China
Africa
Explore chapters and articles related to this topic
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Volasertib is a small molecule polo-like kinase (PLK1) inhibitor which was noted to result in remissions in 31% of patients, compared to 13% in the control arm, with an improved disease-free survival but no overall survival in a randomized phase 2 trial in combination with low-dose cytarabine in newly diagnosed older AML patients considered to be unfit for conventional treatment.32 PLK1 is vital for spindle assembly during cellular mitosis. Based on these response rates and acceptable toxicity, the drug is now being tested in a randomized phase 3 trial (POLO-AML-2) and has been accorded a ‘breakthrough therapy’ designation by the US Food and Drug Administration (FDA).
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Clofarabine, a novel second-generation deoxynucleoside analogue developed from two other purine analogues, fludarabine and cladribine, has now been in clinical trials for almost two decades. It doubles response rates in older patients with AML but does not improve overall survival, but is not currently licensed; it is, however, licensed for patients with ALL. The results of a recent randomized phase II study of clofrabine-based consolidation, compared with high-dose cytarabine, for patients <60 years of age with AML in first remission, support the use of a clofarabine-based combination as a reasonable post-remission consolidation treatment. This approach appears particularly attractive for patients who are considered for an allo-SCT and a suitable donor is not available or not identified. A similar drug, troxacitabine, is currently in clinical trials. Cloretazine, a novel DNA alkylating agent, is being tested in newly diagnosed older patients with AML. Volasertib, a polo-like kinases (PLK1) inhibitor is being tested in a randomized phase III study, in combination with low-dose cytarabine or decatibine in newly diagnosed older AML patients considered to be unfit for conventional treatment. Several other new (and not so new) agents are at an early stage of development in AML. These include elacytarabine (a cytotoxic nucleoside analogue), tosedostat (an aminopeptidase inhibitor), vosaroxin (a novel topo II anthracycline-like inhibitor), sapacitibine (a novel nucleoside), EPZ-5676 (DOT1L inhibitor), ABT (BCL-2 inhibitors), BET bromodomain inhibitors, vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate similar to GO and the next-generation DNA hypomethylating agents, guadecitabine (SGI-110). And based on recent enhanced biological understanding, there is interest in testing BCL2 inhibition, for example, with venetoclax, in combination with standard AML drugs. Indeed, preliminary results of venetoclax in combination with azacytidine, decitabine and cytarbine are encouraging. There is also some interest, though a sound scientific rationale is lacking, of using the ATRA-ATO combination in non-APL NPM1-mutant AML patients.
Non-intensive acute myeloid leukemia therapies for older patients
Published in Expert Review of Hematology, 2023
Rodrick Babakhanlou, Farhad Ravandi-Kashani
Volasertib is a polo-like kinase (PLK) inhibitor that selectively binds to the ATP binding pocket of the human PLK1 [6,56]. PLKs are involved in the regulation of cell-cycle progression and mitosis and are overexpressed both in solid and hematologic malignancies [6,56]. In a phase 2 trial, LDAC alone was compared to LDAC in combination with volasertib in 87 patients not fit for intensive therapy [57]. Although toxicity was greater in the combination arm, CR rates, EFS, and OS were higher in the volasertib arm [57]. A randomized, double-blind, placebo-controlled phase 3 trial was conducted to evaluate the efficacy and safety of volasertib combined with LDAC in previously untreated older patients with AML, who were considered unsuitable for intensive chemotherapy [56]. The combination of volasertib with LDAC did not show a significantly higher ORR compared to LDAC alone. In patients in the ECOG 2 group, the addition of volaserib seemed to negatively impact the ORR [56].
Precision medicine for TP53-mutated acute myeloid leukemia
Published in Expert Review of Precision Medicine and Drug Development, 2019
Marte Karen Brattås, Håkon Reikvam, Tor Henrik Anderson Tvedt, Øystein Bruserud
The p53 protein is important in cell cycle regulation, but the G1 arrest function is lost in TP53-mutated cells, and these cells rely solely on the G2/M checkpoint for DNA repair; targeting of this second checkpoint may therefore be a possible therapeutic strategy [54]. Polo-like kinase 1 (PLK-1) is a cell cycle regulator expressed only in dividing cells which reaches peak expression during the G2/M phase; two different clinical studies have reported antileukemic effects of the PLK-1 inhibitor volasertib in AML [76,77]. Volasertib was combined with low-dose cytarabine in both studies. The toxicity was acceptable and the response rate was increased by the combination compared with low-dose cytarabine alone [76]. However, the efficiency of this combination in TP53-mutated AML was not investigated in these studies.
Emerging strategies to target the dysfunctional cohesin complex in cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Konstantinos Mintzas, Michael Heuser
PLK-1 inhibitor BI2536 has been an effective anti-cancer treatment in several cancer cell lines, such as oral cancer cell lines SAS and OECM1[74], and gastric SGC-7901 cells[75], and currently only phase I studies have been performed. Another PLK-1 inhibitor, volasertib, has been successfully tested in a phase II study in older patients with AML. Combined treatment with low dose cytarabine (LDAC) improved complete remission rate, prolonged median event-free survival, and increased median overall survival by almost 3 months[76]. A phase III study with the same drug could not reproduce these results, as the study showed a higher rate of fatal infections due to prolonged cytopenias in patients receiving volasertib compared to placebo[77].