AML World Awareness Day 21 April 2019

Treatment

This section of the website is designed to highlight the latest guidelines for acute myeloid leukemia (AML) for healthcare professionals (HCPs)

The aim of AML therapy and the probability of success vary significantly according to disease and patient characteristics. Thus, the treatment options will vary depending on the genetic abnormalities present at diagnosis, as well as patient age and co-morbidities. The general therapeutic strategy in patients with AML consists of an induction therapy, and if complete remission is achieved, appropriate post-remission therapy is essential.

Induction therapy

The main aim of induction therapy is to decrease the quantity of leukemia cells to a cytogenetically undetectable level. The conventional “7+3” induction regimen of cytarabine and an anthracycline (idarubicin, daunorubicin, mitoxantrone) is still the mainstay induction therapy for AML patients and both the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) guidelines recommend this regimen for young and fit older AML patients. With this regimen, complete response is achieved in 60–80% of younger adults (60 years or younger) and in 40–60% of older adults (61 years or older). The choice and optimal dose of anthracycline may have an impact on the survival of AML patients. Addition of cladribine to a standard induction regimen, and high-dose cytarabine combined with an anthracycline are also recommended regimens for induction therapy.

Post-remission therapy

Standard post-remission strategies for AML patients in remission consists of intensive chemotherapy (consolidation) and high-dose chemotherapy (conditioning) followed by either autologous or allogeneic stem cell transplantation. Recommendation of transplant is determined by the leukemic genetic-risk profile, scores on established scales that predict the risk of treatment-related death, and specific transplantation-associated factors in the patient. The most commonly used consolidation regimens often include repetitive cycles of single-agent high-dose cytarabine alone or cytarabine treatment followed by transplantation.

Monitoring of minimal residual disease can guide post-remission therapy in patients, and preemptive salvage therapy, including transplantation, may be performed when there is molecular detection of persistent or relapsed AML.

Treatment for AML patients who are ineligible for intensive therapy

There is currently no widely accepted algorithm for the treatment of older or frail AML patients who are considered unfit for intensive remission induction therapy. Several treatment options are recommended for this group of patients including low-dose cytarabine, best supportive care and hypomethylating agents such as azacitidine and decitabine. Treatment of unfit older or frail AML patients is currently unsatisfactory and both the ELN and NCCN guidelines recommend enrolling these group of patients in clinical trials.

Treatment of relapsed or refractory AML

Relapse occurs in most AML patients within 3 years after diagnosis. There is currently no standard regimen for the treatment of relapsed or refractory AML patients. However, treatment for this group of patients depends on an assessment of the likely benefit of further therapy as opposed to the potential complications associated with salvage chemotherapy. A short duration of remission, adverse genetic factors, prior allogeneic transplantation, older age, and poor general health status are major determinants of outcome after relapse.

There is no standard regimen for salvage therapy. Recommended salvage chemotherapy regimens for patients with relapsed or refractory AML fit for intensive chemotherapy include intermediate-dose cytarabine (IDAC) with or without anthracycline, mitoxantrone, etoposide and cytarabine (MEC), cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and fludarabine, cytarabine, idarubicin, and filgrastim (FLAG-IDA). In patients unfit for intensive chemotherapy, effective salvage treatment options are lacking. Enrollment in a clinical trial is highly recommended for this patient group, where possible.

New therapies in AML

Recent advances in research have identified new treatment pathways in AML, which transcend the conventional 7+3 induction chemotherapy regimen. These new regimens are targeted (targeted therapy) at a variety of cellular processes including signaling pathways, epigenetic regulation of DNA and chromatin, nuclear export of proteins, and antigens that are expressed on leukemia cells via antibody based therapies. In 2017 and 2018, five new drugs have been approved for AML including:

Midostaurin (Rydapt):

Midostaurin is a multi-kinase targeted kinase inhibitor with FLT3 inhibitory activity. In the randomized phase III clinical trial (RATIFY), midostaurin in combination with standard chemotherapy significantly prolonged the survival of young adult patients with FLT3 mutated AML. In the United States and Europe, midostaurin is approved in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly-diagnosed AML who are FLT3 mutation-positive.

Gemtuzumab ozogamicin (Mylotarg): Gemtuzumab ozogamicin (GO) is a monoclonal antibody-targeted chemotherapeutic agent consisting of a recombinant humanized murine CD33 antibody, which is linked to calicheamicin, an anti-tumor antibiotic. Data from a phase III clinical study (ALFA-701) demonstrated that combination of gemtuzumab ozogamicin with a standard chemotherapy regimen in adult newly diagnosed de novo AML patients significantly improved 3-year event-free survival and relapse-free survival compared to chemotherapy alone. In the United States, gemtuzumab ozogamicin is FDA-approved for adult newly diagnosed adult AML patients and relapsed or refractory adults and children (over the age of 2) with CD33-positive AML. In Europe, gemtuzumab ozogamicin is approved in combination therapy with daunorubicin and cytarabine for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive AML. . Side effects from gemtuzumab ozogamicin may include liver problems, and infusion reactions.

CPX-351 (Vyxeos): CPX-351 is a liposomal formulation of daunorubicin and cytarabine co-encapsulated at a 1:5 molar ratio. In the United States and Europe, CPX-351 is approved  for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Side effects of CPX-351 may include haemorrhage, cardiotoxicity, hypersensitivity reactions, tissue necrosis and embryo-fetal toxicity.

Enasidenib (Idhifa): Enasidenib is an orally administered inhibitor of isocitrate dehydrogenase 2 (IDH2), which effectively suppresses the production of 2-hydroxyglutarate. In the United States, enasidenib is approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation. It is important to note that patients treated with enasidenib may experience differentiation syndrome. Differentiation syndrome is a potentially serious condition that is associated with the proliferation of differentiated leukemic cells that can alter cytokine balance leading to tissue damage and inflammation. Symptoms include dyspnea, fever, pulmonary infiltrates and hypoxia. Differentiation syndrome can become fatal if not treated. If differentiation syndrome is suspected, recommendations are to initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Ivosidenib (Tibsovo): Ivosidenib is an orally administered inhibitor of isocitrate dehydrogenase 1 (IDH1), which effectively suppresses the production of 2-hydroxyglutarate. In the United States, ivosidenib is approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-1 (IDH1) mutation. It is important to note that patients treated with ivosidenib may experience differentiation syndrome.

Clinical trials

Investigators are currently conducting clinical trials of newer agents either as a single agent or in combination with standard chemotherapy or other agents. These trials are aiming to improve or identify new treatment strategies for specific mutations or chromosomal abnormalities found in AML. Many of these newer agents have fewer side effects compared to conventional chemotherapy and have shown promising efficacy. Some of the newer mutant-targeted agents in current clinical trials in AML have received positive signals from the regulatory agencies. This will hopefully lead to more approvals and better available treatment options for patients in the future.

There are also on-going risk-adapted clinical trials which aim to incorporate measureable residual disease (MRD) and cytogenetic/molecular data to identify AML patients who would benefit from a particular therapy.

Measurable residual disease (MRD)

Most AML patients present with an abnormal immunophenotypic and/or mutational profile at the time of diagnosis, which does not necessarily clear at the time of remission and the question remains on what exactly happens to these mutations after treatment. As a result, these patients are defined as presenting with measurable residual disease (MRD). MRD is an important independent prognostic indicator in AML, highly predictive for relapse estimation, that can be used to inform treatment.

There are several methods used to evaluate MRD in various settings, including multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction (RQ-PCR), next generation sequencing (NGS) and digital PCR. In 2018, the ELN MRD Working Party published a consensus document for MRD assessment in AML and recommends the inclusion of MRD monitoring as part of the standard of care for AML patients.

Follow us

Connect with our social channels to stay up-to-date with the latest Know AML information and activities.