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Impact of targeted therapy on outcome of chronic lymphocytic leukemia patients with relapsed del(17p13.1) karyotype at a single center

Leukemia volume 28, pages 1365–1368 (2014)Cite this article

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Chronic lymphocytic leukemia (CLL) patients with del(17p13.1) exhibit short survival once disease progression necessitates therapy and respond poorly to traditional treatments compared with other cytogenetic subgroups.1 Poor outcome associated with del(17p13.1) is at least partially linked to malfunction of the tumor suppressor gene TP53 (located on 17p ref. 2), which repairs apoptosis induced by chemotherapy.3, 4, 5 Therefore, despite general advances in CLL therapy with chemoimmunotherapy, progress in this subgroup has been limited. Current guidelines suggest allogeneic stem cell transplant as part of initial therapy,6 as salvage treatment for del(17p13.1) portends an even graver prognosis. Recently, novel therapeutic agents have demonstrated promising clinical activity in del(17p13.1) patients, specifically, cyclin-dependent kinase inbibitors (CDKis; flavopiridol and dinaciclib) and a Bruton’s tyrosine kinase inhibitor (BTKi; ibrutinib).7, 8, 9 To elucidate the potential impact of CDKi and BTKi in this population, we examined outcomes of consecutive relapsed/refractory del(17p13.1) patients seen at Ohio State University (OSU), who received salvage therapy with one of these agents or alternative therapy. Our data demonstrate significant impact of both classes of these agents on outcomes of del(17p13.1) patients.

We examined 174 consecutive relapsed/refractory del(17p13.1) CLL patients for outcome following initial salvage treatment given at OSU (OSUTx1) from 2002 to 2013. Patients were treated on previously reported clinical trials or received standard-of-care treatment according to NCCN guidelines. Patients provided informed consent for data collection through the Institutional Review Board-approved study OSU-0025. Stimulated cytogenetic and FISH analyses were performed on blood or bone marrow samples (previously described10, 11). FISH analyses probed for the chromosome 12 centromere, ATM (11q22.3), D13S319 (13q14.3) and TP53 (17p13.1) (Abbott Molecular, Des Plaines, IL, USA). Karyotypes with ⩾3 independent aberrations were defined as complex.12

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References

  1. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  2. Isobe M, Emanuel BS, Givol D, Oren M, Croce CM . Localization of gene for human p53 tumour antigen to band 17p13. Nature 1986; 320: 84–85.

    Article  CAS  PubMed  Google Scholar 

  3. Pietsch EC, Sykes SM, McMahon SB, Murphy ME . The p53 family and programmed cell death. Oncogene 2008; 27: 6507–6521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Levine AJ . P53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323–331.

    Article  CAS  PubMed  Google Scholar 

  5. Wickremasinghe RG, Prentice AG, Steele AJ . p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies. Leukemia 2011; 25: 1400–1417.

    Article  CAS  PubMed  Google Scholar 

  6. Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012; 26: 1458–1461.

    Article  CAS  PubMed  Google Scholar 

  7. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 2009; 27: 6012–6018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007; 109: 399–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muthusamy N, Breidenbach H, Andritsos L, Flynn J, Jones J, Ramanunni A et al. Enhanced detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide in combination with pokeweed mitogen and phorbol myristate acetate. Cancer Genet 2011; 204: 77–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Heerema NA, Byrd JC, Dal Cin PS, Dell'Aquila ML, Koduru PR, Aviram A et al. Stimulation of chronic lymphocytic leukemia cells with CpG oligodeoxynucleotide gives consistent karyotypic results among laboratories: a CLL Research Consortium (CRC) Study. Cancer Genet Cytogenet 2010; 203: 134–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaffer L, Slovak M, Campbell L ISCN 2009: an international system for human cytogentetic nomenclature 2009.

  13. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446–5456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. van Buuren S . Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res 2007; 16: 219–242.

    Article  PubMed  Google Scholar 

  15. Blum KA, Ruppert AS, Woyach JA, Jones JA, Andritsos L, Flynn JM et al. Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. Leukemia 2011; 25: 1444–1451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work supported by Four Winds Foundation, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158, R01 CA177292, P01 CA095426, Leukemia and Lymphoma Society, Conquer Cancer Foundation, and ASH Scholar Award.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    D M Stephens, J A Jones, J Woyach, K Maddocks, S M Jaglowski, L A Andritsos, J M Flynn, M R Grever, A J Johnson, N Muthusamy & J C Byrd

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    D M Stephens, A S Ruppert, J A Jones, J Woyach, K Maddocks, S M Jaglowski, L A Andritsos, J M Flynn, M R Grever, A J Johnson, N Muthusamy, N A Heerema & J C Byrd

  3. Division of Cytogenetics, Department of Pathology, The Ohio State University, Columbus, OH, USA

    N A Heerema

  4. Division of Hematopathology, Department of Pathology, The Ohio State University, Columbus, OH, USA

    G Lozanski

  5. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    A J Johnson & J C Byrd

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  1. D M Stephens
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Correspondence to J C Byrd.

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Author contributions

All authors critically revised the manuscript and approved the final submitted version. DS and AR acquired, analyzed and interpreted data and drafted the manuscript. JJ, JW, KM, SJ, LA, JF, MG, GL, AJ, NM and NH contributed to acquisition of data. NH acquired and analyzed cytogenetic data. DS and JB developed the concept for the study.

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Stephens, D., Ruppert, A., Jones, J. et al. Impact of targeted therapy on outcome of chronic lymphocytic leukemia patients with relapsed del(17p13.1) karyotype at a single center. Leukemia 28, 1365–1368 (2014). https://doi.org/10.1038/leu.2014.42

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