AML Genomic Landscape Plays Key Role in Treatment

Among the many subtypes of leukemias in the United States, acute myeloid leukemia (AML) is the most commonly diagnosed form in adults and causes the highest number of deaths.¹

During 2020, the United States had an estimated 20,000 new patient cases of AML, with more than half of these resulting in death.2 Leukemia, a cancer of the blood and bone marrow, affects the function and production of blood cells.^2,3 In AML, immature myeloid cells (myeloblasts) accumulate and are unable to mature into functioning platelets, red blood cells (erythrocytes), or white blood cells (neutrophils).^2,3 Compared with other types of leukemias, AML occurs more frequently in older adults, with a median age at diagnosis of 67.^1,2 Increasing age; exposure to benzene, chemotherapy, or radiation; family history; genetic mutations; male gender; and smoking are risk factors for developing AML.^2,3 Because blood cells are not maturing, AML presents similarly to anemia, neutropenia, and thrombocytopenia (Figure 1^1,2). Symptoms commonly include bleeding, fatigue infection, and pallor.²

Evaluation for suspected AML initially involves assessment of medical history and a physical exam.^2,4 Essential laboratory data include a blood sample with a complete blood count with differential, a peripheral blood smear, and a bone marrow biopsy.^2,4 Based on these results, the presence of at least 20% of blast cells in peripheral blood or marrow generally confirms the diagnosis of acute leukemia, as defined by the World Health Organization (WHO) in 2016.⁴ Immunophenotyping and cytogenetic studies are used to confirm cell lineage, establish risk stratification, and classify subtypes.4 In accordance with the WHO classification system, AML is classified into 1 of 6 groups based on clinical features, genetics, immunophenotype, and morphology. Prognosis and treatment selection are increasingly determined by expression or absence of several key gene mutations (Figure 2.^1,5,6)

Treatment Options

AML treatment options mainly include chemotherapy, stem cell transplant, and targeted therapy (Figure 3^1,2,7,8). AML was considered an oncologic emergency requiring treatment initiation as soon as possible upon diagnosis.⁶ However, new evidence suggests less of a correlation between time to treatment and prognosis than previously thought.⁶ As treatment is being targeted to patient-specific gene mutations, there may be benefit to first obtaining genetic and laboratory tests to initiate the most appropriate treatment.⁶

Treatment of AML generally occurs in 2 phases: remission induction therapy and postremission (consolidation) therapy.^1,2 Choice of treatment differs based on age and medical fitness of the patient.^1,2 Healthy patients under age 60 often qualify for “intensive” therapy, whereas older patients who present with a combination of risk factors, such as multiple comorbidities, poor performance status (PS), and unfavorable cytogenetics, may better tolerate a less-intense regimen.^1,7 PS in oncology is often assessed using the ECOG scale, which is the standard for quantifying the functional capacity of a patient and predicting chemotherapy tolerability.

The cornerstone of intensive induction therapy is a regimen of 7 days of continuously infused cytarabine, plus a 3-day course of an anthracycline called “7 + 3 induction therapy,” which results in a complete remission rate of about 65%.^1,2 If remission is achieved, medically fit patients have options for consolidation therapy: an allogeneic (donor) or an autologous (patient’s own) stem cell transplant, or several cycles of chemotherapy with high-dose cytarabine.^1,2 Nonintensive induction therapy includes less-aggressive treatments, such as hypomethylating agents such as azacitidine and decitabine, or low-dose cytarabine (LDAC).^1,8 However, some patients may not receive any antileukemic therapy, depending on their fitness.⁸ Although less-intensive therapy results in lower rates of treatment-related mortality, median survival time is much lower with these regimens, about 6 to 10 months.⁸

In patients who are too frail to be considered for nonintensive therapy, supportive care is offered.² This includes management and prophylaxis of hematologic abnormalities and infections with antimicrobial agents, growth factors, hydroxyurea, and transfusions.^1,2

For medically fit and unfit patients, targeted therapy may be added to both consolidation and induction therapy based on patient-specific cancer characteristics (Figure 4²).

On the Horizon

Research emphasis is primarily targeted toward improving outcomes, specifically in elderly patients. A high incidence and poor prognosis of AML exists within this population. A 75-year-old patient recently diagnosed with AML has a 20% chance of 1-year survival.⁸

AML in an older adult is associated with poor outcomes because of higher rates of unfavorable cytogenetic abnormalities, cellular mutations that develop resistance to first-line chemotherapy, and a higher prevalence of secondary AML.^8,9 Resistance can manifest as a cellular mutation capable of altering the drug binding site or modifying the apoptotic abilities of the drug.⁸

In August 2020, the American Society of Hematology (ASH) released updated guidelines for the management of AML in older patients.⁸ Recent literature supports guideline recommendations encouraging antileukemic therapy over supportive treatment and more-intensive therapy over less-intensive treatment whenever possible.⁸ Overall, the potential benefit of overtreating the elderly population outweighs the risk of toxicities when considering survival rates.⁸

The ASH panel recommends against combination therapy with the following exceptions: LDAC in combination with glasdegib or hypomethylating agents in combination with venetoclax.⁸ The data supporting these combinations are derived from small and recent phase 2 trials, so the panel states this as a weak recommendation until stronger analyses are published.⁸ Glasdegib and venetoclax are 2 of 8 agents that the FDA approved between 2017 and 2019 for the treatment of AML.⁹ The surge in drug development is the result of improved understanding of the chemotherapy resistance mechanisms, as well as apoptotic machinery elucidation.⁹

Venetoclax inhibits an antiapoptotic protein family commonly overexpressed in AML, B-cell lymphoma 2 (BCL2), which has been associated with chemotherapy resistance and poor survival.¹⁰ The recently published VIALE-C trial found that the addition of venetoclax to nonintensive azacitidine induction therapy versus azacitidine monotherapy prolonged survival (14.7 months versus 9.6 months) and increased the likelihood of remission in patients with untreated AML.¹⁰

Glasdegib is a potent and selective oral inhibitor of the Hedgehog signaling pathway, which is often overactive in AML.¹¹ This pathway aids in the development and proliferation of leukemic stem cells, which play a major role in development of resistance to chemotherapy and disease relapse.¹¹ A phase 2 trial (NCT01546038) published in 2018 found that the combination of glasdegib and LDAC significantly improved overall survival and response rates compared with LDAC alone.¹¹ These results were consistent across various combinations of genetic mutations, suggesting the potential for a more universal application of this drug combination.11 A larger phase 3 trial is under way.¹¹

Conclusion

The AML genomic landscape plays a vital role in patient prognosis and treatment decisions. Numerous therapeutic options for AML have become available within the past 3 years, but continued research is needed to determine their place in therapy and introduce more-standardized treatment approaches. The risk versus benefit of more-intense treatment options must be heavily weighted in the frail and medically unfit AML population. The rapid rate of chemotherapy resistance and disease relapse in compromised patients makes it imperative to continue research initiatives to develop optimal and safe therapeutic approaches within this population.

JERRY A. BARBEE JR, PHARMD, BCPS, CPH; and GLENN SCHULMAN, PHARMD, MS, BCPS, BCACP, BCGP, BCIDP, are clinical pharmacists in Pensacola, Florida. CAITLIN M. SACCO is a PharmD candidate at Belmont University in Nashville, Tennessee.

REFERENCES

• Tallman MS, Wang ES, Altman JK, et al. Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17(6):721-749. doi:10.6004/jnccn.2019.0028
• Adult acute myeloid leukemia treatment (PDQ)-health professional version. National Cancer Institute. Updated August 11, 2020. Accessed October 28, 2020. http://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq
• Acute myeloid leukemia. Leukemia & Lymphoma Society. Accessed October 28, 2020. http://www.lls.org/leukemia/acute-myeloid-leukemia
• Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141:1342-1393.doi:10.5858/arpa.2016-0504-CP
• Yu J, Li Y, Zhang D, Wan D, Jiang Z, Jiang Z. Clinical implications of recurrent gene mutations in acute myeloid leukemia. Exp Hematol Oncol. 2020;9:4.doi:10.1186/s40164-020-00161-7
• Röllig C, Kramer M, Schliemann C, et al. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia? Blood. 2020;136(7):823-830. doi:10.1182/blood.2019004583
• Rao AV. Fitness in the elderly: how to make decisions regarding acute myeloid leukemia induction. Hematology Am Soc Hematol Educ Program. 2016(1):339-347.doi:10.1182/asheducation-2016.1.339
• Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv.2020;4(15):3528-3549.doi:10.1182/bloodadvances.2020001920
• Short NJ, Konopleva M, Kadia TM, et al. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 2020;10:506-25. doi:10.1158/2159-8290.CD-19-1011
• DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617-629.doi:10.1056/NEJMoa2012971
• Cortes JE, HeidelFH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33(2):379-389. doi:10.1038/s41375-018-0312-9