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Mitochondrial priming of chronic lymphocytic leukemia patients associates Bcl-xL dependence with alvocidib response

Leukemia volume 28, pages 2251–2254 (2014)Cite this article

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Chronic lymphocytic leukemia (CLL) patient outcomes may benefit from targeting therapies to individuals with favorable molecular profiles. We assessed mitochondrial functionality in apoptosis signaling for CLL patient response to alvocidib (flavopiridol). Pretreatment patient specimens from Trials OSU0055 and EFC6663 (relapsed/refractory patients) were assessed for mitochondrial outer membrane permeabilization following BH3-only peptide incubation. Training and test cohort analyses established an association between Bim and Hrk biomarkers and patient response that benefitted from inclusion of trisomy 12 status. Separately, tumor lysis syndrome (TLS) occurrence was found to be associated with Bad priming, which benefitted from inclusion of ECOG status and patient age. Taken together, the association of Bim and Hrk with CLL patient response is consistent with Bcl-xL dependence as a driver of alvocidib efficacy. Concurrently, Bad’s association with TLS, which is indicative of Bcl-2’s dependency, may help identify patients at risk for treatment-related toxicity.

Alvocidib has demonstrated single-agent activity in relapsed/refractory CLL patients in Phase I and Phase II clinical studies although the activity was originally limited, presumably due to high protein binding in plasma attenuating the levels of available drug in patients.1,2 However, Byrd and colleagues3–6 recently identified a hybrid intravenous dosing schedule that utilizes a 30-min loading dose (30 mg/m2) followed by a 4-h infusion (50 mg/m2). This novel dosing schedule has allowed for improved single-agent activity in relapsed and refractory CLL patients in multiple clinical studies, with overall response rates between 30 and 53%, including favorable responses in high-risk patients with 17p13.1 deletions.3, 4, 5, 6 Response rate limitations have been compounded by treatment-related toxicities including TLS. Patient enrichment strategies that include molecular and cytogenetic approaches may enhance development of alvocidib in CLL by targeting the drug to patients who are most likely to exhibit response and least likely to experience adverse events.

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Authors and Affiliations

  1. Eutropics Inc., Cambridge, MA, USA

    W E Pierceall, R J Lena, C Doykan, N Blake, M Elashoff & M H Cardone

  2. Tolero Pharmaceuticals, Inc., Lehi, UT, USA

    S L Warner, D V Hoff & D J Bearss

  3. Translational Genomics Research Institute, Scottsdale, AZ, USA

    D V Hoff

  4. Department of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    L Andritsos, J C Byrd, M R Grever & A J Johnson

  5. Department of Medicine, Duke Cancer Institute, Durham, NC, USA

    M C Lanasa

Authors
  1. W E Pierceall
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  2. S L Warner
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  3. R J Lena
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  4. C Doykan
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  5. N Blake
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  6. M Elashoff
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  7. D V Hoff
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  8. D J Bearss
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  9. M H Cardone
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  10. L Andritsos
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  11. J C Byrd
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  13. M R Grever
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  14. A J Johnson
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Corresponding authors

Correspondence to W E Pierceall or A J Johnson.

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Competing interests

WEP, CD, RJL, NB, ME, and MHC are employees of Eutropics, Inc. SLW and DJB are employees of Tolero Pharmaceuticals, Inc. JCB and MRG are co-inventors of a patent pending for the use of alvocidib. The remaining authors declare no conflict of interest.

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Pierceall, W., Warner, S., Lena, R. et al. Mitochondrial priming of chronic lymphocytic leukemia patients associates Bcl-xL dependence with alvocidib response. Leukemia 28, 2251–2254 (2014). https://doi.org/10.1038/leu.2014.206

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