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.