STEP 6: Managing refractory, relapsed, residual or progressive disease
Patients who present with relapsed or progressive disease should be managed by a multidisciplinary team and offered timely referral to appropriate physical, practical and emotional support.
Step 6 is concerned with managing relapsed or progressive disease.
CLL 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 CLL but no symptoms can be safely and appropriately monitored.
Therapy should only be restarted when there are other signs or symptoms of disease progression.
Five to 10 per cent of patients with CLL will develop a more aggressive form of lymphoma (diffuse large B-cell lymphoma or Hodgkin lymphoma) at some point during their disease course (termed Richter’s transformation). The managing team need to consider this possibility at every instance of disease recurrence, and weigh up the potential need for a tissue biopsy to investigate. For more information see the optimal care pathway for people with people with Hodgkin and diffuse large B-cell lymphomas Features that can suggest the presence of Richter’s transformation and prompt repeat tissue biopsy of the most suspicious site include (Petrackova et al. 2021): Signs and symptoms of recurrent or progressive CLL such as lymphadenopathy, increasing fatigue, fevers, sweats or unintentional weight loss and recurrent infections are usually recognised by the patient and reported at routine reviews. Lymphocytosis or developing cytopenias may be identified by regular full blood counts. Routine surveillance imaging is not recommended and rarely identifies an otherwise unrecognised manifestation of disease recurrence, and provides no long-term survival benefit for the patient. The signs of active disease are:
Managing relapsed or progressive 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, 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. Survivorship care should be considered and offered at an early stage. Many people live with advanced CLL for many 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. Access to the best available therapies, including clinical trials, as well as treatment overseen by a multidisciplinary team, are crucial to achieving the best outcomes for anyone with relapsed or progressive disease. The multidisciplinary team may include new members such as palliative care specialists.
Treatment will depend on the features of recurrent disease, previous management and the patient’s preferences. In managing people with CLL, treatment may include these options: targeted agents (generally the preferred approach), repeat chemo-immunotherapy, investigational treatment on clinical trials or allogeneic bone marrow transplantation. In some patients the disease is unlikely to respond well to second-line chemoimmunotherapy. This includes patients whose disease didn’t respond to first-line chemoimmunotherapy, patients who experienced disease progression within two to three years after first-line fludarabine-based chemoimmunotherapy, and those with leukaemia cells with del(17p) or TP53 mutations. If abnormalities were not previously detected, it is important to reassess TP53 status (by FISH and sequencing) at each episode of disease recurrence/progression (Eichhorst et al. 2021; Hallek et al. 2018). Options for these patients are: 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.
Early referral to palliative care can improve the quality of life for people with cancer 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 4.3 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 take part 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: 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.
