Clinical Guidelines and Standards of Care for the Treatment of AML

Anna Love, M.B.S., Ph.D.

The first line of therapy to induce remission for AML patients, excluding those with the acute promyelocytic leukemia (APL) subtype, is typically intensive chemotherapy using cytarabine plus an anthracycline drug, such as daunorubicin or idarubicin

ACUTE MYELOID leukemia (AML) contains a relatively large number of molecular subtypes, indicating a broad range of clinical standards of care for optimal treatment. Molecular profiling at the time of diagnosis is essential for targeting these individualized subtypes. Common point mutations include: FLT3 (28% prevalence), NPM1 (27% prevalence), DNMT3A (26% prevalence), IDH1/2 (20% prevalence), NRAS/KRAS (12% prevalence), RUNX1 (10% prevalence), TET2 (8% prevalence), TP53 (6-8% prevalence), and CEBPA (6% prevalence). Oncogenic fusions are also associated with AML; these include PML-RARA (9% prevalence), AML1-ETO (4- 10% prevalence), and CBFB-MYH11 (5% prevalence). Chromosomal losses or deletions such as loss of chromosome 5 or 5q deletions (7-8% prevalence) and loss of chromosome 7 or 7q deletions (10% prevalence) are also seen in AML patients. 36

AML Standards of Care

AML treatments are delivered in three phases, remission induction, consolidation, and maintenance. The first line of therapy to induce remission for AML patients, excluding those with the acute promyelocytic leukemia (APL) subtype, is typically intensive chemotherapy using cytarabine plus an anthracycline drug, such as daunorubicin or idarubicin. These intensive induction therapies are optimal for patients under 60 years of age lacking certain comorbidities, which would make them poor candidates for intensive chemotherapy regimens. Along with these first-line chemotherapies, clinicians may add midostaurin for FLT3- mutant or gemtuzumab ozogamicin for CD33-positive AML patients. In some instances, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia, cladribine is added to the remission induction therapy phase. If the patient has high levels of leukemia cells in the blood, leukapheresis to treat the leukostasis may precede chemotherapy. 37

During the consolidation phase, the standard treatment plan for AML patients under 60 years of age includes multiple cycles of cytarabine and/or either allogeneic or autologous stem cell transplant. Midostaurin or gemtuzumab ozogamicin may be added to this consolidation phase regimen if it was used during the induction phase. Older patients receive less intensive treatment during the consolidation phase, which may consist of slightly lower high-dose cytarabine, standard-dose cytarabine with or without idarubicin, daunorubicin, or mitoxantrone, and/or non-myeloablative stem cell transplant (mini-transplant). If the older AML patient received mitoxantrone during the induction phase, it may be continued during the consolidation phase.

AML Standards of Care for Elderly Patients

For frail or elderly patients, alternate, less intensive standards of care are applied during the consolidation phase. Low-dose cytarabine or demethylating agents like azacitidine or decitabine can be used alone. In addition to lowintensity chemotherapy, targeted agents such as the BCL2 inhibitor, venetoclax, or sonic hedgehog (SHH) pathway inhibitor, glasdegib, can be useful for some AML patients. Patients with known IDH1 or IDH2 mutations can be treated, respectively, with ivosidenib or enasidenib alone. Gemtuzumab ozogamicin may also be used alone if the AML cells are CD33 positive. 37

PML Standards of Care

PML standards of care are different from other AML subtypes and rely on differentiating agents, like all-trans-retinoic acid (ATRA), which targets RARα of the PML-RARα fusion protein seen in 8% of AML patients.36 Other PML treatments might include chemotherapy and transfusions of platelets or other blood products. Like AML, PML treatments are administered in three phases, remission induction, consolidation, and maintenance. Usually for induction therapy, ATRA is combined with either: arsenic trioxide (ATO)

with the addition of gemtuzumab ozogamicin for those with high risk for recurrence, an anthracycline chemotherapy with the addition of cytarabine for those at high risk for recurrence, or anthracycline chemotherapy plus ATO. 37 Consolidation therapy consists of either ATRA plus ATO, ATRA plus an anthracycline chemotherapeutic agent, ATO plus an anthracycline chemotherapeutic agent, or chemotherapy alone using anthracycline and cytarabine. Patients with high risk of recurrence are given maintenance therapies, including ATRA alone or ATRA along with chemotherapy, such as 6-mercaptopurine and/or methotrexate. 37

Targeted Therapies for AML Molecular Subtypes

Targeted therapies for AML allow clinicians to provide a tailored regimen to suit a patient’s molecular profile. With FLT3 being the most prevalent mutation in AML, FLT3 inhibitors currently available include midostaurin and gilteritinib. Midostaurin can be administered with certain chemotherapeutic agents as a first-line treatment, while gilteritinib is indicated for adults who have not responded to initial treatment or with recurrent AML. Gilteritinib can result in a serious but rare complication referred to as differentiation syndrome, treatable with a pause in gilteritinib treatment and a round of steroids such as dexamethasone. 37

Similar to other tyrosine kinase inhibitors, a major obstacle for FLT3 therapies is acquired resistance. Studies have shown that using a combination of FLT3 inhibitors can help combat acquired resistance. 36

IDH1 and

IDH2 mutations occur in approximately 20% of AML patients. Ivosidenib targets IDH1-mutant AML, while enasidenib targets IDH2-mutant AML. Both of these drugs are suitable first-line therapies for IDH1- or IDH2- mutant patients who cannot tolerate intensive chemotherapy. Both of these drugs can result in differentiation syndrome. Like with gilteritinib, IDH-targeted drugs should be halted and the patient should be treated with steroids before resuming treatment if differentiation syndrome occurs. 37

In 20% of AML patients,

DNMT3A is altered, resulting in hypermethylation of important tumour suppressor genes, rendering their tumour suppressor function useless. DNMT3A-mutant patients tend to benefit from hypomethylating agents, such as azacitidine and decitabine, which have generated higher response rates and overall survival, particularly in elderly patients. 37

For CD33-positive AML patients, a monoclonal antibody-chemotherapeutic conjugate gemtuzumab ozogamicin, can be added to first-line chemotherapy treatment. Most AML cells are CD33 positive. By targeting CD33 protein, the monoclonal antibody component of gemtuzumab ozogamicin acts as a homing agent for the cytotoxic component, making it more target specific. As previously mentioned, gemtuzumab ozogamicin is also an appropriate first-line therapy for patients who cannot tolerate intensive chemotherapy or when the patient is no longer responsive to other therapies. 37

For patients over 75 years old who cannot tolerate intensive chemotherapy as a first-line therapy, venetoclax in combination with a lessintensive chemotherapeutic agent, such as cytarabine, is the standard of care. Venetoclax inhibits BCL-2, a protein known to promote cancer cell survival. Along with typical side effects, tumour lysis syndrome can occur in these patients. Tumour lysis syndrome occurs when the apoptotic leukemia cell fragments overwhelm the kidneys. Therefore, clinicians are advised to gradually titrate the dose of venetoclax to avoid tumour lysis syndrome. 37 In patients with hedgehog pathway mutations or overactivity, glasdegib can be given in combination with less intensive chemotherapy, such as low dose cytarabine, as a first-line therapy for patients 75 years or older who cannot tolerate intensive chemotherapy. Because the hedgehog pathway is essential for fetal development, glasdegib should not be used in patients who are pregnant or who could become pregnant. 37

The Role of Stem Cell Transplants in the AML Landscape

Stem cell transplants are often used for AML patients who are amenable to higher doses of chemotherapy and radiation for stem cell ablation. Allogeneic stem cell transplant (alloSCT) is the most common type of stem cell transplant, with emphasis placed on the donor human leukocyte antigen (HLA) compatibility. For older patients who cannot tolerate high doses of chemotherapy and radiation, nonmyeloablative transplants (mini-transplants) are available. The second major class of stem cell transplants are autologous stem cell transplants, during which the patient’s own stem cells are removed and frozen while the patient receives high-dose radiation and chemotherapy. After treatment, the stem cells are reintroduced into the patient. Autologous transplants are suitable when the patient does not have an adequate HLA match or for patients in remission. 37

Stem cell transplants are often used for AML patients who are amenable to higher doses of chemotherapy and radiation for stem cell ablation. Allogeneic stem cell transplant (allo-SCT) is the most common type of stem cell transplant, with emphasis placed on the donor human leukocyte antigen (HLA) compatibility