An alvocidib-containing regimen is highly effective in AML patients through a mechanism dependent on MCL1 expression and function.

Smith, B. Douglas; Warner, Steven L.; Whatcott, Clifford J.; Siddiqui‐Jain, Adam; Bahr, Brigham L.; Dettman, Elisha J.; Doykan, Camille; Cardone, Michael H.; Weitman, Steven; Bearss, David J.

doi:10.1200/jco.2015.33.15_suppl.7062

Cited by 8 publications

(5 citation statements)

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“…The ability to define who can reap benefit from FLAM without incurring overwhelming toxicity is dependent both on clinical observations and molecular biomarkers. 24,25 An international randomized trial of FLAM vs. cytarabine plus mitoxantrone (AM) without alvocidib (NCT02520011) is currently recruiting patients.…”

Section: Discussionmentioning

confidence: 99%

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

et al. 2018

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To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for five days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared to 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%−35%), 28% in the FLAM arm (10/36, 90% CI, 16%−43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%−36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.

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Section: Discussionmentioning

confidence: 99%

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

et al. 2018

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“…A NOXA mimetic peptide (T-MS1) "primes" cells for apoptosis, and high priming scores reflect cells that are considered to be MCL-1 dependent. We previously found that MCL-1 dependence was associated with response to treatment with TST ACM induction in newly diagnosed AML (44). Thus, we performed an exploratory prospective analysis of MCL-1 dependence on response to alvocidib followed by 7+3.…”

Section: Recent Data Suggest That Among Older Patients With Intermedmentioning

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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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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“…Despite the lack of improvement in OS when compared with 7 + 3, these findings corroborate alvocidib's activity in AML and support further development. Retrospective mitochondrial profiling revealed that NOXA, a BH3 pro-apoptotic protein that antagonizes myeloid leukemia cell-1 (MCL-1), priming in the bone marrow was significantly higher in patients achieving CR compared with non-responders (45% versus 5%, respectively) treated with FLAM [14]. A high NOXA priming score reflects dependence of leukemic cells on MCL-1 for survival.…”

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confidence: 99%

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)

et al. 2018

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An alvocidib-containing regimen is highly effective in AML patients through a mechanism dependent on MCL1 expression and function.

Cited by 8 publications

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A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

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

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)

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