Treatments

Historically, the cornerstone of acute myeloid leukemia (AML) treatment was intensive chemotherapy, specifically the “7+3” regimen, which combines cytarabine and an anthracycline such as daunorubicin. This approach remained virtually unchanged for over 40 years until the emergence of targeted therapies beginning in 2017, revolutionizing AML treatment.1 Below is a summary of recent developments and the impact of these new therapies.

Traditional Chemotherapy Approaches:

The standard treatment for young and fit patients is still intensive chemotherapy. The “7+3” regimen remains a first-line induction therapy, followed by high-dose cytarabine-based consolidation for patients who achieve remission. However, despite decades of use, this regimen has significant toxicities, including cytopenias, infections, and organ damage, prompting the need for more targeted therapies.1

New Targeted Therapies Since 2017:

With the introduction of novel targeted therapies, treatment of AML has expanded to include multiple classes of agents, designed to target specific mutations or pathways in leukemic cells (Table). These drugs offer alternatives for specific populations, particularly those ineligible for traditional chemotherapy.1

  • FLT3 Inhibitors: FLT3 inhibitors treat AML by binding to the FLT3 receptor, blocking its activation and downstream signaling, which leads to cell cycle arrest, differentiation, and apoptosis of leukemic cells, particularly those with FLT3 mutations (Figure 1).2 Midostaurin (frontline) and gilteritinib (relapsed/refractory) target FLT3 mutations, common in AML patients.1 The RATIFY trial demonstrated that adding midostaurin to standard chemotherapy improved survival rates, and gilteritinib is now approved for relapsed/refractory AML.3,4

  • IDH1/IDH2 Inhibitors: Ivosidenib (IDH1) and enasidenib (IDH2) offer targeted treatment for patients with IDH mutations.1 In the AGILE trial, combining ivosidenib with azacitidine significantly improved event-free and overall survival in older patients or those ineligible for intensive chemotherapy.5
  • BCL-2 Inhibitor Venetoclax: Venetoclax has transformed the treatment landscape, especially for elderly patients and those unfit for chemotherapy. Venetoclax works by inhibiting the anti-apoptotic protein BCL-2, leading to cancer cell death (Figure 2).6 Approved in 2020 for newly diagnosed AML in older adults or those with comorbidities, it is used in combination with hypomethylating agents (HMA; azacitidine or decitabine) or low-dose cytarabine (LDAC).1,6 The phase 3 VIALE-A trial demonstrated superior outcomes with venetoclax, including improved remission rates and overall survival, particularly in patients with IDH mutations.8 This regimen is now a preferred option in patients not suited for intensive chemotherapy.1 The VIALE-C Trial showed that venetoclax plus LDAC improved survival in patients unfit for chemotherapy, although the primary endpoint of overall survival was not met initially.9 However, extended follow-up demonstrated significant survival benefits with this combination therapy.10
  • CPX-351: This liposomal formulation of daunorubicin and cytarabine is approved for treatment-related AML (t-AML) and AML with myelodysplastic-related changes.11 CPX-351 has shown superior survival compared to the standard 7+3 regimen, particularly in older patients.1
  • Gemtuzumab Ozogamicin: A CD33-directed antibody-drug conjugate, gemtuzumab is effective in CD33-positive AML and has improved event-free survival when combined with chemotherapy. It is used in both newly diagnosed and relapsed/refractory AML.1

Postremission Therapy:

For patients who achieve remission, consolidation therapy is critical to long-term outcomes. For favorable-risk patients, high-dose cytarabine remains the standard, while intermediate- and high-risk patients often proceed to allogeneic stem cell transplant (allo-HCT).1 Oral azacitidine (CC-486) has also emerged as an important option for postremission maintenance therapy, especially in patients not suited for intensive therapy or transplantation, as shown by the QUAZAR AML-001 trial.13

Relapsed/Refractory AML:

Relapsed or refractory AML remains a significant challenge, but targeted therapies have provided new hope:

  • FLT3 Inhibitors: Gilteritinib offers better survival and fewer side effects compared to standard chemotherapy for relapsed/refractory FLT3-mutated AML, based on the ADMIRAL trial.14
  • IDH Inhibitors: Ivosidenib and enasidenib are critical for treating relapsed or refractory AML in patients with IDH1/IDH2 mutations. New combinations with venetoclax and other agents are also showing promise in early trials.1

Investigational Therapies and Combinations1:

Research into new drug combinations continues to evolve, with promising results:

  • Venetoclax Combinations: Studies have explored venetoclax in combination with other agents, showing high response rates in both frontline and relapsed settings.
  • Menin Inhibitors: New agents like SNDX 5613 target menin, offering hope for patients with MLL rearrangements or NPM1 mutations.
  • CAR-T and Bispecific Antibodies: Innovative immunotherapies are being tested, including chimeric antigen receptor (CAR) T cells targeting AML-specific antigens.

Allogeneic Stem Cell Transplantation1:

For patients with high-risk cytogenetics or measurable residual disease, allo-HCT remains the only curative option. Reduced-intensity conditioning (RIC) is an option for older or less fit patients, while myeloablative conditioning (MAC) is preferred for younger, fit patients.

In summary, modern AML treatment has moved beyond the traditional chemotherapy regimens, with new targeted therapies transforming care for patients with specific mutations, those unfit for intensive chemotherapy, and those with relapsed or refractory disease. As more agents and combinations gain approval, treatment personalization based on molecular profiles and patient characteristics will continue to improve survival outcomes in AML.

References

  1. Roman Diaz JL, Vazquez Martinez M, Khimani F. New approaches for the treatment of AML beyond the 7+3 regimen: Current concepts and new approaches. Cancers. 2024;16(3):677. doi:10.3390/cancers16030677
  2. Marjoncu D, Andrick B. Gilteritinib: A novel FLT3 inhibitor for relapsed/refractory acute myeloid leukemia. J Adv Pract Oncol. 2020;11(1):104-108. doi:10.6004/jadpro.2020.11.1.7
  3. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359
  4. Pulte ED, Norsworthy KJ, Wang Y, et al. FDA approval summary: Gilteritinib for relapsed or refractory acute myeloid leukemia with a mutation. Clin Cancer Res Off J Am Assoc Cancer Res. 2021;27(13):3515-3521. doi:10.1158/1078-0432.CCR-20-4271
  5. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344
  6. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106-1117. doi:10.1158/2159-8290.CD-16-0313
  7. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. US Food and Drug Administration (FDA). October 10, 2020. Accessed October 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia
  8. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
  9. Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145. doi:10.1182/blood.2020004856
  10. Wei AH, Panayiotidis P, Montesinos P, et al. Long-term follow-up of VIALE-C in patients with untreated AML ineligible for intensive chemotherapy. Blood. 2022;140(25):2754-2756. doi:10.1182/blood.2022016963
  11. FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia. US Food and Drug Administration (FDA). August 3, 2017. Accessed October 1, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-certain-types-poor-prognosis-acute-myeloid-leukemia
  12. Tolcher AW, Mayer LD. Improving combination cancer therapy: the CombiPlex® development platform. Future Oncol. 2018;14(13):1317-1332. doi:10.2217/fon-2017-0607
  13. Wei AH, Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383(26):2526-2537. doi:10.1056/NEJMoa2004444
  14. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688