STEP 6: Managing refractory, relapsed, residual or progressive disease
Step 6 is concerned with managing refractory or relapsed disease. Patients should be provided care under the guidance of a treating specialist and each patient should be evaluated to determine if referral to multidisciplinary team is necessary. Patients should also be offered timely referral to receive appropriate physical, practical and emotional support.
Step 6 is concerned with managing relapsed or progressive disease.
Cml is rarely cured and, in most cases, disease will recur or progress after initial therapy. The rate of progression is usually gradual, although typically it is slightly more rapid after initial diagnosis. An increase in lymphocyte count does not automatically mean further treatment is needed. Many patients who have relapsed cml but no symptoms can be safely and appropriately monitored.
Therapy should only be restarted when there are other signs or symptoms of disease progression.
Nearly all patients with CML are asymptomatic, so refractory or relapsed disease is generally picked up during monitoring of molecular response. This can be assessed using the ratio of BCR-ABL1 transcripts to the control gene transcripts. According to the European LeukemiaNet
2020 recommendations for treating CML, a BCR-ABL1 of greater than 10 per cent at three months indicates treatment failure when confirmed (Hochhaus et al. 2020).
It is important to assess for the reason why the patient is not responding well to treatment. They may be resistant to TKIs, they may not be adhering to treatment for various reasons, or they may be experiencing drug interactions (Hochhaus et al. 2017).
Patients with treatment failure should have a bone marrow examination to determine/confirm the CML phase and document clonal cytogenetic changes. CML cells should be tested for their BCR–ABL1 mutational profile to help select an appropriate TKI (Hochhaus et al. 2017).
Mutational analysis is recommended for patients who:
- develop accelerated or blast phase CML
- experience treatment failure on their current TKI therapy.
According to the European LeukemiaNet 2020 guidelines (Hochhaus et al. 2020), mutations account for about a third of treatment-resistant cases in patients in the chronic phase and about two-thirds of treatment-resistant cases in patients in accelerated or blast phase.
Managing patients who are not achieving optimal response is complex. Each patient should be evaluated to determine if referral to a multidisciplinary team is necessary. 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, B and C should be offered to assist patients and their families and carers to cope. These measures should be updated as the patient’s circumstances change.
If there is an indication that a patient’s CML is not responding optimally or has re-emerged after a period of control, care should be provided under the guidance of a treating specialist. Each patient should be evaluated to determine if referral to a multidisciplinary team is necessary.
When managing people with CML who have treatment failure or resistance, treatment will depend on the degree and timing of failure, mutation analysis, age, comorbidities and adherence and toxicity to prior TKIs. Note that poor compliance with TKI therapy is the most common reason for treatment failure.
Treatment may include:
- second-line treatment with a second- or third-generation TKI
- third-line treatment with an alternative TKI such as ponatinib or asciminib, or an allogeneic stem cell transplant
- allogeneic stem cell transplantation for eligible patients who no longer have an effective TKI option or for those with blast phase disease who have achieved a second chronic phase.
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 (Australian Government Department of Health 2021a).
More information
Refer to section 4.3 ‘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.
Timely referral to palliative care can improve the quality of life and in some cases may be associated with survival benefits. 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 4.3 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.
More information
Refer to the end of section 4.3 ‘Palliative care’ for links to resources.
The treatment team should support the patient to participate in research and clinical trials where available and appropriate.
For more information visit:
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)
- management of physical symptoms such as fatigue and musculoskeletal pain
- decline in mobility or functional status (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 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.
Rehabilitation may be required at any point of the 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 consequences.
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.
More information
Refer to Principle 6 ‘Communication’ for communication skills training programs and resources.
