following relapse are immense; the psychological support required is complex and largely falls to the nurse to coordinate and deliver regardless of the selected treatment approach.

#### **Keywords**

Graft versus malignancy (GvM) or leukaemia (GvL) · Donor lymphocyte infusions (DLI) · Relapse · Chimerism

# **13.1 Introduction**

The concept of allogeneic haematopoetic stem cell transplant (HSCT) relies upon both the conditioning or preparative regimen used for the recipient and the graft versus malignancy (GvM) or leukaemia (GvL) effect provided by the donor T cells and NK cells. The autoimmune attack on the malignancy helps eradicate the disease in the recipient with the aid of the condition regimen. The susceptibility of a malignant condition being eradicated by GVM of GvL effect varies with the most sensitive conditions being chronic myeloid leukaemia, chronic lymphocytic leukaemia, lowgrade B-lymphoproliferative disorders, mantle cell lymphoma and EBV lymphoproliferative conditions. Most other conditions have an intermediate sensitivity to the GvM or GvL effect with conditions that have a special proliferation or that are advanced or chemo-refractory having the least response.

# **13.2 Mechanism of GvM/GvL Efect**

Both T lymphocytes and NK cells participate in the GvL effect, and it is believed that cytotoxic T cells recognise several classes of antigens on leukaemic cells. The NK cells target MMag selfproteins (present on the tissues of the recipient), which are overexpressed by the leukaemia, e.g.

**Graft Versus Tumour Efect 13**

M. NíChonghaile (\*) HOPE Directorate, St James's Hospital, Dublin, Ireland

<sup>©</sup> The Author(s) 2023 M. Kenyon, A. Babic (eds.), *The European Blood and Marrow Transplantation Textbook for Nurses*, https://doi.org/10.1007/978-3-031-23394-4\_13

proteinase 3 and elastase tumour-specifc antigens, e.g. Wilms tumour 1, and fused proteins, e.g. BCR-ABL, by using the perforin-granzyme pathway to kill their targets. However, they are only activated when inhibitory signals from self (recipient) MHC class 1 molecules on the target are missing or overcome by activating signals through the NKG2D receptor. The suppressor of the recipient's immune system allows the donor cells to provoke this effect.

# **13.3 Minimal Residual Disease (MRD)**

The purpose of monitoring MRD in the posttransplant setting is to track disease response or remission or low-level disease recurrence when the quantity of a particular marker starts to increase. This enables a therapeutic intervention to be implemented very early and may optimise the chance of success.

MRD can be monitored using molecular methods—this is where the underlying condition has a specifc market or protein that can be monitored by using fow cytometry. Table 13.1 shows the cytogenetic abnormalities that can be targeted in some diseases (adapted from Treleaven and Barrett 2009 page 410), and Table 13.2 shows some of the molecular targets (adapted from Apperly et al. 2012) if they were present at diagnosis.

**Table 13.1** Common cytogenetic targets for MRD screening in different malignancies

**Table 13.2** Examples of molecular targets in different malignancies

# **13.4 Chimerism**

Chimerism analysis is another important tool in the post-HSCT follow-up of the recipient. It demonstrates the degree of engraftment of donor cells and offers the possibility to identify impending graft rejection and can also be an indicator of disease relapse or recurrence. Chimerism can also be used as a basis for treatment intervention to prevent graft rejection and maintain engraftment and is used as a mechanism to administer pre-emptive immunotherapy to provoke the GvM or GvL effect particularly in high-risk patients.

Chimerism allows the monitoring of the ratio of donor- and recipient-derived cells in nongenetically identical donor and recipient pairs, allowing for timely intervention in the recipient. The term "chimerism" comes from Greek mythology where the chimera was a fre-spitting monster with the head of a lion, body of a goat and the tail of a serpent and is used to describe the fact of two entities—DNA from two people existing in the one person.

Initially it was felt that in order for all HSCT to be considered successful, an individual would have to be 100% donor chimerism, and this is certainly the case with malignant conditions. However, in non-malignant conditions (e.g. aplastic anaemia or haemoglobinopathies), a mixed chimerism may be enough to restore normal haematopoiesis.

While the total (unfractionated) chimerism result is important, more information can be elicited if lineage-specifc chimerism is performed, allowing separate tracking of lymphoid and myeloid engraftment and in itself can provide very useful information about possible disease relapse. This should be used in conjunction with other means of MRD analysis and diagnosis where indicated.

Schedule and protocols for chimerism analysis are centre, disease and treatment specifc, and reference should be made to your institution's policy.

# **13.5 Management of Relapsed Disease**

When a recipient has evidence of MRD or a decrease in chimerism, there are a number of strategies that can be followed. In the case of mixed chimerism, the schema in Fig. 13.1 can be followed.

Relapse usually occurs in the BM but may also be at extramedullary sites, thought to be due to immune escape from patrolling lymphocytes. It is also thought that leukaemia can escape from the immune control provided by the donor's T cells by mutating or becoming a more resistant clone of the original disease. The cause of the relapse may also be different in different haematological malignancies. While relapses can occur many years after HSCT, suggesting that perhaps the underlying disease was never eradicated and was held in control by the donor immune system, it is more common with CML, and in this disease, the administration of DLI can often restore remission.

However, the outlook for the recipient who relapses post-HSCT is poor and requires frank discussion with the recipient and their family to defne the likely outcomes and success. Care for the relapsed patient revolves around fve potential strategies:

**Fig. 13.1** Patients with increasing MC post-transplant (5% or more autologous cells) compared to the previous sample are offered further therapy. Immunotherapy for patients receiving CSA consists of immediate discontinuation of the immunosuppressive agent. Chimerism is then assayed weekly until CC status is restored. If MC continues to increase after cessation of CSA, a DLI is given. Immunotherapy for patients not receiving CSA consisted of DLI as frontline treatment. The cell dose administered

is based on the number and potential severity of HLA mismatches between the donor and recipient, and starting doses range from 2.5 × 104 to 1 × 106 /kg BW. After DLI, chimerism status is assayed weekly until CC status is restored. Patients who show a further increase in MC are given an additional DLI after at least 3 weeks have elapsed. If no GVHD occurs, the dose of DLI is doubled (Bader et al. 2005)

The timing of relapse is extremely important. Early relapses are diffcult to treat, and any intervention may be challenging for the patient or precluded due to the proximity to the HSCT and complications experienced by the recipients. Patients who relapse after HSCT may fnd it extremely diffcult to adapt to and accept the fact that further treatment may not be possible or may be ineffective particularly if they have already received intensive treatment prior to HSCT.

However, it is important to provide ongoing support so that patients do not feel abandoned at this stage, and this helps patients maintain realistic levels of hope and optimism. Palliative and supportive care measures are valid and realistic options to help maintain a good quality of life and should not be ignored. The help and support of the medical team, recipient's local doctor, referring hospital and often primary care services, e.g. GP and hospice, are essential in the management and treatment of the relapsed patient. Referral to psychology, social work/services, counselling or psychiatric teams may also beneft the patient and their family.

# **13.6 Treatment Approaches for Post-Allogeneic HSCT Relapse**

# **13.7 Management of Relapsed Disease**

# **13.7.1 Immunotherapy**

This is an important tool in the management of the relapsed patient and can range from withdrawal of immunosuppression (if the patient is still on it) to the administration of donor lymphocyte infusions (DLI) infusions in incremental doses.

# **13.8 Withdrawal of Immunosuppression**

The GvL or GvM effect of HSCT can be enhanced by reducing and stopping the IS (immunosuppressive) agent that the patient may be taking. Nursing care and education are essential in this circumstance as along with GvL, the patient needs to be monitored for the development of GVHD, which is extensively discussed in another chapter.

# **13.8.1 DLI**

DLI alone can induce permanent remission of the underlying disease particularly in the case of CML where relapses occur at a molecular level. In other diseases, the response can be varied from effective to ineffective (Fig. 13.2). The recipient should be educated regarding the rationale for DLI and the benefts and potential risk of GvHD with written information given to support the education. Consent for the DLI should be obtained as per the policy of the centre administering DLI. Most centres adopt an approach with the administration of graduated doses between 1 × 106 CD3 cells per kg and 1 × 108 per kg recipient body weight, depending on time from transplant, patient performance status and type of donor.

Level C evidence

a A DLI can be repeated at 1-log higher 6-8 weeks after the first DLI, when, e.g., MRD is still present and no GVHD is observed. GVHD as endpoint of repetitive DLIs for preemptive DLIS is in the era of MRD monitoring no longer recommended

After chemotherapy

Falkenberg, JHF et al. 2019 p.445 EBMT Handbook

Relapse in combination with chemotherapy<sup>c</sup>

DLI may also be administered as an adjuvant therapy to chemotherapy or targeted therapies to augment the effect of that treatment or sustain a remission if achieved.

DLI may not be administered where the recipient has already had signifcant acute GVHD or is receiving treatment for chronic GVHD.

It is rare to experience side effects while having a DLI. Recipients often experience a smell or taste from the DMSO preservative used in cryopreservation or may rarely experience a reaction to the DMSO. A nurse should remain with the recipient while having the DLI, and the recipient should remain under observation for a period of time following the DLI dose, which should be mandated in the centre DLI administration protocol. The main side effect of DLI is the development of GVHD, and the nurse should educate the recipient again regarding the signs and symptoms of GVHD. The treatment for GVHD has already been outlined in chapter(11).

1 × 107 /kg

# **13.8.2 Chemotherapy**

1 × 10<sup>7</sup> /kg

This may be used to palliate the patient, to attempt to reduce the disease burden to facilitate DLI or targeted therapy or to achieve a remission. Patients relapsing within 6 months of HSCT often require reduced or modifed dosing due to the toxicity of previous treatment or having reached the dosing limits of particular chemotherapeutic agents. Regimens for relapsed patients tend to be patient specifc, and there are currently very few standardised approaches. The

# nursing care for these patients has been well documented in previous chapters.

# **13.9 Molecular or Targeted Therapies**

Consideration needs to be given to the administration of molecular or targeted therapies to patients who relapse post-HSCT if they are available. Disease-specifc monoclonal antibodies, e.g. brentuximab, in some lymphomas; anti-CD33 agents, e.g. gemtuzumab, in myeloid malignancies; and TKIs in BCR-ABL-positive malignancies, can have an important role in this setting, and with new targeted therapies emerging, the number of available treatments is increasing.

# **13.10 Second HSCT**

If a patient experiences a relapse later post-HSCT, consideration may be given to a second HSCT using stem cells either from the original donor or an alternative donor. In malignant disease, usually, a second procedure is only feasible when remission has been achieved following successful administration of chemotherapy, a molecular or targeted therapy. The morbidity and mortality associated with a second HSCT are often signifcant, and the patient and family should be carefully counselled before such an undertaking.

# **13.11 Conclusion**

The treatment of relapsed disease remains challenging, and further research is required to identify new strategies and therapies to improve the outcome for this group of patients.

The nursing challenges are immense, and the psychological support required is complex and largely falls to the nurse to coordinate and deliver regardless of the subsequent treatment approach. The nursing team will continue to support patients and their families and help them adjust to the changes ahead. The demands on the team can mean that it is diffcult to take the time to refect and deal with the changing care and focus for the patients. The adjustments and diffculties experienced in caring for the relapse patient need to be matched by a team that continues to support each other.

# **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

**Engraftment, Graft Failure, and Rejection 14**

Daphna Hutt

#### **Abstract**

Engraftment following HSCT is an essential goal for sustained long-term and effective hematopoiesis. It is the most important criteria for a better overall survival. However, stem cell engraftment may be accompanied with a clinical condition known as engraftment syndrome (ES) that could have a devastating outcome. Nurses caring for HSCT recipients must be aware of ES symptoms in order to intervene quickly and appropriately. Conversely, graft failure (GF) is a major complication and is associated with a dismal prognosis. It is classically divided into primary or secondary graft failure. The risk factors associated with GF may be related to characteristics of the graft, the patient, the donor, or the transplant procedure. The conditions that are associated with an increased occurrence of GF and the available treatment options will be thoroughly discussed in the chapter along with the nursing considerations.

#### **Keywords**

Engraftment · Engraftment syndrome · Graft failure · Graft rejection · Pediatrics · Nursing

# **14.1 Engraftment**

Engraftment is the process by which hematopoietic stem cells (HSC) make their way (homing) to free bone marrow (BM) niches where they can fnd optimal conditions to survive and proliferate. Once they have reached the BM microenvironment, HSC have to proliferate to generate all hematopoietic cell subsets (Servais et al. 2013). A fundamental goal for successful engraftment is that the transplanted HSC are capable of sustaining long-term effective hematopoiesis; production of red blood cells, white blood cells, and platelets; and their release to peripheral blood (Locatelli et al. 2014). Engraftment is the most important variable for a better overall survival after stem cell transplant (Cluzeau et al. 2016).

# **14.2 Engraftment Defnition**

Various defnitions of engraftment exist in the literature. Engraftment is most commonly defned as the frst of three consecutive days of achieving a sustained peripheral blood neutrophil count of >500 × 106 /L (Wolff 2002). Platelet engraftment is usually defned as independence from platelet transfusion for at least 7 days with a platelet count of more than >20 × 109 /L (Teltschik et al. 2016). In recent publication by Kharfan-Dabaja et al. (2021) both adult and pediatric transplantation physician panels endorsed the existing def-

D. Hutt (\*)

Department of Paediatric Hematology-Oncology and BMT, Edmond and lily Safra Children Hospital, Sheba Medical Center, Ramat Gan, Israel e-mail<EMAIL_ADDRESS>
<sup>©</sup> The Author(s) 2023

M. Kenyon, A. Babic (eds.), *The European Blood and Marrow Transplantation Textbook for Nurses*, https://doi.org/10.1007/978-3-031-23394-4\_14

nitions but suggested that using the word "recovery" instead of "engraftment" is more appropriate because confrmation of donor source ideally requires also proof of at least mixed/partial donor chimerism, which generally occurs later in the course of transplantation. The two major factors affecting engraftment are the graft source and the hematopoietic stem cell transplant (HSCT) conditioning regimen. Generally, there are three common sources of HSCT grafts: bone marrow (BM), harvested from the iliac crest; peripheral blood stem cells (PBSC), following G-CSF mobilization of HSC to the peripheral circulation with later collection of these cells by leukapheresis; and cord blood (CB). Champlin et al. (2000) published a large retrospective multivariate analysis which compared results of 288 HLA-identical sibling PBSC transplantations with results of 536 HLA-identical sibling BM transplantations. Patients who received PBSC had signifcantly faster recovery of neutrophils and platelets compared to BM transplants. Neutrophils exceed the threshold of 500 × 106 /L between 2 and 6 days earlier with PBSC than after BM. In an EBMT study, the time interval for engraftment was 12 days for PBSC and 15 days for BM. Platelet recovery is also faster by approximately 6 days, i.e., platelet recovery of 20 × 109 /L was reached at day +15 for PBSC patients and day +20 for patients receiving BM (Schmitz et al. 2002). CB transplant is associated with longer time to engraftment. A large study of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia (ALL), 36% acute myeloid leukemia) in remission analyzed engraftment kinetics and outcomes after a single-unit CB transplantation with myeloablative conditioning regimen. The median time to neutrophil engraftment was 25 days (range 11–108) for children and 23 days (range 11–116) for adult recipients (*P* = 0.6) (Ruggeri et al. 2014). Furthermore, when comparing intensity of conditioning regimens, Slavin et al. (1998) described for the frst time that allogeneic nonmyeloablative HSCT was better tolerated than any standard myeloablative conditioning, with a shorter period of neutropenia and a shorter period of platelet dependence.

Methods of determining donor engraftment rely on the assessment of donor and recipient cell components in the recipient BM or PB, termed as chimerism analysis (see Chap. 12).

# **14.3 Engraftment Syndrome**

Engraftment syndrome (ES) is a clinical condition that is characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy. It occurs at the time of neutrophil recovery after stem cell transplantation (SCT) (Chang et al. 2014; Grant 2020). Most data suggest that ES results from a pro-infammatory state caused by the release of diverse cytokines and other mediators of infammation. Clinical features of ES are similar in children and adults. Criteria for the diagnosis of ES typically include fever (thought to be not from infection) and features of systemic vascular leak, as ES was previously referred to as capillary leak syndrome. ES can resemble acute or hyperacute GvHD giving rise to the question of whether ES is an early manifestation of GvHD (Spitzer 2015).

# **14.4 Management of ES**

ES may be self-limited and require no therapy. Indications for treatment include a temperature of >39 °C without an identifable infectious etiology and clinically signifcant manifestations of vascular leak, especially pulmonary edema. ES is corticosteroid responsive, and treatment is given only as long as symptoms persist, usually for 1 week (Spitzer 2015).

# **14.5 Nursing Considerations**

Due to the potentially devastating outcomes associated with ES, nurses caring for SCT recipients must be aware of ES and its symptoms in order to intervene quickly and appropriately (Thoele 2014). Nursing assessment, in order to identify changes, should include the assessment of the clinical manifestation of ES, with anticipated presentation 9–13 days post-transplantation:

Nursing care should include symptom relief by administration of antipyretics; oxygen for hypoxia; diuretics for weight/fuid gain, edema, ascites, and effusions; and a renal dose of dopamine if needed. Nurses should educate patients and caregivers about the signs and symptoms of ES as well as the treatment and management.

# **14.6 Graft Failure**

Although incidence is relatively low, graft failure (GF), when it does occur, is a major complication associated with a dismal prognosis, particularly in recipients of alternative donor HSCT (Ayas et al. 2015). It remains an important contributor to morbidity and mortality after allogeneic SCT. Recent studies indicate that patients experiencing GF have a lower probability of survival in comparison to those with sustained engraftment of donor cells (Olsson et al. 2013; Locatelli et al. 2014; Wobma et al. 2020).

GF is defned as the lack of hematopoietic cell engraftment following autologous or allogeneic SCT (Lowsky and Messner 2016). It is classically divided into primary or secondary graft failure.

*Primary graft failure* is defned as no evidence of engraftment or hematological recovery of donor cells, of an ANC >500/mL by day +30 in PBSC and BM transplants with associated pancytopenia or by day +42 in CB transplants (2), without evidence of disease relapse.

*Secondary graft failure* is defned as a decline in hematopoietic function (may involve hemoglobin and/or platelets and/or neutrophils) necessitating blood products or growth factor support, after having met the standard defnition of hematopoietic (neutrophils and platelets) recovery (2).

Primary graft failure is usually associated with a more signifcant risk of morbidity and mortality in comparison with secondary graft failure (Olsson et al. 2013; Kato et al. 2013).

# **14.7 Graft Rejection**

The term graft rejection refers to immunemediated rejection of the donor cells by residual host cells because of genetic disparity between the recipient and the donor. Therefore, this term is only relevant to allogeneic transplants (Lowsky and Messner 2016). Immunological rejection of the hematopoietic stem cell graft is a major cause of graft failure (Olsson et al. 2013) primary as well as secondary GF (Wobma et al. 2020). Marrow graft rejection is usually defned by the absence of donor cells in a patient with pancytopenia and reduced marrow cellularity (Martin 2016). Chimerism studies performed by methods of FISH (in sex-mismatched transplant) or by microsatellites enable early diagnosis of GF, and it could be crucial of optimizing the chance of rescuing patients with graft failure (Locatelli et al. 2014). They should be carried out routinely especially in patients who have inadequate marrow function and might be candidates for donor lymphocyte infusion (DLI) or a second transplant (Martin 2016).

# **14.8 Incidence of Graft Failure**

The incidence of GF varies between different transplant modalities, studies, and reports. In autologous transplants, a reasonable estimate of GF is between 1 and 3%. The incidence of GF is higher in allogeneic transplant recipients especially if the patient receives an HLA-mismatched or T-cell-depleted graft or a single-unit CB transplant (Lowsky and Messner 2016). Several studies report the incidence of GF in different transplant settings ranging from 3.8% to 6.8%. Olsson et al. (2013) reported a large retrospective study of 967 transplants performed between 1995 and 2010 an overall GF rate of 5.6%, with a higher incidence of GF in recipients of SCT for nonmalignant disorders. Analysis of 23,272 patients from the CIBMTR database produced a similar incidence of primary GF (5.5%) in patients with hematological malignancies after myeloablative conditioning (Olsson et al. 2015). A retrospective study of a large cohort of 4684 unrelated donor HSCT in the period (2006–2012) confrmed a low rate of graft failure (3.8%) (Cluzeau et al. 2016). In a single center pediatric study that included 290 patients the incidence of neutropenic (failure of neutrophil engraftment by day +28) and non-neutropenic (with neutrophil recovery) GF was 6.6% and 3.8%, respectively (Wobma et al. 2020).

# **14.9 Risk Factors Associated with Graft Failure**

Several risk factors that are associated with GF have been identifed over the years (Fig. 14.1). They may be related to characteristics of the graft, the patient, the donor, or the transplant procedure (Olsson et al. 2015) and in most of the cases the etiology of GF is multifactorial (Valcarcel and Sureda 2018). The conditions that are associated with an increased occurrence of graft failure include:

**Fig. 14.1** Risk factors for graft failure include

Patients with severe aplastic anemia (SAA) have higher incidence of GF due to sensitization to components of red blood cells caused by multiple transfusions; therefore, in SAA transfusions should be minimized prior to transplant.

Hemoglobinopathies (Thalassemia, Sickle-Cell Disease): The incidence of GF or rejection remains high probably due to an intact immune system. GF is particularly high in patients who have heavy iron overload and organ damage due to excessive transfusion and inadequate chelation treatment (Gaziev et al. 2008).

Myeloid Disorders (Myelodysplastic Syndrome (MDS) and Myelofbrosis (MF)): These patients generally do not receive prior intensive chemotherapy and might resist donor cell engraftment, due to the presence of residual host cells (Lowsky and Messner 2016). In addition, patients with absence of complete remission (CR) prior to transplant have more GF compared to patients in CR (*P* < 0.0001) (Cluzeau et al. 2016).

Identifying and assessing the risk factors for GF, prior to transplant, allow clinicians to make more informed choices for their patients with respect to BM versus PB, donor selection, immunosuppressive regimens, and when to plan for a rescue transplant (Olsson et al. 2015). Ensure to include those while facilitating patients' informed consent prior to SCT.

# **14.10 Treatment Options for GF**

Whatever the etiology of graft failure or rejection is, it should be identifed as early as possible and recognized as a serious and life-threatening issue requiring immediate intervention (Wolff 2002; Wobma et al. 2020). Routine monitoring of donor cell engraftment is recommended since the evaluation of chimerism status can be crucial for optimizing the chance of rescuing patients from graft failure (Locatelli et al. 2014). No single drug or strategy has incontrovertibly proven to be superior to others for reversing graft failure; current approaches to limit the detrimental impact of this complication are primarily based on its prevention (Locatelli et al. 2014). No standard approach to the management of graft failure exists (Hege et al. 2016), and the rescue strategies are limited (Servais et al. 2013). The common approaches are listed below.

# **14.10.1 Changes to Immune Suppression**

Early detection of decrease in donor chimerism enables prompt modifcation of the immunosuppressive treatment (Dubovsky et al. 1999). With the exception of patients transplanted for aplastic anemia it is commonly recommended to increase IST (Valcarcel and Sureda 2018). Withdrawal of the immunosuppressive drugs is usually the frst measure, which by itself can control leukemia in a limited number of patients (Yoshimi et al. 2005). In case of persistent mixed chimerism after allogeneic transplant, it remains unclear if withdrawal of immunosuppressive drugs will accelerate or prevent GF. The limitation of this method includes an increased risk of graftversus-host disease.

# **14.10.2 Donor Lymphocyte Infusion**

Donor lymphocyte infusion (DLI) has a potent immunological effect and has been increasingly used to treat relapse, especially molecular relapse, but may also be used to overcome rejection in cases of decreasing donor cell chimerism (Mattsson et al. 2008). Persistent mixed chimerism or declining level of donor cell chimerism is associated with increased risk for GF both in adult and pediatric transplant recipients. A large (*n* = 163) prospective multicenter trial of children with acute lymphoblastic leukemia (ALL) after allogeneic SCT demonstrated that children who developed increased mixed chimerism were at higher risk of developing relapse and can be rescued by preemptive DLI (Bader et al. 2004). Administration of preemptive DLI after day +100 to patients that were withdrawn from immunosuppressive medications enabled 50% of the patients in that study to convert to complete donor type. The majority of the patients required multiple administrations of DLIs. Therefore, DLI may convert mixed donor-host chimerism to full donor chimerism as a surrogate measure to prevent relapse in patients with hematological malignancies (Hale and Petrovic 2014). Frugnoli et al. (2010) reported that escalating doses of DLI is a treatment option for emerging rejection in patients with mixed chimerism following SCT for β-thalassemia. The origin of lymphocytes for DLI could be either frozen aliquots collected from the donor at the time of the original harvest or collected peripherally by leukapheresis or phlebotomy from the donor before DLI (Haines et al. 2015). Side effects of DLI include increased risk of GvHD (Lowsky and Messner 2016) and, in few cases, can lead to marrow aplasia (Mattsson et al. 2008).

# **14.10.3 CD34+ Boost**

Poor graft function is defned by cytopenia of at least two lineages beyond day +28 in patients with complete or near-complete chimerism (Lowsky and Messner 2016). It is manifested by the development of a neutrophil count of <1 × 109 /L (grade 4) and/or platelet count of <50 × 109 /L (grade 3, 25–50 × 109 /L; grade 4, <25 × 109 /L) (Frugnoli et al. 2010). Cytopenias may be due to viral infection, medication side effect, or GvHD (Lowsky and Messner 2016). In patients with continued poor graft function in the absence of graft rejection, a boost of donor stem cells without additional preparative chemotherapy may improve overall function of the graft. Because this boost may induce GvHD, T-cell depletion of the stem cells can prevent this and improve survival in some patients (Mattsson et al. 2008). CD34+-selected cell boosts without a conditioning regimen prior to infusion can be a valid option in order to improve poor graft function, and fully reverse graft failure, especially in patients with complete donor chimerism or predominance of donor hematopoiesis (Locatelli et al. 2014; Servais et al. 2013).

# **14.10.4 Autologous Backup**

Infusion of autologous hematopoietic stem cells (HSC) that were collected and stored prior to transplant can restore hematopoiesis in case of GF. The collection of autologous backup prior to allogeneic transplant is according to center policy. In patients with hematological malignancies or with marrow failure syndromes, the collection of autologous backup is controversial (Lowsky and Messner 2016).

# **14.10.5 Growth Factors**

Administration of growth factors, after autologous transplant, signifcantly shortens the time for neutrophil recovery. In case of poor graft function or GF, it is a reasonable approach until a more defnitive intervention is decided. Following allogeneic transplants, the role of growth factors for patients with poor graft function or GF is unclear. It is a reasonable approach for the management of low blood counts, and depending on the cause, it may or may not be effective (Lowsky and Messner 2016). Certainly, hematopoietic growth factors should be considered in the management of graft dysfunction, especially with partial donor chimerism (Wolff 2002).

# **14.10.6 Regrafting**

A second allogeneic transplant is the only potential long-term curative option for patients with GF and rejection (Remberger et al. 2011; Servais et al. 2013; Locatelli et al. 2014; Cesaro et al. 2015). There are no conclusive data for supporting the choice of using either the same donor of the frst allograft or an alternative donor (Mattsson et al. 2008; Locatelli et al. 2014; Mallhi et al. 2017). Different studies recommend a variety of options depending on the availability of a donor, the patient's clinical condition, and the underlying disease. Gaziev et al. (2008) recommend using the initial donor for second transplant for patients with thalassemia recurrence following the frst graft. The use of the same donor was more frequent in the sibling group compared with the unrelated group, in a report of second transplant in SAA patients. This might be due to the availability of the donor for transplant (Cesaro et al. 2015). However, in patients with an immune-mediated graft rejection, the use of an alternative donor, whenever possible, is recommended (Locatelli et al. 2014). HLAhaploidentical related donors represent an attractive alternative donor source (Albert et al. 2021) for salvage treatment (Teltschik et al. 2016). PB might be the best stem cell source for salvage transplantation (Servais et al. 2013) in order to improve engraftment and thus achieve faster hematopoietic recovery (Cesaro et al. 2015).

There are no uniform criteria about the best conditioning approach for a second SCT in patients who have developed GF although it should differ from that used at the frst transplant (Mattsson et al. 2008; Cesaro et al. 2015; Mahadeo et al. 2019). Many transplant teams favor using an immunosuppressive nonmyeloablative, reduced-intensity conditioning (RIC) regimen in order to avoid unacceptable cumulative toxicities of two consecutive high-dose conditionings given in a short interval of time (Remberger et al. 2011; Servais et al. 2013; Ferrà et al. 2015; Cesaro et al. 2015; Cluzeau et al. 2016; Klein et al. 2021). The optimal reconditioning regimen after graft failure still needs to be defned, and standardized proto-

**Table 14.1** Graft failure and graft rejection

cols are lacking (Teltschik et al. 2016; Sun et al. 2021). It should maintain suffcient immunosuppressive effects to promote engraftment, as well as reduced intensity to lessen the toxicity given that patients are soon after the frst transplantation (Sun et al. 2021).

In general, a second unrelated HSCT is considered a risky procedure with a lower probability of long-term survival on account of a high incidence of GF, noninfectious organ toxicity, and infectious complications. This negative outcome is also infuenced by the type of underlying disease. However, second transplant using related and unrelated donors in SAA patients is feasible with a good chance of long-term overall survival in more than 60% of cases (Cesaro et al. 2015). Second transplant should be considered especially for patients with nonmalignant diseases (Remberger et al. 2011).

In conclusion, GF is a rare complication after allogeneic transplant but is associated with poor outcome. Early identifcation of the patients at risk and aggressive intervention could rescue or prevent some patients from developing GF and limit morbidity and mortality. Table 14.1 summarizes the differences between graft failure and graft rejection.

# **14.11 Pediatric Considerations**

The aim of allogeneic transplant in nonmalignant disease is to achieve sustained engraftment in order to improve the hematopoietic function, to correct the immunocompetence, and/or to increase or normalize the respective enzyme shortage (Bader et al. 2005). Children who may have more than 60- to 70-year life expectancy after undergoing allogeneic transplant may beneft from the approach of reduced-intensity conditioning (RIC) or reduced-toxicity conditioning regimens prior to transplant versus myeloablative conditioning. This is especially true in those with nonmalignant diseases and those with malignant diseases that may have a profound graft-versustumor effect (Satwani et al. 2013). In the last several years, the use of RIC has expanded from adults with high indices of comorbidity to candidates without comorbidities (Satwani et al. 2013) as well as to the pediatric population. In pediatric nonmalignant diseases, RIC is an attractive alternative with the potential for decreased regimenrelated toxicities, lower incidence of long-term complications, as well as preserving fertility. Graft rejection rates are low, especially when stable mixed chimerism is curative if ensured in the lineage that corrects function (Madden et al. 2016). Graft rejection, in children with inborn errors of metabolism undergoing RIC transplants, still remains an obstacle to the success of the transplant since they are immunocompetent (Kato et al. 2016). The incidence of GF in children varies in the different studies. In a large report of 240 classical SCID patients who received allogeneic transplant between 2000 and 2009 by Pai et al. (2014), 18% of the patients received a boost, an additional transplant from the same donor without conditioning (23 children), or a second transplant from a different donor (with or without conditioning) or from the same donor with conditioning (34 children), and 11 children received both a boost and a second transplant at 5 years. A retrospective study by Mitchell et al. (2013) of 135 children with primary immunodefciency reported that 18 patients (13%) required a second SCT due to graft failure or rejection. Satwani et al. (2013) reported a large study of reduced-toxicity conditioning allo-SCT, using both related and unrelated allogeneic stem cell sources in pediatric recipients, with both malignant and nonmalignant diseases. Primary GF occurred in 16 patients (16%) all in unrelated CBT recipients and none in MUD/MSD graft recipients. Chemotherapy naivety was the only signifcant risk factor for primary GF. In a singlecenter study by Balashov et al. (2015), the incidence of primary and secondary GF in primary immunodefcient patients undergoing MUD and haploidentical transplants was 27% (10 out of 37 patients). This accrued in patients that were initially in high risk for graft failure, such as chronic granulomatous disease (CGD) and congenital neutropenia.

However, as with the adult patients, evidence on the optimal management of GF in children is limited; therefore, analysis of pediatric GF is important in order to establish a standard treatment strategy against this rare event (Kato et al. 2013). In recent years several studies have been published recommending using HLAhaploidentical transplant as salvage transplant with variety of reconditioning regimens in nonmalignant disease using post-transplant cyclophosphamide that resulted in excellent engraftment and overall survival (Albert et al. 2021). As well as reconditionig protocoles based on total nodal irradiation (TNI) in both malignant and non-malignant diseases (Wegener et al. 2019). The case report (Fig. 14.2) demonstrates the process of graft rejection, its consequences, and treatment options.

# **14.12 Nursing Considerations**

When a patient fails to engraft, he or she faces a life-threatening situation. Patients experiencing disappointment and fear from the failure of the transplant might express feelings of anger, betrayal, grief, depression, and hopelessness. Similarly, healthcare personnel involved in the patient's care may also feel a sense of failure and grief (Wilson and Sylvanus 2005). General nursing care of patients experiencing GF does not differ from the treatment during the neutropenic period of the transplant, as described in Chap. 7, although nurses should routinely monitor the patient engraftment by daily CBC during the engraftment phase, as it enables to assess for signs of GF as well as delayed engraftment. Chimerism analysis should be evaluated frequently as per local policy, especially in patients that are at risk for GF (Fig. 14.3).

Equally important to the physical care is the emotional support for the patient and family experiencing this devastating, disappointing, and life-threatening situation. Nurses can help to reduce patients' fears by providing accurate, timely information about procedures, symptoms, and feelings that the transplant recipient may experience or is experiencing. Nurses should provide support and education on the diagnosis of GF, treatment options, and decisions regarding the care plan. All information must be individually tailored to the patient and family needs (Wilson and Sylvanus 2005).

Nurses caring for patients who undergo SCT should be aware of the possibility of graft failure following the transplant. They should know the risk factors associated with GF and the treatment options available. This will lead to a better understanding and recognition of this rare but lifethreatening situation. The possibility of GF should be discussed with the patient and his family prior to transplant, and they should be counseled with regard to the risk factors for developing GF. The nursing literature regarding graft failure remains scarce with no recent study on the implications and the support needed for the patient who develops graft failure.

#### **Case report- Late graft rejection Fig. 14.2** Case report

An 8 month old baby was initially referred for an evaluation due to BCGigitis after a BCG vaccine. He was diagnosed with X**-** linked chronic granulomatosis disease (CGD) GP91 deficiency. Prophylactic antibiotics with resprim and sporanox were started and he had no further infections. He underwent a bone marrow (BM) transplant on 09-03- 2017 from his HLA-matched healthy sister. The conditioning regimen was according to the EBMT/ESID guidelines for hematopoietic cell transplant for primary immunodeficiencies ESID D- reduced intensity protocol, including treosulfan, fludarabine and ATG. GvHD prophylaxis was based on mycophenolate (MMF) and cyclosporine (CSA). He developed CMV reactivation on day -2 that was successfully treated with Foscarnet. He suffered from peri-orbital cellulitis during neutropenic period and was treated with Tazocin. The remaining course of the transplant was uneventful. He engrafted on day + 12 with 96% donor cells by XX FISH analysis. MMF was stopped on day +97 post-transplant with no signs of GvHD. On day +147, he developed skin rash suspected of GvHD which resolved without treatment**.** CSA was stopped 8 month post-transplant. During the follow-up month post-transplant, the % of donor cells was gradually decreasing reaching 10% at one year post-transplant. Of note, the patient was in good clinical condition with no infections. Additional test included CGD-DHR (diagnostic test for CGD), that was abnormal. Split chimerism test showed that only 3.5% of the granulocytes were of donor origin. He was diagnosed with late graft rejection. On 22-10-2018 he was hospitalized due to fever and lung infection diagnosed by CT scan and was treated empirically with Voriconazole with resolution of the fever. The need for second transplant was discussed with family. In the absence of another matched family donor, it was decided to use the same donor as in the first transplant. A second BM transplant was performed on 08-09-2019; two years and a half post the first transplant .The conditioning regimen was based on ESID A- myeloablative protocol with busulfan and fludarabine. GvHD prophylaxis was based on CSA, MTX and MMF. Engraftment was on day +12 post-transplant with 85% donor cells by XX FISH analysis which gradually increased to 99%. His second transplant course was uneventful and he was discharged on day +21. Currently, he is in a very good general condition, good immune reconstitution and started his re-immunization program. Chimerism is stable with 99.8% of donor cells by FISH analysis.

This unique case presents the development of late graft rejection that was successfully treated with a second transplant. In non-malignant disorders as CGD stable mixed chimerism (>20% myeloid) is sufficient to protect against the risk of infections (Lankester et al. 2021(1)). The first transplant failed to correct the underlying dysfunction of the neutrophils. Since the patient was without immune suppression therapy, the only curative option was a second transplant. A second transplant after reduced intensity conditioning, with myeloablative protocol is feasible and safe with very good outcome, especially when performed late when the patient recovered from the first transplant.

Using the same minor sibling donor is a matter of concern for the family, but in a situation without another suitable donor, the benefit should be explained to the parents and the donor.

The donor that was 6 years and 9 month old gave her assent for the donation as per local protocol and was followed by a donor advocate

Emotional support for patient experiencing graft failure

**Fig. 14.3** Be aware of

# **References**

immunodefciency: a report from the Australian and New Zealand Children's Haematology oncology group and the Australasian bone marrow transplant recipient registry. Biol Blood Marrow Transplant. 2013;19:338–43.

lative allogeneic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2019;104(1):137–43.

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# **Late Efects and Long-Term Follow-Up 15**

Michelle Kenyon, John Murray, Barry Quinn, Diana Greenfeld, and Eugenia Trigoso

#### **Abstract**

Allogeneic stem cell transplantation was successfully performed in 1968, and its use has grown signifcantly over the past fve decades with the total number now exceeding 1.5 million patients (Niederwieser et al. Haematologica. 107:1045–1053, 2022). HSCT is a curative treatment for many haematological cancers and other disorders. Almost 40,000 HSCT procedures are performed Europe-wide per annum (Passweg et al. Bone Marrow

M. Kenyon (\*)

Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK e-mail<EMAIL_ADDRESS>
J. Murray

Haematology and Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK e-mail<EMAIL_ADDRESS>
#### B. Quinn

School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK e-mail<EMAIL_ADDRESS>
#### D. Greenfeld

Paeidatric Transplant Unit, Hospital Universitario y Politécnico LA FE, Valencia, Spain

Transplant. 51(6):786–92, 2016), and the number of transplant recipients achieving 'longterm survival' and with late effects directly related to their treatment (Majhail et al. Hematol Oncol Stem Cell Ther 5(1):1–30, 2012) is increasing (Penack et al. Blood Adv 4:6283–6290, 2020). This growth in survivors is the result of improvements in transplant knowledge and expertise, refnements to conditioning regimes, developments in supportive care and increased numbers of procedures due to broadening transplant indications.

The most common cause of death after transplant is relapsed disease. Yet, even without disease relapse, long-term survival is complex for many as other causes of mortality such as graft versus host disease (GvHD), infection, second malignancy, respiratory disease and cardiovascular disease (CVD) (Savani et al. Blood. 117:3002–9, 2011) prove diffcult to address.

Recovery post-HSCT is challenging, lasting several months to years. These individuals are susceptible to the development of posttreatment physical and psychological sequelae years to decades after completion of treatment leading to a reduced life expectancy with greater morbidity when compared to an ageadjusted population (Socié et al. N Engl J Med 341:14–21, 1999). Survivors with late effects experience signifcantly poorer physical and mental health, report more unmet needs for

Specialised Cancer Services, Sheffeld Teaching Hospital NHS Foundation Trust, & Department of Oncology and Metabolism, The University of Sheffeld, Sheffeld, UK

e-mail<EMAIL_ADDRESS>
E. Trigoso

Furthermore, as the number of survivors continues to grow, their long-term health problems and subsequent needs demand increasing resource and attention from late effects services. These services must remain agile and responsive, develop capacity to provide continuing expertise and oversight and collaborate with the other specialist services for input when needed.

The unpredictable, complex and multifactorial nature of these long-term and late effects in HSCT survivors means that patients require regular life-long assessment guided by rigorous protocols. However, it is important to remember that even using standardised protocols, these should be different for adults and children and the resulting care must be tailored to the needs of the individual. And fnally, further consideration is needed for the growing number of young people and adult survivors in long-term follow-up who have been treated in childhood and transitioned into adult long-term followup care.

#### **Keywords**

Late effects · Survivorship · Survivors · Follow-up

# **15.1 Principles of Care**

Protocol-led assessment and treatment is included in the current FACT-JACIE standards (version 8, 2021), which has evolved the standard of care recommending the assessment of recipients for evidence of acute and chronic GVHD, need for vaccinations and post-transplant late effects.

*B7.12 54 There shall be an infrastructure and policies or standard operating procedures in place for provision of appropriate long-term follow-up, treatment and plans of care.*

*B7.12.1 There should be policies or standard operating procedures in place for post-transplant vaccination schedules and indications.*

*B7.12.2 There shall be policies and standard operating procedures for monitoring by appropriate specialists of recipients for post-cellular therapy late effects, including at a minimum:*

*B<IP_ADDRESS> Endocrine and reproductive function and osteoporosis*

*B<IP_ADDRESS> Cardiovascular risk factors*

*B<IP_ADDRESS> Respiratory function*

*B<IP_ADDRESS> Chronic renal impairment*

*B<IP_ADDRESS> Secondary malignancies*

*B<IP_ADDRESS> Growth and development of paediatric patients.*

B7.12.3 There shall be policies or standard operating procedures describing the transition of long-term paediatric recipients to adult care as appropriate*.*

A further beneft of life-long survivorship care is the acquisition of knowledge and understanding through data collection and analysis which in turn facilitates the design and delivery of appropriate services that will better meet the needs of future survivors.

*Late effect: A health problem that occurs months or years after a disease is diagnosed or after treatment has been administered. Late effects may be caused by the primary disease or its treatment and may include physical, mental or social problems and/or secondary cancers* (ISCT, FACT-JACIE standards 2021).

# **15.2 Survivorship and Quality of Life**

While there are many defnitions of survivorship, it is widely accepted that a survivor is anyone living after a diagnosis of cancer or 'living with and beyond cancer'.

Survivorship includes 'those who are undergoing primary treatment, those who are in remission following treatment, those who are cured and those with active or advanced disease' (DoH 2010).

By developing and implementing strategies to improve the care and support for HSCT survivors, we will also improve their quality of life and experience of care.

There are a broad range of issues experienced by HSCT survivors which are detrimental to overall quality of life (QoL) and have been reported in the literature.

Unmet physical or psychological needs are reported in 60% of cancer survivors. Beyond the frst post-HSCT year, a ffth report psychosocial diffculties including fatigue, social reintegration, fnance and employment. A third worry about the future and their health (Baker et al. 1999; Andrykowski et al. 2005; Gielissen et al. 2006).

Finance, employment and education are leading survivor concerns. The economic cost of cancer is a substantial personal and societal problem; 92% of sufferers lose income, impacting adversely on QoL for 40% (Bieri et al. 2008). These are among the major challenges that significantly hinder the cancer patient survivorship transition from treatment phase to reintegration phase and limit the post-HSCT potential for personal growth and fulfilment. A more recent study (Hahn et al. 2017) using Survivor Unmet Needs Survey (SUNS) in HSCT recipients attending a long-term follow-up clinic between 2006 and 2012 supports the finding from these earlier works. The top 5 specific unmet needs for autologous HSCT patients were inability to set future goals/ long-term plans, changes in appearance, bad memory/lacking focus, losing confidence in abilities, and paying household or other bills. For allogeneic HSCT patients these 5 unmet needs were: ability to earn money, pay bills, feeling tired, feeling depressed and dealing with others' expectations of 'returning to normal'.

Work and education are immensely important to cancer survivors (Snyder et al. 2002) and have health benefts, and interventions addressing return to work are cost-effective (Waddell and Burton 2006). Reintegrated survivors are more likely to self-manage (Richards et al. 2013), make a positive contribution to self and society, depend less on the state fnancially and potentially reduce healthcare costs.

A range of psychological and psychosocial interventions including education, exercise, counselling, cognitive behavioural therapy (CBT) and psychotherapy have been investigated, aiming to address survivor concerns and improve overall quality of life.

# **15.2.1 Quality of Life Assessment**

There is a new emphasis on understanding and monitoring the concerns and outcomes for cancer survivors through the routine use of patientreported outcome measures (PROMs) in followup services. Quality of life (QoL) is an important outcome measure following HSCT. Treatmentspecifc QoL tools exist and have been validated in patients receiving haematopoietic stem cell transplant.

Instruments for assessing QoL can be general or specifc to a certain disease or treatment. A number of cancer-specifc tools (QLQ-LEU, EORTC SF 36, FACT-G/ FACT-BMT) exist and can be seen in publications of large-scale studies. They are often holistic, assessing different dimensions of well-being, such as physical, emotional, social/family and functional. Many of the commonly used scales such as EORTC and FACT are self-complete and produce a numeric score from which an inference on the relative QoL can be drawn.

These holistic assessments can be used to collect information on individuals at set time points during treatment and recovery and also can increase our knowledge of our patients as a group or groups. QoL data can help us to understand the differences between groups, e.g. comparing QoL in male versus female recipients or haploidentical versus cord recipients.

Standardised assessment tools can reveal information in certain groups or individuals that may not have been previously identifed through conventional outpatient consultation alone. This can lead to increases in referrals to other services such as counselling, assisted conception, sexual dysfunction, social work, etc.

At a local level, this increase in referrals can have resource implications, but it can also lead to:

Furthermore, this information can be used to:

This holistic approach to assessment can be validated for patients while identifying individual information and supportive care needs. These needs can be met through a discussion with a healthcare professional, which is supported by written or multimedia materials and offers signposting for individuals to high-quality information and support (Table 15.1). The table below illustrates the most common issues expressed through assessment. They are multidimensional in nature representing psychological, physical and functional concerns.

**Table 15.1** Top 10 common concerns (www.eHNA/ Macmillan.org.uk analysis 2015)

Accessed May 2022 https://www.macmillan.org.uk/\_ images/using-ehna-data-to-explore-needs\_tcm9-298084. pdf

# **15.2.2 Common Post-HSCT Concerns**

#### **<IP_ADDRESS> Physical Well-Being**

Most studies found that survivors report resumption of routine physical activities but describe a greater number of medical problems (Mosher et al. 2009). Fatigue is one of the most commonly reported concerns, and many HSCT patients are dissatisfed with their energy levels many years after treatment. More recently, a systematic review (Oberoi et al. 2018) concluded that physical activity was effective at reducing fatigue in cancer and HSCT recipients and determining the best approaches for safe implementation should be a priority for further research.

Additionally, providing information materials and education on fatigue management is a key area where nurses can positively infuence this troubling issue (Anderson et al. 2007; Andorsky et al. 2006).

#### **<IP_ADDRESS> Psychological Distress**

It is known that 5–19% of HSCT survivors exhibit symptoms that are consistent with posttraumatic stress disorder (PTSD). In those without PTSD, four out of ten report clinically signifcant psychological distress at an average of 3.4 years post-transplant. The same study found that there was no difference by age, gender, transplant type or time following transplant (Rusiewicz et al. 2008). Kuba's more recent study (Kuba et al. 2017) investigated cancer-and-treatmentspecifc distress (CTXD) and its impact on symptoms of post-traumatic stress disorder (PTSD) in patients undergoing allogeneic HSCT. The results emphasise the major burden of uncertainty pre-HSCT and the impact of uncertainty and concerns regarding appearance and sexuality on PTSD symptomatology. Understanding the subtleties of psychological distress more generally (e.g. fear, guilt, loss of control) in HSCT patients is imperative to optimising the psychological well-being of this vulnerable population (Amonoo et al. 2020).

#### **<IP_ADDRESS> Return to Work (RTW)**

HSCT survivors return to work despite ongoing physical and psychological symptoms. Younger age and higher levels of education have been linked to a higher probability of post-transplant employment. Those who are unsuccessful in returning to work have poorer physical, cognitive and social functioning and report more pain, sleep disorders and distress (Mosher et al. 2009).

With this in mind, improving our understanding of the issues around work for these patients is highly relevant. Persoon et al. (2019) conducted a qualitative study to identify HSCT survivors' work perceptions; barriers to and facilitators of return to work (RTW); and possible solutions to improve RTW generating some important insights. RTW was often characterised as a complex and prolonged trajectory. Work perceptions varied between patients; most valued work as positive, but some also reported a decline in work capacity and/or in importance. Perceived barriers included treatment duration and side effects, presence of comorbidity and poor health pre-diagnosis and diffculties commuting. Perceived facilitators were fnancial incentives, keeping in touch with the workplace and support of other patients and family. Proposed solutions to improve RTW included discussing RTW at the hospital, enhanced employer support and improved access to rehabilitation programs.

While return to work or education is important to survivors, in guiding our patients, it is essential to consider the following:

	- Physical demand
	- Environment
	- Routine
	- Hours
	- Phased return is usually the optimal way of enabling people to return to work progressively.
	- Many people need to return to work due to mounting fnancial diffculties.

– Some people feel 'lost' without their work identity and feel a sense of urgency to return.

#### **<IP_ADDRESS> Sexuality**

Evidence suggests that sexual function is one of the most prevalent and persistent long-term concerns after HSCT.

Despite its prevalence and the range of concerns that can be experienced across the entire sexual response cycle (El-Jawahri et al. 2018; Majhail 2017) sexuality and sexual function issues are under-reported. A range of sexual concerns have been described with a tendency for women to report more problems than men and women continue to describe more sexual concerns a number of years post-transplant (Mosher et al. 2009). Sexual function is typically multifactorial in origin with endocrine, mechanical and psychological factors. In their review on HSCT and sexuality, Thygesen et al. (2012) report on 14 quantitative studies that examined sexual function after HSCT. Sexual dysfunction is common following both autologous and allogeneic HSCT. Those that resume sexual relations in the frst post-transplant year tend to experience fewer long-term issues (Jean and Syrjala 2009), but many survivors continue to experience profound sexual dysfunction even 5–10 years post-HSCT (Thygesen et al. 2012). The partners of patients who have undergone allogeneic HSCT are also negatively impacted. Poloméni et al. (2016) found that 75% of both patients and partners reported negative effects on their sexual life, and 30% of patients and 50% of partners reported negative effects on their couple life.

More recently, Gjærde et al. (2022) reported their European multicentre cross-sectional study of adult allo-HSCT recipients surviving >2 years and their partners. They focused on sexual functioning after transplant and evaluated whether a discussion of sexual functioning was perceived to have taken place between the transplant team and the survivor and partner. Of the 136 survivor and 81 partner participants, 47% of male and 65% of female survivors and 57% of male and 59% of female partners reported clinically relevant sexual problems. Sixty-two percent of survivors and 79% of partners reported that sexual functioning had not been discussed with them during transplant.  A key factor is to make no assumptions about the person or their sexuality or their choice of sexual expression. Make it clear to the person that you are willing to help and support them with any sexual concerns and questions. In a busy technical environment, the person may be seeking permission from those caring for them, to talk about these important concerns.

Sexuality is also about more hidden elements, including how people perceive themselves as sexual beings and the need to be recognised, respected, connected with, loved and cared for by others (Quinn 2010). Whether the person is in a relationship (gay, lesbian, heterosexual), is single or enjoys sex with one or multiple partners, most people will have sexual needs and desires throughout their lifespan (Oskay et al. 2014). There is a danger that in seeing sexuality as merely a physical expression that the haematology and transplant care team may fail to see that sexuality is about the whole person including how they relate to others in an intimate way (Oskay et al. 2014).

Whether the patient is or is not sexually active during the prolonged treatment period, before, during and after transplant, patients will need support and advice from the team caring for them, on sexual changes, choices and concerns. Sex and sexuality are largely seen as a very private matter, and a patient and/or partner may be reluctant to talk about their concerns or unexpected changes to a member of the transplant team who appear busy dealing with other aspects of the treatment process (Jean and Syrjala 2009, Roth et al. 2010, Mulhall 2008). It is important that the team makes it clear that they are there to help, and that support is available. There may be a misconception from some members of the transplant team that a person undergoing a stem cell transplant will not have an interest in sex.  What that means for each person and how they will express that need throughout periods of their life may change and develop.

For some, people being sexually intimate with their partner during the treatment and transplant process may bring comfort, reassurance and hope, amidst ongoing uncertainty and change, while others will have no interest in being sexually active. However, feeling loved, accepted and cared for as one faces the uncertainty of transplantation may bring great comfort to the person and their partner (Jean and Syrjala 2009; Schover 1997).

In a busy haematology or transplant setting, the team can help to facilitate times of privacy when the individual can be alone or with their partner, if this is what they wish. The transplant team who recognise the importance of these intimate moments can often organise and plan treatments and interventions, at less acute points in the transplant process, in order to provide these moments or times of privacy. The diagnosis of any serious illness and the treatments and changes required may have a profound impact on the person and/or partner, affecting them physically, emotionally, socially and spiritually (Brandenburg et al. 2010). People may beneft from times of relaxation, massage therapy, aromatherapy or other complementary procedures.

Facing the reality of temporary or permanent infertility and the multiple body and life changes secondary to disease and treatments can affect a person's identity and how they perceive themselves. The physical and psychological demands of dealing with a serious illness, the transplant demands and setting, can interfere with the human sexual response cycle (desire/interest, arousal, readiness (penetration), orgasm and resolution, satisfaction). Any of these points on the response cycle may be affected, but these can be sensitively addressed by a caring practitioner (Quinn 2010; Schover 1997).

# **15.3.1 Providing Support and Information**

The team can sensitively support the person and the partner through the transplantation process and treatments, mindful of the impact on the person's sexual being. This includes providing accurate information on potential sexual changes that may occur, practical advice on the choice of treatment and interventions and a listening ear. Many sexual concerns arising in the haematology and transplant setting can be resolved or certainly reduced by a member of the team simply listening to the person's concerns and knowing how and where to access practical and expert help, if required (Katz and Dizon 2016; Quinn 2010). It is worth considering the impact of other co-existing morbidities, and the treatments required for these conditions on the person's sexuality and their ability to have sex.

In addressing sexual concerns, the transplant team can be proactive in supporting the person with body changes and psychological concerns. Members of the team who are aware of the possible impact that treatments, the transplant and supportive medications may have on a person's sexuality will be better able to speak to the person sensitively, honestly and clearly before the commencement of treatment. These issues should be an important part of the preparation for treatment and transplantation (Quinn 2010; Jean and Syrjala 2009).

Facing the reality of temporary or permanent infertility and the multiple body and life changes secondary to disease and treatments can affect a person's identity and how they perceive themselves. The physical and psychological demands of dealing with a serious illness, the transplant demands and setting, can interfere with the human sexual response cycle (desire/interest, arousal, readiness (penetration), orgasm and resolution, satisfaction). Any of these points on the response cycle may be affected, but these can be sensitively addressed by a caring practitioner (Quinn 2010; Schover 1997).

# **15.3.2 Addressing Fertility Concerns**

Many of the chemotherapy agents used in the haematology and transplant setting can affect the person's fertility including alkylating agents which are known to cause most damage, resulting in either temporary or permanent infertility. For many young patients, this may be the frst time that they have had to consider the possibility of planning children, and this will require support from the team, family and friends. Facing the possibility of being infertile can have a profound effect on how the person feels about themselves and their place in the world. Patients will be advised not to plan children during the treatment as the drugs and the demanding treatment requirements will affect the development of the embryo leading to foetal defects and miscarriage. For some people/couples, it may be very painful having to put their plans for a family on hold during the treatment and transplant period.

Occasionally a woman may discover a cancer diagnosis during her pregnancy and may be advised to undergo a medical termination because the pregnancy will not be viable and/or in order to proceed with necessary treatment. This can be a very diffcult time for the woman and her partner; sometimes the full impact of this loss becomes more apparent following the completion of treatment. The team can be there to talk about the impact of treatment and to support and advice on the possible options available to support fertility (Schover 1997).

For men this may include sperm banking and the possibility of cryopreservation of testicular tissue, generally used for younger patients. For women, this may include cryopreservation of embryos or eggs and ovarian preservation. In some cases, the urgency of treatment may mean that fertility-saving options are not possible. During the transplant process, the focus for everyone including the patient may be on treating the disease, and the reality of being infertile becomes more important in the months and years following transplantation. This can be extremely diffcult for patients who are beginning new relationships and have to disclose this to their new partner. This reality can be addressed at follow-up clinics both in the hospital and community, ensuring the person has support that they can access. Individuals and couples may need support and advice over their concerns of having passed or passing on genes to their children predisposing them to a higher risk of cancer (Quinn 2010).

Support may take the form of practical advice, including adjusting to an altered sex life during treatment, adequate pain/symptom control, comfortable positioning during sex, contraception, providing private moments, advice on sexual aids and medical treatments or simply an opportunity to talk about concerns and fears (Table 15.2). Practical support and guidance can help the person returning to sexual activity after transplantation or simply regaining confdence in being sexually expressive again.

Many of the treatment agents (chemotherapy, targeted therapies and radiation) used in the feld of haematology and transplantation are known to cause specifc problems which can lead to lower sex drive, vaginal dryness (which may cause pain during intercourse), erection concerns, ejaculation and orgasm diffculties (which may lead to loss of confdence and lack of sexual enjoyment) (Brandenburg et al. 2010). Some drugs including the vinca alkaloids and some targeted therapies may cause nerve damage giving rise to erectile dysfunction and to ejaculation and orgasm diffculties. Following total body irradiation, a small number of patients may experience damage to the

nerve, vascular and muscle tissue giving rise to possible erectile diffculties, including the inability to get or maintain an erection suitable for sexual penetration or vaginal changes including stenosis and/or dryness which may cause pain during sexual intercourse. Women may beneft from the team explaining the use of vaginal lubricants and dilation to prevent vaginal stenosis.

Men may require support in exploring treatment options for erectile concerns. These complications may require interventions including advice on oral medications (sildenafl, tadalafl, vardenafl), pellet (intraurethral alprostadil) (MUSE), injection (intracavernosal alprostadil) and appliances (vacuum device) to address erectile dysfunction (Katz and Dizon 2016).

Hormone replacement therapy unless contraindicated may have a role to play, alongside, an opportunity to talk through fears and concerns and/or psychosexual therapy support (Brandenburg et al. 2010). If patients are sexually active during treatment, the team may advise them to use some form of barrier method (condoms, femidoms, dental dams) (Quinn 2010). This is to prevent pregnancy and to protect the patient's partner from the minimal risk of irritation caused by a small amount of chemotherapy agents remaining in bodily fuids such as semen, urine and rectal and vaginal secretions. These barrier methods may also reduce the risk of infection especially if the patient is at risk of neutropenia and prolonged immunosuppression. While individuals are advised to take steps to prevent infection, rarely should this prevent the person from enjoying sex with a partner. Occasionally the team may learn of partners no longer sleeping in the same bed for fear of contamination to their partner; the team can reassure the couple that this is not necessary and they can continue with their usual sleeping arrangements.