Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Samra, Bachar; Konopleva, Marina; Isidori, Alessandro; Daver, Naval; DiNardo, Courtney D.

doi:10.3389/fonc.2020.562558

Cited by 57 publications

(67 citation statements)

References 73 publications

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“…Venetoclax has become the most clinically effective BH3-targeting drug approved by the FDA for leukemia treatment and has received FDA approval in several different contexts [136][137][138]. A comprehensive review of venetoclax's use and function has recently been published [139], so it will not be discussed in depth here.…”

Section: Mitochondrial Priming and Bcl-2 Protein Familymentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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Acute myeloid leukemias (AML) are a group of aggressive hematologic malignancies resulting from acquired genetic mutations in hematopoietic stem cells that affect patients of all ages. Despite decades of research, standard chemotherapy still remains ineffective for some AML subtypes and is often inappropriate for older patients or those with comorbidities. Recently, a number of studies have identified unique mitochondrial alterations that lead to metabolic vulnerabilities in AML cells that may present viable treatment targets. These include mtDNA, dependency on oxidative phosphorylation, mitochondrial metabolism, and pro-survival signaling, as well as reactive oxygen species generation and mitochondrial dynamics. Moreover, some mitochondria-targeting chemotherapeutics and their combinations with other compounds have been FDA-approved for AML treatment. Here, we review recent studies that illuminate the effects of drugs and synergistic drug combinations that target diverse biomolecules and metabolic pathways related to mitochondria and their promise in experimental studies, clinical trials, and existing chemotherapeutic regimens.

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Section: Mitochondrial Priming and Bcl-2 Protein Familymentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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“…The potent apoptotic effect of BCL-2 inhibition with venetoclax makes TLS a significant risk of treatment [29]. However, incidence of this adverse effect appears to be higher in studies of chronic lymphocytic leukemia (CLL) as compared to the pivotal studies in AML [9]. TLS incidence was noted to be up to 13% with initial phase 1 studies in CLL, which had shorter ramp-up phase and higher starting doses.…”

Section: Lower Intensity Treatmentsmentioning

confidence: 99%

“…Potential risk factors for TLS in AML include bulky disease, leukocytosis, high levels of lactate dehydrogenase, hyperuricemia, and concomitant kidney disease, indicating that uric acidlowering therapy with allopurinol or rasburicase may be important. Caution also may be warranted in AML patients with NPM1 and IDH1/2 mutations, who may also have increased risk of TLS due to an increased sensitivity to venetoclax in these mutation-defined subgroups of AML [9]. Furthermore, Esparza and co-authors reported on 2 patients with venetoclax-induced TLS that had similar genomic profiles (ASXL1, RUNX1, and TET2 mutations), suggesting the potential of this mutational spectrum as a predictor of venetoclax sensitivity [32].…”

Section: Lower Intensity Treatmentsmentioning

confidence: 99%

“…In contrast to 7+3, the induction regimen is administered via intravenous infusion over 90 minutes on days 1, 3, and 5 of induction and days 1 and 3 of consolidation, and thus is more amenable to administration in an outpatient setting with careful monitoring [8]. In addition, venetoclax combined with azacitidine has demonstrated substantially improved outcomes in older, unfit AML patients, leading to rapid and widespread uptake of venetoclax-based combinations in both academic and community-based settings [9]. The risk of tumor lysis syndrome (TLS) is associated with venetoclax, prompting the need for risk assessment and prophylaxis, with more intensive measures (including hospitalization) recommended as risk increases.…”

Section: Introductionmentioning

confidence: 99%

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Moving the Treatment of Acute Myeloid Leukemia to the Outpatient Setting: Current Expert Perspectives and Consensus Findings

2021

Journal of Clinical Haematology

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Intensive treatments for acute myeloid leukemia (AML) have traditionally been administered on an inpatient basis due in part to chemotherapy regimen infusion requirements, transfusion support, and the need for close monitoring for infectious complications and adverse events. However, hospitalization is a major component of burgeoning healthcare costs and may contribute to impaired quality of life in patients with AML. To help inform the ongoing discussion regarding the merits and challenges of outpatient administration of AML therapy, a multidisciplinary panel of experts were engaged to identify areas of consensus, explore ongoing uncertainties, and develop an algorithm that may help inform discussions on outpatient treatment between healthcare providers and patients. Based on available evidence and clinical experience, inpatient treatment remains appropriate for majority of patients with AML undergoing conventional intensive induction chemotherapy. The more recently introduced liposomal formulation of cytarabine and daunorubicin (CPX-351) has an infusion schedule that is more amenable to outpatient administration. Outpatient administration of CPX-351 for select patients with close daily monitoring has been implemented via a multidisciplinary team-based model. The feasibility of safely managing AML patients receiving outpatient CPX-351 is being prospectively evaluated in an ongoing phase 4 study. Panelists generally agreed that lower-intensity regimens including venetoclax combined with hypomethylating agents or lowdose cytarabine (LDAC), glasdegib plus LDAC, enasidenib, ivosidenib, and gilteritinib can be administered safely in the outpatient setting for most newly diagnosed AML patients. Venetoclax-based combinations are also promising for outpatient administration but may require risk stratification due to the potential for tumor lysis syndrome (TLS). The proposed algorithm developed to inform consideration of outpatient treatment is focused on consideration of patient fitness, the treatment regimen selected, infrastructure in place to support outpatient administration, and patient/caregiver agreement with the outpatient approach. Educational needs for clinicians and recommendations to overcome knowledge gaps regarding outpatient therapy were also formulated. Outpatient administration of AML therapy is feasible in the appropriate clinical setting and patient. However, further research is needed regarding feasibility, logistics, safety, and patient outcomes including quality of life.

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“…The high death rate is often a result of mutations that form a difficult -to-treat heterogenous tumor microenvironment [ 1 , 3 ]. With the current therapy, AML patients frequently enter remission, but nearly always relapse and tend to develop resistance to most existing standard-of-care treatments (e.g., induction cytotoxic chemotherapy or venetoclax-based therapy) [ 1 , 4 , 5 , 6 ]. Current targeted therapies are directed towards gene mutations found in AML, such as FMS-like tyrosine kinase 3 (FLT3) [ 7 , 8 , 9 ], KIT [ 10 , 11 ], BCR-ABL [ 12 ], TP53 [ 13 , 14 ], isocitrate dehydrogenase (IDH1 and IDH2) [ 1 , 15 , 16 ], or mixed lineage leukemia (MLL) [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia

Golla

Ehudin

Annageldiyev

et al. 2021

Cancers

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The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the disease motivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for various actin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not being successfully utilized clinically towards cancer treatment. This work establishes the therapeutic activity of ROCK inhibitor (5Z)-2–5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one (DJ4) in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors. Herein, DJ4 induced cytotoxic and proapoptotic effects in a dose-dependent manner in human AML cell lines (IC50: 0.05–1.68 μM) and primary patient cells (IC50: 0.264–13.43 μM); however, normal hematopoietic cells were largely spared. ROCK inhibition by DJ4 disrupts the phosphorylation of downstream targets, myosin light chain (MLC2) and myosin-binding subunit of MLC phosphatase (MYPT), yielding a potent yet selective treatment response at micromolar concentrations, from 0.02 to 1 μM. Murine models injected with luciferase-expressing leukemia cell lines subcutaneously or intravenously and treated with DJ4 exhibited an increase in overall survival and reduction in disease progression relative to the vehicle-treated control mice. Overall, DJ4 is a promising candidate to utilize in future investigations to advance the current AML therapy.

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Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

Cited by 57 publications

References 73 publications

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Moving the Treatment of Acute Myeloid Leukemia to the Outpatient Setting: Current Expert Perspectives and Consensus Findings

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia

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