Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

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Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

First line standard therapeutic approaches in elderly highrisk (HR) MDS or AML patients are largely based on hypomethylating agents (HMAs) including azacitidine (AZA) or decitabine (DAC), but responses are generally short-lived and occur only in 50–60% of patients [1, 2]. Patients failing HMAs have a dismal prognosis with a median survival of around 5 months [3]. The high unmet medical need for new treatment options makes this patient population an important target of ongoing clinical research. CD123 (Interleukin-3 receptor alpha chain [IL3RA]) is a potential target for antibodyor cell-based therapies directed towards leukemic stem cells (LSCs) [4], because CD123 is overexpressed on leukemic blasts and an important growth and differentiation receptor for early LSCs [5]. Upregulated expression of CD123 has been associated with higher blast cell counts at diagnosis and poorer complete response (CR) and survival rates in AML [6]. Moreover, the CD123 expression is low/absent on normal hematopoietic stem cells, making CD123 an attractive and specific target for immunotherapy-based approaches [7, 8]. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells [9] and has been shown to induce potent in vitro ADCC against IL3RA-expressing AML blasts/LSC and to reduce leukemic cell growth in murine xenograft models of human AML [10]. In addition, the antibody inhibits signaling by IL-3, the main ligand of CD123, to reduce the proliferation of leukemic progenitor cells [11]. The SAMBA trial, a phase II investigator-initiated study (NCT02992860) of the German and French MDS study groups within the EMSCO network, assessed as primary endpoint the overall hematological response rate (CR, These authors contributed equally: Anne Sophie Kubasch, Freya Schulze

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Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents

Targeting LSD1 for acute myeloid leukemia (AML) treatment.

Near-infrared-responsive functional nanomaterials: the first domino of combined tumor therapy

Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success.

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6–3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27–7.95) months for combination therapy versus 7.26 (6.47–8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79–1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee’s recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.

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Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study.

Indrajeet Singh

Papers

Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study.