4.2 Treatment options
Disease-directed therapy should not be initiated unless there are disease-related symptoms or evidence of disease progression. According to the iwCLL guidelines (Hallek et al. 2018), signs of ‘active disease’ include any of the following:
- new or worsening anaemia or thrombocytopenia
- massive, progressive or symptomatic splenomegaly or lymphadenopathy
- sustained progressive lymphocytosis (50 per cent or greater increase over two months or lymphocyte doubling time in under six months)
- autoimmune complications including anaemia or thrombocytopenia that respond poorly to corticosteroids
- extranodal involvement impacting organ function or causing symptoms (e.g. skin, kidney, lung, spine)
- any of these disease-related symptoms: unintentional weight loss of more than 10 per cent within the last six months; extreme fatigue (unable to work or perform usual activities), fever of 38°C
for two or more weeks without evidence of infection; night sweats for a month or longer without evidence of infection.
For more detailed information on the criteria for initiating treatment, see the iwCLL guidelines
Treatment decisions will be based on TP53 mutation or del(17p), IGHV mutational status, age, comorbidities, potential interactions with other medicines and patient preference (Eichhorst et al. 2021).
Treating asymptomatic early-stage CLL does not improve survival, so an initial ‘watch and wait’ approach is recommended.
Patients with early asymptomatic CLL (Rai 0–1) should be monitored every three months during the first year, and then every three to 12 months, depending on the stability and specific characteristics of their disease (Eichhorst et al. 2021). For those with asymptomatic Rai 0 or 1 disease, this can be with local blood tests and telehealth review if such processes align with the patient’s wishes.
Chemotherapy is not recommended for patients with TP53 mutation or del(17p) due to its poor efficacy in this setting. However, a number of patients may benefit from systemic therapy.
Fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapy has established curative potential for the subset of patients with favourable biologic features (IGVH mutated status and absence of TP53 dysfunction), and can be considered in younger, fit patients with adequate renal function (age < 65 with creatinine clearance ≥ 70 mL/min).
In patients with significant comorbidities or impaired organ function, less intensive chemoimmunotherapy such as chlorambucil and obinutuzumab or bendamustine and rituximab is also available. These treatments can be life-prolonging but do not have curative potential.
An allogeneic bone marrow transplant can be curative in patients with CLL but is rarely indicated. However, potentially suitable patients should be identified, and discussions with a linked transplantation service should begin early in the patient’s disease course.
Timeframes for starting treatment
Rate of disease progression is usually gradual and treatment initiation is rarely urgent. Timing should be discussed to align with the patient’s preferences but not delayed to the point where impaired performance status, compromised organ function or recurrent severe infections occur.
Training and experience required of the appropriate specialists
Haematologists/medical oncologists must have training and experience of this standard:
- Fellow of the Royal Australian College of Physicians (or equivalent)
- adequate training and experience that enables institutional credentialing and agreed scope of practice within this area (ACSQHC 2015).
Cancer nurses should have accredited training in these areas:
- anti-cancer treatment administration
- specialised nursing care for patients undergoing cancer treatments, including side effects and symptom management
- the handling and disposal of cytotoxic waste (ACSQHC 2020).
Systemic therapy should be prepared by a pharmacist whose background includes this experience:
- adequate training in systemic therapy medication, including dosing calculations according to protocols, formulations and/or preparations, such as those provided by eviQ .
If no haematologist/medical oncologist is locally available (e.g. regional or remote areas), some components of less complex therapies may be delivered by a general practitioner, general physician or nurse with training and experience that enables credentialing and agreed scope of practice within this area. This should be in line with a detailed treatment plan or agreed protocol, and with communication as agreed with the primary managing specialist or as clinically required.
The training and experience of the appropriate specialist should be documented.
Health service characteristics
To provide safe and quality care for patients having systemic therapy, health services should have these features:
- a clearly defined path to emergency care and advice after hours
- access to diagnostic pathology including basic haematology and biochemistry, and imaging
- access to appropriate molecular pathology access (not required on site and can be through central specialist laboratory)
- access to cytotoxic drugs prepared in a pharmacy with appropriate facilities
- occupational health and safety guidelines regarding handling of cytotoxic drugs, including preparation, waste procedures and spill kits (eviQ 2019)
- guidelines and protocols to deliver treatment safely (including dealing with extravasation of drugs)
- coordination for combined therapy with radiation therapy, especially where facilities are not co-located.
Targeted therapies are the preferred treatment approach in all patients with TP53 mutation or del(17p) and can be considered in other patient subgroups:
- time-limited therapy with the combination of venetoclax plus obinutuzumab – for patients with a cumulative illness rating scale (Al-Sawaf et 2020) score of 6 or above or patients with impaired renal function
- continuous treatment with Bruton’s tyrosine kinase (BTK) inhibitors, including ibrutinib (Burger et al. 2015) and acalabrutinib (Sharman et al. 2020), until disease progression or intolerance.
The funding status of various treatment approaches is dynamic and prescribers should ensure familiarity with eligibility criteria and discuss any financial implications of all treatment recommendations with patients prior to treatment initiation.
There is no routine therapeutic role for surgery in managing patients with CLL, except for very rare instances where splenectomy can be beneficial (Cusack et al. 1997).
Radiation therapy can be used to treat obstructive/bulky nodes or massive symptomatic splenomegaly, or to reduce symptoms during palliative treatment (e.g. pain resulting from lytic bone lesions).
Timeframe for starting treatment
Where organ preservation is the goal (e.g. hydronephrosis) radiation should be commenced within 72 hours of recognition of the issue.
Where applied with symptomatic/palliative goals, appropriate timing is guided by the severity of the relevant symptoms but is rarely urgent and can be commenced within two weeks in most cases. This is due to the chronic nature of the underlying process.
Training and experience required of the appropriate specialists
There are no specific sub-specialty skill needs required for the delivery of palliative radiation in CLL beyond those generally required for registration and practice as a radiation oncologist.
The training and experience of the radiation oncologist should be documented.
Health service unit characteristics
To provide safe and quality care for patients having radiation therapy, health services should have these features:
- linear accelerator (LINAC) capable of image-guided radiotherapy (IGRT)
- dedicated CT planning
- access to MRI and PET imaging
- automatic record-verify of all radiation treatments delivered
- a treatment planning system
- medical physicists, radiation therapists and nurses with radiation therapy experience
- coordination for combined therapy with systemic therapy, especially where facilities are not co-located
- participation in Australian Clinical Dosimetry Service audits
- an incident management system linked with a quality management
Emerging therapies include:
- newer generation BTK inhibitors such as zanubrutinib (Tam et al. 2020) and pirtobrutinib (LOXO-305) (Mato et al. 2021)
- CAR T-cell therapy, a cellular therapy, directed against the CD19 surface molecule (Mancikova & Smida 2021)
- other emerging monoclonal
There are currently no approved therapies for CLL that specifically target acquired genomic mutations beyond TP53 dysfunction identifying a subgroup of patients where chemoimmunotherapy is contraindicated.