IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA
Clinical Guidelines and Standards of Care for the Treatment of AML Anna Love, M.B.S., Ph.D.
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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
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CUTE 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 subt ypes. 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 (410% 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 RARÎą of the PML-RARÎą 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)
