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The “How I Treat” series in Blood aims to offer diagnostic or therapeutic advice for a disease or several distinct aspects of a single disorder.1 There have been several that have focused on acute myeloid leukemia (AML) covering a range of different topics.2-9 With the numerous new drug approvals by the U.S. Food and Drug Administration (FDA), there are now overlapping treatment options, which whilst welcoming for patients can be challenging for treating physicians.
In a recent “How I Treat” article,10 Courtney DiNardo from the MD Anderson Cancer Center, Texas, US, and Andrew Wei of the Alfred Hospital and Australian Centre for Blood Disease, Monash University, Melbourne, AU, highlight the current key issues. These include the identification of mutations at both diagnosis and relapse, deciding which treatment to use from the many therapeutic options, and increasing awareness on how to manage the common complications that are associated with these newer therapies. They go on to present three case studies to demonstrate the use of these newly approved drug options, keeping the aforementioned key issues in mind.
Due to severe marrow suppression, management should utilize bone marrow assessment in the third week with appropriate dose interruption, delay, and duration reduction, as required. As highlighted in the case study, dose duration reduction from 28-day to 14- or 21-day cycles may be required to prevent cytopenias. DiNardo and Wei recommend using the combination of LDAC/HMA + venetoclax in older unfit patients with NPM1 mutant AML having seen recovery rates of 93% and relapse free survival (RFS) of >4 years.13
As an initial treatment option, midostaurin combined with intensive chemotherapy is suggested for younger patients with FLT3 mutant AML.17 DiNardo and Wei note that although both the ELN 2017 classification18 and NCCN AML guidelines19 recommend stratifying AML risk based on FLT3-ITD allelic ratio and NPM1 mutation status, FLT3-ITD allelic ratio is not standardized and should be considered alongside other risk factors. FLT3 inhibitors may also have a role in maintenance therapy, and were used here following HSCT. The authors recommend restarting FLT3 inhibition 30 days after HSCT, following confirmation of no clinically significant graft-versus-host disease (GvHD), infection or other toxicity.
This particular case study was highlighted as challenging, with a median overall survival (OS) of <5 months in patients who relapsed following treatment with HMAs (azacitidine).21,22 The identification of actionable mutations is particularly important in older patients as IDH1 mutations occur more frequently in that population. With ivosidenib (an inhibitor of IDH1 mutant enzyme), higher response rates were seen in patients who had failed one treatment rather than patients who had failed ≥3 treatments, yet 50% of patients with relapsed or refractory disease who responded to ivosidenib were still alive after 18 months. IDH inhibitor monotherapy is currently advised but there are ongoing trials to determine its role in combination therapies.10 Professors DiNardo and Wei went on to discuss IDH inhibitor complications, and particularly the possible development of differentiation syndrome (DS) that can occur approximately 29 days following IDH inhibitor initiation. As the symptoms (dyspnea, fever, pulmonary infiltrates, hypoxia, pleural or pericardial effusions, peripheral edema, and weight gain) overlap with symptoms of infection and/or progression, the authors highlight the importance of clinician awareness when using these therapies.
In conclusion, the paper highlights how treatment for AML is moving away from the two main options of “curative, intensive” and “palliative, low intensity” treatments to a more diverse range of options. The authors recommend caution in the use of combinations of the newer drugs, unless as part of a clinical trial, so as to avoid unanticipated side effects due to drug interactions.10
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