STEP 6: Managing relapsed or refractory disease
Patients who present with relapsed or refractory disease should be managed by a multidisciplinary team and offered timely referral to appropriate physical, practical and emotional support.
The likelihood of relapsed or refractory disease is increased in patients who cannot tolerate standard consolidation treatment and in patients with intermediate/adverse risk factors not proceeding to transplantation.
Supportive care is integral to the care of all patients with relapsed or refractory AML.
For patients suitable for active anti-leukaemia therapy, repeat assessment of relevant genomic abnormalities is appropriate, even if no targetable lesions were identified in the initial diagnostic assessment.
Where patients have exhausted specific anti-leukaemic therapies or are intolerant of further anti-leukaemic therapy, symptomatic management is preferred, with the priority focused on quality of life.
Relapse occurs in more than 50 per cent of patients, and treatment outcomes will vary depending on individual prognostic factors. Most cases of relapsed AML are diagnosed through routine follow-up or by the patient presenting with symptoms.
Molecular monitoring for MRD is recommended for patients with APL, CBF leukaemia and NPM1 mutant AML (Döhner et al. 2010, 2017; Sanz et al. 2019). Comprehensive guidelines about the performance, monitoring frequency and interpretation of MRD technologies (flow cytometry and molecular) are available (Schuurhuis et al. 2018).
In general, bone marrow sampling is more sensitive than peripheral blood monitoring. The optimal frequency and duration of testing continues to be refined, with current guidelines provided by Schuurhuis et al. (2018).
If relapse is suspected, investigations should include:
- full blood count with blood film examination
- bone marrow aspiration and trephine, including flow cytometry, cytogenetic analysis and molecular testing (depending on clinical context).
Managing relapsed or refractory disease is complex and should therefore involve all the appropriate specialties in a multidisciplinary team including palliative care where appropriate. From the time of diagnosis, the team should offer patients appropriate psychosocial care, supportive care, advance care planning and symptom-related interventions as part of their routine care. The approach should be personalised to meet the patient’s individual needs, values and preferences. The full complement of supportive care measures as described throughout the optimal care pathway and in Appendices A and B, and in the special population groups section should be offered to assist patients and their families and carers to cope. These measures should be updated as the patient’s circumstances change.
Access to the best available therapies, including clinical trials are crucial to achieving the best outcomes for anyone with relapsed or refractory disease. Novel therapies are becoming available for patients with relapsing and refractory disease. Identification of relevant targets may require repeat molecular assessment to identify lesions newly emergent at the time of treatment failure.
Survivorship care should be considered and offered at an early stage. Many people live with advanced cancer for many months or years. As survival is improving in many patients, survivorship issues should be considered as part of routine care. Health professionals should therefore be ready to change and adapt treatment strategies according to disease status, prior treatment tolerance and toxicities and the patient’s quality of life, in addition to the patient’s priorities and life plans.
If there is an indication that a patient’s cancer has returned, care should be provided under the guidance of a treating specialist. Each patient should be evaluated to determine if referral to the original multidisciplinary team is necessary. Often referral back to the original multidisciplinary team will not be necessary unless there are obvious aspects of care involving different therapeutic and supportive care disciplines not otherwise accessible. The multidisciplinary team may include new members such as palliative care specialists.
The intent and nature of treatment will depend on the location, extent of relapsed or refractory disease, previous management, comorbidities and the patient’s preferences.
In managing people with relapsed AML, anti-leukaemia treatment may include these options:
- intensive re-induction – chances of success are better after a longer duration of the first remission and can be estimated using the European Prognostic Index (Breems et al. 2005)
- enrolment into a clinical trial – trials evaluating the use of novel agents should be strongly considered
- allo-SCT
- irradiation of infiltrative/mass lesions (solitary chloromas) and craniospinal irradiation in the event of central nervous system disease
- regular transfusional support with red cells and platelets should be administered where appropriate.
If treatment is given with curative intent, the facilities need to be of the same level as for the initial therapy. Palliative chemotherapy may be delivered in a less specialised environment. Allo-SCT must be delivered only in specialised units with appropriate accreditation as well as human and physical resources.
The potential goals of treatment should be discussed, respecting the patient’s cultural values. Wherever possible, written information should be provided.
Encourage early referral to clinical trials or accepting an invitation to participate in research.
Advance care planning is important for all patients with a cancer diagnosis but especially those with advanced disease. Patients should be encouraged to think and talk about their healthcare values and preferences with family or carers, appoint a substitute decision-maker and consider developing an advance care directive to convey their preferences for future health care in the event they become unable to communicate their wishes (AHMAC 2011).
Refer to section 4.4 ‘More information’ for links to resources.
Refer patients and carers to Advance Care Planning Australia or to the Advance Care Planning National Phone Advisory Service on 1300 208 582.
Early referral to palliative care can improve the quality of life for people with AML and in some cases may be associated with survival benefits (Haines 2011; Temel et al. 2010; Zimmermann et al. 2014). The treatment team should emphasise the value of palliative care in improving symptom management and quality of life to patients and their carers. Refer to section 4.4 for more detailed information.
The lead clinician should ensure timely and appropriate referral to palliative care services. Referral to palliative care services should be based on the patient’s need and potential for benefit, not prognosis.
Refer to the end of section 4.4 ‘Palliative care’ for links to resources.
Participation in clinical trials, registries and tissue banking, where available, is considered tandard of care for patients with AML. Cross-referral between clinical trials centres should be encouraged to facilitate participation.
For more information visit the Cancer Australia website.
See validated screening tools mentioned in Principle 4 ‘Supportive care’.
A number of specific challenges and needs may arise at this time for patients:
- assistance for dealing with emotional and psychological distress resulting from fear of death or dying, existential concerns, anticipatory grief, communicating wishes to loved ones, interpersonal problems and sexuality concerns
- potential isolation from normal support networks, particularly for rural patients who are staying away from home for treatment
- cognitive changes as a result of treatment and disease progression such as altered memory, attention and concentration (a patient may appoint someone to make medical, financial and legal decisions on their behalf – a substitute decision-maker – before and in case they experience cognitive decline)
- side effects resulting from high-dose chemotherapy including alopecia, fatigue, damage to the bone marrow and other quickly growing tissues, immunosuppression, fluid retention, dyspnoea, GVHD, organ toxicity (interstitial pneumonitis, veno-occlusive disease), episodic hypotension and pulmonary infiltrates
- chemically induced menopause that leads to atrophic vaginitis and dyspareunia, and changes in androgens that may alter libido function and orgasm (these issues require sensitive discussion)
- differentiation syndrome – early recognition and prompt initiation of corticosteroids is required (NCCN 2019) and consideration given to interrupting therapy
- gastrointestinal symptoms such as nausea, vomiting, severe mucositis, loss of appetite, dysgeusia, diarrhoea or constipation as a result of treatment, which requires optimal symptom control with medicine, total parenteral nutrition, analgesia and mouth care (referral to a dietitian may be required if dietary intake is affected)
- decline in mobility or functional status as a result of recurrent disease and treatments (referral to physiotherapy or occupational therapy may be required)
- coping with hair loss and changes in physical appearance (refer to the Look Good, Feel Better program– see ’Resource List’)
- appointing a substitute decision-maker and completing an advance care directive
- financial issues as a result of disease recurrence such as gaining early access to superannuation and insurance
- legal issues (completing a will, care of dependent children) and making an insurance, superannuation or social security claim on the basis of terminal illness or permanent disability.
For patients treated with allo-SCT, additional supportive care may be required to address the immunosuppressive and long-term side effects of therapy. Issues may include infertility, GVHD, increased risk of infection, anaemia, bleeding, mouth ulcers and fatigue.
Rehabilitation may be required at any point of the metastatic care pathway, from preparing for treatment through to palliative care. Issues that may need to be dealt with include managing cancer-related fatigue, improving physical endurance, achieving independence in daily tasks, returning to work and ongoing adjustment to cancer and its sequels.
Exercise is a safe and effective intervention that improves the physical and emotional health and wellbeing of cancer patients. Exercise should be embedded as part of standard practice in cancer care and be viewed as an adjunct therapy that helps counteract the adverse effects of cancer and its treatment.
The lead clinician should ensure there is adequate discussion with patients and carers about the diagnosis and recommended treatment, including treatment intent and possible outcomes, likely adverse effects and the supportive care options available.
Refer to Principle 6 ‘Communication’ for communication skills training programs and resources.
