Annals of Hematology

, Volume 97, Issue 12, pp 2269–2278 | Cite as

Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation

  • Valeria BuccheriEmail author
  • Wolney Gois Barreto
  • Laura Maria Fogliatto
  • Marcelo Capra
  • Mariana Marchiani
  • Vanderson Rocha
Review Article


Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.


(MeSH) Chronic lymphocytic leukemia Chromosome 17p deletion TP53 B cell receptor BCL-2 



AbbVie participated in the interpretation of data, review, and approval of the content. All authors participated in writing, review, and approval of this manuscript. Medical writing services and editorial support was provided by Everardo D. Saad and Ana Elisa B. Bueno da Silva of Dendrix and was funded by AbbVie.


Dendrix provided medical writing services in the development of this manuscript, funded by AbbVie.

Compliance with ethical standards

Conflict of interest

Valeria Buccheri has declared no conflicts of interest for this publication. Clinical research activities as PI: Janssen, Takeda, AbbVie, Roche, Merck; speaker: Janssen, Takeda.

Wolney Barreto has declared no conflicts of interest for this publication. Speaker: Roche, Janssen.

Laura Fogliatto has declared no conflicts of interest for this publication. Clinical research activities as PI: Janssen, Takeda, AbbVie, Roche, Merck, Celgene; speaker: Novartis, Roche.

Marcelo Capra has declared no conflicts of interest for this publication. Clinical research activities as: Janssen, Takeda, AbbVie, Roche; advisory board: Janssen, Takeda, Cellgene; speaker: Janssen.

Mariana Marchiani has declared no conflicts of interest for this publication. AbbVie employee and may own AbbVie stock or stock options.

Vanderson Rocha has declared no conflicts of interest for this publication. National advisory board: Amgen, Celgene, Takeda, Zodiac; international advisory board: Pfizer, Jazz Therapeutics; speaker: Amgen, Celgene, Takeda, Zodiac, Pfizer, Jazz Therapeutics, Janssen.


  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M (2005) Chronic lymphocytic leukemia. N Engl J Med 352(8):804–815CrossRefGoogle Scholar
  2. 2.
    Dighiero G, Hamblin TJ (2008) Chronic lymphocytic leukaemia. Lancet 371(9617):1017–1029CrossRefGoogle Scholar
  3. 3.
    Seiffert M, Dietrich S, Jethwa A, Glimm H, Lichter P, Zenz T (2012) Exploiting biological diversity and genomic aberrations in chronic lymphocytic leukemia. Leuk Lymphoma 53(6):1023–1031CrossRefGoogle Scholar
  4. 4.
    Hallek M (2015) Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am J Hematol 90(5):446–460CrossRefGoogle Scholar
  5. 5.
    Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343(26):1910–1916CrossRefGoogle Scholar
  6. 6.
    Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94(6):1840–1847Google Scholar
  7. 7.
    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6):1848–1854Google Scholar
  8. 8.
    Montillo M, Hamblin T, Hallek M, Montserrat E, Morra E (2005) Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk-adapted therapeutic strategies. Haematologica 90(3):391–399Google Scholar
  9. 9.
    Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea S, Gonzalez-Diaz M, Bassaganyas L, Baumann T, Juan M, Lopez-Guerra M, Colomer D, Tubio JM, Lopez C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernandez JM, Puente DA, Freije JM, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes A, Hernandez L, Yague J, Nicolas P, Romeo-Casabona CM, Himmelbauer H, Castillo E, Dohm JC, de Sanjose S, Piris MA, de Alava E, San Miguel J, Royo R, Gelpi JL, Torrents D, Orozco M, Pisano DG, Valencia A, Guigo R, Bayes M, Heath S, Gut M, Klatt P, Marshall J, Raine K, Stebbings LA, Futreal PA, Stratton MR, Campbell PJ, Gut I, Lopez-Guillermo A, Estivill X, Montserrat E, Lopez-Otin C, Campo E (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475(7354):101–105CrossRefGoogle Scholar
  10. 10.
    Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ (2004) ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351(9):893–901CrossRefGoogle Scholar
  11. 11.
    Rossi D, Gaidano G (2016) The clinical implications of gene mutations in chronic lymphocytic leukaemia. Br J Cancer 114(8):849–854CrossRefGoogle Scholar
  12. 12.
    Foa R, Del Giudice I, Guarini A, Rossi D, Gaidano G (2013) Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica 98(5):675–685CrossRefGoogle Scholar
  13. 13.
    Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S, De Paoli L, Spina V, Gattei V, Capello D, Forconi F, Lauria F, Gaidano G (2009) The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res 15(3):995–1004CrossRefGoogle Scholar
  14. 14.
    Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T, Helfrich H, Heuberger M, Hoth P, Fuge M, Denzel T, Habe S, Malcikova J, Kuglik P, Truong S, Patten N, Wu L, Oscier D, Ibbotson R, Gardiner A, Tracy I, Lin K, Pettitt A, Pospisilova S, Mayer J, Hallek M, Dohner H, Stilgenbauer S, European Research Initiative on CLL (2010) TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia 24(12):2072–2079CrossRefGoogle Scholar
  15. 15.
    Greipp PT, Smoley SA, Viswanatha DS, Frederick LS, Rabe KG, Sharma RG, Slager SL, Van Dyke DL, Shanafelt TD, Tschumper RC, Zent CS (2013) Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis. Br J Haematol 163(3):326–333CrossRefGoogle Scholar
  16. 16.
    Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S et al (1995) p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 85(6):1580–1589Google Scholar
  17. 17.
    Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foa R, Dalla-Favera R, Gaidano G (2013) Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121(8):1403–1412CrossRefGoogle Scholar
  18. 18.
    Zenz T, Krober A, Scherer K, Habe S, Buhler A, Benner A, Denzel T, Winkler D, Edelmann J, Schwanen C, Dohner H, Stilgenbauer S (2008) Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 112(8):3322–3329CrossRefGoogle Scholar
  19. 19.
    Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, Kluth S, Bozic I, Lawrence M, Bottcher S, Carter SL, Cibulskis K, Mertens D, Sougnez CL, Rosenberg M, Hess JM, Edelmann J, Kless S, Kneba M, Ritgen M, Fink A, Fischer K, Gabriel S, Lander ES, Nowak MA, Dohner H, Hallek M, Neuberg D, Getz G, Stilgenbauer S, Wu CJ (2015) Mutations driving CLL and their evolution in progression and relapse. Nature 526(7574):525–530CrossRefGoogle Scholar
  20. 20.
    Rossi D, Khiabanian H, Spina V, Ciardullo C, Bruscaggin A, Fama R, Rasi S, Monti S, Deambrogi C, De Paoli L, Wang J, Gattei V, Guarini A, Foa R, Rabadan R, Gaidano G (2014) Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 123(14):2139–2147CrossRefGoogle Scholar
  21. 21.
    Malcikova J, Tausch E, Rossi D, Sutton LA, Soussi T, Zenz T, Kater AP, Niemann CU, Gonzalez D, Davi F, Gonzalez Diaz M, Moreno C, Gaidano G, Stamatopoulos K, Rosenquist R, Stilgenbauer S, Ghia P, Pospisilova S, European Research Initiative on Chronic Lymphocytic Leukemia TPn (2018) ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation. In: LeukemiaGoogle Scholar
  22. 22.
    Zent CS, Burack WR (2014) Mutations in chronic lymphocytic leukemia and how they affect therapy choice: focus on NOTCH1, SF3B1, and TP53. Hematology Am Soc Hematol Educ Program 2014(1):119–124CrossRefGoogle Scholar
  23. 23.
    Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K, Buhler A, Bottcher S, Ritgen M, Kneba M, Winkler D, Tausch E, Hoth P, Edelmann J, Mertens D, Bullinger L, Bergmann M, Kless S, Mack S, Jager U, Patten N, Wu L, Wenger MK, Fingerle-Rowson G, Lichter P, Cazzola M, Wendtner CM, Fink AM, Fischer K, Busch R, Hallek M, Dohner H (2014) Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 123(21):3247–3254CrossRefGoogle Scholar
  24. 24.
    Tsimberidou AM, Tam C, Abruzzo LV, O’Brien S, Wierda WG, Lerner S, Kantarjian HM, Keating MJ (2009) Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer 115(2):373–380CrossRefGoogle Scholar
  25. 25.
    Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, Buhler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Dohner H, Stilgenbauer S (2010) TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 28(29):4473–4479CrossRefGoogle Scholar
  26. 26.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008) 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 111(12):5446–5456CrossRefGoogle Scholar
  27. 27.
    Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M, Buske C, Committee EG (2015) Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 Suppl 5v78–84CrossRefGoogle Scholar
  28. 28.
    Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD (2016) Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood 127(14):1752–1760CrossRefGoogle Scholar
  29. 29.
    Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46(2):219–234Google Scholar
  30. 30.
    Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48(1):198–206CrossRefGoogle Scholar
  31. 31.
    Rodrigues CA, Goncalves MV, Ikoma MR, Lorand-Metze I, Pereira AD, Farias DL, Chauffaille ML, Schaffel R, Ribeiro EF, Rocha TS, Buccheri V, Vasconcelos Y, Figueiredo VL, Chiattone CS, Yamamoto M, Brazilian Group of Chronic Lymphocytic L (2016) Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia. Rev Bras Hematol Hemoter 38(4):346–357CrossRefGoogle Scholar
  32. 32.
    Pepper C, Majid A, Lin TT, Hewamana S, Pratt G, Walewska R, Gesk S, Siebert R, Wagner S, Kennedy B, Miall F, Davis ZA, Tracy I, Gardiner AC, Brennan P, Hills RK, Dyer MJ, Oscier D, Fegan C (2012) Defining the prognosis of early stage chronic lymphocytic leukaemia patients. Br J Haematol 156(4):499–507CrossRefGoogle Scholar
  33. 33.
    Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marce S, Lopez-Guillermo A, Campo E, Montserrat E (2003) ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348(18):1764–1775CrossRefGoogle Scholar
  34. 34.
    Vasconcelos Y, Davi F, Levy V, Oppezzo P, Magnac C, Michel A, Yamamoto M, Pritsch O, Merle-Beral H, Maloum K, Ajchenbaum-Cymbalista F, Dighiero G (2003) Binet’s staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia. J Clin Oncol 21(21):3928–3932CrossRefGoogle Scholar
  35. 35.
    Bulian P, Shanafelt TD, Fegan C, Zucchetto A, Cro L, Nuckel H, Baldini L, Kurtova AV, Ferrajoli A, Burger JA, Gaidano G, Del Poeta G, Pepper C, Rossi D, Gattei V (2014) CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J Clin Oncol 32(9):897–904CrossRefGoogle Scholar
  36. 36.
    Jewell RC, Kipps TJ, Durig J, Griskevicius L, Stilgenbauer S, Smolej L, Mayer J, Hess G, Hernandez-Ilizaliturri FJ, Padmanabhan-Iyer S, Fang L, Goldstein N, Gorczyca M, Gupta I, Lisby S, Wierda WG, Hx CDSI (2017) Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy. Leuk Lymphoma 58(2):348–356CrossRefGoogle Scholar
  37. 37.
    Bulian P, Rossi D, Forconi F, Del Poeta G, Bertoni F, Zucca E, Montillo M, Pozzato G, D’Arena G, Efremov DG, Marasca R, Lauria F, Gaidano G, Gattei V, Laurenti L (2012) IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia. J Transl Med 1018:10–18Google Scholar
  38. 38.
    Pflug N, Bahlo J, Shanafelt TD, Eichhorst BF, Bergmann MA, Elter T, Bauer K, Malchau G, Rabe KG, Stilgenbauer S, Dohner H, Jager U, Eckart MJ, Hopfinger G, Busch R, Fink AM, Wendtner CM, Fischer K, Kay NE, Hallek M (2014) Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood 124(1):49–62CrossRefGoogle Scholar
  39. 39.
    Molica S, Giannarelli D, Mirabelli R, Levato L, Russo A, Linardi M, Gentile M, Morabito F (2016) Unavailability of thymidine kinase does not preclude the use of German comprehensive prognostic index: results of an external validation analysis in early chronic lymphocytic leukemia and comparison with MD Anderson Cancer Center model. Eur J Haematol 96(1):72–77CrossRefGoogle Scholar
  40. 40.
    Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G, Cortes J, Thomas D, Koller CA, Burger JA, Lerner S, Schlette E, Abruzzo L, Kantarjian HM, Keating MJ (2011) Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol 29(31):4088–4095CrossRefGoogle Scholar
  41. 41.
    Eichhorst B, Hallek M (2016) Prognostication of chronic lymphocytic leukemia in the era of new agents. Hematology Am Soc Hematol Educ Program 2016(1):149–155CrossRefGoogle Scholar
  42. 42.
    International CLLIPIwg (2016) An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 17(6):779–790CrossRefGoogle Scholar
  43. 43.
    Mougalian SS, O’Brien S (2011) Adverse prognostic features in chronic lymphocytic leukemia. Oncology (Williston Park) 25(8):692–696 699 Google Scholar
  44. 44.
    Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, Flinn IW, Tallman MS, Appelbaum FR, Larson RA, Paietta E, Jelinek DF, Gribben JG, Byrd JC (2007) Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25(7):799–804CrossRefGoogle Scholar
  45. 45.
    Jain N, O’Brien S (2015) Initial treatment of CLL: integrating biology and functional status. Blood 126(4):463–470CrossRefGoogle Scholar
  46. 46.
    Gonzalez D, Martinez P, Wade R, Hockley S, Oscier D, Matutes E, Dearden CE, Richards SM, Catovsky D, Morgan GJ (2011) Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol 29(16):2223–2229CrossRefGoogle Scholar
  47. 47.
    Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84(9):3148–3157Google Scholar
  48. 48.
    Zaja F, Mian M, Volpetti S, Visco C, Sissa C, Nichele I, Castelli M, Ambrosetti A, Puglisi S, Fanin R, Cortelazzo S, Pizzolo G, Trentin L, Rodeghiero F, Paolini R, Vivaldi P, Sancetta R, Isola M, Semenzato G (2013) Bendamustine in chronic lymphocytic leukemia: outcome according to different clinical and biological prognostic factors in the everyday clinical practice. Am J Hematol 88(11):955–960CrossRefGoogle Scholar
  49. 49.
    Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376(9747):1164–1174CrossRefGoogle Scholar
  50. 50.
    Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Bottcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Dohner H, Stilgenbauer S, Hallek M (2016) Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127(2):208–215CrossRefGoogle Scholar
  51. 51.
    Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dohner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370(12):1101–1110CrossRefGoogle Scholar
  52. 52.
    Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P (2012) Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 30(14):1647–1655CrossRefGoogle Scholar
  53. 53.
    Stilgenbauer S, Zenz T, Winkler D, Buhler A, Schlenk RF, Groner S, Busch R, Hensel M, Duhrsen U, Finke J, Dreger P, Jager U, Lengfelder E, Hohloch K, Soling U, Schlag R, Kneba M, Hallek M, Dohner H, German Chronic Lymphocytic Leukemia Study G (2009) Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 27(24):3994–4001CrossRefGoogle Scholar
  54. 54.
    Jeyakumar D, O’Brien S (2016) The next generation of targeted molecules for the treatment of chronic lymphocytic leukemia. Oncology (Williston Park) 30(11)Google Scholar
  55. 55.
    Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ (2008) Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 22(11):2048–2053CrossRefGoogle Scholar
  56. 56.
    Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P, Investigators R (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371(3):213–223CrossRefGoogle Scholar
  57. 57.
    Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O’Brien S (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369(1):32–42CrossRefGoogle Scholar
  58. 58.
    Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M, investigators H (2016) Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 17(2):200–211CrossRefGoogle Scholar
  59. 59.
    Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-Gonzalez GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O’Brien S (2014) Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 15(10):1090–1099CrossRefGoogle Scholar
  60. 60.
    Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O’Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ, Investigators R- (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373(25): 2425–2437CrossRefGoogle Scholar
  61. 61.
    Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Xue L, Li DH, Steggerda SM, Versele M, Dave SS, Zhang J, Yilmaz AS, Jaglowski SM, Blum KA, Lozanski A, Lozanski G, James DF, Barrientos JC, Lichter P, Stilgenbauer S, Buggy JJ, Chang BY, Johnson AJ, Byrd JC (2014) Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med 370(24):2286–2294CrossRefGoogle Scholar
  62. 62.
    Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR (2016) Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 374(4):323–332CrossRefGoogle Scholar
  63. 63.
    Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O’Brien SM (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370(11):997–1007CrossRefGoogle Scholar
  64. 64.
    O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE (2015) A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood 126(25):2686–2694CrossRefGoogle Scholar
  65. 65.
    Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374(4):311–322CrossRefGoogle Scholar
  66. 66.
    Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Bottcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17(6):768–778CrossRefGoogle Scholar
  67. 67.
    Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, Anderson MA, Beaven AW, Rosen ST, Tam CS, Prine B, Agarwal SK, Munasinghe W, Zhu M, Lash LL, Desai M, Cerri E, Verdugo M, Kim SY, Humerickhouse RA, Gordon GB, Kipps TJ, Roberts AW (2017) Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol 18:230–240CrossRefGoogle Scholar
  68. 68.
    Eapen M, O’Donnell P, Brunstein CG, Wu J, Barowski K, Mendizabal A, Fuchs EJ (2014) Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant 20(10):1485–1492CrossRefGoogle Scholar
  69. 69.
    Xavier E, Cornillon J, Ruggeri A, Chevallier P, Cornelissen JJ, Andersen NS, Maillard N, Nguyen S, Blaise D, Deconinck E, Veelken H, Milpied N, Van Gelder M, Peffault de Latour R, Gluckman E, Kroger N, Schetelig J, Rocha V (2015) Outcomes of cord blood transplantation using reduced-intensity conditioning for chronic lymphocytic leukemia: a study on behalf of Eurocord and cord blood Committee of Cellular Therapy and Immunobiology Working Party, chronic malignancies working Party of the European Society for blood and marrow transplantation, and the Societe Francaise de Greffe de Moelle et Therapie Cellulaire. Biol Blood Marrow Transplant 21(8):1515–1523CrossRefGoogle Scholar
  70. 70.
    Montserrat E, Dreger P (2016) Treatment of chronic lymphocytic leukemia with del(17p)/TP53 mutation: allogeneic hematopoietic stem cell transplantation or BCR-signaling inhibitors?. Clin Lymphoma Myeloma Leuk 16 SupplS74–81, 16, S74, S81CrossRefGoogle Scholar
  71. 71.
    Kharfan-Dabaja MA, Kumar A, Hamadani M, Stilgenbauer S, Ghia P, Anasetti C, Dreger P, Montserrat E, Perales MA, Alyea EP, Awan FT, Ayala E, Barrientos JC, Brown JR, Castro JE, Furman RR, Gribben J, Hill BT, Mohty M, Moreno C, O’Brien S, Pavletic SZ, Pinilla-Ibarz J, Reddy NM, Sorror M, Bredeson C, Carpenter P, Savani BN (2016) Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the guidelines Committee of the American Society for blood and marrow transplantation. Biol Blood Marrow Transplant 22(12):2117–2125CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hospital das Clínicas da Faculdade de MedicinaUniversidade de São Paulo/ICESPCerqueira CesarBrazil
  2. 2.Hospital Santa MarcelinaSão PauloBrazil
  3. 3.Hospital das Clínicas de Porto Alegre, Santa Casa de Porto AlegreFundação Universidade Federal de Ciências da Saúde de Porto AlegrePorto AlegreBrazil
  4. 4.Hospital Nossa Senhora da ConceiçãoPorto AlegreBrazil
  5. 5.AbbVieSão PauloBrazil
  6. 6.Faculdade de MedicinaUniversidade de São Paulo/Hospital Sírio LibanêsSão PauloBrazil
  7. 7.Churchill HospitalNHS-BTOxfordUK

Personalised recommendations