Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML)

Zeidner, Joshua F.; Foster, Matthew C.; Blackford, Amanda L.; Litzow, Mark R.; Morris, Lawrence E.; Strickland, Stephen A.; Lancet, Jeffrey E.; Bose, Prithviraj; Levy, Moshe; Tibes, Raoul; Gojo, Ivana; Gocke, Christopher D.; Rosner, Gary L.; Little, Richard F.; Wright, John J.; Doyle, L. Austin; Smith, B. Douglas; Karp, Judith E.

doi:10.1016/j.leukres.2018.08.005

Cited by 31 publications

(20 citation statements)

References 14 publications

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“…Our findings demonstrate that alvocidib combined with standard 7+3 induction chemotherapy is feasible and effective for younger patients (≤65 years) with newly diagnosed AML. As seen in our previous studies with alvocidib in AML, the most frequent treatment-related AEs were fatigue, nausea, diarrhea, and TLS (11)(12)(13)(14)(15)17,19). The most significant of these, TLS and diarrhea, were manageable with appropriate prophylaxis and supportive interventions and were not dose-limiting.…”

Section: Discussionsupporting

confidence: 58%

“…Given the ease of administration, bolus alvocidib was chosen for further development in newly diagnosed AML. Subsequently, a randomized phase 2 clinical trial of bolus ACM led to higher CR rates compared with 1 or 2 cycles of 7+3 induction therapy (70% vs. 57%; p=0.07) in newly diagnosed AML patients with non-favorable-risk cytogenetics (17,19). However, alvocidib has not been studied in the context of conventional induction therapy with 7+3.…”

Section: Downloaded Frommentioning

confidence: 99%

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Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Zeidner

Lee

Frattini

et al. 2021

Clinical Cancer Research

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Standard frontline therapy for younger fit patients with newly diagnosed AML includes induction chemotherapy with continuous infusion cytarabine and an anthracycline (i.e., 7+3) with or without targeted agents such as midostaurin or gemtuzumab ozogamicin. However, overall outcomes are poor with 5-year survival rates <50%. Alvocidib is a cyclin-dependent kinase-9 (CDK9) inhibitor that leads to transcriptional suppression of MCL-1, an anti-apoptotic BCL-2 family member that is up-regulated in AML. Prior studies showed that alvocidib followed by cytarabine and mitoxantrone has anti-leukemic activity in both newly diagnosed and relapsed/refractory AML. This phase 1 study revealed that alvocidib 30 mg/m 2 IV over 30minutes followed by 60 mg/m 2 IV over 4-hours on days 1-3 can be administered prior to 7+3 induction in newly diagnosed AML patients with overall CR rates of 69% in patients with nonfavorable cytogenetics. Preliminary clinical activity was seen in secondary AML patients who have poor outcomes with conventional chemotherapy. Research.

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Section: Discussionsupporting

confidence: 58%

Section: Downloaded Frommentioning

confidence: 99%

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Zeidner

Lee

Frattini

et al. 2021

Clinical Cancer Research

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“…MA therapy, which comprises MIT combined with Ara-c, is now widely used for the treatment of elderly patients with AML (11)(12)(13). Ahmed et al (14) previously reported the use of L-asparaginase (L-Asp) in combination with other conventional chemotherapeutic drugs in the treatment of elderly patients with refractory AML.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative effects of L‑asparaginase in acute myeloid leukemia

et al. 2020

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“…The ACM/FLAM regimen led to higher complete response rates compared with patients who received either 7 + 3 alone (46%; P = 0.003) or 7 + 3 followed by an additional dose of cytarabine on days 1-5 and daunorubicin on days 1-2 (5 + 2; 57%; P = 0.08), and without an increase in toxicity; however, relapse and overall survival rates remained similar (3). Final results of the study data (median follow-up, 1,644 days) confirmed the similar overall survival and higher CR rates in the ACM/FLAM treatment arm compared with the 7 + 3 arm (174). Phase 1 trials of atuveciclib in AML and other acute leukemias (NCT02345382) and TG02 in AML and other advanced hematologic malignancies (NCT01204164) have been completed; however, results have not yet been published.…”

Section: Clinical Development Of Cdk9 Inhibitors In Amlmentioning

confidence: 61%

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

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Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML)

Cited by 31 publications

References 14 publications

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Antiproliferative effects of L‑asparaginase in acute myeloid leukemia

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

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