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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
CD33 antibody-drug conjugates such as gemtuzumab ozogamicin and vadastuximab talirine (SGN-CD33A) (Burnett et al., 2012; Daver et al., 2016; Minagawa et al., 2016; Table 10.9); Hedgehog inhibitors like sonidebig (erismodegib, LDE255), glasdegib (PF-04449913), and vismodegib; neddylation and subsequent ubiquitination inhibitors (pevonedistat); and Wnt signaling pathway inhibitors (Fukushima et al., 2016; Hanna and Shevde, 2016; Ma et al., 2015; Medler et al., 2015; Swords et al., 2017) together with standard chemotherapy are in ongoing trials. Further therapeutic approaches including NF-κB signaling pathway inhibition (Bosman et al., 2016; Fuchs 2010; Siveen et al., 2017; Zhou et al., 2015), PI3 K/AKT/mTOR signaling pathway inhibition, (Brenner et al., 2016; Fuchs 2011; Hauge et al., 2016) and targeting the S100A8/S100A9-TLR4-ERK/JNK/p38 pathway (Laouedj et al., 2017; Tamburini, 2017) were studied. Cell division cycle 25 (CDC25) protein phosphatases inhibition had antiproliferative effects on primary human AML cells for a subset of patients identified by gene expression profiling (Brenner et al., 2017).
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Erythropoiesis-maturing agents (EMAs), which are specific activin fusion proteins that act as ligand traps to neutralize negative regulators of erythropoiesis, have now been tested in patients with LR-MDS. Luspartercept (ACE-536) has shown ability to increase hemoglobin levels in LR-disease and is approved for patients with beta-thalassemia. The Phase II LR-MDS study reveals 63% erythroid responses with 38% achieving red-cell transfusion independence, particularly in patients with ringed sideroblasts or SF3B1-defined LR-MDS. The study met its primary end-points and is anticipated to be approved in 2020.131 Roxadustat (FG-4592) is an oral hypoxia-inducible factor inhibitor being tested in a Phase III study in LD-MDS in an effort to improve anemia.132 Imetelstat, a telomerase inhibitor, is in a Phase II/III study in red-cell transfusion-dependent and ESA-relapsed/refractory LR-MDS patients. Drugs aimed at improving thrombocytopenia, noted in about 50% of all LR-MDS patients, are also being tested. The TPO-receptor agonists romiplostim and elthrombopag have now been tested in Phase III studies and found to have platelet responses associated with survival benefits but are not approved as yet. Several other novel approaches are being tested, including second-generation HMAs, guadecitabine and ASTX727, and combinations of azacytidine with either lenalidomide, vorinostat (a TPO-receptor agonist), or pevonedistat (an NEDD8-activating enzyme).133 Several combination trials of venetoclax with azacytidine, including those adding tagraxofusp, a CD123-targeted drug, in the untreated and relapsed/refractory setting, and studies of immune checkpoint modulation with HMAs are also in progress. Other candidate approaches include vyxeos (CPX-351), a novel liposomal formulation of cytarabine and daunorubicin recently licensed for secondary AML or tMN, targeted IDH1/2 or FLT3 inhibitors, splicesome-modulator H3B-8800, CAR T-cells, and bispecific antibodies.
Biological therapy in elderly patients with acute myeloid leukemia
Published in Expert Opinion on Biological Therapy, 2023
Giulia Ciotti, Giovanni Marconi, Alessandra Sperotto, Maria B Giannini, Michele Gottardi, Giovanni Martinelli
Overexpression of MDM2 ubiquitin-ligase is recognized as a mechanism of resistance of AML blasts to therapy and leads to inactivation of the p53 pathway by directing the p53 protein to proteasomal degradation. MDM2-inhibitors Idasanutlin failed to demonstrate effectiveness in combination with intermediate-dose of cytarabine in r/rAML patients [149] and association with VEN showed only modest improvement [150]. MDM2 also promotes conjugation of ubiquitin-like protein NEDD8 to p53 protein. MDM2-mediated NEDDylation inhibits the transcriptional activity of p53 with consequent downregulation of its grown-suppressing effects [151]. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor and it’s being investigated in several clinical trials. Despite strong rationale, randomized phase 3 trial of pevonedistat plus AZA vs azacitidine alone failed to demonstrate advantage of the combination [152]. Triple therapy with VEN and AZA showed more promising activities in an elderly and unfavorable population, and randomized phase 3 trial results are expected [153].
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
Pevonedistat, a NEDD8 inhibitor, was evaluated in combination with AZA in patients with MDS, non-proliferative chronic myelomonocytic leukemia or low blast AML. In the randomized proof of concept study with OS as the primary endpoint, high-risk MDS patients treated with pevonedistat+AZA combination had clinically meaningful improvement in median OS compared to AZA monotherapy (23.9 vs 19.0 months, respectively, P = 0.2). Similarly, in patients with low blast AML, there was a trend toward improved survival with the pevonedistat+AZA combination compared to AZA monotherapy (23.6 vs 16.0 months respectively, P = 0.08). Pevonedistat+AZA combination was well tolerated with TEAEs comparable to that of AZA monotherapy [77]. In the subsequent phase 3 PANTHER study with event-free survival (EFS) as the primary endpoint, pevonedistat+AZA combination did not achieve its primary endpoint (17.7 vs 15.7 months with AZA, P = 0.56) [78]. No new safety signals were observed. Of note, there was incremental survival benefit in patients who remained longer on therapy (>3 cycles: 23.8 vs 20.6 months, P = 0.021; >6 cycles: 27.1 vs 22.5 months, P = 0.008). In the recent preliminary report of triplet combination of pevonedistat+AZA+VEN in patients with secondary-AML including those with therapy-related AML and AML with myelodysplasia-related changes, the CR+CRi rate was 64%. In this high-risk cohort, the median OS was 8.2 months. TEAEs were comparable to that of AZA+VEN combination therapy [79]. The path forward for pevonedistat remains uncertain.
Emerging therapies for AML with myelodysplasia-related changes: slowly but surely moving the needle
Published in Expert Opinion on Emerging Drugs, 2021
Davis F. Phillips, Joshua F. Zeidner
Pevonedistat, a small molecule inhibitor of the NEDD8-activating enzyme, affects the ubiquitin-proteasome system and is thought to disrupt homeostasis of proteins important for AML cell survival [66]. Pre-clinical studies have shown promising anti-leukemic activity and early phase clinical studies suggest synergistic activity in combination with azacitidine [66–68]. In a phase 1b study with 64 patients with AML who were ≥60 years old and medically unfit for IC, pevonedistat (20 mg/m2 or 30 mg/m2 IV on days 1, 3, 5) in combination with azacitidine (75 mg/m2 IV/SQ on days 1–5, 8, 9, every 28 days) led to an overall response rate (CR/CRi/PR) of 50% [68]. Overall response was 46% in patients with s-AML (n = 28) on subset analyses. Median OS was 11.2 months for patients with s-AML compared to 5.6 months for patients with de novo AML. Given these findings, pevonedistat is being investigated in a triple combination with azacitidine and venetoclax for patients with AML-MRC or t-AML in a phase 1/2 study (NCT03862157) as well as in a randomized phase 2 trial of pevonedistat/azacitidine/venetoclax versus azacitidine/venetoclax for patients with newly diagnosed AML who are unfit for IC (NCT04266795).