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Targeting AML
The Importance of Molecular and Cytogenetic Targets in AML

Released: September 12, 2018

Expiration: September 11, 2019

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Tremendous advances in our understanding of the molecular drivers of acute myeloid leukemia (AML) have yielded effective targeted therapeutics. Yet the arrival of these agents challenges clinicians: How should we update our standard diagnostic and therapeutic approaches for AML?

AML Diagnosis: Then and Now
Before 2016, the standard of care at my institute was to confirm diagnosis of AML by morphology and flow cytometry and then initiate cytarabine and anthracycline-based (7+3) intensive chemotherapy in fit patients or hypomethylating agents in unfit patients. In newly diagnosed AML, karyotype has long been considered the most important independent prognostic factor following 7+3 induction. Cytogenetic and molecular information was reported several weeks after diagnosis and was used mainly for determining post-remission therapy.

We now individualize therapy using molecular and cytogenetic analyses completed within the first 72 hours before starting treatment (Figure 1). For example, fit, younger patients with favorable and intermediate karyotype are now considered for fractionated-dose gemtuzumab ozogamicin (GO) administered with intensive induction chemotherapy. A meta-analysis reported that the addition of GO increased 6-year survival by an impressive 20.7% in those with favorable-risk cytogenetics and by 5.7% with intermediate-risk cytogenetics. However, individuals with adverse risk cytogenetics had no improvement with GO.

Figure 1. Selection of optimal AML therapy based on cytogenetic and molecular profiling.

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Poor-Risk Karyotype
Treatment decisions are now also guided by identification of poor-risk karyotype involving chromosomes 7 and/or 5 or comprising ≥ 3 cytogenetic aberrations (complex karyotype). Typically, these patients are older with known or suspected history of myelodysplastic syndrome (MDS) or chemotherapy or radiation exposure. Although AML with previous MDS-related changes (AML-MRC) can be defined by clinical history, marrow morphology, or karyotypic abnormalities, the first 2 criteria are unreliable and subjective, and we prefer karyotype.

Optimal treatment of older, fit patients with secondary therapy-related AML and AML-MRC consists of liposomal cytarabine and daunorubicin followed by allogeneic stem cell transplantation (alloSCT). Phase III data showed significantly improved survival and remission rates with the liposomal formulation vs 7+3. We recommend clinical trials or low-dose chemotherapy for unfit, poor-karyotype patients.

Mutational Profiling in AML
Mutational profiling is also crucial for clinical decision making. We routinely test for FLT3-ITD, FLT3-TKD, and IDH1/2 mutations in all newly diagnosed patients. Newly diagnosed, fit patients with the FLT3 mutation receive 7+3 plus the oral FLT3-TKD inhibitor midostaurin, followed by alloSCT. My institute and others are also evaluating novel FLT3 inhibitors more potent and specific for mutant FLT3 AML, such as quizartinib and gilteritinib. Because FLT3 status can change based on previous therapy and clonal evolution or expansion, we retest for FLT3 mutations at disease recurrence. We hope that quizartinib and gilteritinib will soon be approved and available; these agents are under FDA evaluation for relapsed/refractory FLT3-mutant disease, with early-phase studies reporting response rates > 50% and 40%, respectively, as well as suggesting prolonged survival.

IDH1/2 mutations render patients eligible for oral inhibitors of IDH1 (ivosidenib) or IDH2 (enasidenib) or investigational IDH inhibitors in relapsed/refractory AML. Although not curative, both agents are well tolerated and can stabilize disease and prolong survival for several months.

Next-Generation Sequencing
Lastly, we perform next-generation sequencing in all newly diagnosed and relapsed/refractory patients with AML. Detecting other mutations (ie, p53 mutations) can affect clinical trial eligibility and treatment outcomes. This is particularly true in normal karyotype AML where the risks and benefits of chemotherapy vs transplantation must be carefully weighed.

Your Thoughts
How do you approach cytogenetic and molecular profiling of your patients with newly diagnosed AML? Share your perspective in the comments box!

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