STEP 4: Treatment

Step 4 describes the optimal treatments for AML, the training and experience required of the treating clinicians and the health service characteristics required for optimal cancer care.

All health services must have clinical governance systems that meet the following integral requirements:

  • identifying safety and quality measures
  • monitoring and reporting on performance and outcomes
  • identifying areas for improvement in safety and quality (ACSQHC 2020).

The resources below serve as guidelines. Treatment plans for patients should be individualised and discussed in MDMs. The choice of treatments depends on the registration and reimbursement status of the drugs and the availability of clinical trials.

The intent of treatment can be defined as one of the following:

  • curative
  • anti-leukaemia therapy to improve longevity and quality of life without expectation of cure
  • symptom palliation including active supportive care.

The treatment intent should be documented in the patient’s medical record. Achieving a complete remission is the first goal for patients receiving either curative intent therapy or treatment designed to improve longevity and quality of life without expectation of cure.

The potential benefits need to be balanced against the morbidity and risks of treatment.

The lead clinician should discuss the advantages and disadvantages of each treatment and associated potential side effects with the patient and their carer or family before treatment consent is obtained and begins so the patient can make an informed decision. Supportive care services should also be considered during this decision-making process. Patients should be asked about their use of (current or intended) complementary therapies (see Appendix D).

Timeframes for starting treatment should be informed by evidence-based guidelines where they exist. The treatment team should recognise that shorter timeframes for appropriate consultations and treatment can promote a better experience for patients.

Initiate advance care planning discussions with patients before treatment begins (this could include appointing a substitute decision-maker and completing an advance care directive). Formally involving a palliative care team/service may benefit any patient, so it is important to know and respect each person’s preference (AHMAC 2011).

Patients fit for intensive chemotherapy

Systemic chemotherapy for AML is a key component of treatment and is divided into two phases: induction therapy to achieve complete remission; and consolidation therapy once a remission has been achieved to maintain ongoing remission or as a bridge to curative treatment – that is, an allogeneic bone marrow transplant (also known as stem cell transplant).

Induction chemotherapy should ideally only be started when all diagnostic criteria have been satisfied (Döhner et al. 2017). In patients with suspected APL and hyperleukocytosis, the risk of severe complications is high and chemotherapy poses the risk of worsening disseminated intravascular coagulation. Leukopheresis is contraindicated in this scenario. Starting differentiation therapy immediately needs to be considered in consultation with an expert in this area. Treatment with ATRA is frequently initiated on the suspicion of APL. In these circumstances, emergency therapy may be required before completing diagnostic sampling.

All patients undergoing intensive chemotherapy will need a central intravenous line inserted (with platelet transfusion and correction of coagulopathy if necessary). Such devices should only be inserted by proceduralists experienced in such procedures.

After recovering from induction therapy, it is important to assess the response to initial treatment, including complications (e.g. the severity of side effects and sepsis), in order to plan future therapy. Patients who fail to achieve remission have a poor prognosis (McMahon & Perl 2019), while the outcome for patients in remission depends on subsequent therapy.

Once patients are in remission, consolidation therapy is always indicated when cure is the intention (Döhner et al. 2010). Following induction therapy, additional treatment should be given because the median disease-free survival for patients who receive no additional therapy is only four to eight months (Cassileth et al. 1998). The aim of consolidation therapy is to prevent relapse with maximal efficiency and minimal toxicity. Current approaches to induction and consolidation therapy include short-term, relatively intensive chemotherapy, or high-dose chemotherapy (summarised in Döhner et al. 2015). There is no consensus on a single ‘best’ post-remission treatment schedule, nor the optimal number of cycles of consolidation chemotherapy.

Consequently, consolidation therapy for AML patients who have achieved complete remission is determined after considering a combination of the following factors:

  • the patient’s age and fitness
  • prognosis
  • tolerance of prior therapy
  • minimal (also called measurable) residual disease (MRD) status in selected AML subtypes
  • whether the patient is a candidate for an allogeneic stem cell transplant.

Patients not fit for intensive chemotherapy

New therapies are starting to emerge that may offer meaningful clinical activity in patients considered unfit for intensive chemotherapy. This may not necessarily be based on age. Referral to a clinical trial should be a priority. Available current treatment options include low-dose chemotherapy or hypomethylating agents for older patients (> 75 years) or for patients with significant comorbidities. Alternatively, palliative/supportive care therapy to control symptoms will be appropriate for some people. Emerging therapies, including those not currently approved by the Therapeutic Goods Administration (TGA) or reimbursed in Australia, are outlined in the National Comprehensive Cancer Network’s clinical guidelines (NCCN 2019).

Timeframe for starting treatment

  • Induction therapy should start promptly once a diagnosis is made and a treatment plan for intensive chemotherapy is confirmed.
  • Consolidation therapy should start within six weeks of induction chemotherapy beginning.

Allogeneic stem cell transplant

Potential candidates for allo-SCT (scheduled for the consolidation phase) should be identified at diagnosis. These considerations can change based on the patient’s response to initial treatment, overall tolerance and complications of subsequent treatment. A formal recommendation to proceed to allo-SCT should only occur after discussion at a focused bone marrow transplant MDM. Factors that need consideration include disease prognosis (incorporating response to treatment), comorbidities and functional status, and availability of suitable donor(s). Part of this assessment should include a formal haematopoietic cell transplantation (HCT)-comorbidity assessment.

Allo-SCT should be considered for:

  • all younger patients depending on prognostic factors and patient preferences
  • patients with non-favourable AML in first remission who have an acceptable allogeneic donor(s), noting that only a proportion of patients will benefit
  • some patients whose disease fails to go into remission with intensive chemotherapy
  • patients with rising MRD
  • selected patients beyond CR1.

For patients with good-prognosis AML in their first complete remission (APL, core-binding factor AML, CEBPA with double mutation and NPM1 mutation in the absence of FLT3-ITD), the risks of allo-SCT exceed the benefits and a survival advantage has not been proven, especially if patients have low or absent levels of MRD after achieving remission.

Autografting may be appropriate for patients with relapsed acute promyelocytic leukemia in second molecular remission (Ganzel et al. 2016; Holter Chakrabarty et al. 2014; Lengfelder et al. 2015). Autograft may be considered in select favourable and intermediate-risk AML patients in stringent first remission in the absence of a suitable allogeneic donor (Gorin et al. 2008; Venditti et al. 2019). The role of autografting in managing other forms of AML is contentious. Autografting in these circumstances should be carried out in a clinical trial.

Timeframes for starting treatment

  • Donor searches should begin for all anticipated allo-SCT candidates in first remission (CR1) patients as soon as the patient’s risk status is known.
  • Individual treating units should ensure referral pathways for transplantation are established to minimise delays. Rapid-access pathways are required for patients for whom urgent transplantation may be appropriate.

Radiation therapy

Radiation therapy may be used for symptom control in palliation and occasionally to treat extramedullary disease.

Total body irradiation (TBI) may also be indicated as part of conditioning for allo-SCT and should only be given in centres with appropriately qualified and experienced staff and equipment.

Treatment of APL differs in several important aspects from therapy of all other AML types. The presentation of APL is a medical emergency because of the high risk of death as a result of the associated coagulopathy. Rapid initiation of APL-specific therapy is essential and, in some cases, may precede formal confirmation of the diagnosis. Treating units must have protocols for intensive supportive care including guidelines for blood product administration in managing coagulopathy.

Patients should undergo molecular monitoring after treatment to guide further therapy.

Resistance to therapy (refractory AML) is the major cause of treatment failure, rather than mortality due to infections and other treatment-related complications. Patients failing to respond to one or two cycles of induction treatment can be considered chemotherapy refractory and are at very high risk of ultimate treatment failure. In this circumstance other alternatives should be explored (non-chemotherapy options or clinical trials). While there are no standard salvage regimens for AML, intensive salvage chemotherapy can result in a second remission in approximately 55 per cent of patients aged 16–49, of which approximately two-thirds can then proceed to an allo-SCT (Döhner et al. 2017).

Patients offered an allo-SCT are carefully selected and must have an appropriately HLA-matched donor. It should be noted that patients with refractory disease who undergo an allo-SCT have limited chances of success and considerable morbidity from this procedure. For patients unsuited to this approach, palliative systemic treatment is often a reasonable option with limited toxic effects (Döhner et al. 2010).

Currently, midostaurin is the only Pharmaceutical Benefits Scheme (PBS)-listed targeted therapy approved to be used in combination with induction chemotherapy for newly diagnosed AML with a FLT3 internal tandem duplication (FLT3-ITD) or tyrosine kinase domain-activating mutation (FLT3-TKD) (DHS 2020; eviQ 2019b).

Enasidenib is a targeted oral therapy used as a single agent for treating refractory or relapsed IDH2-mutated AML. This drug has provisional TGA approval but is not PBS listed (February 2021). A phase 3 randomised trial of enasidenib or placebo in combination with induction chemotherapy for newly diagnosed IDH-mutated AML began in Australia in 2020. This trial also includes a randomisation of patients with IDH1-mutated AML to induction chemotherapy with or without the targeted IDH1 inhibitor ivosidenib.

Gilteritinib is a second-generation FLT3-inhibitor, approved by the TGA for patients with relapsed or refractory FLT3-mutant AML. This drug is not listed on the PBS (February 2021). It is administered as a single agent. A randomised trial of gilteritinib versus standard therapy (ADMIRAL) showed a survival benefit for patients receiving gilteritinib (Perl et al. 2019). A randomised trial of gilteritinib versus midostaurin in combination with induction chemotherapy in newly diagnosed FLT3-mutated AML began in Australia in 2020.

No immunotherapy drugs are TGA approved for treating AML.

A number of emerging therapies are being investigated for AML. Therapies that show promise for treating AML include novel targeted therapies, epigenetic therapies, immunotherapies and cell therapies (Davis et al 2018; DiNardo & Wei 2020; Wingelhofer & Somervaille 2019). These novel therapies are in various stages of clinical trial development and assessment. It is anticipated that some will become TGA-approved in the coming years.

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

  • Haematologists, radiation oncologists or medical oncologists (FRACP or equivalent) must have adequate training and experience with institutional credentialing and agreed scope of practice within this area (ACSQHC 2015).
  • Nurses must have adequate training in systemic therapy administration, specialised nursing care for patients undergoing cancer treatments, including side effects and symptom management, and handling and disposal of cytotoxic waste.
  • Interventional radiology and/or certified proceduralists must be competent in inserting central venous access devices.
  • Systemic therapy should be prepared by a pharmacist with adequate training in systemic therapy medication, including dosing calculations according to protocols, formulations and/or preparation.

In a setting where no haematologist 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 accordance with a detailed treatment plan or agreed protocol, and with communication as agreed with the medical oncologist or as clinically required.

Hospital or treatment unit characteristics for providing safe and quality care include:

  • dedicated standard isolation rooms (single rooms with ensuite and clinical handwashing facilities)
  • access to a cell separator for collecting peripheral blood progenitor cells
  • HEPA-filtered environment/rooms in the inpatient setting
  • immediate blood product support
  • a clearly defined path to emergency care and advice after hours
  • access to total parenteral nutrition
  • access to a dental service familiar with mouth care issues experienced by haematology patients
  • accessible emergency apheresis for managing hyperleukocytosis
  • access to diagnostic pathology including basic haematology and biochemistry, and imaging
  • rapid access to an interventional radiologist/proceduralist
  • an infectious disease specialist
  • 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 2019a)
  • guidelines and protocols to deliver treatment safely (including dealing with extravasation of drugs)
  • timely access to pathology
  • coordination for combined therapy with radiation therapy, especially where facilities are not co-located.

Radiation oncology centre characteristics for providing safe and quality care include:

  • linear accelerator (LINAC) capable of image-guided radiation therapy (IGRT)
  • staff to be familiar with AML-specific radiation therapy techniques
  • TBI-based preparative regimens only being delivered in centres with experience using TBI conditioning and autologous/allogeneic transplantation (minimum 10 procedures per year)
  • 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 system.

Centres that do not have sufficient caseloads (for TBI and for overall management) should refer cases to a high-volume centre.

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 at al. 2010; Zimmermann et al. 2014). This is particularly true for poor-prognosis AML to ensure optimal symptom control from treatment toxicity or progressive disease.

The lead clinician should ensure patients receive timely and appropriate referral to palliative care services. Referral should be based on need rather than prognosis. Emphasise the value of palliative care in improving symptom management and quality of life to patients and their carers.

The ‘Dying to Talk’ resource may help health professionals when initiating discussions with patients about future care needs (see ‘More information’). Ensure that carers and families receive information, support and guidance about their role in palliative care (Palliative Care Australia 2018).

Patients, with support from their family or carer and treating team, should be encouraged to consider appointing a substitute decision-maker and to complete an advance care directive.

Refer to step 6 for a more detailed description of managing patients with recurrent, residual or metastatic disease.

More information

These online resources are useful:

The team should support the patient to participate in research or clinical trials where available and appropriate. Many emerging treatments are only available on clinical trials that may require referral to certain trial centres.

For more information visit the Cancer Australia website

See validated screening tools mentioned in Principle 4 ‘Supportive care’.

Therapy is often associated with a number of symptoms and physiological abnormalities. Patients are highly susceptible to infection from prolonged neutropenia and this can result in significant comorbidity and mortality. Patient education and strict adherence to universal neutropenic guidelines, access to infection control specialists, close monitoring of full blood count, and early intervention of neutropenic sepsis is essential. Patients need to be educated on the importance of personal hygiene and particularly dental care to minimise infection. Antimicrobial therapy including antiviral, antifungal and antibiotic therapy is often administered prophylactically to reduce risk of infections.

A number of specific challenges and needs may arise for patients at this time:

  • assistance for dealing with emotional and psychological issues, including body image concerns, fatigue, quitting smoking, traumatic experiences, existential anxiety, treatment phobias, anxiety/depression, interpersonal problems and sexuality concerns
  • potential isolation from normal support networks, particularly for rural patients who are staying away from home for treatment
  • side effects resulting from high-dose therapy including alopecia, fatigue, cytopenias, mucositis (oral and bowel), immunosuppression resulting in increased infection, fluid retention, dyspnoea, graft-versus-host disease (GVHD; following allo-SCT) and organ toxicity (interstitial pneumonitis, veno-occlusive disease)
  • additional supportive care required to address the immunosuppressive effects and long-term side effects of therapy for patients treated with allo-SCT – issues may include infertility, GVHD, increased risk of infection, anaemia, bleeding, mouth ulcers and fatigue
  • early recognition and prompt initiation of corticosteroids for differentiation syndrome (NCCN 2015) and consideration for interruption of therapy when required
  • chemically induced menopause that leads to atrophic vaginitis and dyspareunia, and changes in androgens that may alter libido and orgasm – these require sensitive discussion
  • gastrointestinal symptoms, such as nausea, vomiting, severe mucositis, loss of appetite, dysgeusia, diarrhoea or constipation, as a result of treatment require optimal symptom control (with medication, total parenteral nutrition, analgesia and mouth care) and referral to a dietitian if dietary intake is affected
  • malnutrition, which can occur as a result of disease or treatment (validated malnutrition screening tools should be used at the key points in the care pathway to identify patients at risk of malnutrition and refer to a dietitian for nutrition intervention)
  • cognitive impairment, which patients treated with allo-SCT report to be a major component of quality-of-life impairment and can last for years post procedure (Buchbinder et al. 2018)
  • assistance with managing complex medication regimens, multiple medications, assessment of side effects and assistance with difficulties swallowing medications (referral to a pharmacist may be required)
  • decline in mobility or functional status as a result of treatment
  • assistance with beginning or resuming regular exercise with referral to an exercise physiologist or physiotherapist (COSA 2018; Hayes et al. 2019).

Early involvement of general practitioners may lead to improved cancer survivorship care following acute treatment. General practitioners can address many supportive care needs through good communication and clear guidance from the specialist team (Emery 2014).

Patients, carers and families may have these additional issues and needs:

  • financial issues related to loss of income (through reduced capacity to work or loss of work) and additional expenses as a result of illness or treatment
  • advance care planning, which may involve appointing a substitute decision-maker and completing an advance care directive
  • legal issues (completing a will, care of dependent children) or making an insurance, superannuation or social security claim on the basis of terminal illness or permanent disability.

Cancer Council’s 13 11 20 information and support line can assist with information and referral to local support services.

For more information on supportive care and needs that may arise for different population groups, see Appendices A and B, and special population groups.