For stage II FL (non-contiguous lymph nodes, or not amenable to radiation therapy) and advanced stage FL (stages III and IV), the decision to start treatment is guided by symptoms and disease bulk. Approximately one-third of initial presentations occur in patients with low-volume disseminated disease. The importance of ‘watch and wait’ is true even in the modern immunochemotherapy era. The frequency of clinical review during this observation is based on the tempo of the disease, the comfort the patient has with a ‘watch and wait’ approach and the likelihood that they will recognise and re-present in the event of signs of relapse.

Watchful waiting can cause significant anxiety in patients. Appropriate support should be made available (see 3.6.3 Supportive care). Alternate approaches such as treatment with rituximab monotherapy may delay the need for subsequent treatment.

Asymptomatic advance-stage nodal MZL can also be managed with a watchful waiting approach.

An indolent form of MCL, commonly a leukaemic presentation, indicated by lack of symptoms and low tumour burden, can be followed with watchful waiting.

Radiation therapy has an important role in specific scenarios within indolent lymphoma subtypes:

• Early-stage FL (stage I and stage II in which lymph nodes are contiguous) is potentially curable with radiation Further adjuvant immunochemotherapy may confer additional progression-free survival
• In centres with radiation expertise, there may be a role for curative radiation therapy (total nodal irradiation) in a highly select group of patients with low-volume, advanced-stage disease
• Radiation therapy is appropriate in early-stage MZL (including gastric, cutaneous, unilateral and bilateral orbital MALT, and other localised MZLs) with potential curative intent. Note eradication of Helicobacter pylori infection should be performed first – it may induce remission without the need for radiation therapy in some cases
• In localised relapse of low-grade lymphomas, it may defer the need for systemic immunochemotherapy
• It may be used for symptom control in advanced-stage low-grade lymphomas, where lymphoma is impairing quality of life.

Timeframe for starting treatment

Begin within four weeks, as prioritised by a multidisciplinary team decision (see 3.4 Treatment planning). Start earlier for life- or organ-threatening indications. Delaying radiation therapy (e.g. for further monitoring) may cause distress and should be discussed with the patient.

Training and experience required of the appropriate specialists

Fellow of the Royal Australian and New Zealand College of Radiologists or equivalent, with adequate training and experience, institutional credentialing and agreed scope of practice in lymphoma management.

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 radiation therapy (IGRT)
• dedicated CT planning
• access to MRI and PET imaging
• automatic record-verify of all radiation treatments delivered
• a treatment planning system
• trained 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

Systemic therapy is appropriate in most patients with non-contiguous stage II or stage III–IV disease who are symptomatic by GELF/BCNI criteria, and considered fit enough to experience a positive risk-benefit balance of undergoing treatment (Ardeshna et al. 2003; Brice et al. 1997). The choice of initial systemic therapy needs to consider the potential for sequencing of subsequent therapies, including potential future stem cell mobilisation.

Follicular lymphoma

Initial treatment with chemotherapy and anti-CD20 monoclonal antibody is often followed by continued therapy with anti-CD20 antibody maintenance for another two years. Given that ongoing maintenance antibody therapy increases progression-free survival but does not prolong overall survival, it is important the patient understands both the benefits in prolonging remission as well as the additional infectious toxicities of using maintenance antibody therapy.

Nodal marginal zone lymphoma

Initial treatment with chemotherapy and anti-CD20 monoclonal antibody is recommended.

Extranodal marginal zone lymphoma

Helicobacter pylori eradication therapy should be given to all patients with gastric MALT, irrespective of stage and Helicobacter pylori status. In those who remain Helicobacter pylori positive, second- line eradication therapy is recommended. Regression of lymphoma following successful eradication of Helicobacter pylori may be delayed, and so it is appropriate to wait 12 months before starting another treatment.

In other instances of localised MALT (e.g. conjunctival MALT), a trial of systemic therapy with antibiotics may be appropriate before radiation therapy.

MALT can also be treated with chemotherapy and anti-CD20 monoclonal antibody.

Splenic marginal zone lymphoma

Recognised first-line therapeutic options are rituximab monotherapy, splenectomy (after appropriate vaccinations) or chemotherapy and anti-CD20 monoclonal antibody combinations. While half of splenectomised patients do not need further treatment for SMZL, splenectomy may bring about complications and is increasingly being replaced with rituximab +/- chemotherapy as initial therapy, especially in patients with a heavy bone marrow disease burden.

Mantle cell lymphoma

MCL causing symptoms should be treated with systemic chemotherapy and anti-CD20 monoclonal antibody combination, incorporating high-dose cytarabine in younger, fitter patients, followed by consolidation with autologous stem cell transplantation (ASCT). Rituximab maintenance after ASCT has been shown to improve overall survival.

In older, more frail patients, chemotherapy and anti-CD20 monoclonal antibody combinations is appropriate. Where bendamustine-containing regimens are used, meticulous monitoring for infections is necessary.

Timeframes for starting treatment

The decision to start treatment may occur after a long period of watch and wait. In FL and MZL, the decision of when to start systemic therapy is guided by the presence of symptoms and organ dysfunction according to the GELF/BCNI criteria. Once the patient meets the criteria to start, treatment should begin within four weeks. Most symptomatic MCL patients should begin treatment with systemic therapy within two weeks of completing staging.

Training and experience required of the appropriate specialists

The following training and experience is required of the appropriate specialist(s): Haematologists and 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

If no haematologists or medical oncologist is locally available (e.g. regional or remote areas), some components of less complex therapies may be delivered by a general practitioner 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 haematologists or medical oncologist or as clinically required.

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 basic haematology and biochemistry testing
• cytotoxic drugs prepared in a pharmacy with appropriate facilities
• occupational health and safety guidelines for handling cytotoxic drugs, including safe prescribing, preparation, dispensing, supplying, administering, storing, manufacturing, compounding and monitoring the effects of medicines (ACSQHC 2011)
• guidelines and protocols for delivering treatment safely (including dealing with extravasation of drugs)
• coordination for combined therapy with radiation therapy, especially where facilities are not co-located
• timely access to pathology and blood

Antimicrobial prophylaxis and immunoglobulin supplementation (in hypogammaglobulinaemic patients who meet national prescribing criteria) is recommended. Specific antimicrobial prophylaxis should be prescribed based on established guidelines (national guidelines and eviQ) and the results of tests for occult or latent infection (see 3.1 Specialist diagnostic work-up). This includes, but

is not limited to, the particular risk of reactivation of latent hepatitis B associated with anti-CD20 monoclonal antibodies. Patients with hepatitis B core antibody require a documented plan for antiviral therapy and ongoing monitoring.

Yearly seasonal flu vaccination and five-yearly pneumococcal vaccination should be encouraged in accordance with the Australian National Immunisation Schedule, as should COVID vaccination boosters as/if the evolving evidence supports this approach.

The primary role of surgery in low-grade lymphomas is to obtain a biopsy specimen. Surgery is

a beneficial component of indolent lymphoma treatment in a minority of cases such as in relieving mechanical obstruction caused by lymphoma (e.g. an acute bowel obstruction in duodenal follicular lymphoma).

Splenectomy is an important therapeutic option for SMZL (see 4.2.3 Systemic therapy).

Documented evidence of the surgeon’s training and experience, including their relevant organ- specific sub-specialty experience with low-grade lymphomas and procedures to be undertaken, should be available.

Health service characteristics

To provide safe and quality care for patients having surgery, health services should have these features:

• critical care support
• 24-hour medical staff availability
• 24-hour operating room access and intensive care unit
• diagnostic imaging
• pathology
• PET

While chemoimmunotherapy has been the cornerstone of frontline treatment for advanced disease in cases of relapse, several other therapeutic strategies are under development.

Promising therapeutic agents include:

• small molecules targeting signal transduction (PI3K inhibitors, BTK inhibitors)
• monoclonal antibodies targeting other cell surface proteins (CD19, CD47)
• epigenetic modifiers (EZH2 and HDAC inhibitors)
• immune checkpoint inhibitors (PD1, PD-L1, TIGIT)
• engineered CARs (CAR T- and CAR NK-cells)
• bispecific T-cell engagers
• antibody drug conjugates
• radioimmunoconjugates
• cancer vaccines
• immunomodulatory

Many of these agents are in advanced stages of development and have proven efficacy and manageable toxicity. Clinical trial participation is a good therapeutic consideration, particularly for patients who have progressed after two lines of therapy. ASCT and sometimes allogeneic stem cell transplantation is still a good option for certain patients with relapsed disease.