Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study

DiNardo, Courtney D.; Pratz, Keith W.; Letaï, Anthony; Jonas, Brian A.; Wei, Andrew H.; Thirman, Michael J.; Arellano, Martha; Frattini, Mark G.; Kantarjian, Hagop M.; Popovic, Relja; Chyla, Brenda; Xu, Tu; Dunbar, Martin; Agarwal, Suresh; Humerickhouse, Rod; Mabry, Mack; Potluri, Jalaja; Konopleva, Marina; Pollyea, Daniel A.

doi:10.1016/s1470-2045(18)30010-x

Cited by 581 publications

(564 citation statements)

References 21 publications

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“…The future of MPN‐AP/BP treatment will probably encompass different associations of AZA with new and promising drugs still under evaluation in de novo naïve or resistant/relapsed AML patients. Among these, the association of venetoclax with AZA has already shown very positive preliminary results, which have led to a FDA fast‐track approval …”

Section: Discussionmentioning

confidence: 99%

Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Andriani¹,

Elli

Trapè

et al. 2019

Hematological Oncology

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There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia‐negative myeloproliferative neoplasms (MPN‐AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN‐AP/BP treated frontline with AZA at the standard dosage (75 mg/m2). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9‐180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2‐18.7). There was no difference in median OS among patients with HI, PR, or CR (P = .908). These three subgroups as “responders” having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1‐25.0) versus 4.1 months (95% CI, 0.4‐10.0) (P = .001) Only female gender was significant for both achievement of response (.010) and OS duration (P = .002). In conclusion, AZA is useful for the management of MPN‐AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.

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Section: Discussionmentioning

confidence: 99%

Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Andriani¹,

Elli

Trapè

et al. 2019

Hematological Oncology

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“…Results of a phase II clinical trial have shown that ABT‐199 has promising clinical activity compared to current alternatives, but relapse remains a concern . Combinations such as ABT‐199 with decitabine or azacitidine can help induce remission but lack improvement in overall survival . Thus, new therapeutic combinations involving ABT‐199 are urgently needed to eradicate bulk AML cells and LSCs responsible for relapse.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Luedtke

Liu

et al. 2018

J Cellular Molecular Medi

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The antiapoptotic Bcl‐2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl‐2‐selective inhibitor ABT‐199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl‐1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl‐1 levels in cancer cells. Thus, we hypothesized that the XPO1‐selective inhibitor KPT‐330 (Selinexor) can synergize with ABT‐199 to induce apoptosis in AML cells through down‐regulation of Mcl‐1. The combination of KPT‐330 and ABT‐199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT‐330 treatment decreased Mcl‐1 protein after apoptosis initiation. However, binding of Bim to Mcl‐1 induced by ABT‐199 was abrogated by KPT‐330 at the same time as apoptosis initiation. KPT‐330 treatment increased binding of Bcl‐2 to Bim but was overcome by ABT‐199 treatment, demonstrating that KPT‐330 and ABT‐199 reciprocally overcome apoptosis resistance. Mcl‐1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT‐330 treatment, alone and in combination with ABT‐199, modulates Mcl‐1, which plays an important role in the antileukaemic activity of the combination.

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“…The potent and selective orally bioavailable BCL2 inhibitor (BCL2i) venetoclax 44 showed modest anticancer activity when evaluated as single therapy, since only 16 out of 32 patients affected by refractory and relapsed AML involved in phase 2 clinical trial NCT01994837 achieved an overall response . Dose‐escalation phase Ib study involving 57 elderly patients (>65 years) based on venetoclax 44 and decitabine 2 or azacytidine 1 (Combination P, Figure ) combination resulted well tolerated showing high survival and low early mortality (NCT02203773) . The dose‐escalation stage has been conducted with the aim to evaluate the PK and the safety of this combination.…”

Section: The Mmt Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study

Cited by 581 publications

References 21 publications

Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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