As you know, AML is a diverse disease in terms of how it affects each person, which treatments are used and overall outcomes. Although cytogenetic evaluation (looking at your chromosomes) at diagnosis has been utilized for decades to identify if you have low, intermediate or high risk AML, it has unfortunately seen few meaningful therapeutic breakthroughs. However, recent advances in the study of AML biology and its treatments have led to more refined risk assessment.  This new assessment includes genomic abnormalities that help doctors pick new targeted therapies. Since 2017, the number of medications available to treat AML has expanded dramatically, with many new treatments receiving regulatory approval.

The “Current” Standard of Care

Among younger AML patients, 10 to 40 percent of long-term cure rates have been associated with cytarabine and anthracyclines' anti-AML activity discovery in the 1970s, and their combination to form the "7 + 3 regimen" (7 days of cytarabine overlapped initially with 3 days of daunorubicin). Earlier studies focused on patients aged 50 to 55, with 5-year survival rates ranging between 40 and 45 percent. Later studies with patients up to 60 indicated five-year survival rates of 30–35 percent. Other studies in patients aged 60+ showed that these harsh chemotherapy regimens resulted in 5-year survival rates ranging from 10 to 15%.

The Shift

While some AML experts still believe the “7 + 3” regimen is the standard of therapy, it's clear that many others disagree and are shifting away from it towards targeted therapies. Until 2015, the AML community was filled with pessimism, but that has changed since research in AML's clinical led to the FDA's approval of various AML targeted treatments in 2017. This research on the genetic and genomic diversity of AML improved the identification of prognostic, predictive, and targetable molecular abnormalities. An example of this occurred in acute promyelocytic leukemia (APL), where chemotherapy-free regimens that included arsenic trioxide and all-trans retinoic acid (ATRA) revealed cure rates of 90%. 

Such tremendous progress over such a short period was halted briefly by some decisions before 2017. One example is the history of gemtuzumab ozogamicin (GO), a monoclonal antibody targeting CD33 conjugated to a calicheamicin payload. The makers of GO voluntarily withdrew the drug from clinical usage in the United States after a disappointing study by the Southwest Oncology Group (SWOG) in June 2010. Fortunately, the drug received FDA approval for a lower dose in 2017 after a meta-analysis of five AML frontline trials convincingly demonstrated its efficacy. The use of GO in the treatment of APL and Core binding factor (CBF) AML is currently highly relevant. High doses of cytarabine chemotherapy in addition to gemtuzumab ozogamicin increased the long-term survival rate from 50% to 75% or more.

The New FDA Approved Therapies

The following table shows the treatments approved since 2017 (extracted from the Blood Cancer Journal review of 2021):

What’s Next

Ongoing studies and recently approved drugs discussed in the Blood Cancer Journal of 2021 that might soon be part of a new standard of care include: 

• Combinations of epigenetic therapy with hypomethylating agents and venetoclax in patients unfit for intensive chemotherapy; and combinations of intensive chemotherapy and venetoclax in fit patients. 
• FLT3 inhibitors (gilteritinib, midostaurin, sorafenib, quizartinib, crenolanib, etc.) plus intensive chemotherapy or low-intensity therapy in FLT3-mutated AML.
• The use of IDH inhibitors (ivosidenib, enasidenib) and/or venetoclax in IDH1/2-mutated AML.
• In TP53-mutated AML, APR246 (TP53 modulator) and magrolimab (anti-CD47 monoclonal antibody)  
• Menin inhibitors in mixed-lineage leukemia (MLL1)-rearranged acute leukemia. 
• To improve possible cure rates in previously incurable AML subgroups by combining small-molecule targeted treatments with or without standard intense chemotherapy or hypomethylating agents (+/- venetoclax; at the expense of myelosuppression).
• Establish maintenance therapy as an important strategy in AML. 
• Extend the effects of oral anti-AML therapies (e.g., decitabine, azacitidine).
• Enhance T-cell immune responses against AML with T-cell engagers, checkpoint inhibitors, and CAR-T cells.

For more information on personalized medicine, watch this previously recorded Adult AML Chapter event we hosted with Dr. Stein:

The Power of Personalized Medicine for Treating Your AML