Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

Haematologica (Impact Factor: 5.87). 06/2012; 97(11). DOI: 10.3324/haematol.2012.062539
Source: PubMed

ABSTRACT Background. Flavopiridol is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A Phase II trial of flavopiridol followed by ara-C and mitoxantrone (FLAM) with flavopiridol given by one hour bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia (AML) yielded 67% complete remission (CR) with median disease-free survival (DFS) 13.6 months. Design and Methods. We compared FLAM using bolus flavopiridol (50 mg/m2/day, Arm A) vs. "hybrid" flavopiridol (30 mg/m2 over 30 minutes followed by 40 mg/m2 over 4 hours, Arm B) in 78 patients (39 per arm) with newly diagnosed, poor-risk AML. To mitigate imbalance, patients were stratified by presence or absence of secondary AML and therapy for antecedent disorder. Results. Death < day 60 occurred in 8% per arm. CR+CR with incomplete recovery (CRi) was 68% (A, 62%; B, 74%). CR+CRi rates were > 65% in both arms for patients with secondary AML and AML with adverse genetics. 91% A and 86% B received chemotherapy and/or allogeneic transplantation in CR. Median OS for CR+CRi patients has not been reached for either arm, with median DFS 13.6 months for A and 12.0 months for B. Conclusions. Both FLAM schedules produce comparably encouraging results in adults with poor-risk AML. Given the greater ease of bolus administration, we are conducting a randomized Phase II study of bolus FLAM vs. conventional induction therapy for patients < 70 years with intermediate or poor-risk AML. This study is registered at as #NCT 00407966.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and PurposeThe cyclin-dependent kinase CDK9 is an important therapeutic target but currently available inhibitors exhibit low specificity and/or narrow therapeutic windows. Here we have used a new highly specific CDK9 inhibitor, LDC000067 to interrogate gene control mechanisms mediated by CDK9. Experimental ApproachThe selectivity of LDC000067 was established in functional kinase assays. Functions of CDK9 in gene expression were assessed with in vitro transcription experiments, single gene analyses and genome-wide expression profiling. Cultures of mouse embryonic stem cells, HeLa cells, several cancer cell lines, along with cells from patients with acute myelogenous leukaemia were also used to investigate cellular responses to LDC000067. Key ResultsThe selectivity of LDC000067 for CDK9 over other CDKs exceeded that of the known inhibitors flavopiridol and DRB. LDC000067 inhibited in vitro transcription in an ATP-competitive and dose-dependent manner. Gene expression profiling of cells treated with LDC000067 demonstrated a selective reduction of short-lived mRNAs, including important regulators of proliferation and apoptosis. Analysis of de novo RNA synthesis suggested a wide ranging positive role of CDK9. At the molecular and cellular level, LDC000067 reproduced effects characteristic of CDK9 inhibition such as enhanced pausing of RNA polymerase II on genes and, most importantly, induction of apoptosis in cancer cells. Conclusions and ImplicationsOur study provides a framework for the mechanistic understanding of cellular responses to CDK9 inhibition. LDC000067 represents a promising lead for the development of clinically useful, highly specific CDK9 inhibitors.
    British Journal of Pharmacology 01/2014; 171(1). DOI:10.1111/bph.12408 · 4.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The NUT midline carcinoma (NMC) is a rare but fatal cancer for which systematic testing of therapy options has never been performed. Methods: On the basis of disease biology, we compared the efficacy of the CDK9 inhibitor flavopiridol (FP) with a panel of anticancer agents in NMC cell lines and mouse xenografts. Results: In vitro anthracyclines, topoisomerase inhibitors, and microtubule poisons were among the most cytotoxic drug classes for NMC cells, while efficacy of the bromodomain inhibitor JQ1 varied considerably between lines carrying different BRD4 (bromodomain-containing protein 4)–NUT (nuclear protein in testis) translocations. Efficacy of FP was comparable to vincristine and doxorubicin, drugs that have been previously used in NMC patients. All three compounds showed significantly better activity than etoposide and vorinostat, agents that have also been used in NMC patients. Statins and antimetabolites demonstrated intermediate single-agent efficacy. In vivo, vincristine significantly inhibited tumour growth in two different NMC xenografts. Flavopiridol in vivo was significantly effective in one of the two NMC xenograft lines, demonstrating the biological heterogeneity of this disease. Conclusions: These results demonstrate that FP may be of benefit to a subset of patients with NMC, and warrant a continued emphasis on microtubule inhibitors, anthracyclines, and topoisomerase inhibitors as effective drug classes in this disease.
    British Journal of Cancer 02/2014; 110(5). DOI:10.1038/bjc.2014.54 · 4.82 Impact Factor
  • Blood 05/2014; 123(21):3211-2. DOI:10.1182/blood-2014-04-568725 · 9.78 Impact Factor

Full-text (2 Sources)

Available from
Jun 3, 2014