Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as FLT3, IDH1/2 and TP53, and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

“…[1][2][3][4][5][6] Antibodydrug conjugates (ADCs), comprising monoclonal antibodies conjugated to cytotoxic agents (payloads) via a linker, have emerged as novel therapeutic options. [7][8][9][10] ADCs have been approved for the treatment of metastatic urothelial cancer (mUC), metastatic breast cancer, and hematological malignancies, [11][12][13][14][15][16][17][18][19][20][21] and several are currently in clinical development. 7 They represent significant progress for the treatment of advanced cancers, as ADCs offer tumor specificity and potency not achievable with traditional therapeutic options while limiting the toxicity associated with an unconjugated payload.…”

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

“…There was no significant difference in the survival analysis of GNA15 expression in the entire cohort, which may be caused by the complicated prognostic analysis of AML. For example, the application of hematopoietic stem cell transplantation, targeted drugs and immunotherapy could greatly improve the prognosis of high-risk patients ( 24 , 25 ). Therefore, we further performed the prognostic analysis in adult AML with normal karyotype and found that high GNA15 expression was independently associated with poor OS and RFS in this subgroup, which was consistent with the survival analysis results of the GEO database.…”

Evolving Therapeutic Approaches for Older Patients with Acute Myeloid Leukemia in 2021

“…The identification of targetable AML-specific surface markers, driver oncogenes and cellular pathways finally led to the development of new effective treatments; see Figure 1 [132,133] In the last few years, six new drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of newly diagnosed or relapsed or refractory (R/R) AML in UNFIT patients: the FLT3 inhibitor gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax [10]. In this new context, a detailed genetic characterization of the disease with early identification of targetable mutations has become essential.…”